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SINCE 1994, THE AVAILABILITY OF INcreasingly effective antiretroviral drugs for both the prevention of perinatal human immunodeficiency virus (HIV) transmission and maternal treatment has resulted in a greater emphasis on prenatal HIV testing and substantial increases in prenatal testing rates.In 2000, preliminary data indicated that 766 (93%) of 824 HIV-infected women in 25 states knew their HIV status before delivery (CDC, unpublished data, 2002).However, an estimated 280-370 perinatal HIV transmissions continue to occur in the United States each year.1 The primary strategy to prevent perinatal HIV transmission is to maximize prenatal HIV testing of pregnant women.States and Canadian provinces have implemented three different prenatal HIVtesting approaches.To assess their effectiveness, CDC reviewed prenatal HIVantibody testing rates associated with these approaches.Medical record data suggest that the "opt-in" voluntary testing approach is associated with lower testing rates than either the "opt-out" voluntary testing approach or the mandatory newborn HIV testing approach.
Under the opt-in approach, women typically are provided pre-HIV test counseling and must consent specifically to an HIV-antibody test.Under the opt-out approach, women are notified that an HIV test will be included in a standard battery of prenatal tests and procedures and that they may refuse testing.2 Under mandatory newborn HIV testing, newborns are tested for HIV, with or without the mother's con-sent, if the mother's HIV status is unknown at delivery.
Three methods were used to estimate prenatal testing rates among all women who delivered, regardless of whether they received prenatal care.First, eight U.S. areas that participated during 1998-1999 in CDC's Active Bacterial Core Surveillance/Emerging Infections Program (ABC) Network assessed HIV testing during prenatal care and Յ2 days before delivery by reviewing a stratified random sample of labor and delivery records and prenatal records forwarded to birthing hospitals 3 ; in collaboration with CDC, network staff received a sample of records from all birthing hospitals in the surveillance areas and weighted testing rates to represent all live-born infants in those areas.Second, public health investigators in each of the five Canadian provinces tallied the number of HIV tests among pregnant women that were submitted to provincial laboratories and divided the total by an estimate of all live and stillborn births in each province during the same year.Third, CDC analyzed weighted data collected in 1999 by interviewers in nine states for CDC's Pregnancy Risk Assessment Monitoring System (PRAMS) (an ongoing, populationbased survey conducted in 32 states and New York City among women who have given birth during the preceding 2-6 months 4 ), who had asked women if they had been tested for HIV during pregnancy.Data on state prenatal HIVtesting policies were obtained from the American College of Obstetricians and Gynecologists.5 HIV-testing rates varied depending on which approach to testing was used.Rates for states using the opt-in approach to prenatal HIV testing included in the ABC Network ranged from 25% to 69%, testing rates in Canada ranged from 54% to 83%, and rates derived from PRAMS data ranged from 61% to 81%.Two U.S. states (Arkansas and Tennessee) and two Canadian prov-inces (Alberta, and Newfoundland and Labrador) reported using an opt-out prenatal HIV-testing policy.ABC CDC Editorial Note: Prenatal HIV testing affords the best opportunity for the prevention of perinatal HIV transmission.On the basis of clinical trial data, perinatal HIV-transmission rates among HIV-infected women who begin antiretroviral treatment during pregnancy are as low as Յ2%, 6 compared with 12%-13% early transmission rates among women who do not begin preventive treatment until labor and delivery or after birth 7 and 25% among women who receive no preventive treatment.8 Among the three prenatal HIV testing approaches assessed in this report, opt-out voluntary testing and the mandatory testing of newborns appear to be associated with the highest testing rates.On the basis of the chart-review methodology, prenatal testing rates were higher in Tennessee, which uses the opt-out approach, than rates in states using the opt-in approach and similar to rates achieved with mandatory newborn testing in New York during the same time period.A similar trend was observed among Canadian provinces.In New York and Connecticut, mandatory HIV testing of newborns was associated with increases in prenatal testing rates.On the basis of PRAMS data, three of seven states using the opt-in approach achieved lower prenatal HIV-testing rates than states using the opt-out or mandatory newborn testing approaches.
Increases in prenatal HIV-testing rates were noted in states that shifted from an opt-in approach to either an opt-out or mandatory newborn testing approach and were probably associated with a greater likelihood that woman were offered HIV testing during prenatal care.Data from the Perinatal Guidelines Project indicated that the majority of women will accept HIV testing if it is rec-ommended by their health-care provider.9 Perinatal HIV experts and professional organizations have advocated streamlining prenatal HIV pre-test counseling and consent procedures to reduce barriers to the offer of testing by health-care providers.1,2,10 The findings in this report are subject to at least seven limitations.First, testing results for each strategy are for all women, and the proportion of HIVpositive women who accepted testing under each strategy is not known.Second, among women who did not receive prenatal testing, the proportion of women who were not tested because they did not seek prenatal care is unknown.Third, among women who did not receive prenatal testing, the proportion of women who were tested at labor and delivery or whose infants were tested at birth is not known.Fourth, maternal self-reported data from PRAMS collected 2-6 months after delivery might be subject to recall bias.Fifth, PRAMS data do not indicate whether a prenatal-care provider was aware of the woman's HIV status.Sixth, among the women interviewed in PRAMS, up to 16% (in Arkansas) indicated they did not know if they had been tested.Finally, chart abstraction can document only prenatal HIV testing recorded in maternal medical records; without such documentation, clinicians might not be aware of the need to offer effective perinatal interventions to infected women and their HIVexposed infants.
This report emphasizes the need for better data to assess perinatal HIV testing rates in the United States.Ongoing, randomized reviews of prenatal, labor/ delivery, and pediatric charts, with a sampling framework ensuring that the sample is representative of the population of women delivering, might provide the most valid approach to assessing a state's progress on perinatal HIV testing and prevention.CDC is working with states with high HIV prevalence rates among women of childbearing age and high numbers of pediatric AIDS cases to ensure standardized monitoring of prenatal testing rates.The data suggest that jurisdictions that use an opt-in approach and that have low prenatal HIV-testing rates should reevaluate their approach.The primary goal of these assessments was to determine the vulnerability of building air environments, including heating, ventilation, and airconditioning (HVAC) systems, to a terrorist attack with chemical, biologic, and radiologic (CBR) agents and to develop cost-effective prevention and control strategies.At each facility, CDC investigators performed onsite evaluations to assess the building's vulnerability to CBR attack from internal and external sources.The investigators also FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION reviewed security and safety plans at each facility.Facility owners received confidential reports identifying observed vulnerabilities and possible remedial options.Collectively, the field observations and prevention recommendations from the building assessments were combined with input from government and industry experts to identify general guidance that encourages building owners, facility managers, and engineers to review design, operational, and security procedures at their own facilities.
# Protecting Building
The recommendations include measures that can transform buildings into less attractive targets by increasing the difficulty of introducing a CBR agent, increasing the ability to detect terrorists before they carry out an intended release, and incorporating plans and procedures to mitigate the effects of a CBR release.These recommendations are presented in the recently completed NIOSH guidelines, 1 which address physical security, airflow and filtration, maintenance, program administration, and staff training.The guidelines recommend that building owners and managers first understand their buildings' systems by conducting walk-through inspections of the HVAC, fire protection, life-safety, and other systems.Security measures should be adopted for air intakes and return-air grills, and access to building operation systems and building design information should be restricted.The guidelines also recommend that the emergency capabilities of the systems' operational controls should be assessed, filter efficiency should be evaluated closely, buildings' emergency plans should be updated, and preventive maintenance procedures should be adopted.The guidelines also caution against detrimental actions, such as permanently sealing outdoor air intakes.
The recommendations are intended for building owners, managers, and maintenance personnel responsible for public, private, and government buildings, including hospitals, laboratories, offices, retail facilities, schools, transportation facilities, and public venues.
The recommendations do not address single-family or low-occupancy residences or higher-risk facilities such as industrial or military facilities, subway systems, or law-enforcement facilities.
Copies of these recommendations are available at or by telephone, 800-356-4674. 1 Because of recent terrorist attacks involving the intentional exposure of U.S. civilians to Bacillus anthracis spores and concerns that the current anthrax vaccine supply is limited, ACIP developed supplemental recommendations on using anthrax vaccine in response to terrorism.These recommendations supplement the previous ACIP statement in three areas: use of anthrax vaccine for pre-exposure vaccination in the U.S. civilian population, the prevention of anthrax by postexposure prophylaxis (PEP), and recommendations for additional research related to using antimicrobial agents and anthrax vaccine for preventing anthrax.
# Use of Anthrax Vaccine in
# Use of Anthrax Vaccine for Pre-Exposure Vaccination
In December 2001, the U.S. Department of Health and Human Services obtained a limited supply of anthrax vaccine (BioThrax , BioPort, Lansing, Michigan), allowing ACIP to reconsider using anthrax vaccine in the U.S. civilian population.ACIP reaffirms that pre-exposure use of anthrax vaccine should be based on a quantifiable risk for exposure.1 ACIP recommends that groups at risk for repeated exposures to B. anthracis spores should be given priority for pre-exposure vaccination.Groups at risk for repeated exposure include laboratory personnel handling environmental specimens (especially powders) and performing confirmatory testing for B. anthracis in the U.S. Laboratory Response Network (LRN) for Bioterrorism Level B laboratories or above, workers who will be making repeated entries into known B. anthracis-spore-contaminated areas after a terrorist attack, 2 and workers in other settings in which repeated exposure to aerosolized B. anthracis spores might occur.Laboratory workers using standard Biosafety Level 2 practices in the routine processing of clinical samples or environmental swabs (Level A laboratories 3 ) are not considered by ACIP to be at increased risk for exposure to B. anthracis spores.
For persons not at risk for repeated exposures to aerosolized B. anthracis spores through their occupation, preexposure vaccination with anthrax vaccine is not recommended.For the general population, prevention of morbidity and mortality associated with anthrax will depend on public vigilance, early detection and diagnosis, appropriate treatment, and PEP.
# Prevention of Anthrax by PEP
Because of a potential preventive benefit of combined antimicrobial PEP and vaccine and the availability of a limited supply of anthrax vaccine for civilian use, ACIP endorses CDC making anthrax vaccine available in a 3-dose regimen (0, 2, 4 weeks) in combination with antimicrobial PEP under an Investigational New Drug (IND) application with the Food and Drug Administration for unvaccinated persons at risk for inhalational anthrax.However, anthrax vaccine is not licensed for postexposure use in preventing anthrax.
Use of anthrax vaccine for PEP could have additional benefits, including reducing the need for long-term antimicrobial therapy with its associated problems of nonadherence and possible adverse events.After the anthraxrelated terrorist attacks in 2001, approximately 10,000 persons were recommended to receive a 60-day regimen of antimicrobial prophylaxis for suspected or confirmed exposure to B. anthracis spores, but adherence to the recommended 60-day antibiotic regimens was as low as 42%.4 In addition, because studies of the 2001 terrorist attacks suggest that some persons might be exposed to B. anthracis spores in excess of those studied in animal models, the effectiveness of antimicrobial prophylaxis in such persons is unclear.4 However, no cases of anthrax have been detected among persons recommended to take antimicrobial prophylaxis after the terrorist attacks of 2001.
The provision of anthrax vaccine for PEP under an IND application should provide an opportunity to reduce the risk to the greatest extent possible with current medical knowledge and might provide data to support developing additional recommendations for preventing anthrax.To better document the immunogenicity of anthrax vaccine in the postexposure setting, ACIP encouraged CDC to obtain serologic testing on a subset of vaccinees.
ACIP recommended previously that if antimicrobial therapy is used alone for postexposure prevention of anthrax, at least a 30-day course of treatment should be provided.Previous recommendations noted that longer courses (42-60 days) might be indicated.On the basis of limited data from both unintentional human exposures and animal studies, ACIP now recommends that the duration of postexposure antimicrobial prophylaxis should be 60 days if used alone for PEP of unvaccinated exposed persons.
Data are insufficient to clarify the duration of antimicrobial use in combination with vaccine for PEP against anthrax.Antibody titers among vaccinated persons peak at 14 days after the third dose.8 If antimicrobial prophylaxis is administered in combination with postexposure vaccination, it might be prudent to continue antibiotics until 7-14 days after the third vaccine dose.
Few data exist about the effectiveness of postexposure antimicrobial prophylaxis among exposed persons who have been partially or fully vaccinated.In the only human clinical trial of anthrax vaccine, cases occurred among participants who had received Ͻ4 doses.9 Recognizing these limited data, but considering a potential undefined benefit, ACIP recommends that persons who have been partially or fully vaccinated receive at least a 30-day course of antimicrobial PEP and continue with the licensed vaccination regimen.Antimicrobial PEP is not needed for vaccinated persons working in Biosafety Level 3 laboratories under recommended conditions 10 nor for vaccinated persons (six vaccinations according to the current label) wearing appropriate personal protective equipment (PPE) while working in contaminated environments in which inhalational exposure to B. anthracis spores is a risk, unless their respiratory protection is disrupted.
# Additional Considerations
For most occupational settings, recommendations about anthrax vaccine and antimicrobial PEP might be implemented in combination with use of appropriate PPE.2 In addition to receiving PEP for preventing anthrax, potentially exposed persons should be observed for signs of febrile illness.CDC has published guidelines on clinical evaluation of persons with possible anthrax, including antimicrobial treatment.1,2 Because the current vaccine supply is limited, ACIP recommends expanded and intensive efforts to improve anthrax vaccine production.
# Recommendations for Additional Research
Because of the absence of data to guide public health recommendations in these critical areas, ACIP recommends studies on the safety and immunogenicity of anthrax vaccine for use in children, additional studies on the safety of anthrax vaccine during human pregnancy, and reproductive toxicology studies on anthrax vaccine in laboratory animals.To strengthen public health recommendations for PEP, ACIP recommends expanded animal studies to evaluate further the effectiveness of antimicrobial prophylaxis with and without anthrax vaccine, define the optimal duration of antimicrobial PEP for the prevention of inhalational anthrax, and evaluate alternative antimicrobial PEP regimens.Additional research also should be directed toward developing an improved vaccine for preventing anthrax and new therapeutic strategies, including use of antitoxin (e.g., hyperimmune globulin) for treating anthrax. |
These revised recommendations o f the Immunization Practices Advisory Commit tee (ACIP) on Measles Prevention replace previous recommendations published in 1987 f l ) and 1989 (2).The recommendations include a basic change in the routine childhood vaccination schedule from a one-dose to a two-dose schedule using combined measles-mumps-rubella (MMR) vaccine.Routine revaccination w ill gener ally be implemented one age group at a time starting with school enterers.New recommendations are also included for vaccination o f preschool children at high risk of contracting measles, for students in colleges and other institutions o f higher education, for health-care personnel and international travelers, and for outbreak control.#INTRODUCTION
Measles (rubeola) is often a severe disease, frequently complicated by middle ear infection or bronchopneumonia.Encephalitis occurs in approximately one of every 1,000 reported cases; survivors of this complication often have permanent brain damage and mental retardation.Death, usually from respiratory and neurologic causes, occurs in one of every 1,000 reported measles cases.The risk of death is greater for infants and adults than for children and adolescents.
Subacute sclerosing panencephalitis (SSPE) is a "slow virus" infection of the central nervous system associated with measles virus.Widespread use of measles vaccine has led to the virtual disappearance of SSPE from the United States (3).
Measles illness during pregnancy leads to increased rates of premature labor, spontaneous abortion, and low-birth-weight infants (4,5).Whether measles infection in the first trimester of pregnancy is associated with an increased rate of congenital malformations is still unresolved.
Before measles vaccine was available, more than 400,000 measles cases were reported each year in the United States (6).However, since virtually all children acquired measles, the true number of cases probably exceeded 4 million per year (i.e., the entire birth cohort).Since 1963, when both an inactivated and a live attenuated vaccine (Edmonston B strain) were licensed for use in the United States, both the type of measles vaccine and the recommended age for measles vaccination have changed several times.After 1967 and 1975, the inactivated and the Edmonston B vaccine, respectively, were no longer distributed.A live, further attenuated vaccine (Schwarz strain) was first introduced in 1965, and a similar vaccine (Moraten strain) was licensed in 1968.These further attenuated vaccines cause fewer reactions than the Edmonston B vaccine, yet are equally effective.The Moraten vaccine is the vaccine used currently in the United States.
A single dose of live measles vaccine had been recommended since measles vaccine was first licensed (1).In 1963, the recommended age for vaccination was 9 months, but in 1965 it was changed to 12 months, and in 1976 it was changed to 15 months because of evidence demonstrating greater efficacy when children were vaccinated at these ages.Persons vaccinated before the first birthday needed to be revaccinated.
# MEASLES EPIDEMIOLOGY AND ELIMINATION EFFORTS
Since vaccine licensure in 1963, the collaborative efforts of professional and voluntary medical and public health organizations in vaccination programs have resulted in a 99% reduction in the reported incidence of measles.During the late 1960s and early 1970s, the number of reported cases decreased to between 22,000 and 75,000 cases per year.Although incidence fell dramatically in all age groups, children <10 years of age showed the greatest decline, while older children had a slightly less dramatic decrease.As a result, the proportion of total cases occurring in different age groups changed.From 1984 to 1988, 58% of reported cases affected children ^10 years of age, compared with 10% during the period 1960 to 1964 (6).
In 1978, the Department of Health, Education, and Welfare initiated a Measles Elimination Program, with a goal to eliminate indigenous measles from the United States by October 1, 1982.The three components of this program have been 1) maintenance of high levels of immunity, 2) careful surveillance of disease, and 3) aggressive outbreak control.As a result of these efforts, the number of cases reported annually dropped from 26,871 in 1978 to an all-time low of 1,497 in 1983.The number of cases reported then increased until 1986 (6,282) cases (7).Reported cases decreased in 1987 and 1988 but rose again during the first 48 weeks of 1989, when more than 14,000 cases were reported.
Measles cases are routinely reported by state and local health departments to the MMWR.The Division of Immunization, Center for Prevention Services, CDC, collects supplementary data on cases, including information on vaccination status (i.e., vaccinated or unvaccinated).Persons appropriately vaccinated for measles are those who have received a dose of live measles vaccine on or after their first birthday.
Unvaccinated persons with measles can be subclassified into three general groups: those for whom vaccine is not routinely indicated (e.g., those <16 months of age, born before 1957, with prior physician diagnosis of measles, or with medical contraindications), those for whom vaccination is difficult to achieve (e.g., non-U.S. citizens and persons exempted for religious or philosophic reasons), and those for whom vaccine is indicated (e.g., children ^1 6 months of age and children vaccinated before their first birthdays).From 1985 through 1988, information on vaccination status for 16,819 measles cases was collected by the Division of Immunization.Appropriately vaccinated persons accounted for 42%, and 92% of cases in this group occurred among persons ^5 years of age.In 26% of these cases, the patients were unvaccinated persons for whom vaccine was not routinely indicated or for whom vaccination was difficult to achieve.The remaining 32% were unvaccinated persons for whom vaccine was indicated.Forty-two percent of the persons in this latter group were children 16 months to 4 years of age.
In recent years, two major types of outbreaks have occurred in the United States: those among unvaccinated preschool-aged children, including those younger than the recommended age for vaccination (i.e., 98%.These outbreaks have occurred in all parts of the country, including areas that had not reported measles for years.
In general, attack rates in individual schools were low (1%-5%) and the calculated vaccine efficacy high.Most of the persons with measles in college outbreaks were also likely to have been vaccinated, although documentation of vaccination was often lacking.However, in many outbreaks, children vaccinated at 12-14 months of age had higher attack rates than those vaccinated at older ages ( 10).In a few outbreaks, older persons vaccinated in the more distant past were at increased risk for disease; this risk was independent of age at vaccination (77).
The goal of eliminating measles in the United States has not been reached primarily because of 1) failure to implement the current vaccination strategy, resulting in large numbers of unvaccinated preschool-age children in some areas, and 2) vaccine failure.A substantial number of cases occur among persons who previ ously have been vaccinated.Theoretically, vaccine failures may either be primary (i.e., an adequate response to vaccination never developed) or secondary (i.e., an adequate response initially developed, but immunity was lost overtime).Some of the reported vaccine failures may be explained by the fact that a person's records incorrectly indicated appropriate vaccination.Measles vaccine is at least 95% effec tive for children vaccinated at >15 months of age.However, efficacy may be slightly lower for persons vaccinated between 12 and 14 months of age, presumably because transplacental maternal antibody persists beyond the first birthday in some children and interferes with the response to vaccination.Also, secondary vaccine failure could occur after successful vaccination as a result of waning immunity, but the percentage of persons to whom this applies appears to be small (12,13).Overall, the great majority of vaccinees appear to have long-term and probably life-long immunity.Nevertheless, further studies are needed to determine the duration of vaccineinduced immunity.
# CHANGES IN MEASLES VACCINATION POLICY
The Committee reviewed current measles epidemiology and the measles elimina tion strategy and considered modifications.New recommendations were developed to help achieve the goal of measles elimination (Tables 1 and 2).A routine two-dose measles vaccination schedule now is recommended.This schedule is expected to provide protection to most persons who do not respond to their initial vaccination.
The first dose is recommended at 15 months of age for children in most areas of the country but at 12 months of age for children in some areas with recurrent measles transmission.The second dose is recommended at the time a child enters school at kindergarten or first grade (see "Vaccine Usage").Because programs to administer a second dose of measles vaccine at school entry to kindergarten or first grade will not have an immediate effect on the incidence of measles for school-aged children, programs also are recommended for outbreak control (see "Outbreak Control") and for the routine vaccination of students entering college (see "Special Situations").
When fully implemented, this schedule should lead to the elimination of measles among school-aged children and college students.It is expected to prevent the 35%-40% of cases affecting persons ^5 years of age who appear to be vaccine failures, and it may indirectly protect unvaccinated persons since the risk of exposure to measles will decrease.Outbreaks of measles in school settings are likely to cease, thus avoiding the substantial disruption of routine activities and the high cost of outbreak control.However, the overall goal of eliminating measles in the United States also requires more intensive efforts to vaccinate preschool children at the recommended ages, particularly children residing in inner cities.
All contacts with health-care providers in physicians' offices, clinics, emergency rooms, and hospitals are opportunities for evaluating the vaccination status of children, both patients and accompanying siblings, and for offering vaccine to those who need it.Unvaccinated children should not be rescheduled for vaccination; rather, they should be vaccinated immediately if no contraindication exists.Particular attention should be paid to offering simultaneous vaccination.No preschool child
# MEASLES VIRUS VACCINE
Live measles virus vaccine- used in the United States is prepared in chickembryo-cell culture.It is available in monovalent (measles only) form and in two combinations: measles-rubella (MR) and measles-mumps-rubella (MMR) vaccines*.
Measles vaccine produces an inapparent or mild, noncommunicable infection.Measles antibodies develop in at least 95% of susceptible children vaccinated at ^15 months of age.Although the titers of vaccine-induced antibodies are lower than those "Official name: Measles Virus Vaccine, Live Attenuated.^Available in the United States as Attenuvax® (single antigen), M-R-Vax® (measles-rubella) and M-M-R II® (measles-mumps-rubella), from the Merck, Sharp and Dohme Co.
# TABLE 2.Recommendations for measles outbreak control*
# Outbreaks in preschool-aged children
Lower age for vaccination to as low as 6 months of age in outbreak area if cases are occurring in children <1 year of aget .
Outbreaks in institutions: day-care centers, K-12th grades, colleges, and other institutions Revaccination of all students and their siblings and of school personnel born in or after 1957 who do not have documentation of immunity to measles5.
# Outbreaks in medical facilities
Revaccination of all medical workers born in or after 1957 who have direct patient contact and who do not have proof of immunity to measles5.Vaccination may also be considered for workers born before 1957.
Susceptible personnel who have been exposed should be relieved from direct patient contact from the 5th to the 21st day after exposure (regardless of whether they received measles vaccine or IG) o r -i f they become ill-f o r 7 days after they _____________________________________________ develop rash._______________________ "Mass revaccination of entire populations is not necessary.Revaccination should be limited to populations at risk, such as students attending institutions where cases occur. "^Children initially vaccinated before the first birthday should be revaccinated at 15 months of age.A second dose should be administered at the time of school entry or according to local policy.documentation of physician-diagnosed measles disease, serologic evidence of immunity to measles, or documentation of receipt of two doses of measles vaccine on or after the first birthday.
# MMWR December 29, 1989
following natural disease, both serologic and epidemiologic evidence indicate that vaccine-induced protection appears to be long-lasting in most individuals.
# Vaccine Shipment and Storage
The administration of improperly stored vaccine may fail to provide protection against measles.Although the current measles vaccine may be more thermostable than vaccine produced in the past, it should be stored at 2-8 C (35.6-46.4 F) or colder during storage.Vaccine must be shipped at 10 C (50 F) or colder and may be shipped on dry ice.It must be protected from light, which may inactivate the virus.Reconsti tuted vaccine must be stored in a refrigerator (not frozen) and discarded if not used within 8 hours.
# VACCINE USAGE General Recommendations
All vaccines containing measles virus are recommended for routine use for children 15 months of age.Persons born in or after 1957 who lack documentation of measles immunity (see "Measles Immunity") are considered susceptible and should be vaccinated if there are no contraindications (see "Precautions and Contraindica tions").All vaccinations should be documented in the patient's permanent medical record (74).A parental history of vaccination, by itself, is not considered adequate documentation.A physician should not provide an immunization record for a patient unless s/he has administered the vaccine or has seen a record that documents vaccination.Most persons born before 1957 are likely to have been naturally infected with measles virus and generally need not be considered susceptible; however, vaccination may be offered to these persons if there is reason to believe they may be susceptible.
Both doses of measles vaccine should be given as combined MMR vaccine when given on or after the first birthday.The combined vaccine is preferred to assure immunity to all three viruses.Mumps revaccination is particularly important.Recent studies have shown that mumps can occur in highly vaccinated populations, resulting in substantial numbers of cases among persons with histories of prior mumps vaccination.Although rubella vaccine failure has not been a major problem, the potential consequences of rubella vaccine failure are substantial (i.e., congenital rubella syndrome), and the use of MMR should provide an additional safeguard against such failures.
The most commonly used laboratory test for assessing immunity to measles has been the hemagglutination-inhibition (HI) test.Other more sensitive assays, such as the enzyme immuno-assay (EIA), are now being used by many laboratories.Persons with measles-specific antibody, detectable by any test, are considered immune.Routine serologic screening to determine measles immunity is not generally recom mended, although it may be cost-effective in some situations (e.g., large prepaid medical programs).However, the test may not be widely available, and screening requires that tracking systems be established to assure that identified susceptibles return for vaccination.In addition, screening for antibodies for mumps and rubella would further decrease the cost-effectiveness of this strategy.
# Dosage
Two doses of measles vaccine, generally given as MMR, are recommended for all children after the first birthday.The dose is 0.5 ml and should be given subcutane ously.
# Age at Vaccination
# Routine childhood immunization schedule for most areas of the United States
The first dose of measles vaccine should be given when children are =M5 months of age.The second dose should routinely be given when children enter kindergarten or first grade (4-6 years of age).
The recommended time for the second dose is based primarily on administrative considerations.The current childhood immunization schedule recommends other vaccines (diphtheria and tetanus toxoids and pertussis vaccine and oral poliovirus vaccine ) when children enter school; therefore, an additional provider visit for the second dose of measles vaccine is not necessary.In addition, most school authorities have systems at this grade level for identifying and tracking children with incomplete immunizations.
Because many of the vaccine failures in recent outbreaks of measles have occurred among 10 to 19-year-old children and adolescents, administering the second dose at the time of school entry may not achieve full impact on the incidence of measles for 5 to 15 years.For the impact to occur more rapidly, some localities may choose to give students the second dose at an older age (e.g., when they enter middle school or junior high school).In deciding when to administer the second dose, health officials should consider how they can best achieve a high vaccination rate since this is essential to assure maximum impact of a two-dose schedule.Some localities may want to provide a second dose to multiple age groups from kindergarten through 12th grade to achieve complete immunization of all school-aged children more rapidly.
Children who have received two doses of live measles vaccine on or after the first birthday (at least 1 month apart) do not need an additional dose when they enter school.Children who have no documentation of live measles vaccination when they enter school should be admitted after the first dose.A second dose should be given according to local policy, but no less than 1 month later.
# Routine childhood immunization schedule for areas with recurrent measles transmission
Initial vaccination with MMR at 12 months of age is recommended for children living in high-risk areas.This strategy assumes that the benefit of preventing measles cases between 12 and 15 months of age outweighs the slightly lower efficacy of the vaccine when given at this age.A high-risk area is defined as: 1) a county with more than five cases among preschool-aged children during each of the last 5 years, 2) a county with a recent outbreak among unvaccinated preschool-aged children, or 3) a county with a large inner-city urban population.These recommendations may be implemented for an entire county or only in defined high-risk areas.
# Revaccination of Persons Vaccinated According to Earlier Recommendations Previous vaccination with live vaccine
Persons vaccinated with live measles vaccine before their first birthday should be considered unvaccinated.If they are entering kindergarten or first grade, college or other post-high school educational institutions (see ''Special Situations"), or begin ning employment in a medical facility (see "Special Situations") and cannot provide documentation of immunity to measles (see "Measles Immunity"), they should receive two doses of vaccine no less than 1 month apart. |
Live attenuated Edmonston B vaccine (distributed from 1963-1975) was usually administered with immune globulin (IG) or high-titer measles immune globulin (MIG; no longer available in the United States).This vaccine, administered on or after the first birthday, is acceptable as an effective first dose of vaccine.A second dose should be administered as recommended above.However, if a further attenuated measles vaccine (i.e., Schwarz or Moraten) was given simultaneously with IG or MIG, the IG or MIG may have impaired the immune response to vaccination.Persons who received measles vaccine of unknown type or further attenuated measles vaccine accompa nied by IG or MIG should be considered unvaccinated and should be given two doses of vaccine as outlined above.
# Previous vaccination with inactivated vaccine or vaccine of unknown type
Inactivated (killed) measles vaccine was available in the United States only from 1963 to 1967 but was available through the early 1970s in some other countries.It was frequently given as a series of two or three injections.Some persons who received inactivated vaccine are at risk of developing severe atypical measles syndrome when exposed to the natural virus (75).Consequently, such persons should receive two doses of live vaccine separated by no less than 1 month.Persons vaccinated with inactivated vaccine followed within 3 months by live vaccine should be revaccinated with two doses of live vaccine.Revaccination is particularly important when the risk of exposure to natural measles virus is increased, as may occur during international travel.
A wide range (4%-55%) of recipients of inactivated measles vaccine who were later revaccinated with live measles vaccine have had reactions to the live vaccine (76).Most of these reactions have been mild, consisting of local swelling and erythema, with or without low-grade fever lasting 1-2 days.Rarely, more severe reactions, including prolonged high fevers and extensive local reactions, have been reported.However, recipients of inactivated measles vaccine are more likely to have serious illness when exposed to natural measles than when given live measles virus vaccine.
These same recommendations for revaccination apply to persons vaccinated between 1963 and 1967 with vaccine of unknown type, since they may have received inactivated vaccine.Since inactivated measles vaccine was not distributed in the United States after 1967, persons vaccinated after 1967 with a vaccine of unknown type need not be revaccinated routinely unless the original vaccination occurred before the first birthday or was accompanied by IG or MIG.However, such persons should receive a second dose if they are entering college, beginning employment in medical facilities, or planning international travel.
# Measles Immunity
Persons are considered immune to measles if they 1) were born before 1957, 2) have documentation of physician-diagnosed measles, 3) have laboratory evidence of immunity to measles, or 4) have documentation of adequate vaccination.Eventually, adequate vaccination will be defined as receipt of one dose of live measles vaccine on or after the first birthday for children before they enter school and two doses of measles vaccine on or after the first birthday for children who are entering or have entered school.
For localities implementing the second dose for students at ages beyond school entry (e.g., entry to middle school or junior high school), acceptable evidence of immunity will be one dose at school entry and two doses for students older than the routine age of the second dose (see "Age at Vaccination").
Since most areas will implement the two-dose schedule one age group at a time, criteria for adequate vaccination will vary in the interim.For example, if the two-dose schedule is implemented in 1990, children in kindergarten or first grade will need to have documentation of two doses of measles vaccine after the first birthday to be considered adequately vaccinated.However, a single dose of vaccine will be accept able evidence of adequate vaccination for children in higher grades.Two years later, children in kindergarten through second or third grade will need two doses of measles vaccine for acceptable evidence of adequate vaccination.Similar criteria would apply if the second-dose strategy is implemented at an older age (see "Age at Vaccination").
The interim vaccination criteria for adequate measles vaccination noted above apply to routine settings only.During outbreaks, all persons at risk and born in or after 1957 who are in kindergarten, first grade, or beyond will need two doses on or after the first birthday as evidence of adequate vaccination (see "Outbreak Control").
# Individuals Exposed to Disease
# Use of vaccine
Exposure to measles is not a contraindication to vaccination.If live measles vaccine is given within 72 hours of measles exposure, it may provide some protection.This approach is preferable to using IG for persons 2*12 months of age.If the exposure does not result in infection, vaccination should induce protection against subsequent measles infection.
# Use of IG
IG can prevent or modify measles in a susceptible person if given within 6 days of exposure.The recommended dose of IG is 0.25 ml/kg (0.11 ml/lb) of body weight (maximum dose = 15 ml).IG may be especially indicated for susceptible household contacts of measles patients, particularly contacts <1 year of age, pregnant women, or immunocompromised persons, for whom the risk of complications is increased.The recommended dose of IG for immunocompromised persons is 0.5 ml/kg of body weight (maximum dose = 15 ml).Live measles vaccine should be given 3 months later (when passively acquired measles antibodies should have disappeared) if the individual is then at least 15 months old.IG should not be used to control measles outbreaks.
# MMWR December 29f 1989
# Special Situations
# Recommendations for colleges and other institutions
Colleges, technical schools, and other institutions for post-high school education should require documentation of two doses of live measles-containing vaccines, documentation of prior physician-diagnosed measles disease, or laboratory evidence of measles immunity before entry for all students born in or after 1957.Students who have no documentation of live measles vaccination or other evidence of measles immunity at the time of school entry should be admitted after receiving the first dose.A second dose should be given no less than 1 month later.Institutions may wish to extend this requirement to all classes.
# Recommendations for medical facilities
Medical personnel are at higher risk for acquiring measles than the general population (77).Hospitals should require evidence of two live measles vaccinations, documentation of physician-diagnosed measles disease, or laboratory evidence of measles immunity for medical staff beginning employment who will have direct patient contact.Persons born in or after 1957 who have no documentation of vaccination or other evidence of measles immunity should be vaccinated at the time of employment and revaccinated no less than 1 month later.If resources are available, institutions may wish to extend this recommendation to all medical personnel, not just those beginning employment.Since some medical personnel who have acquired measles in medical facilities were born before 1957, institutions may consider requiring at least one dose of measles vaccine for older employees who are at risk of occupational exposure to measles.
# Recommendations for international travel
Persons traveling abroad should be immune to measles.The protection of young adults who have escaped measles disease and have not been vaccinated is especially important.Consideration should be given to providing a dose of measles vaccine to persons born in or after 1957 who travel abroad, who have not previously received two doses of measles vaccine, and who do not have other evidence of measles immunity (see "Measles Immunity").
The age for measles vaccination should be lowered for children traveling to areas in which measles is endemic or epidemic.Children 12-14 months of age should receive MMR vaccine before their departure.Children 6-11 months of age should receive a dose of monovalent measles vaccine before departure, although there is no specific contraindication to the use of MMR for this age group if monovalent measles vaccine is not available.Seroconversion rates observed for measles, mumps, and rubella antigens are significantly less among children vaccinated before the first birthday than among older children.Children who receive monovalent measles vaccine or MMR before their first birthday should be considered unvaccinated and should receive two doses of MMR at later ages.Whereas the optimal age for the first revaccination dose is 15 months, the age for revaccination may be as low as 12 months if the child remains in a high-risk area (see "Routine childhood immunization schedule for areas with recurrent measles transmission").The second revaccination dose would normally be given when a child enters school or according to local policy.
Since virtually all infants <6 months of age will be protected by maternally derived antibodies, no additional protection against measles is necessary in this age group.
# SIDE EFFECTS AND ADVERSE REACTIONS
More than 170 million doses of measles vaccine were distributed in the United States from 1963 through 1988.The vaccine has an excellent record of safety.From 5%-15% of vaccinees may develop a temperature of ^103 F (^39.4 C) beginning 5-12 days after vaccination and usually lasting several days ( 18).Most persons with fever are otherwise asymptomatic.Transient rashes have been reported for approximately 5% of vaccinees.Central nervous system conditions, including encephalitis and encephalopathy, have been reported with a frequency of less than one per million doses administered.The incidence of encephalitis or encephalopathy after measles vaccination of healthy children is lower than the observed incidence of encephalitis of unknown etiology.This finding suggests that the reported severe neurologic disor ders temporally associated with measles vaccination were not caused by the vaccine.These adverse events should be anticipated only in susceptible vaccinees and do not appear to be age-related.After revaccination, reactions should be expected to occur only among the small proportion of persons who failed to respond to the first dose.
# Personal and Family History of Convulsions
As with the administration of any agent that can produce fever, some children may have a febrile seizure.Although children with a personal or family history of seizures are at increased risk for developing idiopathic epilepsy, febrile seizures following vaccinations do not in themselves increase the probability of subsequent epilepsy or other neurologic disorders.Most convulsions following measles vaccination are simple febrile seizures, and they affect children without known risk factors.
An increased risk of these convulsions may occur among children with a prior history of convulsions or those with a history of convulsions in first-degree family members (i.e., siblings or parents) (19).Although the precise risk cannot be determined, it appears to be low.
In developing vaccination recommendations for these children, the Committee considered a number of factors, including risks from measles disease, the large proportion (5%-7%) of children with a personal or family history of convulsions, and the fact that convulsions following measles vaccine are uncommon and have not been associated with permanent brain damage.The Committee concluded that the benefits of vaccinating these children greatly outweigh the risks.They should be vaccinated just as children without such histories.
Because the period for developing vaccine-induced fever occurs approximately 5-12 days after vaccination, prevention of febrile seizures is difficult.Prophylaxis with antipyretics is one alternative, but these agents may not be effective if given after the onset of fever.They would have to be initiated before the expected onset of fever and continued for 5-7 days.However, parents should be alert to the occurrence of fever after vaccination and should treat their children appropriately.December 29, 1989
Children who are being treated with anticonvulsants should continue to take them after measles vaccination.Because protective levels of most currently available anticonvulsant drugs (e.g., phenobarbitol) are not achieved for some time after therapy is initiated, prophylactic use of these drugs does not seem feasible.
The parents of children who have either a personal or family history of seizures should be advised of the small increased risk of seizures following measles vaccina tion.In particular, they should be told in advance what to do in the unlikely event that a seizure occurs.The permanent medical record should document that the small risk of postimmunization seizures and the benefits of vaccination have been discussed.
# Revaccination Risks
There is no evidence of increased risk from live measles vaccination in persons who are already immune to measles, as a result of either previous vaccination or natural disease.
# PRECAUTIONS AND CONTRAINDICATIONS Pregnancy
Live measles vaccine, when given as a component of MR or MMR, should not be given to women known to be pregnant or who are considering becoming pregnant within the next 3 months.Women who are given monovalent measles vaccine should not become pregnant for at least 30 days after vaccination.This precaution is based on the theoretical risk of fetal infection, although no evidence substantiates this theoretical risk.Considering the importance of protecting adolescents and young adults against measles, asking women if they are pregnant, excluding those who are, and explaining the theoretical risks to the others before vaccination are sufficient precautions.
# Febrile Illness
The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the cause of the illness and the severity of symptoms.Minor illnesses, such as a mild upper-respiratory infection with or without low-grade fever, are not contraindications for vaccination.For persons whose compliance with medical care cannot be assured, every opportunity should be taken to provide appropriate vaccinations.
Children with moderate or severe febrile illnesses can be vaccinated as soon as they have recovered.This wait avoids superimposing adverse effects of vaccination on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine.Performing routine physical examinations or measuring temperatures are not prerequisites for vaccinating infants and children who appear to be in good health.Asking the parent or guardian if the child is ill, postponing vaccination for children with moderate or severe febrile illnesses, and vaccinating those without contraindications are appropriate procedures in childhood immuniza tion programs.
# Allergies
Hypersensitivity reactions following the administration of live measles vaccine are rare.Most of these reactions are minor and consist of a wheal and flare or urticaria at the injection site.More than 170 million doses of measles vaccine have been distributed in the United States, but only five reported cases of immediate allergic reactions have occurred among children who had histories of anaphylactic reactions to egg ingestion.These reactions could potentially have been life threatening.Four children experienced difficulty in breathing, and one of these four had hypotension.Persons with a history of anaphylactic reactions (hives, swelling of the mouth and throat, difficulty in breathing, hypotension, and shock) following egg ingestion should be vaccinated only with extreme caution.Protocols have been developed for vacci nating such persons (20,21).However, persons are not at increased risk if they have egg allergies that are not anaphylactic in nature; they can be vaccinated in the usual manner.Persons with allergies only to chickens or feathers are not at increased risk of reaction to measles vaccination.
MMR vaccine and its component vaccines contain trace amounts of neomycin.Although the amount present is less than that usually used for a skin test to determine hypersensitivity, persons who have experienced anaphylactic reactions to neomycin should not be given these vaccines.Most often, neomycin allergy is manifested by contact dermatitis rather than anaphylaxis.A history of contact dermatitis to neomy cin is not a contraindication to receiving measles vaccine.Live measles virus vaccine does not contain penicillin.
# Recent Administration of IG
Vaccine virus replication and stimulation of immunity usually occurs 1-2 weeks after vaccination.When the live measles vaccine is given after IG or specific IG preparations, the vaccine virus might not replicate successfully, and the antibody response could be diminished.Measles vaccine should not be given for at least 6 weeks, and preferably for 3 months, after a person has been given IG, whole blood, or other antibody-containing blood products.If vaccine is given to a person who has received such products within the preceding 3 months, the dose should not be counted and the person should be revaccinated approximately 3 months later unless serologic testing indicates that measles-specific antibodies have been produced.For international travelers, measles vaccination should precede the administration of IG by at least 2 weeks to preclude interference with replication of the vaccine virus.If the interval between measles vaccination and subsequent administration of an IG preparation is <14 days, vaccination should be repeated 3 months later, unless serologic testing indicates that antibodies were produced.
# Tuberculosis
Tuberculosis may be exacerbated by natural measles infection.Live measles virus vaccine has not been shown to have such an effect.Tuberculin skin testing is not a prerequisite for measles vaccination.If tuberculin testing is needed for other reasons, it can be done the day of vaccination.Otherwise, the test should be postponed for 4-6 weeks, since measles vaccination may temporarily suppress tuberculin reactivity.
# Altered Immunocompetence
Replication of vaccine viruses can be enhanced in persons with immune-deficiency diseases and in persons with immunosuppression, as occurs with leukemia, lym phoma, generalized malignancy, or therapy with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids.For this reason, patients with such conditions or therapies (except patients with symptomatic infection with human immunodeficiency virus ; see below) should not be given live measles virus vaccine.
Patients with leukemia in remission who have not received chemotherapy for at least 3 months may receive live-virus vaccines.Short-term (<2 weeks), low-to moderate-dose systemic corticosteroid therapy, topical steroid therapy (e.g., nasal, skin), long-term alternate-day treatment with low to moderate doses of short-acting systemic steroids, and intra-articular, bursal, or tendon injection of corticosteroids are not immunosuppressive in their usual doses and do not contraindicate the adminis tration of measles vaccine.
The growing number of infants and preschoolers with HIV infection has directed special attention to the appropriate immunization of such children.Asymptomatic children do not need to be evaluated and tested for HIV infection before decisions concerning vaccination are made. |
Asymptomatic HIV-infected persons in need of MMR should receive it.MMR should be considered for all symptomatic HIV-infected children, including children with acquired immunodeficiency syndrome (AIDS), since measles disease in these children can be severe.Limited data on MMR vaccination among both asymptomatic and symptomatic HIV-infected children indicate that MMR has not been associated with severe or unusual adverse events, although antibody responses have been unpredictable (22)(23)(24).
The administration of high-dose intravenous immune globulin (IGIV) at regular intervals to HIV-infected children is being studied to determine whether it will prevent a variety of infections.MMR vaccine may be ineffective if it is administered to a child who has received IGIV during the preceding 3 months.
# Management of Patients with Contraindications to Measles Vaccine
If immediate protection against measles is required for persons with contraindi cations to measles vaccination, passive immunization with IG, 0.25 ml/kg (0.11 ml/lb) of body weight (maximum dose = 15 ml), should be given as soon as possible after known exposure.Exposed symptomatic HIV-infected and other immunocompro mised persons should receive IG regardless of their previous vaccination status; however, IG in usual doses may not be effective in such patients.For immunocom promised persons, the recommended dose is 0.5 ml/kg of body weight if IG is administered intramuscularly (maximum dose = 15 ml).This corresponds to a dose of protein of approximately 82.5 mg/kg (maximum dose = 2,475 mg).Intramuscular IG may not be needed if a patient with HIV infection is receiving 100-400 mg/kg IGIV at regular intervals and the last dose was given within 3 weeks of exposure to measles.Because the amounts of protein administered are similar, high-dose IGIV may be as effective as IG given intramuscularly.However, no data are available concerning the effectiveness of IGIV in preventing measles.
# Simultaneous Administration of Vaccines
In general, simultaneous administration of the most widely used live and inacti vated vaccines does not impair antibody responses or increase rates of adverse reactions (25).The administration of MMR vaccine yields results similar to the administration of individual measles, mumps, and rubella vaccines at different sites or at different times.
There are equivalent antibody responses and no clinically significant increases in the frequency of adverse events when DTP, MMR, and OPV or inactivated poliovirus vaccine (IPV) are administered either simultaneously at different sites or at separate times.Routine simultaneous administration of MMR, DTP, and OPV (or IPV) is recommended for all children 2*15 months of age who are eligible to receive these vaccines .Vaccination with MMR at 15 months followed by DTP, OPV (or IPV), and Haemophilus influenzae b conjugate vaccine (HbCV) at 18 months remains an acceptable alternative for children with caregivers known to be generally compliant with other health-care recommendations.No data are available on the concomitant administration of HbCV or H. influenzae b polysaccharide vaccine (HbPV) and OPV and MMR vaccine.If the child might not be brought back for future vaccinations, the simultaneous administration of all vaccines (including DTP, OPV, MMR, and HbCV or HbPV) is recommended, as appropriate to the recipient's age and previous vaccina tion status.
# OUTBREAK CONTROL
All reports of suspected measles cases should be investigated promptly.A measles outbreak exists in a community whenever one case of measles is confirmed.Once this occurs, preventing the dissemination of measles depends on the prompt vaccination of susceptible persons.Control activities should not be delayed for laboratory results on suspected cases.Persons who cannot readily provide documen tation of measles immunity (see "Measles Immunity") should be vaccinated or excluded from the setting (e.g., school).Documentation of vaccination is adequate only if the date of vaccination is provided.Almost all persons who are excluded from an outbreak area because they lack documentation of immunity quickly comply with vaccination requirements.Persons who have been exempted from measles vaccina tion for medical, religious, or other reasons should be excluded from the outbreak area until at least 2 weeks after the onset of rash in the last case of measles.
# School-based Outbreaks
During outbreaks in day-care centers; elementary, middle, junior, and senior high schools; and colleges and other institutions of higher education, a program of revaccination with MMR vaccine is recommended in the affected schools.Consider ation should be given to revaccination in unaffected schools that may be at risk of measles transmission.Revaccination should include all students and their siblings and all school personnel born in or after 1957 who cannot provide documentation that they received two doses of measles-containing vaccine on or after their first birthday or other evidence of measles immunity (see "Measles Immunity").Persons revacci nated, as well as unvaccinated persons receiving their first dose as part of the outbreak control program, may be immediately readmitted to school.Mass revacci nation of entire communities is not necessary.
# Quarantine
Imposing quarantine measures for outbreak control is both difficult and disruptive to schools and other organizations.Under special circumstances restriction of an event might be warranted; however, such action is not recommended as a routine measure for outbreak control.
# Outbreaks Among Preschool-aged Children
The risk of complications from measles is high among infants <1 year of age.Therefore, considering the benefits and risks, vaccination with monovalent measles vaccine is recommended for infants as young as 6 months of age when exposure to natural measles is considered likely.MMR may be administered to children before the first birthday if monovalent measles vaccine is not readily available.Children vaccinated before the first birthday should be revaccinated when they are 15 months old and when they enter school to ensure adequate protection (see " General Recommendations").
# Medical Settings
If an outbreak occurs in the areas served by a hospital or within a hospital, all employees with direct patient contact who were born in or after 1957 who cannot provide documentation they they received two doses of measles vaccine on or after their first birthday or other evidence of im m unity to measles (see " Measles Immu nity") should receive a dose of measles vaccine.Since some medical personnel who have acquired measles in medical facilities were born before 1957, vaccination of older employees who may have occupational exposure to measles should also be considered during outbreaks.Susceptible personnel who have been exposed should be relieved from direct patient contact from the fifth to the 21st day after exposure regardless of whether they received vaccine or IG after the exposure.Personnel who become ill should be relieved from patient contact for 7 days after they develop rash.
# DISEASE SURVEILLANCE AND REPORTING OF ADVERSE EVENTS Disease Surveillance
As the incidence of measles declines in the United States, aggressive surveillance becomes increasingly important.Effective surveillance can delineate inadequate levels of protection, define groups needing special attention, and assess the effec tiveness of control activities.
Known or suspected measles cases should be reported immediately to local health departments.Serologic confirmation should be attempted for every suspected case of measles that cannot be linked to a confirmed case.Reporting of suspected cases and implementation of outbreak-control activities should not be delayed pending laboratory results.
The traditional serologic diagnosis of measles requires a significant rise in antibody titer between acute-and convalescent-phase sera.However, the diagnosis can also be made by demonstrating the presence of IgM antibody in a single specimen.Correct interpretation of serologic data depends upon the proper timing of specimen collection in relation to rash onset.This timing is especially important for interpreting negative IgM results, since IgM antibody peaks approximately 10 days after rash onset and is usually undetectable 30 days after rash onset.
Asymptomatic reinfection can occur in persons who have previously developed antibodies, whether from vaccination or from natural disease.Symptomatic reinfec tions are rare.These reinfections have been accompanied by rises in measles antibody titers.
# Reporting of Adverse Events
The National Childhood Vaccine Injury Act of 1986 requires physicians and other health care providers who administer vaccines to maintain permanent immunization records and to report occurrences of adverse events specified in the Act (14 ).These adverse events, as well as other adverse events that require medical attention, must be reported to the U.S. Department of Health and Human Services.Although there eventually will be one system for reporting adverse events following immunizations, two separate systems currently exist.The appropriate reporting method depends on the source of funding used to purchase the vaccine.If a vaccine was purchased with public funds, adverse events should be reported to the appropriate local, county, or state health department.The state health department submits its report to CDC.If vaccine was purchased with private money, adverse events should be reported directly to the Food and Drug Administration. |
# Preface
We see it on the nightly news, read about it in the newspaper, hear about it from our children, and witness it firsthand-young people getting in fistfights and shoot-outs in our neighborhoods, in shopping malls, on the playground, and in school.It's disturbing and frightening, both for our nation's youth and for society as a whole.
If you've wanted to do something to stop this violence, then Best Practices of Youth Violence Prevention: A Sourcebook for Community Action is for you.We've pulled together the best practices known for four promising strategies to prevent youth violence, and we've organized them in a way that's easy to follow and use.And because it's often best to get expert advice "straight from the horse's mouth," we've included numerous resources to put you in touch with the people who have implemented these practices and seen the results.
Whether you're part of a grass-roots movement or involved with a large, established organization, you'll find this sourcebook to be a valuable asset to your youth violence prevention effort.
# Introduction
Violence among children and adolescents is a significant public health concern.In 1999, 1 violence claimed the lives of more than 3,200 Americans ages 19 and under-that's an average of 9 deaths per day-making the homicide rate for young people in the United States the highest among developed countries.Homicide is the second leading cause of death among 15-to 19year-olds and the thrid leading cause of death among children ages 10 to 14.
Highly publicized school shootings have sobered communities that may have believed they were immune to youth violence.Once viewed as a problem only in inner-city neighborhoods, youth violence is now perceived as a nationwide crisis, and communities are eager to find ways to stop it.
Experts in youth violence prevention do not have all the answers for solving this public health problem; we must do a lot more research and evaluation.But we know enough to offer the public some insight into what works to prevent violence by children and adolescents.This book-which builds on CDC's 1993 publication The Prevention of Youth Violence: A Framework for Community Action-shares that insight.
We developed this book with input from individuals working to prevent youth violence and from individuals whose positions made them likely to play a role in violence prevention efforts.We interviewed teachers, school administrators, members of community-based organizations, employees and volunteers at social service agencies, health department personnel, program planners and practitioners, and researchers from universities across the country to find out what they would like to see in a sourcebook for preventing violence by children and adolescents.Their responses guided the content and shaped the format of this book.
In addition to gathering information from experts, we conducted an extensive review of the scientific literature on youth violence prevention to collect the most up-to-date information available in the field.This literature review provides the science base on which our recommendations for best practices rest.
# Sourcebook Contents
This sourcebook places at your fingertips the best knowledge available about several strategies designed to prevent youth violence.These strategies are among those with the strongest evidence base for reducing youth violence.
Chapter 1 reviews general principals of intervention planning, implementation, and evaluation.This chapter will be especially helpful to readers who are new to developing prevention efforts.For seasoned program planners, it will be a useful refresher.
Chapter 2, the "meat" of the sourcebook, builds on the experiences of others who have worked to prevent violence by children and adolescents.It discusses in depth the best practices of four key youth prevention strategies and documents the science behind those best practices.Also in Chapter 2, you will find resources for more information about programs that have used these practices.We encourage you to talk with the organizations listed and to review the publications described to find out what worked particularly well and identify potential pitfalls and challenges.
The sourcebook also includes two appendices:
- Appendix A provides a fact sheet on the problem of youth violence.This information will be useful if you need to formulate a convincing appeal for support from organizations and community leaders.
- Appendix B provides an overview of the public health approach, the process by which public health problems are identified and addressed-and the underlying reason for our developing this sourcebook.
# Introduction
Planning, implementing, and evaluating an intervention can be a daunting project, especially for someone who has never been involved in such an effort.However, you can improve your chances of success if you follow certain steps.This chapter gives a brief overview of those steps.
In this chapter, we will explain how-and why-to do the following:
- Describe the problem of youth violence in your community If after reading this chapter, you have questions or concerns about developing an intervention for your community, take a look at the Additional Resources section at the end of the chapter.The publications listed there contain helpful information about such topics as assessing a community's resources and readiness to change, working with diverse populations, and evaluating a program.
# Definitions
You will see the terms strategy, intervention, and program repeated many times throughout this sourcebook.Because these terms may mean slightly different things to people in different professions, we have defined them here so all readers will know how they are used in this publication.
# Strategy:
A general conceptual approach to preventing violence by children and adolescents.For example, home visiting can offer basic training in parenting skills for pregnant teens.
Intervention: A specific set of activities and accompanying materials developed to prevent youth violence and the factors that contribute to it.For example, a school may implement a curriculum and role-playing activities to help students develop conflict-resolution skills.
Program: A grouping of strategies (and, therefore, of various kinds of interventions) designed to prevent youth violence.For example, a community might combine a school-based curriculum with a home-visiting intervention.
# Describe the Problem
Before you can plan an intervention to prevent violence committed by children and adolescents in your community, you need an accurate description of the problem.This description will help you identify who is affected most by the problem and where the problem occurs most frequently so you can better target an intervention.It will guide you in developing realistic objectives for your intervention and will provide a baseline against which to measure progress.You also need a clear definition of the problem to convince lawmakers, community leaders, parents, volunteers, and potential funders that your intervention is necessary.
The information you need to describe the problem can be obtained from several sources.Quantitative data is available from a number of agencies and organizations that collect statistics on youth violence, and you can interview or survey members of your community to get qualitative information (e.g., opinions, attitudes).Regardless of where you get your information, be sure the individuals collecting it are respected and trusted by the community.
# Factual information
Many sources of data exist to help you define the problem of youth violence in your community.Table 1 lists some of those sources.Appendix A at the end of this sourcebook also provides data about youth violence at a national level.Before asking agencies and organizations for information, do a little research.
# Table 1
# Sources of Factual Information about Youth Violence
# At-risk and high-risk children and adolescents
Research has shown that certain factors make children and adolescents more susceptible to developing violent behavior.These factors include an individual's characteristics or behaviors, including a history of aggression; beliefs that support the use of violence; social or cognitive problems; and the use of alcohol or drugs.They also include family and community circumstances such as a parent's use of alcohol or drugs; a lack of parental supervision or discipline; spousal abuse or child abuse; poor emotional attachment between parent and child; access to firearms; and divorce, relocation, or other family disruption.Problems at school, such as chronic discipline problems and associating with peers who are violent, can also put a young person at risk for developing violent behavior (Dahlberg 1998).
Chapter 1 -9 High-risk individuals are those who consistently engage in physical fights to resolve problems, have a criminal record, have a history of inflicting violent injury, have been the victim of violence, have failed or dropped out of school, carry a weapon, belong to a gang, or use drugs.Children and adolescents who move a lot, including children of immigrants or migrant workers, are also considered high risk.
If you choose to target at-risk or high-risk groups, be prepared for special challenges.You may need to enlist outreach workers to locate and engage high-risk youths, many of whom are no longer in school.You may also find it hard to establish trust and receptiveness among these young people.
# Young children (10 years and younger)
Violence is a learned behavior.The values, attitudes, and interpersonal skills acquired early in life play a key role in the development of violent behavior.Because a person's violent or nonviolent tendencies may be set in early childhood, preschooland elementary school-age children are often thought to be ideal participants in interventions that promote nonviolent values and enhance conflict-resolution skills.
# Parents and other family members
Family experiences play a critical role in causing, promoting, or reinforcing violent behavior by children and adolescents.Therefore, it is important to develop interventions targeted to parents, siblings, or the entire family unit.Interventions that involve the family often complement interventions carried out in the schools or other parts of the community.
# Other influential adults
Parents are not the only adults who shape the beliefs and behavior of young people.Individuals such as teachers, coaches, child care providers, and neighbors often influence how a child or adolescent feels about violence.As with interventions targeting family members, interventions that involve other adults in the community may be effective in supporting the interventions that target the young people themselves.
# General population
Social norms affect how violence is portrayed, whether violence by young people is tolerated, and how many resources a community will devote to stopping youth violence.Interventions for the general population can increase knowledge about the magnitude of youth violence in a community, help inform legislation or policies regarding youth violence, and create an environment that fosters and supports other interventions to
# The values, attitudes, and interpersonal skills acquired early in life play a key role in the development of violent behavior.
Chapter 1 -11 prevent violence by young people.However, as with interventions targeting all young people in a community, efforts designed to change the values, attitudes, or behaviors of the entire community are costly.And they may fail to reach those most in need of change.
# Select a Setting
The setting for an intervention is where activities will occur.Select a setting that is convenient and comfortable for participants; ask them where they would like to meet.Also consider the type of intervention you are planning.While many interventions have a logical setting, others-especially those targeting high-risk youth-may be less obvious.You may need to collect additional data about your intended participants to determine where your intervention can be carried out most effectively.
# Set Goals and Objectives
Once you have identified whom you should reach with an intervention and where to reach them, 2 decide what the goal of your intervention will be.Your goal should be a broad statement of what you want to achieve.Then determine the specific things you will need to do to achieve your goal.These are your objectives.Objectives should be measurable and attainable given the resources you have.They should tell who should achieve how much of what, where it should occur, and by when (NCIPC 1993).Table 4 provides an example of a goal and its corresponding objectives.
Objectives are important because they clarify the tasks to be done and provide a means of tracking an intervention's progress.
If you have many objectives, consider grouping them by the type of outcome-health effects such as injuries or deaths; behaviors such as fighting, expulsions, or dropping out of school; or other aspects of the program such as the number of students in a class or the number of newspaper articles published about youth violence.Presenting the objectives this way may make it easier for community leaders, supporters, funders, and others to see what you are trying to achieve.
Keep these important guidelines in mind when developing your goal and objectives:
- Make sure they fit the characteristics and resources of your community.
If you are working with other organizations, get their input to ensure that the goals and objectives of the intervention are consistent with those of each organization. -Do not include objectives to satisfy another organization's research agenda if they are unrelated to your goal. (However, it may be worthwhile to make minor additions to your objectives if doing so will generate substantial resources for your effort.)
Remember, your objectives are not static.Modify them as new information becomes available, as resources change, or as activities proceed faster or more slowly than planned.
2 As discussed previously, you may select your intervention before making a final decision on the setting.
# Objectives clarify the tasks to be done and provide a means of tracking an intervention's progress.
Chapter 1 -13
# Select an Appropriate Intervention
We can teach young people how to avoid violent situations.We can help them develop the skills they need to resolve conflicts without resorting to violence.We can help parents provide a nonviolent home for their children.We can provide young people with mentors who serve as nonviolent role models.
With so many types of interventions, how do you choose?Start by reviewing the characteristics of your community and your intended participants.Also consider the most appropriate settings for your intervention, based on research about the intended participants.And review your goals and objectives.The intervention you choose should best suit all of these factors.It should also be appropriate given your resources.
Build on the experience of others.If you know of interventions that have worked in other communities similar to yours, use them as models for your effort.Chapter 2 of this sourcebook offers many examples of interventions and the best practices for planning and implementing them.Keep in mind, however, that you may need to modify an intervention to make it appropriate to your community.
# Selecting multiple interventions
A single intervention conducted in isolation is not likely to solve the problem of youth violence; too many factors contribute to violent behavior to be addressed by one strategy.The most effective programs include several types of interventions and strategies that complement one another.For example, a mentoring program to help teens avoid gang membership may be complemented by an intervention that offers alternative afterschool activities.Instruction on nonviolent conflict resolution for school children may be complemented by an intervention that teaches families how to foster nonviolence at home.Carefully consider your resources, community support, and level of experience when selecting interventions.And make sure that the interventions you choose fit together well.
# Locate Resources for Your Intervention
Implementing an intervention to prevent violence by young people takes a variety of resources.Funding and other material resources-such as office space, equipment, and supplies-are critical to your effort.But they, alone, do not ensure success.You also need a commitment of time, effort, and support from the members of your community.These resources may come from public or private sources.You can also generate your own resources by organizing fundraisers and other events that publicize your effort.
# Build on the experience of others.If you know of interventions that have worked in other communities similar to yours, use them as models for your effort.
It may be easiest to start with local and state government agencies.If they don't have funds available, they can refer you to other government sources.Contact your local health department, department of housing, human resources or social services agency, department of parks and recreation, and department of education or school board.While few states publish a directory of available funds, many have web sites that tell you whom to contact about potential funding.You might also identify funding sources through personal contacts, such as elected officials.The Public Health Foundation is also a valuable source for funding information.They compile information on program areas that are funded in each state.You can reach the Foundation at www.phf.org or 202-898-5600.
When contacting state and local officials, ask about block grants.Each state receives federal block grants to support activities in four key public health areas: preventive health; maternal and child health; alcohol, drug abuse, and mental health; and primary care.Table 5 provides contacts for information about block grants.
Federal agencies offer other funding in addition to block grants.There are several ways to find these resources.Agencies solicit proposals and grant applications in the Federal Register and the Commerce Business Daily.You can subscribe to these publications through the Government Printing Office by calling 202-512-1800 or visiting their web site at www.access.gpo.gov/su_docs.However, these subscriptions are expensive.You may find it more practical to review these publications in your local library or to access them on the Internet.Research using these two publications will be timeconsuming, regardless of how you access them.
The Catalog of Federal Domestic Assistance is another source of information about federal funding.Published annually, the catalog describes major federal grants and contracts, outlines eligibility requirements, identifies criteria for selection, explains financial details, and provides contact information.Because the information in this publication can become outdated quickly, you should contact each agency before submitting a proposal.The Catalog of Federal Domestic Assistance is available from the Government Printing Office: 202-512-1800 or www.access.gpo.gov/su_docs.
The Additional Resources section of this chapter can also help you locate potential public funding sources. |
It contains a list of federal agencies with an interest in youth violence prevention, some of which provide grant money.You will need to contact them directly to find out if your intervention is of interest to them and if you meet their criteria.
# Private sources
Private funds come from corporations and other businesses, voluntary organizations, foundations, charitable institutions, churches, and other local establishments.Private organizations are typically more flexible than public agencies in the types of interventions they fund, and they often have less direct involvement in and oversight of the intervention.These organizations may also offer facilities, equipment, and volunteers.
While the process for requesting support tends to be less formal with private entities, you still need to convince their decision makers that your intervention is worthy of their resources.Provide them with data you gathered about youth violence in your community and explain how your intervention will address the problem.Share your goals and objectives.You may also need to show the business or organization how their involvement will benefit them directly (for example, increased visibility if you list them as a sponsor).
# Corporations and businesses
Ask local businesses-including banks and stores-to support your program.They can often provide funds or give you office space, equipment, and other supplies needed for your intervention.U.S. corporations donate a great deal of money each year to help communities address public health issues.Look for a large company with facilities in your area and ask for their financial support.
Voluntary, community service, and religious organizations Community groups or local divisions of state or national voluntary organizations (such as the Child Welfare League of America, Children's Safety Network, National Crime Prevention Council, and KidsPeace) may be willing to donate funds or other materials to your effort.Community service groups such as sororities, fraternities, and associations of retired teachers will often provide volunteers to carry out your intervention.Churches and religious organizations may offer resources such as meeting space for intervention activities.
# Hospitals and other health care facilities
These facilities may have meeting space you can use for intervention activities.Mental health services staff and pediatricians may help you enroll participants by referring patients to your program.
# Local television and radio stations and newspapers
Community media may be willing to provide free publicity for your program, through announcements, interviews, and human interest stories.Local media personalities may also take part in fundraising efforts and other activities.
#Chapter 1
Educational institutions Schools, including local colleges and universities, may be able to provide volunteers for your intervention and help conduct fundraisers.Universities may be willing to help you conduct research and develop your intervention.
# Foundations
A foundation's sole purpose is philanthropic giving.Many foundations are willing to fund programs with good ideas but little experience.They are more likely than public agencies to take a chance on a new intervention.Because foundations may limit the types of interventions they fund or the geographic areas they serve, it is important to find out which foundations support violence prevention interventions.The Foundation Center can help you do that.
The Foundation Center provides detailed information about the interests and restrictions of individual foundations and about the money they have granted.They have four main offices as well as libraries in all 50 states.To locate the nearest Foundation Center library, call 800-424-9836 or visit www.fdncenter.org.You can also find listings of foundations and their areas of interest in your public library.
After identifying a foundation as a potential funding source, write a letter to the foundation that briefly states what you want to do in the community and ask whether the foundation is interested in this type of project.Through this inquiry, you will also find out the process for submitting a grant proposal.
# Involve the Community
Involving the community in planning your intervention will benefit you, the intended participants, and the community as a whole.When community members are asked to help plan and implement the intervention, they develop a sense of ownership.They want the intervention to succeed and are more willing to invest the effort and resources needed to sustain it.Involving the community also makes it easier to obtain the resources and volunteers you need to carry out your intervention.
So what's the best way to involve the community?From the very beginning, enlist organizations and agencies that know about the youth in your community and have an interest in preventing injury and death among young people.Institutions that frequently get involved in efforts to prevent youth violence include schools, churches, parks and recreation centers, businesses, and civic, service, and cultural groups.
# The Foundation
Center: 800-424-9836 www.fdncenter.org
# Coordinating efforts
Once you have commitments from organizations that want to help you develop and implement your intervention, you need to decide what they are going to do and how to keep them working in harmony.Establish a leadership structure that includes members of the community and intended participant groups.Leadership roles may be informal and flexible until your intervention takes shape.However, as activities develop, leaders will be more formally designated, and their responsibilities-as well as those of the others involved in the effort-will be clearly delineated.Documenting the division of duties before an intervention is launched will help prevent duplication of effort and potential "turf wars" between organizations.It will also help you identify organizations that need technical assistance in order to prepare for and carry out their assigned activities.
# Develop Your Activities and Materials
At this point, you have planned many of the key elements of your intervention-who your intended participants are, where you can reach them, what your goals and objectives are, and whom you will work with to achieve them.Now, it's time to develop the activities and materials that your intervention will comprise.
Involving representatives of your intended participant group in this process is crucial.Conduct focus groups and surveys to identify participants' needs, potential barriers, and cultural issues.This input will help you tailor your intervention to meet the needs and preferences of participants.
# Pretesting materials and activities
Before you launch your intervention, test the activities and materials with representatives of your intended participant group.Pretesting will allow you to see whether your materials and activities achieve the desired outcome.It will also reveal any undesired effects.It will help you verify whether messages are accepted and understood by participants and whether the reading level of written materials is appropriate.
# Staff Your Intervention
Once your intervention is developed, you need a staff to implement it.The composition of your staff will depend on several factors.First, think about the activities to be conducted.Some interventions will require a staff with specialized skills or formal education.For example, you may need registered nurses or licensed social workers to perform home visits.You must also consider the needs and preferences of your intended participants.If, for example, you learn that young boys prefer male mentors of the same race and ethnicity, staff your intervention accordingly.
Another big consideration is the resources available for your effort.If your intervention is well-funded, you may be able to hire several paid staff members.On the other hand, if you have limited resources (which is often the case) you will need to enlist volunteers.You may have already identified volunteers when you secured funding and other resources.
Also think about how much time your staff will need to spend working on your intervention.An intervention that involves home visits may require full-time staff members who can visit several homes each day.In contrast, an intervention that involves parenting classes at a community center may need only part-time staffers to teach classes a few evenings a week.In many cases, you may need individuals who can implement your intervention in conjunction with their other job duties.For example, you may ask coaches at the YMCA to implement a violence prevention curriculum during team practices.
# Train Your Staff
Whatever the content of your intervention or the staff you select, everyone involved in implementing the intervention-including the administrative staff and others working behind the scenesmust receive training.This training should inform staff members about the problem of youth violence in your community and teach them how to carry out your intervention's activities.Even professionals who have completed formal education or who have worked on violence prevention efforts before will benefit from training specific to your intervention.
# Training content and schedule
Training content will depend, of course, on your intervention activities and materials, but the following elements are applicable to all staff members and all interventions.
- Communication skills.
# Before training begins
Before you conduct training, assess each staff member's readiness to learn violence prevention skills and implement the activities that compose your intervention.You can do this by measuring the extent to which individuals agree with three statements (Slaby 1998):
- People's violent behavior can be prevented (general beliefs). -Particular interventions can be effective in helping to prevent violence (specific beliefs). -I, myself, can make a difference in helping to prevent violence (personal beliefs).
If you find that members of your staff do not agree with these statements, you will need to start your training session with activities to help individuals overcome their doubts.Providing evidence of successful interventions may help convince your staff that its efforts can, in fact, impact youth violence.
# Implement Your Intervention
You've developed your materials and activities.You've secured resources and personnel.You've trained your staff.Now it's time to implement your intervention.
Implementation will vary greatly from intervention to intervention in terms of duration (how long the intervention lasts), frequency (how many times in a given period activities occur), and intensity (how much material is covered and how much time is spent during each activity).Chapter 2 addresses these issues for each of four strategies for preventing youth violence.With all interventions, however, you will need to supervise and support your staff, maintain a consistent level of participation, and keep the community interested in your intervention.Chapter 2 offers guidance on these matters, as well.
# Monitor Your Intervention
During all phases of your intervention, monitoring the implementation process is essential.Intervention monitoring will let you see if activities are occurring according to your plan.It will also allow you to identify unanticipated problems or barriers.
# With all interventions, you will need to supervise and support your staff, maintain a consistent level of participation, and keep the community interested in your intervention.
Chapter 1 -25
Methods for monitoring interventions will vary (Chapter 2 addresses some issues specific to the four strategies), but at a minimum, intervention monitoring should include the following:
- Measurement of key variables to see if your objectives are being met.For example, if one of your objectives is to implement a schoolwide program to improve students' conflictresolution skills, you might measure how many times in a semester skill-building activities were conducted.You might also measure student attendance during the activities.
Evaluations by intervention staff.This information can tell you whether staff members feel their training prepared them adequately for conducting a particular activity, whether participants seem comfortable with staff members and with the activity, and whether instructions for the activity were clear to participants.
Feedback from participants about the intervention's activities.For example, you might assess whether participants enjoyed a particular activity and how well they understood the materials presented.You might also ask whether participants would change anything about the activity.
Review the data regularly.If you find that an activity is not achieving the outcome you desired, you may need to alter it.If staffers report that they are having a hard time implementing an activity, you may need to provide additional training.If you discover that activities are not being implemented as often as planned or that participation is much lower than anticipated, you may need to reexamine your objectives; perhaps they were overly ambitious for your intervention's time frame or resources.Whatever changes you make-whether to activities, materials, or objectives-be sure to inform all intervention staff members and supporters.
# Evaluate Your Intervention
Throughout your intervention you will monitor progress to make sure you are on track and on schedule.At the end of your intervention, you must do a final (or summative) evaluation to determine how well you achieved your goals and objectives.You'll assess how well you reached your intended participants and whether the outcomes you obtained were what you planned.You'll also compare the costs of the program with the benefits of the program.You may also plan a follow-up study to assess the long-term effects of your efforts.
Many organizations have limited resources and may be tempted to skip evaluation, instead dedicating that money to intervention activities.However, evaluation is a critical step.It will enable you to demonstrate to funders, community leaders, and intervention staff that your efforts were a success.And if your intervention fell short of expectations, evaluation will help you identify what went wrong so you can make necessary changes to the intervention (Thompson and McClintock 1998).
If your organization does not have the expertise needed to evaluate your intervention but has resources to devote to it, you can hire a consultant.If you lack resources for evaluation, partner with a local university that would be willing to design and carry out a scientific evaluation.
# Summary
The steps involved in intervention planning, implementation, and evaluation may seem time-consuming, labor-intensive, even overwhelming.However, by following this systematic process, you will increase the likelihood of your intervention's success and enable others to repeat your intervention in their communities.This chapter discusses the importance of community analysis, the process of assessing and defining needs, opportunities, and resources of a community.It identifies methods for collecting both quantitative and qualitative data, including suggestions for special studies to increase information about selected social groups in a community.Community analysis is a critical first step in shaping the design of an intervention and in tailoring the implementation plan to a community's characteristics.
# Introduction
Youth violence is a complex public health problem with many risk factors, including individual beliefs and behaviors such as early aggression and use of alcohol or other drugs; family characteristics such as spousal abuse and lack of parental supervision; peer and school influences such as associating with delinquent friends; and environmental factors such as access to firearms.This complexity presents many challenges for those who are working to prevent youth violence (Dahlberg 1998).
This chapter discusses four distinct strategies for combating the problem of youth violence and offers for each strategy best practices-the elements and activities of intervention design, planning, and implementation that are recommended on the basis of the best knowledge currently available.Identified through extensive literature reviews and interviews with experts, these best practices will guide you in developing interventions that meet your community's and participants' needs and fit your goals and objectives.They will help you engage the community in your effort, hire and train an intervention staff, and locate resources and partners.They will also help you determine the time frame for your intervention, support and encourage your staff, and keep participants interested and engaged.And they will direct you in monitoring your intervention's progress and evaluating its final outcome.
The goal of this chapter-and of the sourcebook overall-is to share the experiences of others who have implemented interventions to prevent youth violence.In addition to the best practices for each strategy, we have included an Additional Resources section.We encourage you to contact the organizations listed and to review the publications described to learn what works particularly well and what barriers and problems may exist for interventions of interest to you.You may also want to review the studies listed in each strategy's reference section (the first strategy includes references for this introduction).
# A Note about the Best Practices
Ideally, best practices are based on knowledge derived from rigorous evaluations of interventions reported in peer-reviewed literature.However, a number of factors complicate this approach to identifying best practices for youth violence prevention efforts.
First, because the field of research in youth violence prevention is young, few longitudinal and randomized-control studies have been conducted.Second, while studies have evaluated the outcome of interventions, they have not typically evaluated the effectiveness of individual implementation practices.Therefore, the majority of best practices presented in this sourcebook are based on the hands-on, empirical observations of intervention practitioners and evaluators.
Because youth violence is such a high-priority public health concern, and because it may be years until we can report a significant number of science-based best practices, we felt it was important to include in this sourcebook promising intervention practices as well as scientifically proven ones.
# Overview of the Parent-and Family-Based Strategy
Parents' interactions with each other, their behavior toward their children, and their emotional state have been shown to be important predictors of children's violent behavior (Webster-Stratton 1997).Hendrix and Molloy (1990), for example, found that poor interactions between a mother and a child at age 1 year predict behavioral problems and aggression at age 6.Having an emotionally distressed parent at age 4 years has been found to contribute to a child's developing conduct disorders and antisocial behaviors (Buka and Earls 1993).Marital conflict and a lack of communication between parents have also been identified as risk factors for youth violence (Biglan and Taylor 2000;Buka and Earls 1993;Tolan and Guerra 1994).
# Best Practices of Parent-and Family-Based Interventions
While the evidence base for parent and family interventions is growing, there is a need for more evaluation research.Those interventions that have been evaluated have typically not set violence reduction as an outcome measure.More commonly, they have measured reductions in delinquent behaviors, conduct disorders, or drug use, all of which are considered precursors to violence.
Despite the need for more evaluation, however, we have learned many lessons about what works using this strategy. |
This section offers the best practices of parent-and family-based interventions, combining recommendations by experts with general conclusions found in a review of the literature.We have organized the best practices around the steps involved in planning, implementing, and evaluating an intervention (see Chapter 1 for a review of those steps).
# Identify the Populations You Want to Reach
Parenting interventions are generally more successful if they are implemented with the unique characteristics and needs of the intended participants clearly in mind.Before you develop your intervention, identify the group you want to reach.
# At-risk populations
Substantial research has been devoted to identifying factors within the family unit that put a child at risk for developing violent behaviors.These factors may be related to behaviors and characteristics of either the parents or the child.
Parents' risk factors Some risk factors that parents possess are dramatic and obvious, such as criminal and violent behavior, alcohol and other drug abuse, child abuse, and child neglect.Other, more subtle predictors include harsh or inconsistent discipline, lack of emotional interaction between the parent and child, and lack of parental supervision (Patterson, Reid, and Dishion 1992;Buka and Earls 1993).Many other behaviors, although not related directly to parenting, are also associated with children's violent behavior.Examples include lack of communication between spouses, marital conflict and divorce, parental social isolation, and parental depression or stress (Buka and Earls 1993;Tolan and Guerra 1994).
# Avoid identifying socioeconomic status only as the determinant of risk.
The perception that an intervention targets individuals simply because they are poor is highly stigmatizing.
One study found that poor, single mothers-faced with many challenges and stressors-are at highest risk for developing parenting patterns that can lead to violent behavior by their children (Patterson, Reid, and Dishion 1992).Parents whose first language is not English often exhibit risk factors resulting from acculturation conflicts.And targeting low-income families has been shown to reduce child abuse and neglect (Campbell and Taylor 1996).
Avoid identifying socioeconomic status only as the determinant of risk.The perception that an intervention targets individuals simply because they are poor is highly stigmatizing.Find nonpejorative ways to identify people at different levels of risk.
# Children's risk factors
Research has found that children at risk for violence can be identified by the time they are 3 years old (Olweus 1978).
Factors that put children at risk include living in neighborhoods where violence commonly occurs, witnessing severely violent acts, being a victim of abuse, and associating with "rough" or antisocial peers.Other less obvious factors have also been associated with the development of violent behaviors.These include learning problems, a history of absenteeism from school, and frequent visits to the school counselor.A sudden change in behavior can also signal the beginning of violent tendencies.
# High-risk populations
Some children are considered to be at high risk for developing violent behaviors.These children already exhibit clear behavioral markers of violent activity, including the following:
# Young children (10 years and under)
The effectiveness of parenting interventions seems to increase exponentially when children are very young, before antisocial or aggressive behaviors are fully developed (Webster-Stratton and Hancock 1998;Webster-Stratton and Spitzer 1996).By the time a child reaches adolescence, both the child and the parents are following well-established patterns and are more resistant to long-term change (Patterson, Reid, and Dishion 1992;Taylor and Biglan 1998).And a 14-year-old boy relies much less on his family and is much more susceptible to external influences than a 7-year-old boy (Hendrix and Molloy 1990).
# Expectant parents
The earlier in a child's life a parent-based intervention begins, the greater the likelihood it will be effective.With this fact in mind, you may want to consider targeting parents who are expecting a child.Previous research suggests that intervening with a mother during the latter part of pregnancy and continuing with intervention activities during the first few years of her child's life can significantly reduce the risk of conduct disorder and violence (Olds 1997).
# Consider the Cultural and Demographic Context of Intended Participants
When selecting your intended participants, consider their location, age, life circumstances, ethnicity or race, and needs.Try to select a group of people who live near each other and are alike in key characteristics.By targeting a group that is fairly homogeneous, you can better tailor materials and activities so they are more meaningful to participants.
Selecting a homogeneous group increases the likelihood that participants will form support groups and friendships that extend beyond the environment of the intervention.Such an outcome was achieved by the Houston Parent-Child Development Center, which targeted low-income, Mexican American parents (Johnson 1988).
You can also meet the needs of your participants more effectively when participants are alike.Wood and Baker (1999) developed a questionnaire to examine parent preferences, behaviors, and beliefs toward school-based parent-education programs among 395 low-income, culturally diverse parents from two elementary schools.Results indicated that parents of low socioeconomic status wanted to participate in parenteducation events, but they were less likely than parents with higher levels of education to attend events at school.The greatest barriers to their participation were difficulty in getting time off from work (27%), cost (27%), lack of transportation (21%), and inability to find or afford babysitting (18%).
# Select an Appropriate Setting
The setting for a parenting intervention will likely be a school, community center, church, or other location where a group of people can meet.Make sure your setting is conducive to interactive exercises and discussions.
To reach people who live in remote areas or who have difficulty getting to and from an intervention site, you may need to bring the intervention to them.For example, in remote and rural areas in South East Queensland, Australia, a self-directed intervention delivered by telephone contact and written information was implemented (Connell, Sanders, and Markie-Dadds 1997).
Twenty-four preschool children with problem behaviors and their families were recruited for a randomized, controlled study of the parenting intervention.Participants assigned to the intervention read sections of a book on parenting weekly for 10 weeks, completed tasks in the accompanying workbook, and participated in weekly telephone consultations (lasting up to 30 minutes) with a therapist.Parents were prompted to monitor their own and their child's behavior, set goals for behavior change, select strategies, identify strengths and areas for improvement, and select contingent rewards for themselves and their children.Results indicated that this self-directed, minimal intervention increased parents' perception of competency; reduced dysfunctional parenting practices; reduced disruptive behavior by the child; and significantly reduced mothers' feelings of anxiety, depression, and stress.Improvements in child behavior and parenting practices achieved at the end of the intervention were maintained at follow-up four months later.
Another self-directed intervention is Parenting Adolescents Wisely, a CD-ROM-based program.It was successfully implemented in Appalachia, where participants had little or no computer literacy (Olds 1997).Because the skill-building exercises require no orientation or supervision by staff, they can be conducted at any time, in locations most convenient to participants (Kacir and Gordon 1999).This intervention has also been successful with teen mothers and clinic-referred teens and parents (Lagges 1999;Segal 1995).With no other intervention or support, the rate of problem behaviors for children in the intervention dropped by half at one, three, and six months after their mothers participated in the intervention.
# Involve the Community and Parents in Planning the Intervention
Organizations sponsoring parent-and family-based interventions should participate in developing the intervention.This involvement will help them feel ownership of the intervention so they are more likely to support its objectives, commit to evaluating outcomes, and hold themselves accountable for the impact of the intervention.
Parents also need to participate in the development process.The more active a role parents play in an intervention from its inception, the greater their sense of empowerment and accountability both during and after the intervention.Parents can also provide unique insight to help practitioners more closely tailor the intervention to participants' needs and priorities.
# Set Clear Goals and Objectives for Intervention Outcomes and Implementation
Set clear, specific, observable goals and objectives for each intervention.They will help you evaluate an intervention's effectiveness and give parents and staff a sense of day-to-day accomplishment.Make sure goals and objectives are behaviorbased and outcome-oriented-for example, reducing school truancy by 50 percent or establishing and keeping a weekly family budget.If you are modeling your intervention after one that has been proven effective, use the original intervention's evaluation framework to shape your goals and objectives.
Involve parents in setting objectives.Have them outline, with the practitioner's guidance, what they think their family can achieve and in what time period.Starting this kind of new initiative may seem overwhelming to parents: they are being asked to change the way they parent their child, even the way they conduct their daily affairs.Setting clear, definable goals enhances parents' sense of control and accountability (McMahon et al.1996).
# Select the Best Intervention for Your Participants and Develop Appropriate Materials
The intervention you select must be appropriate for the ages of the participants' children, the degree of violent behavior or level of risk for such behavior, and participants' cultural characteristics.It must also take into account family dynamics (how members interact with one another), the external environment (e.g., schools, housing), and the family's financial situation.
# If you are modeling your intervention after one that has been proven effective, use the original intervention's evaluation framework to shape your goals and objectives.
# Consider the children's ages
A child's age influences many factors of parenting, from nurturing to discipline.For example, parents of a young child should set limits for their child's behavior, but with an older child, parents may want to negotiate those limits.Therefore, the contents of your intervention will be driven, in part, by the age of the children.
# Young children (ages 10 and under)
Interventions for parents of young children often have the best chance of effecting long-term, positive change because the behavior patterns of both parents and children have not been firmly established; they are still fairly malleable (Taylor and Biglan 1998).When developing an intervention for parents of preschool-and elementary school-age children, include an overview of child development so participants can set realistic, age-appropriate expectations about their children's behavior.
The following are other principles to include in an intervention for parents of young children: The Adolescent Transition Program is one intervention that has been proven effective for families with older children.Designed for parents of middle-school students at risk for substance use, academic failure, and antisocial behavior, this intervention seeks to improve seven classic parenting skills: making neutral requests, using rewards, monitoring, making rules, providing reasonable consequences for rule violations, problem solving, and active listening.Classes are conducted weekly for 12 weeks in groups of eight to 16 parents and follow a skill-based curriculum.In a randomized control trial of the program, which involved 303 families over a four-year period, participants were compared with parents on a three-month waiting list.Parents in the program reported a lower tendency to overreact to their child's behavior, greater diligence in dealing with problem behavior, and less depression.There was also some indication of lower levels of daily antisocial behavior from the child.The more sessions a parent attended (many did not complete the 12week program), the greater the reported improvements in behavior.We should note, however, that this evaluation is limited because it was based on the parents' assessment and interpretation of behavior rather than on objective measures (Irvine, Biglan, Smolkowski, Metzler, et al.1999;Irvine, Biglan, Smolkowski, and Ary 1999).
# Research has demonstrated the effectiveness of working with
parents who are at increased risk for raising antisocial children.after the birth of a child.These initiatives were designed to help parents manage their children and their lives more effectively and reduce the stress typically experienced by parents in the first few years of a child's life.The interventions offered a range of services: parent counseling, strategies for problem-solving, training in parenting techniques, and help in developing social support systems.Some even covered the children's childcare and healthcare expenses.One example of such an intervention has been offered by the Houston Parent-Child Development Center, which serves as a "parent college" for Mexican American families.Up to eight years after the intervention, children of participating parents had a lower incidence of reported problem behaviors in school than did control children (Johnson 1988).
# Interventions for parents of delinquent children
Many parents of children with serious behavior problems use ineffective disciplinary techniques.For example, parents of delinquent children tend to be inadequately involved in monitoring their child's day-to-day activities, to be inconsistent in applying discipline, and to display marginal levels of involvement in such areas as the child's academic progress (Dishion, Patterson, and Kavanagh 1992;Buka and Earls 1993;Bank et al.1991).Often, a destructive pattern of "coercive interaction" exists between the child and the parents, characterized by a cycle of the child misbehaving and the parents threatening the child (Patterson, Reid, and Dishion 1992).While this reaction by the parents may be effective in the short-term, it promotes further aggression by the child in the long run.The first step in breaking this cycle is to change the parents' tactics and teach them alternative responses to their child's negative actions.
The coercion model is one intervention that can break this cycle. (Patterson, Reid, and Dishion 1992).
Another effective intervention for families with chronically delinquent children was developed by the Oregon Social Learning Center (OSLC).In this study, 55 families of boys who had multiple arrest histories and had committed at least one offense deemed "serious" by the court were assigned to either the OSLC parenting-training intervention or to a community treatment group involving 90-minute family-therapy sessions for approximately five months.Parents in the OSLC group were taught to monitor, record, and react to the daily behavior of their boys.Parents and children developed behavior contracts that specified prosocial and antisocial behavior and the positive and negative consequences that would result.Each family received an average of 21.5 hours of therapy and 23.3 hours of phone contact.Families were free to contact intervention staff for "booster shots" of support after the treatment year.
A significant reduction in arrests was achieved for both the intervention and the control group.However, the OSLC treatment produced results more quickly and with one-third less reliance on incarceration.The researchers state that the main outcome of the treatment may have been to help the parents remain actively involved and responsible for the conduct of their boys.We should note that researchers found the clinical work with these families to be extraordinarily difficult, and it took tremendous effort to prevent staff burnout (Bank et al.1991).
# Parents who abuse their children need to build nurturing skills as alternatives to their abusive parenting behaviors and attitudes.
Interventions for abusive parents Parents who abuse their children need to build nurturing skills as alternatives to their abusive parenting behaviors and attitudes.The initial Nurturing Program for Parents and Children 4 to 12 Years was extensively field-tested with 121 abusive adults and 150 abused children.Significant improvements were found in the attitudes of both parents and children, in personality characteristics of both parents and children, and in patterns of family interaction.Evaluations of subsequent nurturing programs have shown similar results (Bavolek 1996).
# Empower parents
A fundamental principle of effective parenting interventions is empowering parents to deal with their children.Parentsespecially those of delinquent children-tend to feel out of control in many aspects of their lives.They may feel demoralized, frustrated, or depressed by their inability to parent effectively (Dishion, Patterson, and Kavanagh 1992).
Interventions should increase parents' sense of self-control and self-efficacy, giving them confidence in their interactions with their children and making them feel accountable in a positive way for improvements in their children's behavior (Prinz and Miller 1996).
One way to empower parents is to give them information that will help them understand and react appropriately to their children's behavior.Interventions should provide training on how to nurture and communicate effectively with children, negotiate family rules and consequences, praise and reward children for prosocial behavior, and discipline without violence.They should teach parents effective means of punishment, such as "time outs" and loss of privileges, that do not promote aggressive interactions between parent and child.
Another empowering technique is to encourage parents to participate in the problem-solving process (Cunningham 1996).For example, in a collaborative group-therapy model used at the University of Washington Parenting Clinic, the therapist solicits parents' ideas, feelings, and information about their cultural background.In this model, therapists and parents feel joint ownership of solutions and outcomes (Webster-Stratton and Herbert 1994).In Los Niños Bien Educados, a program targeting Latino American families, participants were asked to define important cultural concepts about parenting.Participants defined what "bien educados" meant to them and recalled the cultural proverbs that were used in their own and their grandparents' homes (Alvy and Rubin 1981).
You can also build in activities to involve and empower parents, to make them feel that they are vital contributors to the intervention.For example, have parents bring refreshments to meetings, have them monitor their family's progress, or enlist participants to lead pep rallies.
# Consider cultural and demographic issues
Some participant groups have cultural beliefs or behaviors that present unique challenges for practitioners.Identify cultural issues up front and design intervention materials to address them.Culturally relevant content promotes a strong sense of group ownership, ethnic identity, community-building, and advancing one's group as a whole (Alvy 1994).
The Effective Black Parenting Program is a cultural adaptation of a generic parenting skill-building intervention called Confident Parenting (Alvy and Rubin 1981).This program reduced parental rejection, improved the quality of family relations, and reduced child behavior problems among African American families living in South Central Los Angeles. |
Key intervention components, in addition to skill building, included discussions contrasting "traditional" discipline (e.g., punishment, spanking) with "modern" self-discipline (internalized standards of effective behavior); discussion and reinforcement of issues related to "pride in blackness"; and the use of a black achievement perspective to link the life goals the parents had for their children with the abilities and characteristics the children need to achieve them (Myers et al.1992).
Among some families of low socioeconomic status, parents' low level of education can make traditional communication channels ineffective.To address this challenge, program planners have developed interventions that de-emphasize written materials and verbal teaching methods, opting instead for role-playing and modeling techniques (Knapp and Deluty 1989).
# To achieve longterm effects, interventions must also address the context in which parenting takes place.
For many groups, interactive teaching techniques are most effective.These techniques incorporate not only didactic teaching but methods such as role-playing and problem-solving exercises.However, some parents prefer didactic authority figures and mistrust overly friendly strangers.With these groups, a practitioner would want to begin with a more formal style and ease into interactive teaching methods to avoid being viewed as disrespectful.
# Address environmental and financial concerns
Interventions that focus solely on parents' behavior may not result in changes that parents can sustain in the environment outside the intervention.To achieve long-term effects, interventions must also address the context in which parenting takes place.Today, the most successful interventions have been expanded to help parents improve their "life skills" and help them deal with issues such as social isolation, stress, depression, marital conflict, housing, and money matters.The general principle behind these broad interventions is that parents who are better able to manage everyday life issues will have the physical, psychological, and social resources to parent more effectively.
A variety of interventions integrate parenting life skills.One of the most researched, Henggeler's Multisystemic Therapy Program operates on the premise that a family is an interconnected unit in which a series of individuals (parent, child, siblings, extended family members) and external factors (work, school, housing situation) interact with one another to create an ongoing family dynamic (Borduin et al.1990).Intervention activities are designed for each family on the basis of the family's risk and protective factors.
In a series of randomized control trials, in a variety of settings, the multisystemic approach has been successful.A study in Simpsonville, North Carolina, involved adjudicated youths who had at least one violent offense.After 59 weeks, the youths who received the multisystemic therapy (MST) had significantly fewer arrests (.87 versus 1.52) and fewer weeks incarcerated (5.8 versus 16.2) than youths receiving the usual services.The MSTintervention families also reported improved family cohesion.A study in Columbia, Missouri, compared MST with individual therapy (IT) among 17-year-old multiple offenders and their families.At 5-year follow-up, MST youths were less likely to be arrested again, the families receiving MST reported and showed more positive changes in their overall family environment, and the MST parents showed greater reductions in psychiatric symptoms (Henggeler et al.1996).MST was also found to be effective in the treatment of adolescent sexual offenders.Youths in the MST group had significantly fewer subsequent arrests for sexual crimes than did youths in the IT group (Borduin et al.1990).
# Select Staff Appropriate For Your Intervention
With the parent-and family-based strategy, the quality of the relationship between the practitioner and the parent can profoundly affect the outcome of your intervention.Therefore, your staff must be selected with great care, keeping in mind both the needs and desires of participants and the requirements of your intervention.In addition, staff members should live near enough to participants to allow for frequent contact.They must also be available to work during the times that are most convenient to participants, usually during evenings and weekends.
It may be helpful to select staff members who have characteristics like those of participants.For example, you could pair single mothers with staff who are also single mothers or African American participants with staffers of the same race.The Strengthening Families Program finds it effective to match therapists with parents as similar as possible in age, social standing, and cultural background (Kumpfer, Molgaard, and Spoth 1996).
Consider involving alumni of previous interventions to help bridge the gap between the practitioners and parents and to provide parents with support from someone who's "been there."Patterson's Coercion Model, for example, involves parent alumni as mentors to participating parents; the Strengthening Families Program hires parent alumni to support and reassure participants in an attempt to reduce drop-outs (Dishion, Patterson, and Kavanagh 1992;Kumpfer, Molgaard, and Spoth 1996).
# The quality of the relationship between the practitioner and the parent can profoundly affect the outcome of your intervention.
# Train Staff Members
In successful parenting interventions, the practitioner must form a bond of trust, respect, and collaboration with parents (Taylor and Biglan 1998;Johnson 1988;Webster-Stratton and Spitzer 1996;Prinz and Miller 1996).Training for your intervention should prepare staff members to play the role of teacher, supporter, and facilitator.
In addition to teaching your staff how to carry out the activities of your intervention, training should include information about child-rearing principles, participants' values, and other cultural and religious beliefs that may affect how parents interact with their children or with intervention staff.It should also show staff members how to employ an interactive teaching method, engaging participants in group discussions and role playing exercises; this technique is more effective than a formal, didactic style.Provide staffers with a training manual they can refer to throughout the intervention.
# Recruit Families
To recruit participants for your parenting intervention, work with community groups, churches, mental health facilities, law enforcement agencies, and schools in your area.Get involved personally in the recruitment process.Phone or visit parents at home or speak with them in public places, communicating to them that you understand and respect the challenges they face.Consider hiring or assigning administrative or public-relations staff to assist with recruitment.When targeting high-risk families, you may need to enlist the help of a community gatekeeper-for example, a trusted school official, community elder, or minister-to facilitate referrals.
You may need to offer parents incentives to encourage participation, especially if you are targeting at-risk parents.You are, after all, asking them to commit to making profound changes, something parents may not enter into lightly.Think about what would entice parents, such as money, transportation fare (subway, bus, taxi), food, or free childcare.Ask local businesses to contribute products and services that would interest intended participants.
# Implement Your Intervention
How you implement your intervention will depend on many factors, including the activities planned and the participants involved.However, the following principles apply to any parenting intervention:
- Schedule activities at times and locations that are convenient to parents.Offer opportunities for parents to ask questions, offer feedback, and practice the skills taught. -Implement all components of an intervention that has been proven effective.Using only selected components may not produce the results of the original intervention.
It may help to explain the behavioral theories that underlie the parenting techniques being taught.For example, parents are much more likely to persevere in using recommended disciplinary tactics, particularly when they do not result in immediate improvements in their child's behavior, if they have a good overall understanding of the behavioral principles on which the tactics are based.
# Intervention delivery may vary depending on children's ages and families' risk factors
The age of the children in participating families will affect delivery techniques.What works for parents with very young children may not be as effective for parents with older children.When working with high-risk families, it is essential to link parenting interventions to child-based interventions that actively involve the child at risk.The Multisystemic Therapy Program, for instance, develops ongoing strategies and goals for every relevant member of the family.It requires the child to perform certain tasks and follow certain behaviors, and it requires the parent to monitor and reward or discipline the child's actions (Henggeler et al.1996).
# Use the full range of parent-training activities
The most effective parent-and family-based interventions include a variety of activities, including multi-session classes for small groups, one-day seminars for large groups, video and audiotape training materials, self-instruction activities, and home projects to implement skills.
A number of studies have demonstrated the success of videotape modeling as a mechanism for educating parents and stimulating discussion.While video-based interventions can be effectively self-administered, the best results are obtained when the video is combined with group interactions (Webster-Stratton, Kolpacoff, and Hollinsworth 1988).In five randomized studies with more than 500 families, an intervention incorporating the videotape modeling and parent-group discussions resulted in greater reductions in child conduct problems and more significant improvements in parents' disciplinary approaches and parentchild interactions than did one-on-one parent training, discussion groups without videotape modeling, or videotape modeling without discussion (Webster-Stratton 1996). Stratton 1996).
The Functional Family Therapy (FFT) model combines assessment, therapy, and education to address dysfunctional communication styles in families with delinquent children (Alexander and Parsons 1982).In the assessment phase, therapists evaluate family behavior patterns and gather information about problem behaviors.The therapy phase is designed to change attitudes, expectations, emotional reactions, and perceptions to reduce blame among family members.The education phase teaches skills in family communication, relationship building, and problem solving; reinforces positive interactions and manages conflict; and teaches parents how to reward and reinforce prosocial behavior.
# Parenting patterns are hard to change-there are no "quick fixes."
In a number of controlled studies, FFT has been shown to modify dysfunctional communication and reduce rates of delinquency among treated youths and their siblings (Barton et al.1985).Gordon and colleagues (1988) replicated the FFT model in a group of 54 rural, economically disadvantaged juvenile offenders in southeastern Ohio.Half of the group was non-randomly assigned to receive in-home FFT from psychology graduate students.Most of this group had committed multiple serious offenses and had been assigned to family therapy by the court.A control group of 27 lower-risk delinquent youths received only probation services.After 2 1 / 2 years, recidivism rates were 11 percent in the treatment group and 67 percent in the comparison group.A later study that measured changes in the group at the end of an additional 32-month period (after the subjects had become adults) found recidivism rates of 9 percent for misdemeanor and felony offenses in the treatment group and 41 percent in the comparison group (Gordon, Graves, and Arbuthnot 1995).
# Set a realistic time frame for your intervention
Parenting patterns are hard to change-there are no "quick fixes."Expect your intervention to take at least several months.A desirable duration for interventions targeting at-risk families is approximately 22 sessions; 12 sessions is typically appropriate for families not considered at risk.
In most cases, sessions should occur at regular intervals (e.g., weekly or biweekly) and last for no more than two hours.Longer sessions have been successful in some programs, as long as frequent breaks were provided.Formats involving out-ofhome group sessions should be convenient in terms of childcare, transportation, and the availability of food.
# Support intervention staff to prevent burnout
Parent-and family-based interventions can be challenging and emotionally taxing for the intervention staff.It is critical that you provide staffers with support and encouragement.Staff members need coaching and consultation regularly and should be given plenty of opportunities to talk with a supervisor about how well they are meeting the intervention objectives as well as about personal, job-related objectives.Consider hiring staff on a part-time basis or making intervention implementation a component of a full-time position.This may help prevent staff burnout.It is also beneficial to provide staff members with flexible schedules.
# Encourage participants to stay involved
Parent-and family-based interventions can last for many months with results that are subtle and gradual.You will need to maintain participants' interest in your intervention and keep them focused on the long-term goal.In addition to offering incentives like free food, transportation, and childcare, plan events that will entice parents to complete the intervention.For example, hold graduation ceremonies or provide gift certificates as a reward for completion.
# Monitor Progress and the Quality of the Implementation
As your intervention moves along, monitor activities to be sure they are being carried out as planned.This is especially important if you are implementing an evaluated interventionyou need to follow all steps to make sure you achieve the same results.
The following steps will help you determine if your intervention is on track:
# Evaluate Outcomes
From the beginning, consider how to evaluate the outcome of your intervention.Have participants assess changes in their own behavior and that of their children.The intervention staff should also evaluate those changes.You can use a third party to identify changes, as well.For example, review school records of children whose families participated in the intervention to see if rates of delinquent behavior or absenteeism have dropped.
# Expect setbacks
Behavior change does not happen overnight.Long-standing family issues, crises, and disciplinary problems cannot be cured with a single treatment.Set realistic expectations for your intervention and let parents know that obstacles and setbacks will occur along the way (Taylor and Biglan 1998).Informing parents that they will probably face resistance and recurring behavior problems from their children will better prepare them for these difficulties so they can remain committed to the intervention (Prinz and Miller 1996).
# From the beginning, consider how to evaluate the outcome of your intervention.
# Maintain Results After Implementation
Without the guidance and support of intervention staff, participants may find it difficult to keep momentum going after the intervention ends.You can take some steps to maintain the positive results of your intervention after it has been completed.For example:
- Provide a follow-up source for parents to call with questions and concerns.Follow-up activities, conducted several months or more after the original intervention has ended, can also increase the long-term benefits of your effort.These activities can be especially effective when targeting families with young children.Buka and Earls (1993) likened violence prevention strategies to immunization: a "vaccination" at an early age followed by periodic "booster sessions" throughout childhood and adolescence.Scheduling follow-up activities to coincide with difficult developmental periods, such as a child's initial entry into school or transition to a new school (for example, moving from elementary to middle school), can be particularly helpful in addressing behavioral problems.And involving practitioners and staff members from the original intervention can lend continuity to activities.
# Link Parent-and Family-Based Interventions with Other Strategies
While parent-based interventions are among the most effective strategies known thus far for preventing violence by children and adolescents, once children reach school age it is essential to complement this strategy with one that addresses the influence of factors outside the home (Taylor and Biglan 1998;Brestan and Eyberg 1998).
Negative academic and social experiences in school can result in a child's developing violent behavior or associated risk factors.
Evidence has shown that a partnership between parents and the school is more effective than parent-based strategies alone (McMahon et al.1996;Webster-Stratton 1993;Coleman 1997).
A coordinated effort among parents, teachers, school psychologists, and school nurses can identify problems early so practitioners can intervene with programs to teach problemsolving, develop conflict-resolution skills, and enhance academic skills (Honig 1999;Schweinhart 1999).
# Summary
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# Additional Resources on Parent-and Family-Based Interventions to PreventYouth Violence
The following intervention summaries have been adapted from information listed on the Strengthening America's Families web site, a project funded by the Office of Juvenile Justice and Delinquency Prevention.Further details about the interventions are available at www.strengtheningfamilies.org and from the contact person provided with each description.This listing is provided as a service to readers, but the presence of an intervention on this listing does not imply endorsement by CDC or the Department of Health and Human Services.
# Bethesda Family Services Foundation
This foundation provides comprehensive individual and familycentered treatment to children ages 10 to 18 who were referred by the court as a result of delinquent offenses (referral to the program is in lieu of jail time).The intervention provides treatment for the entire family during nontraditional hours.Youths receive at least six months of treatment, and parents attend meetings and training sessions.
# Families and Schools Together Program
FAST is an intervention for at-risk children and adolescents ages 3 to 14.Its structure gives young people and their parents both a voice and a role in the prevention process.The intervention develops separate support networks for youths and parents, using a multi-family format, and brings them together for family activities.
# Families in Focus
This family skills training intervention is designed to strengthen the family and prevent social and behavioral problems.The intervention was originally designed for high-risk youths ages 8 to 14 but has also been delivered to children of all ages.A Home Learning Guide and Family Profile Questionnaire help direct families to specific activities.
# Home-Based Behavioral Systems Family Therapy
This intervention, based on the Functional Family Therapy model (discussed previously), reaches families with lower educational levels and higher levels of pathology than did the original model.The intervention is delivered in five phases, with increasing involvement of therapists.Its long-range goal is to reduce juvenile delinquency and teen pregnancy.
# Nurturing Parent Programs
There are 13 Nurturing Parenting Programs designed for specific cultures, family dynamics, and children's age groups.The programs build nurturing skills to reduce abusive parenting, juvenile delinquency, alcohol abuse, and teen pregnancy.Parents and children attend separate groups that meet concurrently.Each program has been researched and validated as an effective intervention for the treatment and prevention of child abuse and neglect.
Stephen Bavolek, Ph.D.
# Strengthening Hawaii Families
This intervention, based on cultural values, seeks to prevent problems such as substance abuse and domestic violence. |
It aims at increasing resiliency in both the community and family.A 14-session curriculum provides tools and a process for families and children 5 to 12 years old to build on existing family strengths.
# Overview of the Home-Visiting Strategy
Violent and criminal behavior, poor mental health, drug use, and poor school performance have been linked to several childhood risk factors, including child abuse and neglect, poverty, a poor relationship with the parent(s), poor physical and mental health, parental drug or alcohol abuse, and child abuse and neglect (Wolfner and Gelles 1993; Oates et al.1995;Krysik et al.1997;Norton 1998).By eliminating these risk factors, we can help reduce the aggressive and violent behaviors we see in our schools and communities.Home visiting is one effective strategy to address these factors.
Home-visiting interventions bring community resources to atrisk families in their homes.During home visits, intervention staff provides information, healthcare, psychological support, and other services that participants need to function more effectively as parents.These programs have helped improve maternal health and pregnancy outcomes, increase employment and education among young parents, reduce reliance on welfare, improve children's mental and physical health, reduce childhood injuries, and reduce criminal behavior by young people.This strategy is ideally implemented with families who are expecting or have recently had their first child.
# Best Practices of Home-Visiting Interventions
Although additional research is needed to evaluate the effectiveness of home-visiting interventions, several studies have revealed promising findings as well as techniques and principles for planning and implementing these efforts.This section presents the practices identified in those studies, along with recommendations from experts in the field of youth violence prevention.
# Identify the Populations You Want to Reach
Many European countries provide home visits to all families, regardless of risk status.Some advocates have argued that this service should be made available to all families in the United States, as well.But home-visiting interventions are resourceintensive, and few communities have the financial and human resources needed to carry out an effective program on such a large scale.Therefore, targeting select groups for home-visiting services is typically most appropriate.A needs assessment conducted with input from the community will help identify families who could benefit most from a home-visiting intervention.Community leaders should play a key role in this decision, as they are often in a position to direct the allocation of resources.
# Expectant parents and first-time parents
Research suggests that home visiting has the greatest impact when it begins early in the parenting process.Therefore, homevisiting interventions often begin when participants are pregnant and continue through the first few years of the children's lives.Targeting first-time parents seems to be ideal, the rationale being that positive changes will carry over to future pregnancies and children.In addition, research indicates that mothers involved in a home-visiting intervention will likely have fewer unintended pregnancies (Olds and Kitzman 1990).
Olds and colleagues (1998) examined the long-term effects of prenatal and early-childhood home visits on children's antisocial behavior.They found that adolescents whose mothers had been visited by nurses expressed less antisocial behavior and had lower substance-use rates than did adolescents in a comparison group.Adolescents from the study group also reported significantly fewer instances of running away, fewer arrests, fewer convictions and violations of probation, fewer lifetime sex partners, fewer cigarettes smoked per day, and fewer days having consumed alcohol in the six months preceding the study.
# Home visits seem to benefit high-risk families most.
Similar results were achieved by Aronen and Kurkela (1996).They studied the long-term effects of a home-based familycounseling intervention that took place during the first five years of the children's lives.Eighty families experienced 10 home visits per year; another 80 families served as a comparison group.Both groups included low-risk and high-risk families.Each child's mental-health status was assessed at age 15.Adolescents in the intervention families had significantly fewer mental health symptoms on child-behavior checklists filled out by their parents and on the youths' self-reports.The counseling predicted better mental health at year 15 for both high-and lowrisk families.
# High-risk families
Although positive results have been achieved among both highand low-risk families, home visits seem to benefit high-risk families most.One study found that home-visiting interventions produce the greatest benefit when they are focused on single and adolescent parents living in communities with high poverty rates (Olds and Kitzman 1990;Olds et al.1997).Interventions aimed at poor, unmarried mothers have been shown to improve the maternal life course, reduce the number of months that mothers relied on public assistance and food stamps, reduce behavioral problems associated with alcohol and other drug use, and reduce the number of arrests (Olds et al.1997).Daro (1993) found that families exhibiting child abuse and neglect responded best to interventions incorporating home visits.One of the most important benefits reported for these families was the concrete assistance that visiting practitioners offered in resolving childcare problems such as discipline and toilet training.
Remember that, although home visits can bring about substantial changes in the long run, they can rarely bring about immediate changes in the environmental, financial, and psychological issues that high-risk families face.Long-term dedication is needed to affect social adversities such as unemployment, poverty, drug abuse, and malnutrition.
# Other groups
Young people who drop out of high school or show poor school engagement are at increased risk of becoming teen parents (Manlove 1998).As discussed previously, young, unwed parents are often at increased risk of developing parenting styles that are associated with the development of youth violence.And given that dropping out of school, poor academic performance, and a general lack of interest in school are, by themselves, risk factors for developing violent behavior, this group is an appropriate target for home visits.
Parents with limited social support are also ideal participants in home-visiting interventions.These parents need help dealing with the stress of parenting and with other life stressors such as financial and marital difficulties or unemployment.
# Generate Support in the Community
You will need a great deal of support from your community-in the form of both financial and human resources-to carry out a home-visiting intervention.To convince community members and leaders that your intervention is worth their time and money, show them how the intervention will meet the community's perceived needs and goals and explain the long-term benefits of early prevention efforts.Here are a few arguments for conducting a home-visiting intervention:
Helping expectant mothers to stop using drugs or alcohol and to eat a better diet will improve the health and development of their babies. -Improving parent-child interactions from the earliest possible time will help prevent abusive disciplinary tactics. -Addressing parents' physical and emotional needs will increase their patience and tolerance, making them better able to nurture their children.
In addition to preventing the risk factors for violence, homevisiting interventions may save communities money down the road.Data on the cost-effectiveness of home visits are limited, and additional studies must be conducted (Barnett 1993), but a few cost analyses have revealed savings in government spending for food stamps and the Temporary Assistance for Needy Families Program (formerly the Aid to Families with Dependent Children Program).
# Set Clear Goals and Objectives
Setting goals and objectives for home visits must be done on two levels.First, practitioners should identify the desired outcome of the intervention.For example, an overall goal might be to reduce the number of elementary school students who exhibit early warning signs of developing violent behavior, such as withdrawing from classmates and performing poorly in school.Objectives, then, might be to improve the parent-child interactions in families of preschoolers and to help parents develop educational activities to better prepare their children for school.
# The interventions that succeed in helping at-risk families are intensive, comprehensive, and flexible.
On the second level, home visitors must help each family set its own goals and objectives.This will ensure a good balance between the intervention's goals and the family's needs.It will also help parents feel ownership of the intervention because they will be working toward something they feel is important to their family.
# Design the Best Intervention for Your Participants
The activities and materials you develop for your home visits will depend on the characteristics and needs of the participants, your goals and objectives, and the expertise of the home visitors.
Overall, the interventions that succeed in helping at-risk families are intensive, comprehensive, and flexible (Wallach 1994
# For expectant mothers and parents with young babies
In a randomized trial in Elmira, New York (a semi-rural community), demonstrated the effectiveness of nurse home visits for first-time pregnant teens who were poor or unmarried.The home visits were designed to improve the mothers' health, help them develop effective parenting skills, and improve their financial situation by easing the transition into the work force after their children were born.
The goal was to reduce problems resulting from poor prenatal health, dysfunctional caregiving, and financial difficulties caused by closely spaced pregnancies, lack of education, and inconsistent employment.
The study produced encouraging results.Compared with controls, nurse-visited women experienced greater social support-both from family and friends and from government and community services.They also smoked fewer cigarettes, had better diets, and suffered fewer kidney infections during pregnancy.Through age 2, children born to nurse-visited women were 80 percent less likely to be identified as victims of child abuse or neglect and were seen in hospital emergency departments 56 percent fewer times.Four years after delivery of the first child, the women in the intervention group had 42 percent fewer additional pregnancies and participated in the workforce at a rate 84 percent higher than that of the control group.The cost to the government for this intervention was recovered before the children's fourth birthdays .
A follow-up of the original Elmira study revealed that positive results endure (Olds et al.1997;.Fifteen years after the initial intervention, data showed a reduction from 90 months to 60 months of recourse to the Aid to Families with Dependent Children Program among low-income, unmarried mothers.The home visitation program was also replicated in Memphis, Tennessee, among a predominantly black population.
Results, although smaller in magnitude, were similar to those obtained in the semi-rural, mostly white community. (Olds et al.1999;Kitzman et al.1999).
# For families with evidence of child abuse or maltreatment
Previous research suggests that the incidence of child abuse increases the odds of future delinquency and adult criminality by 40 percent (Widom 1992).A high percentage of juvenile sex offenders may have been victims of childhood violence themselves (Feindler and Becker 1994).Studies and interviews with experts have found home-visiting interventions to be effective in reducing the risk for and incidence of child abuse and maltreatment (Brust, Heins, and Rheinberger 1998;Carnegie Corporation 1994).Wasik and Roberts (1994) conducted a survey of 1,904 homevisiting interventions, 224 of which stated their primary focus was to provide services for abused and neglected children and their families.More than three-quarters of respondents rated three key elements of home visits as being of primary importance-improved parent-coping skills, enhanced parenting skills, and emotional support.Stress management, enhanced child development, and child and family advocacy were also rated as high priorities by more than half of respondents.
A successful home-visiting program aimed at preventing child abuse and neglect is Hawaii's Healthy Start Program, established in 1985 as a demonstration project.It now reaches more than half of Hawaii's at-risk population.This program uses home visits to improve families' coping skills and functioning, promote positive parenting skills, foster healthy parent-child interactions, and promote optimal child development.Results of the initial three-year project were conclusive: not a single case of abuse occurred among the project's 241 high-risk families Pratt 1991, 1993).
The Healthy Start Program offers a systematic approach to preventing child abuse among at-risk infants and toddlers.This approach forms the foundation for programs developed through Healthy Families America (HFA), a partnership of Prevent Child Abuse America (formerly the National Committee to Prevent (Krysik et al.1997;Norton 1998).A list of state HFA contacts is included in the Additional Resources section for this strategy.
# Select Staff Appropriate for Your Intervention
Home visits may be conducted by a variety of individualspublic-health or registered nurses, social workers, paraprofessionals, volunteers, and advocates and liaisons.For most home-visiting interventions, however, a health professional or paraprofessional specifically trained to make home visits will be best able to achieve the results desired.
Before you select your staff, develop a framework for your intervention that specifies the job roles and responsibilities of all staff members.Base hiring, training, and supervision on that framework.Be sure to hire staff members whose experience and educational background fit the requirements of your intervention.
For example, if your objectives include improving the health of pregnant women and their babies, nurses will be most appropriate; on the other hand, if your aim is to improve the learning skills of preschoolers in participating families, you may need staff members with a teaching background.
# Nurses
Public health nurses appear to be in a position to detect community problems and trends before other health care providers (Bekemeier 1995).They may be the best choice for your intervention's staff, especially if your intended participants are at-risk pregnant women.
The expertise nurses possess appears to be well accepted and even desired by most expectant parents because their focus is on health-first, that of the pregnant woman and later, that of the baby.In addition, families may feel more at ease in asking for help from a nurse than from social-service professionals or counselors because there is less of a potential stigma associated with nursing assistance.In fact, a pregnant woman's asking for nurse-related assistance may be viewed as a sign of her positive intentions toward her health and that of her baby.
Nurses are also ideal home visitors because:
- they can deliver content that contains a lot of medical information; - they are trained to teach, use good questioning techniques, detect subtle cues, set priorities, and manage cases; - they have an accepted role in the lives of pregnant women that can facilitate early acceptance and trust.
# Paraprofessionals
For some interventions, paraprofessionals-counselors, social workers, and specially trained community volunteers-will be effective home visitors.An intervention implemented as a randomized controlled trial in Denver, Colorado, compared the effectiveness of paraprofessionals and nurses in improving pregnancy outcomes, infant care, and parental life course.Overall, nurses produced a larger and broader range of beneficial effects: improved prenatal health behaviors, improved viability
# Public health nurses may be the best choice for your intervention's staff.
-f the newborn, more effective infant care, increases in the children's language development, and decreased rates of subsequent pregnancy.However, paraprofessionals effected significant changes, as well.The environment of the homes visited by paraprofessional became more conducive to children's development (at 21 months); early postpartum participation in the workforce was achieved by women of low psychological resources; and women had lower rates of subsequent pregnancy.
More studies are needed to determine under what circumstances paraprofessionals trained in home visiting can be most effective.
Researching intended participants can help identify the kinds of paraprofessionals who are most likely to be trusted and accepted by families.With both nurses and paraprofessionals, the beneficial effects of home visits are attributable to the particular program model and to the protocols that guide their visits .
# Staff characteristics
Whether you employ nurses, paraprofessionals, or others, all staff members must be available to conduct home visits when it is most convenient for participants.Since welfare reform, more mothers are working and may only be available on weekends or evenings.Staffers must also be committed to the effort and must get to visits on time, attend every visit, and complete the intervention.To be successful, home-visiting interventions rely on the development of a trusting relationship between the participants and the visitors.Tardiness and inconsistent attendance erode that trust.
The following characteristics are also highly desirable for home visitors:
# Special considerations for home visitors
Because intervention staff will be going into participants' homes and discussing potentially sensitive issues, practitioners must consider several factors when selecting visitors and pairing them with participating families.
# Confidentiality
Staff members must not be allowed to conduct visits in the homes of family members or friends.Participants may be reluctant to share with people they know details about problem behavior (e.g., child abuse, drug use) or concerns about their parenting abilities.All home visitors should sign an agreement of confidentiality to protect the privacy of the participants.However, practitioners should identify emergency circumstances in which home visitors may violate that agreement in order to help the family (e.g., when the health or safety of participants is endangered).
# Male home visitors
Carefully assess the context and sensitivities of the intended participants before selecting men to be home visitors.Some fathers-in particular, single fathers-may be willing to participate in an intervention led by a man.However, other fathers may feel competitive or even hostile toward a male visitor.Many visits are conducted in homes where a father is not present.Single mothers may feel unsafe or uncomfortable with a male visitor.When male visitors are undesirable to your participants, try having them accompany the primary home visitor occasionally as an auxiliary with special expertise.
# Cultural issues
Matching the cultural background of a home visitor with that of the family may or may not be important.The preferences of your intended participants should dictate this decision.Regardless of the cultural background of the home visitor, he or she must portray a neutral orientation toward race, ethnicity, religion, and other cultural factors.
# Train Staff Members
Training that prepares staff members for home-visiting work is essential, regardless of their prior education and experience. |
Practitioners should determine the core competencies staff will need to meet the intervention's goals and objectives and ask staff members to provide input about their training needs.At a minimum, the training curriculum should cover the following topics:
- - - - - - - - protocol
# Recruit Participants
Participation in home-based interventions must be voluntary.In an ideal world, families would jump at the chance to participate in your intervention.But in reality, you will probably need to engage in intensive outreach to bring families into your program.Families may be reluctant to participate because they:
- feel insulted by the implication that they need help; - view intervention staff as "the establishment"; - fear discovery of illicit activities; - view visits as an invasion of privacy.
Additionally, new mothers may be tired or depressed and may not have the energy to engage.They may also feel they do not have time for visits.
# Implement Your Intervention
Implementing home-visiting interventions poses complex challenges.Home visitors must address a variety of oftenchanging issues related to the families' circumstances.And in many cases, a long time period is required to achieve relatively small changes.
# Match the duration, frequency, and intensity of your intervention with families' needs
How long your intervention continues, how often visits occur, and how long each visit lasts will depend on the families' needs and the goals set for your effort (Brust, Heins, and Rheinberger 1998;Powell 1993).On average, home-visiting interventions last about one year; more intensive programs may run as long as three to five years.Home visits most commonly occur on a weekly basis.Monthly visits are the minimum for families with infants and very young children; for families of older children, quarterly visits may be appropriate if the intervention incorporates other forms of community support.Most visits last between 30 minutes and one hour, but they may run longer (Wasik and Roberts 1994).
The frequency of visits may decrease as families mature in the intervention, are successfully linked to needed services, and master the skills and information set forth in the intervention objectives.If parent-group meetings are part of the intervention, alternate the weeks of home visits with those of group meetings.
Each visit should have a clear structure and set activities.To keep activities on track, focus on long-term goals.At the end of each visit, note progress and discuss how upcoming activities reflect mutual expectations.Creating a "contract" with participants might be useful in determining what should be achieved during each visit.While it's important to form a comfortable relationship with participants, visits should not become social gatherings.Also, the content of visits should not be driven by crises.
# Encourage participants to stay involved
Participants in home-visiting interventions often drop out.They may become discouraged when changes occur very slowly, or they may come to believe that they no longer need the services home visits provide
# Support intervention staff
To help prevent staff burnout, limit the caseloads of homevisiting staffers to no more than 15 families; in some communities, caseloads will be significantly smaller (HFA 1996).Strongly caution staff members against getting involved in family problems they are unqualified to handle.For example, home visitors should not play therapist if participants appear to be suffering from depression or other mental health problems.
Families should be referred to community resources for crisis issues.
During implementation, provide your staff with ongoing opportunities for training and group discussions.Keep lines of communication open so staff members can approach supervisors with concerns or questions at any time.Supervisors should watch staff closely for signs of fatigue, discouragement, and difficulty with implementing activities.
# Monitor Progress and the Quality of Your Intervention
As with any prevention effort, a home-visiting intervention must be monitored to make sure it is on schedule and on track.
Collecting data throughout implementation can help you verify that activities are being carried out as planned and help you identify early problems in delivery that may jeopardize the intervention's success.The following suggestions should help you effectively monitor your effort:
- Supervise intervention staffers closely to make sure they are following the protocol for home visits.
# Evaluate Changes
To determine whether your intervention has met its goals, note changes in participants' behaviors and in family interactions as the intervention progresses.Compare them with baseline data established when implementation began to determine if the intervention resulted in positive outcomes.
Have parents note improvements in their behavior and that of their children and in parent-child interactions.Parents can also evaluate their confidence in parenting and handling conflicts that occur in the home.Home visitors, especially nurses, can assess the health and development of the children, as well as evaluate the behavioral changes they observe.If the children attend school or a childcare program, teachers and caregivers can also provide data about the children's behavior.
# Maintain Results After Implementation
To sustain the positive effects of the intervention, develop a strategic plan to help participants with the transition that occurs when the intervention ends.For example, you might schedule quarterly "boosters" or direct parents to community organizations that can provide support.Consider offering incentives such as diplomas and graduation ceremonies to foster transition.
# Link Home Visits with Other Strategies
Home visits are an effective component of programs seeking to prevent violence by young people, but they may not be sufficient on their own (Weiss 1993).Although more research is needed to test the hypothesis, combining early home-based interventions with school programs and other community efforts may be an effective strategy in preventing violence and other negative health outcomes.
# Summary
Home-visiting interventions improve parenting skills, provide social support to families, recognize and manage behavior problems, and promote child health and development.These types of interventions are likely to have a far greater impact on delinquency and violence than secondary and tertiary prevention programs such as those of the criminal justice system (Rivara and Farrington 1995 A compilation of educational materials for use by home visitors to help prevent unintentional injuries and child abuse and neglect.The focus on preventing abuse and neglect is implicit rather than explicit so parents will not feel as though they are being targeted as potential abusers.
# The Future of Children 1993; 3(3).
The Future of Children 1999; 9(1).
# Health Care Coalition on Violence.A Review of the Research on Home Visiting: A Strategy for Preventing Child Maltreatment.Anoka, Minnesota: Health Care Coalition on Violence, 1998.
A review of 42 home-visiting research articles that describe child maltreatment in the United States and Minnesota, summarize the current research on home visiting, and recommend a future research agenda for home-visiting services.The review concludes that home visiting is an effective strategy for reducing the incidence of and risk for child maltreatment, but it leaves unresolved the components necessary for an effective program and the costs and benefits compared with other interventions.
# Journal of Community Psychology 1997; 25(1).
# Journal of Community Psychology 1998; 26(1).
These issues discuss home visiting exclusively.This article reviews the effectiveness of prospective controlled trials, published between January 1979 and May 1993, aimed at the primary prevention of child physical abuse and neglect.
# MacMillan HL, MacMillan
Interventions were classified into six categories within the broad group of perinatal and early childhood programs.Many of these programs did not show a reduction in physical abuse or neglect; however, there is evidence that extended home visitation can prevent physical abuse and neglect among disadvantaged families.This article describes a 5-year longitudinal study to determine the sustainability of promising effects revealed in earlier studies, including better pregnancy outcomes, improved child care practices, fewer cases of child abuse, less reliance on social services, and a better life for mothers.
# Zero to Three, Home Visiting with Families with Infants and Toddlers 1997; 17(4).
The entire issue is about home visiting.Various authors discuss the benefits and dilemmas of home visiting as a strategy to support families with infants and toddlers.Topics include universal access, intensive outreach to at-risk families, and community development as the ultimate goals.The overarching theme is that home visiting is a powerful tool but it is only the beginning of the work at hand.
# Home-Visiting Programs
You may wish to contact the programs listed below, which have home-visiting components.
# First Steps/Fremont County Family Center
First Steps offers comprehensive child-development and parenting services for families with children from birth to 5 years.The intervention, which operates as part of the Fremont County Family Center, also provides monthly home visits.Play groups are held 4 times a week for children, siblings, and parents.
# Overview of the Social-Cognitive Strategy
Researchers have linked a lack of social problem-solving skills to youth violence (Pepler and Slaby 1994;Baranowski et al.1997).When children and adolescents are faced with social situations for which they are unprepared emotionally and cognitively, they may respond with aggression or violence.
Many assert that we can improve children's ability to avoid violent situations and solve problems nonviolently by enhancing their social relationships with peers, teaching them how to interpret behavioral cues, and improving their conflict-resolution skills (Nadel et al.1996).
Social-cognitive interventions strive to equip children with the skills they need to deal effectively with difficult social situations, such as being teased or being the last one picked to join a team.They build on Bandura's social-cognitive theory, which posits that children learn social skills by observing and interacting with parents, adult relatives and friends, teachers, peers, and others in the environment, including media role models (Bandura 1986).Social-cognitive interventions incorporate didactic teaching, modeling, and role-playing to enhance positive social interactions, teach nonviolent methods for resolving conflict, and establish or strengthen nonviolent beliefs in young people.
# Best Practices for a Social-Cognitive Intervention
While evaluations have shown social-cognitive interventions to be effective in the short-term, long-term effectiveness is still unclear.However, even with limited data, we can offer best practices for developing and implementing this type of intervention.The recommendations that follow are based on an extensive literature review and on interviews and surveys conducted with experts in the field of youth violence prevention.
# Identify the Populations You Want to Reach
Social-cognitive interventions are typically aimed at children.The younger participants are when your effort begins, the better your chances of successfully preventing aggressive attitudes and behaviors (Slaby 1998).Ideally, these interventions should reach all young people in a community, not just those with a history of violent behavior.However, if your community is like most, limited resources may prohibit such a large-scale effort.To determine who your intended participants should be, assess the community's needs and the money, time, and human resources available.
If you choose to target both violent and nonviolent children, use caution in planning your intervention activities.While violent children may be positively influenced by nonviolent participants, children with high levels of aggression need special attention.They may not thrive in an intervention intended for a general population.And if the ratio of violent to nonviolent children is too high, the nonviolent children could be negatively influenced.
# Consider the Cultural and Demographic Context of Intended Participants
Social-cognitive interventions must take into account the environment in which participants live and the circumstances they face.Children who exhibit violent behaviors often come from neighborhoods in which risk factors such as poverty, drug or alcohol abuse, and divorce are commonplace.Interventions must address these issues, in addition to teaching social and conflict-resolution skills.They must also be sensitive to the views of individual schools, the school system's administrators, and the community as a whole.
# Select an Appropriate Setting
Most social-cognitive interventions reported in the literature are centered in the schools for practical reasons.Trainers are often already on site, and children gather there for seven to eight hours
# The younger participants are when your effort begins, the better your chances of successfully preventing aggressive attitudes and behaviors.
a day, five days a week.Also, schools can set policies and alter the physical surroundings to minimize risk factors for violence, thus creating a model environment.
However, social-cognitive interventions need not be limited to school settings; they can be conducted wherever children are found in organized groups.Because patterns of violence appear to develop at an early age, researchers suggest that violence prevention efforts begin when children are very young and continue throughout their school years (Kellam et al.1994;Slaby 1998).Therefore, social-cognitive interventions may ideally be introduced in Head Start programs, preschools, and childcare centers.
Additionally, efforts should be made to reach children who have dropped out of school.This may mean developing interventions to be carried out in community centers, churches, and juvenile detention facilities.
# Involve the Community
Social-cognitive interventions cannot succeed in a vacuum.The surrounding community must be engaged in violence prevention activities that support the school-based effort.In addition, parents and caregivers must reinforce the learning that goes on inside the classroom.
# The school community
The effectiveness of social-cognitive interventions depends largely on a whole-school approach (Aber et al.1996;Wiist, Jackson, and Jackson 1996;Orpinas et al.1996).In other words, all members of the school community-from administrators to teachers to students and other school personnel-should have a role.
To achieve such an integrated system, intervention planners should establish a steering committee or core group within the school or school district to coordinate activities.This group should work closely with school principals and other administrators to ensure that the intervention's activities are in line with the school's or district's goals and to increase the commitment level of decision makers (Aber et al.1996;Wiist, Jackson, and Jackson 1996;Orpinas et al.1996).Supervisors should also be encouraged to support the professional development and training that teachers and other educators need to effectively implement the intervention and to allow intervention staff extra time to meet project deadlines.
# Parents and others
No matter how intensive and well-conceived school-based interventions are, they will probably not be successful without the approval, cooperation, and support of parents and the community (Powell, Muir-McClain, and Halasyamani 1995).
Practitioners planning a social-cognitive intervention should recruit one or more credible, respected individuals in the school to promote the intervention and find ways for parents, community leaders, and others to participate in developing the intervention's activities and curriculum.
# Set Clear Goals and Objectives for Intervention Outcomes and Implementation
Social-cognitive interventions promote social competence by building communication skills and facilitating peer relationships.
Their general goal is to improve young people's ability to avoid conflict and handle in nonviolent ways any conflict that does arise.Common objectives of social-cognitive interventions include reducing the number of children suspended for violent acts, reducing the number of students referred to school counselors for aggressive behavior, and increasing positive attitudes toward nonviolence.Of course, goals and objectives for individual schools or communities will vary depending on needs and resources.
# Select the Best Intervention for Your Participants and Develop Appropriate Materials
The intervention selected for a given school or school systemand the activities and curriculum that comprise it-will depend largely on participants' ages and whether the goal is to change the behaviors and attitudes of all students or those of aggressive or violent students only.However, all social-cognitive interventions typically address the beliefs and attitudes that support aggressive behavior and teach the following skills (Greene 1998
# Between ages 6 and 12, children's beliefs about aggression and their tendencies to attribute hostile intent to others' actions are developing rapidly.
When developing the curriculum and activities for your intervention, review interventions that have been tried in other schools.Assess whether the practices that made the intervention effective are applicable to your school or community.You may need to customize some components of the intervention, but do so cautiously.Changing significant elements can alter the intervention's effectiveness.
Experts in the field of youth violence prevention have identified the following additional suggestions for developing socialcognitive intervention materials (Aber et al.1996;Wiist, Jackson, and Jackson 1996;Orpinas et al.1996;Huesmann, Pierce, and Briggs 1996;Greene 1998):
- Involve teachers and principals from the beginning.
# For the general student population
If a school or community wants to prevent aggressive behavior before it starts or wants to improve the overall attitude toward violence, a social-cognitive intervention that's aimed at all students is one possible strategy.This section describes interventions designed for the general student population.
# Elementary school
Research has shown that between ages 6 and 12, children's beliefs about aggression and their tendencies to attribute hostile intent to others' actions are developing rapidly (Aber et al.1996).Therefore, several interventions have been developed to target this age group.
The Resolving Conflict Creatively Program (RCCP) is designed to help elementary-school teachers and students learn nonviolent ways of resolving conflicts, prevent involvement with violent situations, and promote intercultural understanding.It has several components, including the following:
- Teachers are trained to incorporate into a traditional curriculum exercises to improve communication, conflict resolution, and intergroup relations.
- Staff developers guide teachers in applying new skills.
Administrators are briefed about the intervention's concepts and how they can support the effort. -Peer models for nonviolent conflict resolution intervene in arguments and disputes on the playground and in the lunchroom.
The RCCP curriculum contains 51 weekly lessons, each lasting 30 to 60 minutes.These lessons or "workshops" focus on active listening, assertiveness, emotional expression, perspective-taking, cooperation, negotiation, problem solving, conflict analysis, and countering expressions of bias.Teachers facilitate role-playing exercises, interviewing, small-group discussion, and brainstorming to achieve a high level of student interaction (Aber et al.1996).
Evaluation of RCCP has revealed mixed results.The beliefs and thought processes that put students at risk for aggression increased among all students as the school-year progressed.However, when teachers administered many RCCP lessons, students' aggressive attitudes increased much more slowly.When teachers taught only a few RCCP lessons, students experienced a faster increase than average. |
In addition to the number of lessons taught, the context of the child's life was found to impact the effect of this program.The positive effects resulting from frequent exposure to the RCCP curriculum were weakened among children from high-risk classrooms and neighborhoods (Aber et al.1998;Roderick 1998).
PeaceBuilders is a school-wide intervention that teaches five principles: praise people, avoid put-downs, seek wise people as advisors and friends, notice and correct hurts we cause, and right wrongs.The program uses nine broad techniques for behavior change (Embry et al.1996 Initial outcomes over a two-year period showed that exposure to PeaceBuilders significantly increased teacher-rated social competence and student-reported prosocial behavior.Fewer effects were seen for students' aggressive behavior (Flannery et al.,unpublished).Additionally, in a separate study assessing whether the program had any impact on visits to the school nurse, the researchers found that nurse visits-including those related to injuries-decreased 12 percent in intervention schools, while they remained static in comparison schools.The rates of injuries related to fighting showed little change in intervention schools, but they increased 56 percent in the comparison schools (Krug et al.1997).
The PATHS (Promoting Alternative Thinking Strategies) Curriculum was developed to help students in kindergarten through fifth grade develop essential skills in emotional literacy, positive peer relations, and problem solving.Teachers blended intervention materials with the regular curriculum, and activities were conducted both in and out of the classroom.Parents were also given materials for use at home to help students generalize the lessons learned in class.
Four clinical trials of PATHS over the past 15 years have demonstrated improvements in social and emotional competencies and reductions in aggression and other risk factors (e.g., depression) across a wide range of elementary school children, including students with special needs.Some improvements were also seen in cognitive skills.These findings were reflected in teacher ratings, student self-reports, child testing and interviewing, and independent ratings by classroom observers (Greenberg et al.1995;Greenberg and Kusche 1998).
# Second
Step: A Violence Prevention Curriculum was developed to reduce aggression and increase prosocial behavior.Grossman and colleagues (1997) conducted a randomized trial among 790 second-and third-grade students in six matched pairs of urban and suburban elementary schools in Washington state.At both two weeks and six months after the intervention, the researchers found a moderate decrease in physical aggression and an increase in neutral and prosocial behavior in school.There was no measurement of behavior change outside the school setting.
While this intervention appears promising for elementary schools, it has had disappointing effects when implemented in middle schools.In one study, the curriculum led to a decrease in boys' aggressive behaviors, but the results were short-lived (Orpinas et al.1995).In a second study, the curriculum failed to reduce aggressive behaviors (Orpinas et al.2000).
# Middle school
Conflict Resolution: A Curriculum for Youth Providers is an intervention for middle-school students.Teachers present five chapters designed to build skills in communication and nonviolent conflict resolution.Students in classes that followed the curriculum reported significantly fewer violent solutions to hypothetical conflict situations than did students in other classes.
The intervention group also reported significant decreases in the actual use of violence.Although the short-term results appear promising, the study used a quasi-experimental design to evaluate the curricula, and the students were not randomly selected.Therefore, interpretations of the results are limited (DuRant et al.1996).
# High school
The Violence Prevention Project (VPP), which was implemented in three high schools in Boston, involved students in lectures, discussions, and interactive role plays once a week for 10 weeks.Evaluation of the project found that very low suspension rates were maintained among juniors, but these rates were not always significantly different from groups who did not participate in the project.However, in a specialized class with a smaller studentteacher ratio and several services that were not available in the main school system, the project reduced suspension rates by 71 percent.Findings from this project suggest that the VPP can reduce negative school behaviors when other supportive activities and services are provided concurrently (Hausman, Pierce, and Briggs 1996).
# For at-risk and high-risk youth
Aggressive youths tend to have trouble with impulse control, problem solving, anger management, assertiveness, and empathy.Social-cognitive interventions are designed to improve interpersonal and problem-solving skills so these children will be less likely to resort to aggression or to become the target of violence and better able to negotiate mutually beneficial solutions (Slaby et al.1995).
High-risk youth should participate in interventions that use multiple components-for instance, academic enhancement and relationship building with both peers and adults.A broad, intensive intervention is needed to prevent violence by children with chronic aggressive behavior (Orpinas et al.1996;Lochman et al.1993).
# Elementary school
The BrainPower program is an attributional intervention designed to reduce peer-directed aggression among African
# A broad, intensive intervention is needed to prevent violence by children with chronic aggressive behavior.
American and Latino boys.During 60-minute sessions conducted twice weekly for six weeks, students engage in activities designed to reduce their tendencies to attribute hostile intentions in peers following ambiguous negative social interactions (Hudley 1994).A study of the BrainPower intervention was conducted among 384 third-through sixthgrade students in four southern-California elementary schools.The students' behaviors and attitudes were measured for 12 months after the intervention.Boys in the intervention group improved their self-control and made fewer judgments of hostile intent.Although these results diminished over time, the findings suggest that improvements in behavior are related to changes in students' attributions (Hudley et al.1998 (Lochman, Burch, et al.1984;Lochman, Lampron, et al.1989) and reductions in substance use, but not in delinquency (Lochman 1992).The Coping Power Program has a 33-session child-group component and a 16-session parent-group component (Lochman and Welles 1996).Post-intervention and one-year follow-up evaluations showed significant reductions in children's aggression (Lochman, in press).
# Middle school
Positive Adolescent Choices Training (PACT), implemented in Dayton, Ohio, was designed to reach high-risk African American students in seventh and eighth grades.The intervention's principle components include the following Hammond 1995, 1998):
- Social-skills training-expressing anger, frustration, and disappointment constructively; listening and reacting appropriately to criticism or anger of others; and resolving disagreements nonviolently. -Anger-management training-recognizing anger triggers, understanding anger responses, thinking through the consequences of those responses, and using techniques to control anger.
- Education about violence-dispelling myths about violence risks and raising awareness of the dynamics of violence.
Researchers found that youths in the PACT group expressed less physical aggression at school than did students in the control group.This improvement in behavior was observed both during and after the training.They also found that, compared to controls, PACT participants had less involvement with the juvenile court system, fewer violence-related charges, and lower rates of offenses per person (Yung and Hammond 1993).
Responding in Peaceful and Positive Ways (RIPP) is a sixthgrade curriculum that was taught in the Richmond Youth Against Violence Project.It was designed for students with high rates of suspension, low grade-point averages, absenteeism problems, and a history of violent behavior.About 90 percent of the students in the intervention were African American, and many came from low-income, single-parent households in neighborhoods with high rates of crime and drug use.The curriculum-developed from an earlier program based on Prothrow-Stith's model ( 1987) and the Children's Creative Response to Conflict Program (1988)-included 25 50-minute sessions implemented by specialists trained in conflict resolution (Farrell and Meyer 1997).All sessions combined behavioral repetition and mental rehearsal, experiential learning activities, and didactic learning opportunities.Early sessions focused on team building and expanding students' knowledge about nonviolence; later sessions focused on skill building and critical analysis.The skills taught in the sixth grade were reinforced by a school-wide peer-mediation intervention and by seventh-and eighth-grade curricula implemented by teachers (Meyer and Farrell 1998).
Results immediately following the intervention revealed that RIPP participants had significantly fewer disciplinary code violations, carried weapons less often, and were suspended less frequently than controls.Participants also improved their knowledge of intervention material, used their school's mediation program more frequently, and reported fewer injuries from fighting.
In a six-month follow-up study of RIPP, self-report data collected from 169 participants and 184 controls showed significant treatment effects for the frequency of violent behaviors, suppression of aggressive behavior, and knowledge of the intervention material.Impulse control improved significantly among boys, and fewer male students skipped school because of safety concerns.Significant improvement was seen in girls' reported use of nonviolent methods to address hypothetical conflict situations.School disciplinary data from the first semester of the seventh grade showed that RIPP participants had significantly fewer suspensions than the control group (Farrell, Meyer, and White 1998).
The Washington Community Violence Prevention Program offered fifth and seventh graders in high-crime areas of Washington, D.C., a curriculum to highlight the motivation behind aggressive behavior and develop problem-solving skills.The curriculum built on "Viewpoints," a 10-session intervention for violent juvenile offenders to which three sessions were added: one each on drugs and guns, and one to celebrate completion of the intervention (Guerra and Slaby 1990).Students increased their knowledge about risk factors for violence, changed their attitudes toward violence, and increased social skills shown to affect aggressive behavior.These effects were measured only in the short term (Gainer, Webster, and Champion 1993).
Aggressors, Victims, and Bystanders: Thinking and Acting to Prevent Violence is a curricular intervention for middle school students that focuses not only on aggressors, but also on the interrelated roles of victims and bystanders.It is based on the premise that all three players can build the cognitive and social skills needed to resolve problems nonviolently.The curriculum was developed and evaluated in three steps, each involving collaboration among expert advisors, teachers, and students.First, researchers assessed students' cognitive skills, beliefs, and tendency to start a conflict, be a victim, or be a bystander who encourages aggression.Second, a preliminary curriculum was developed, and teachers and students provided feedback on factors such as clarity, relevance, age appropriateness, engagement, and practical utility.Third, the curriculum was evaluated in a study of over 300 high-risk adolescents and a control group.The intervention reduced students' belief that violence is a favorable response to conflict; increased their intent to resolve conflict without aggression, seek relevant information, and avoid conflict; and improved their self-rated behavior, indicating withdrawal of bystander acceptance and encouragement of aggression (Slaby 1998).
# Multi-tier interventions
Interventions designed for the general student population may fail to impact children at high risk for aggression.To address the needs of both the general and high-risk student populations, some practitioners plan interventions with several levels of activities.These multi-tier efforts may combine, for example, a curriculum to be delivered to all students with special smallgroup activities designed for high-risk youth.Some of these interventions also include activities for parents or the entire family.
One example of a multi-tier effort is the Metropolitan Area Child Study (MACS), an eight-year research trial conducted among elementary school students in urban, at-risk communities.Its goal was to change the thought processes and attitudes that are associated with aggressive behavior and to modify the school environment to foster prosocial development.Three components comprised MACS: a general enhancement classroom intervention, the "Yes I Can" curriculum; a small-group intervention for high-risk children; and a family component for the parents or guardians of high-risk children.
The "Yes I Can" curriculum consisted of 40 lessons delivered twice a week for two years (20 per year) by teachers in firstthrough sixth-grade classrooms.In the first year, students were taught self-understanding, relationship of self to others, and moral beliefs in order to motivate students to behave in prosocial ways and decrease their acceptance of aggression in social interactions.Also in the first year, teachers received 30 hours of training to help them model prosocial behaviors in the classroom.Year two introduced the themes of control and prosocial action plans to provide children with the skills needed for daily social interactions.The second year included monthly reviews for teachers to address the issues raised during first-year training and to help them develop plans for dealing with everyday classroom concerns.
The second component of MACS was a more intensive program directed at high-risk students.In addition to following the general enhancement curriculum, high-risk students participated in small-group activities designed to change their aggressive beliefs and attributions and give them opportunities to practice positive reactions to a variety of social situations.The small groups met once a week for 12 weeks in the first year and for 16 weeks in the second year.To increase social interaction, smallgroup participants were designated as leaders for the "Yes I Can" curriculum in the second year.Labeling the small-group activities as "leadership training meetings" helped motivate the high-risk students and improved their social status with peers.
# Incorporate an array of activities and materials in order to hold students' interest and model a variety of ways to prevent or counteract violence.
related to children's antisocial behavior, including inconsistent discipline, low levels of parental monitoring, poor problemsolving skills, defensiveness in family interactions, and a lack of emotional bonding (Huesmann et al.1996).
The results of this multi-level intervention were mixed.In schools with moderate resources, significant decreases in aggression were found among second-and third-grade students who received the most intensive intervention.However, in schools that had limited resources to devote to the intervention, aggression actually increased after the intervention, even when all three components were implemented.Among children in fifth and sixth grades, aggression increased after receiving general and small-group training, regardless of the school's resource level.These results indicate that a program like that tested in MACS can effectively decrease aggression if begun early and implemented in schools with adequate resources, but negative unintended effects may result when such an intervention is implemented among older students or in schools with limited means (Huesmann 2000).
# Diverse activities and materials
Social-cognitive interventions should incorporate an array of activities and materials in order to hold students' interest and model a variety of ways to prevent or counteract violence.Multimedia formats, specifically computer-based interventions, can greatly enhance classroom instruction techniques because they provide flexibility and can spark interest among resistant students (Bosworth et al.1996).The multimedia approach can adjust the intervention to students' responses, provide students control over the choice of information and sequence of materials, offer one-on-one anonymous interaction between the student and computer, and provide an attractive game-like atmosphere.
One multimedia example is SMART Team (formerly SMART Talk), a computer-based intervention for young adolescents that uses games, simulations, cartoons, animation, and interactive interviews to teach new ways of resolving conflict without violence.Computer characters act as role models who demonstrate anger management, dispute resolution, and perspective-taking to give adolescents strategies for conflict resolution and mediation (Bosworth et al.1996).The intervention is composed of six modules that may be used in any order without losing continuity or impact.
SMART Team was pilot tested with 102 seventh-grade students in a small-city middle school for a four-week period.The results showed significant increases in knowledge about conflict management and about behavior that escalates conflict; increases in self-reported prosocial behavior and intentions to use nonviolent strategies; and decreases in self-reported discipline problems at home, at school, and in the community.However, there was no difference in the students' confidence in handling conflict situations using nonviolent strategies (Bosworth, Espelage, and DuBay 1998).
The intervention was subsequently implemented in a large school in a major Midwestern metropolis with a diverse socioeconomic population.An evaluation of 516 sixth, seventh, and eighth graders showed that students found the intervention attractive and useful and that the intervention improved students' attitudes toward violence, increased self-awareness, and increased intentions to use nonviolent strategies.However, there were no significant changes in the frequency of aggressive behavior.The findings suggest that multimedia tools may be useful in changing some of the cognitive and psychological factors associated with violence and, therefore, have the potential for changing violent behavior (Bosworth et al.2000).
# Interventions to address the school setting and social norms
If interventions are to be effective in the school setting, issues about the setting itself must be addressed.Practitioners should include components that promote a nonviolent environment throughout the school.At a minimum, schools should have and enforce policies on safety precautions and student conduct.They should also enact non-punitive methods of control, encourage student involvement in academic and after-school activities, and provide continuous support for staff (Mayer 1995(Mayer , 1999.
A focus on the social context of the schools could help promote social competence and prosocial behavior in children by creating a caring school community (Baker 1998).School psychologists can help assess a school's culture and restructure schools to be more sensitive to social aspects of education, for example, by emphasizing personal responsibility, empathy, and respect for the community.
# Addressing violence in the media
Violence is often glorified or romanticized in the news and entertainment media.This type of media coverage can give young people an unrealistic view of the consequences of violence and lead them to believe that violence is accepted-
# Cultural considerations
Planners and practitioners should carefully review intervention materials and make necessary cultural adaptations for their intended participants.Interventions reaching students living in transient neighborhoods, for example, must address the ethnic and language differences that are found in the community's heterogeneous population (Huesmann et al.1996).
It may be most effective to provide schools with a core curriculum to which they can add culturally appropriate material without compromising the intervention's effectiveness.Each school should research educational techniques that might work best for their students; no one technique is appropriate for all schools.
# Link social-cognitive interventions with other strategies
Interventions to prevent youth violence should involve multiple segments of children's social experiences and interactions.
Studies have suggested that integrating the components of school-based social-cognitive interventions (e.g., social-skills development) with other types of interventions can improve effectiveness (Goldstein and McGinnis 1998;McGinnis and Goldstein 1998). |
The FAST (Families and Schools Together) Track Program is a prime example of blending strategies to prevent youth violence.It combines a social-cognitive curriculum, parent training, and home visits to prevent conduct problems, promote social relations, and improve school performance among elementary school students.It has been implemented in the low-income, high-crime areas of Nashville, Tennessee; Seattle, Washington; Durham, North Carolina; and University Park, Pennsylvania (Bierman and Conduct 1996;Dodge and Conduct 1993).
FAST Track is a multi-level program, consisting of universal and selective components.The universal component has a 57-lesson curriculum (the PATHS curriculum-see page 125) to foster universal development of emotional concepts, social understanding, and self-control.In the target communities, it was delivered to all students in 20-to 30-minute lessons, which were taught approximately three times a week (Catalano et al.1998).
Additional components were administered to high-risk students-
- Parents of high-risk children took part in training groups designed to promote positive family-school relationships and teach nonaggressive parenting skills (e.g., positive reinforcement, use of time outs, improved self-restraint). -Home visits were conducted to foster parents' problemsolving skills, self-efficacy, and coping skills. -High-risk students participated in social-skills training groups.
Children received tutoring in reading.
The at-risk children took part in a friendshipenhancement program called Peer Pairing.
The universal curriculum was applied each year for six yearsfrom first through fifth grade-covering the important developmental transitions of school entry and moving from elementary to middle school.Home visits and tutoring took place weekly in the first-grade year; afterward, these activities occurred as dictated by participants' needs (Bierman and Conduct 1996).
At the completion of the first grade, children's social, emotional, and academic skills increased moderately; peer interactions and social status improved; and disruptive behaviors decreased.
Parents reported decreased use of physical discipline, increased parenting satisfaction, and increased positive involvement with both their children and the school.Additionally, significant effects were seen in observer ratings of the classroom atmosphere, although assessment of classroom functioning varied by the quality of the FAST Track implementation (Conduct Problems Prevention Research Group 1999a, 1999b.
# Coordinating multi-strategy programs
When several strategies are incorporated into a program, you will likely need a diverse implementation staff.Persons best suited to carry out a school-based intervention, for example, may not be qualified to conduct home visits.Select one person or organization to coordinate hiring of staff, keep track of all activities in the various interventions, and monitor staff performance.This will ensure continuity among the interventions and improve the overall effort.
# Select Staff Appropriate for Your Intervention
When staffing a social-cognitive intervention, there are basically three options: 1) teachers deliver the intervention in their classrooms; 2) full-time prevention specialists (who are not Make sure staff members have a strong commitment to nonviolence.
classroom teachers) implement the intervention; or 3) a combination of teachers and other professionals implement it.Each option has advantages and disadvantages, which are discussed below.But regardless of who implements your intervention, make sure staff members have a strong commitment to nonviolence and understand the social and environmental context of participants' lives.
# Teachers as implementers
Having teachers implement a social-cognitive intervention may increase the integration of intervention activities with the regular curriculum.And a teacher-based staff may require little or no additional funding.However, if teachers implement the intervention, students may be reluctant to disclose hostile or sensitive emotions.They may feel there is less confidentiality or fear that an admission of negative or aggressive feelings may result in lower grades or disciplinary action.
Be sure that teachers who participate in the intervention do so voluntarily (Aber et al.1996;Wiist, Jackson, and Jackson 1996;Orpinas et al.1996).Some teachers may resent the burden of adding extra activities to their already busy class schedule or be reluctant to spend extra time at school to carry out extracurricular intervention activities.These teachers may not devote the effort needed to make the intervention a success.Limit intervention staff to those teachers who are enthusiastic about the activities and their intended results.
In addition to being willing to devote extra effort to a socialcognitive intervention, teachers must believe that violence can be prevented and that the intervention they are implementing will have an impact (Slaby 1998).When teachers do not believe in violence prevention interventions but implement those interventions anyway, they may inadvertently weaken the intervention's effect or cause it to fail.You can assess individual teacher readiness by having teachers rate their beliefs about violence prevention efficacy at three levels:
- General beliefs-Do you believe that violence is preventable?If a teacher does not believe it is, he or she may misrepresent or ignore prevention messages. -Specific beliefs-To what extent do you believe that prevention strategies and practices can be effective?If a teacher believes that violence is theoretically preventable but does not believe that intervention materials can be useful, he or she may not deliver activities and lessons effectively.
- Personal beliefs-Do you believe that you, personally, can make a difference in helping to prevent violence?A lack of personal efficacy can also limit effectiveness of intervention activities and messages.
You may need to increase readiness by providing evidence that these interventions work and that teachers can have a profound impact on youth violence prevention.For example, presenting a video or case study that shows skeptical teachers who implemented a violence prevention intervention and then noticed positive behavior changes may help convince staffers of their ability and that of the intervention to prevent violence (Slaby 1998).
# Other professionals as implementers
In some cases, such as when after-school activities form a significant portion of an intervention, non-teachers may be the ideal implementers.Even when activities take place during school hours, you may opt to employ a staff specifically to implement your effort.This will reduce much of the burden on teachers.
Of course, one obvious disadvantage of hiring non-teacher staffers is the need for significant funding.Funding will be required for additional salaries or consulting fees.Additional funds may also be required to conduct interviews and background checks for these individuals.This funding may come from the schools themselves or from other sources, such as government grants or community organizations.
# Both teachers and others as implementers
Having both teachers and other professionals implement your intervention may allow you to reap the benefits and minimize the negative elements that both groups of implementers present.A combined staff can also increase the effectiveness of your intervention.A non-teacher staff can lead intervention activities, and teachers can add reinforcing elements to their regular curriculum.
# Train Staff Members
Teachers and others who implement social-cognitive interventions require significant training.Schools and communities must be willing to devote the resources needed for this professional development.In addition to preparing staff members to carry out intervention activities, training should teach them how to do the following (Slaby et al.1995):
# Having both teachers and other professionals implement your intervention may allow you to reap the benefits and minimize the negative elements that both groups of implementers present.
- Organize the school environment to minimize violence.
# Training duration
Training should begin with at least three days of intensive course work and interactive exercises.But to be effective, training must be continued for as long as the intervention lasts.Ongoing training or consultation does not need to be on site.Follow-up can be through e-mail or videos, for instance.However, we should note that the effectiveness of different methods of followup training has not been determined.
# Recruit Participants
When social-cognitive interventions are incorporated into regular curricula (e.g., a health education curriculum), recruitment is typically not necessary.Students can take part in the intervention simply by attending class regularly.However, if your intervention is targeted to high-risk students, you may need to recruit them to participate in special activities that take place outside of the classroom, such as small-group discussions, peerleadership training, or after-school sessions.
# Implement Your Intervention
The effectiveness of a social-cognitive intervention will depend on many implementation factors, including how often and for how long students are exposed to activities and messages, how well teachers and other intervention staffers are supported, and how interested students remain in the activities.
# Match the intervention's frequency, intensity, and duration with participants' needs
If you are replicating an evaluated intervention, implement it as presented in the research in terms of frequency, intensity, and duration.When implementing a new intervention, the guidance that follows should help.
Students need frequent contact with intervention activities and materials.However, the actual number of contacts will depend on the material, the age or developmental readiness of participants, and the time needed to practice skills.Older students are better able to digest more information in one sitting.Elementary school students, because of their short attention spans, may need small "doses" of content.
# Social-cognitive interventions take a long time to effect changes.
A single curriculum with 10 to 15 sessions is likely to be insufficient (Orpinas 1995).Half a school year of violence prevention programming should be a minimum.For the longestterm impact, school districts should consider multi-year models with continuity across years.And for students who come into daily contact with violence outside the school setting, socialcognitive interventions should be a permanent part of school curricula (Slaby 1997).
# Support teachers and other intervention staff
# Encourage participants to stay involved
To keep students interested in the intervention, connect the activities to their goals.Show them how the behaviors they are learning will help them get what they want-improved safety at school and in their neighborhood, greater respect from peers, improved academic performance, and perhaps a larger circle of friends.
Make the intervention fun, and relate it to "real life."Include games and videotape the intervention activities to engage younger children.Use articles from local newspapers or magazines to start discussions about violence.Have students keep a log of violent images they see in the media and nonviolent examples of conflict resolution; use the log to generate class discussions.Ask young participants to share stories that illustrate nonviolent, prosocial behaviors.
Let students know they will receive a tangible reward for completing the intervention.Students-and implementation staff-need a way to publicly acknowledge and celebrate their accomplishments (Aber et al.1996;Wiist, Jackson, and Jackson 1996;Orpinas et al.1996).
# To keep students interested in the intervention, connect the activities to their goals.
# Monitor Progress and the Quality of Implementation
Monitoring, which focuses on the process of implementation, is necessary to ensure that your intervention is on track.To determine if your social-cognitive intervention is reaching the intended population and being implemented as planned- Review data routinely throughout implementation so you can correct any problems that might jeopardize the success of your effort.
# Evaluate Outcomes
Evaluation allows you to assess the effectiveness of your intervention and identify any unexpected outcomes.For a socialcognitive intervention, you'll want to answer these questions:
- Did participants' knowledge about and attitudes toward violence change? -Did aggressive and violent behaviors decrease? -Were there any negative unintended effects from the intervention?
To obtain this data, review school records for attendance, truancy, and disciplinary actions.Keep in mind the school district's reporting requirements and the variability across schools in how offenses are reported and recorded.Collect teachers' perceptions of participants' behavior changes and ask students to report changes in their own and in peers' behaviors and attitudes.You can also hire someone who was not involved in the intervention to evaluate students' behaviors; this method may produce the most objective data.
# Maintain Results after Implementation
Interventions to prevent youth violence are never finished.While positive changes are often seen right after an intervention ends, those improvements typically dissipate without reinforcement.Orpinas (1995) observed that self-reported aggressive behavior among students who participated in the Second Step program (discussed on page 125) increased as more time passed from the end of program implementation.
To maintain positive effects, practitioners should provide children and adolescents with reinforcing "booster" activities.Lochman (1992), for example, looked at the effects of a schoolbased anger-coping intervention several years after implementation.Although significant post-implementation results had been reported, there were no effects on delinquency rates or classroom behavior for most participants at the threeyear follow-up.A subset of participants who received booster sessions did maintain positive behavior changes.
Planning and implementing booster activities requires support from teachers, administrators, students, and the community.To achieve this support, share evaluation results with teachers and other school staff so they'll know that they made a difference; involve intervention "alumni" in follow-up efforts; and establish collaborative relationships between the school and community organizations (e.g., health and wellness centers, youth centers, churches).
# Summary
Social-cognitive interventions have been shown to reduce aggressive behavior by youth in the short term.Long-term evaluation, although it has been discussed for years (Coben et al.1994), continues to be lacking.There are also several limitations to these interventions.
First, some of the more violent youths are not being reached by social-cognitive interventions because they do not attend traditional schools.Second, even with training, teachers and other implementers may vary in their delivery techniques; this variation can affect intervention outcomes.Third, participants may have difficulty translating the new behaviors they learn in school to the "real world."Finally, improvements in behaviors and attitudes that students and teachers report may not be accurate; awareness of desired outcomes may bias responses of both participants and implementers.Other measures, besides self-and teacher reports, must be developed to obtain more objective data.
To maintain positive effects, provide children and adolescents with reinforcing "booster" activities.Focuses on enhancing decision-making skills as one approach toincreasing adolescents' ability to manage interpersonal violenceand examines data from a pilot study for insights aboutadolescents' ability to make decisions in situations ofinterpersonal conflict.Adolescents can be considered fairlyskilled decision makers, and their unique perspective must beconsidered to develop effective intervention programs.Children who display deviant levels of aggression in school have been found to manifest significantly higher rates of juvenile delinquency, poor overall school adjustment, greater-thanaverage rates of school drop out, and higher-than-average rates of referral for clinical mental-health interventions.Attributions may be internal factors for human aggressive behavior.
# Overview of the Mentoring Strategy
Research has shown that the presence of a positive adult role model to supervise and guide a child's behavior is a key protective factor against violence (National Resource Center 1999).The absence of such a role model-whether a parent or other individual-has been linked to a child's risk for drug and alcohol use, sexual promiscuity, aggressive or violent behavior, and inability to maintain stable employment later in life (Beier et al.2000;Walker and Freedman 1996).
Mentoring-the pairing of a young person with a volunteer who acts as a supportive, nonjudgmental role model-has been touted by many as an excellent means of providing a child or adolescent with a positive adult influence when such an influence does not otherwise exist (Council 1996;Brewer et al.1995).Evidence has shown that mentoring can significantly improve school attendance and performance, reduce violent behavior, decrease the likelihood of drug use, and improve relationships with friends and parents (Sipe 1996).And the Council on Crime in America (1997) identified mentoring as one of three interlocking crime-prevention strategies (the other two-monitoring and ministering 1 -also provide adult contact).
1 Monitoring provides community-based adult supervision of young people who have been in trouble with the law.Ministering means mobilizing and empowering caring adults, through churches, to assume responsibility for the well-being of children in their neighborhoods.
# Best Practices of Mentoring Interventions
Many states and cities, community organizations, fraternities and sororities, professional associations, and schools have launched mentoring efforts in the past decade or two.Anecdotal information from these endeavors has indicated that mentoring can be effective in reducing negative behaviors and associated risk factors.However, structured evaluation of mentoring interventions has only recently begun.And although violence prevention is one of many positive results that can come from the relationships formed through mentoring, few interventions have focused on that outcome specifically.Some researchers note that reliable data about how and why mentoring works is still being developed, but some commonsense wisdom about the best practices for both mentors and programs has emerged (Freedman 1993).Those practices, gleaned from an extensive literature review and consultation with experts in the field of youth violence prevention, are presented here.
# Identify the Populations You Want to Reach
Most mentoring efforts target young people at risk for academic and social problems.In a survey of 722 mentoring programs (Sipe and Roder 1999), the majority of interventions were aimed at youths in need of adult role models; often, this status was defined as children from single-parent homes.Other common participant groups were children from low-income families; youths who had been identified as lacking self-esteem or social skills; young victims of abuse or neglect; and young people whose family members abused drugs or alcohol.To determine whom to target in your community, conduct a needs assessment, consider your resources, and consult with local leaders, policy makers, teachers, and community organizations that serve children.
Keep in mind that mentoring may not be viable for the children and adolescents at highest risk, as these populations typically require efforts that begin at a very young age and last for many years (Freedman 1993).Weigh the costs and benefits of engaging children and adolescents with severe behavioral or emotional problems-such as those who have attempted suicide, use drugs, or are in a position to harm themselves or others-in mentoring programs, and determine if other interventions might be more appropriate.Also, because successful mentoring depends on a long-term relationship, avoid targeting young people from whom there is a demonstrated lack of commitment.
# Mentoring interventions can be community-based or site-based.
# Consider the Cultural and Demographic Context of Intended Participants
In most cases, mentors' backgrounds will be significantly different from those of participants in terms of age, lifestyle, ethnicity, and class. |
Mentoring efforts must take those differences into account and develop activities and techniques for bridging gaps.These interventions must also recognize the power of other influences in the lives of disadvantaged youths, such as poverty, exposure to violence, and lack of parental supervision.For many at-risk young people, mentoring is just a "drop in the bucket."
# Select an Appropriate Setting
Mentoring interventions can be community-based or site-based.The setting should be determined by an intervention's goals, the number of mentors, the number of youths you want to serve, and the types of activities planned.
# Community-based mentoring
In a community-based intervention, there is no set location where sessions must occur; the venue may vary by mentormentee pair and by session.In Sipe and Roder's survey (1999), slightly more than half of the programs were community-based.The majority of these interventions featured one-on-one sessions between mentors and mentees, and many focused on social or recreational activities.Because the location can vary, community-based efforts often include field trips as part of their activities.
Big Brothers/Big Sisters (BB/BS), founded in 1904, is the oldest and best-known community-based mentoring intervention in the United States; it has also been studied most.Its mission is to provide young people with one-on-one relationships that help them develop according to their full potential and become confident, competent, and caring adults.There are more than 500 local BB/BS agencies in all 50 states, serving more than 100,000 youths.Mentor-mentee pairs meet one-on-one for three to five hours each week for at least one year.There are no prescribed activities-they may include taking a walk, watching TV, playing games, attending a movie or sporting event, visiting the library, or just sharing thoughts (Elliott 1997).Public/Private Ventures (P/PV), a nonprofit social-policy development and evaluation firm in Philadelphia, conducted a comparative study of 959 adolescents ages 10 to 16 who applied to BB/BS interventions in 1992 and1993.2 Half of these adolescents were randomly assigned to a treatment group, for which BB/BS matches were made or attempted; the other half were assigned to waiting lists.In the group matched with mentors, the pairs met about three times a month for an average of 12 months; each session lasted about four hours.The treatment and control groups were compared after 18 months to determine what effect one-on-one mentoring had on adolescents' antisocial activities, academic performance, attitudes and behaviors, relationships with family, relationships with friends, self-concept, and social and cultural enrichment.
The study findings, based on self-report data from baseline and follow-up interviews or on evaluation forms completed by agency staff, revealed that the BB/BS program can have a positive effect.Little Brothers and Little Sisters, especially minority adolescents, were less likely than youths in the control group to hit someone or to start using drugs or alcohol.They also had better school attendance, academic performance, and attitudes, and their relationships with parents and peers were better than those for controls.No statistically significant improvements were found in self-concept or in the number of social and cultural activities that participants took part in (Furano et al.1993;Roaf, Tierney, and Hunte 1994;Morrow and Styles 1995;Tierney, Grossman, and Resch 1996).
# Site-based mentoring
Site-based interventions have one particular location where all sessions take place.Most site-based efforts are implemented in schools, but they can also occur in workplaces, churches, community centers, detentions centers, and public housing neighborhoods.Group mentoring interventions with targeted activities-such as academic projects and career-or skillbuilding exercises-are more likely to be site-based (Sipe and Roder 1999).
# School-based mentoring
In school-based mentoring interventions, volunteers meet with children for an hour or two, once or twice a week on school grounds.In these efforts, mentors focus primarily on activities that build academic and social skills, but they also involve the children in fun activities.
School-based mentoring programs are fairly new, and it is uncertain whether they work as effectively as "traditional" community-based efforts.But advocates of school-based mentoring have cited several potential advantages, including the following (Herrera 1999):
They may appeal to volunteers who are reluctant or unable to commit to several hours each week, which is often required in a community-based mentoring program.
Intervention staff may be better able to supervise and support mentors because they all meet at the same place.
Teachers and school administrators can also help monitor the intervention's progress.
Participating in a mentoring program may increase a young person's social standing with peers; having a mentor is often perceived as being "cool."
Another possible benefit of school-based programs is a decreased risk of false accusations of improper conduct.These programs are believed by some mentors-especially males-to be safer than community-based interventions because of the close supervision by teachers and administrators.This perception of safety may increase mentors' willingness to be paired with children of the opposite sex; this flexibility may allow schools to match a larger number of students with mentors (Herrera 1999).
One of the better-known school-based interventions is the Norwalk Mentor Program.Its goal is to improve self-esteem, attitudes, and attendance of students at risk for behavior problems and poor academic performance.The intervention's director is employed by the Norwalk public schools.Schoolbased teams of principals, social workers, guidance counselors, teachers, and nurses serve as in-school resources for mentors, and one individual-for example, a principal or social workerhandles administrative details.Volunteer mentors are recruited from local business and industry as well as from community organizations such as municipal agencies, local church groups, retired-teacher organizations, college alumni associations, and fraternal organizations.A liaison between mentors and the school is designated from each participating organization.
Mentors meet with their students on school grounds for at least one hour each week.Activities vary and may include talking, reading, playing a game, and taking part in physical recreation.For mentees in high school, mentoring sessions typically focus on career development, and meetings may occur at mentors' workplaces.Mentors are encouraged to keep in contact with students over the summer.Parents and guardians are invited to a series of evening workshops and luncheons at the school.Every student who completes high school receives a scholarship for post-secondary education, funded by participating companies through the Norwalk Mentor Scholarship Fund.
Evaluations completed by mentors and teachers after the program's first five years indicate that students benefit from the Norwalk program.As a result of mentoring relationships, 87 percent of students improved their school attendance, 92 percent improved self-confidence, and 96 percent showed greater cooperation in class.Almost all mentors (96 percent) described their relationships with students as excellent or good.And more than 90 percent of mentors and students continue their relationship through elementary and middle school years (Weinberger 1992a;1992b).The intervention, which in 1992 had more than 800 mentors, was the winner of the 1993 President's Volunteer Action Award.It has been replicated in a number of other cities in the United States and Canada.
# Institution-based mentoring
Supplementing traditional services with mentoring may be tempting for institutions that serve young people.However, institutions thinking about implementing a mentoring program must make sure they can dedicate adequate resources to operating that component.Existing staff rarely have enough time or preparation to train, supervise, or support mentors.Additionally, mentors' roles within the institution must be clearly defined so both volunteers and caseworkers understand how mentoring efforts fit with the youths' treatment plans (Mecartney, Styles, and Morrow 1994).
# Involve Parents and the Community
Involvement of parents and the community is paramount to the success of mentoring interventions.Parents must accept and support the presence of mentors in their children's lives.And the community plays a key role by providing volunteers and an infrastructure to support the intervention overall.
# Parents' role
In almost all mentoring efforts, parents are involved at some level.Parental involvement may mean signing a consent form for the child's participation, referring the child to a social-services agency or organization, or taking part in activities along with the mentor and child (Sipe and Roder 1999;Herrera 1999).
# Involvement of parents and the community is paramount to the success of mentoring interventions.
# Community Support
In order to get the human and financial resources needed to implement a mentoring intervention, you will need your community's support.You can establish this support by first demonstrating a need for your effort.Data about the problem of youth violence and about the potential benefits of mentoring should convince local leaders and policy makers.Also ask for input when developing the intervention's goals and operational plan; this should increase the community's sense of ownership in the effort (NMWG 1991).If your intervention is school-based, make sure you have the support of administrators and teachers (Herrera 1999).
Project RAISE (Raising Ambition Instills Self-Esteem), one of four components of the Baltimore Mentoring Partnership (BMP), is a good example of a program whose foundation rests on community support.Organizations-such as churches, universities, businesses, and fraternities-are recruited to sponsor RAISE interventions for seven years.They recruit mentors from their ranks and provide various other activities throughout the intervention.The goal of Project RAISE is to decrease the dropout rate and improve the life chances of students in inner-city public schools by improving students' selfesteem and school-related behavior and progress, reducing highrisk behaviors such as substance abuse and teen pregnancy, increasing graduation rates, and encouraging the pursuit of further education or training (Freedman 1993;NIJ 1994).
Evaluations of Project RAISE have revealed mixed results.According to BMP, graduation rates for RAISE students were about twice that of students in similar schools who did not participate in the intervention (NMP 2000).An independent evaluation of Project RAISE, which used comparison groups and statistical tests, found some positive results after two years of implementation: the intervention improved student attendance and report-card grades for English.However, most participants remained far below average for overall academic performance and were at risk of dropping out.Additionally, promotion rates and standardized test scores were not affected among students in the middle grades.The effects, though sizable, were not sufficient to neutralize the academic risks students exhibited upon entering the intervention (McPartland and Nettles 1991).
The researchers found that the RAISE model was much more likely to show positive effects when one-on-one mentoring was strongly implemented.Program success was also affected by variations in how sponsoring organizations implemented the model and by the size and composition of the student group served (McPartland and Nettles 1991).
# Set Clear Goals and Objectives for Intervention Outcomes and Implementation
Mentoring programs are extremely diverse, in terms of both activities and desired outcomes.Therefore, it is critical that these interventions have clearly stated goals and objectives.These objectives will guide planning decisions for such elements as the number of and qualifications for mentors, and they will provide benchmarks to guide implementation and evaluation.Goals should be set on two levels-the intended accomplishments both for the program as a whole and for individual mentoring sessions.
# Intervention goals
In most programs, the over-arching goal is to develop successful relationships between mentors and mentees.In Sipe and Roder's survey (1999), nearly three-quarters of mentoring programs had the general goal of positively impacting the young person's personal development.In many cases, that meant increasing selfesteem, developing positive values, improving conflict-resolution skills, increasing social skills, or improving relationships with family and peers.Other goals identified in that survey were promoting social responsibility and improving school performance, school behavior, and attitudes.About one-fifth of the programs had a goal of decreasing delinquent behavior among participants.
# Individual goals
The goals and objectives of individual mentoring sessions may differ significantly among pairs.Mentors should work with mentees and their families (and teachers, if appropriate) to determine desired accomplishments and the steps necessary to achieve them.Mentors may find it helpful to establish a growth plan for the mentee and to review it periodically, with both the mentee and his or her family.Setting a series of short-term goals can increase a mentee's confidence and keep him or her focused and enthusiastic (NWREL 1998).In a violence prevention program by Self Enhancement, Inc., for instance, mentors help students develop individual success plans at the beginning of the intervention.These plans, which outline what the students hope to achieve during mentoring sessions, are reviewed throughout the school year to make sure sessions are progressing as planned (Gabriel et al.1996).
# Goals should be set on two levels-the intended accomplishments both for the program as a whole and for individual mentoring sessions.
When setting individuals' goals, keep the following guidance in mind (Freedman 1993;Sipe 1996;Tierney, Grossman, and Resch 1995):
The amount of input a mentee has in setting goals should vary with age-the older the child, the greater the input.
Consider the values and religious beliefs the mentee is exposed to at home-do not try to instill values that may cause conflict between the mentee and his or her family.
Be realistic-mentors can't eliminate all the risk factors young people face, but they can help young people achieve specific goals and learn how to deal effectively with negative situations.
Shift goals as warranted by changes in the mentee's life.
# Select Your Intervention and Develop Appropriate Activities
The variety of activities that can make up a mentoring intervention is nearly infinite.The activities you choose will depend on the intervention's goals, setting (whether communityor site-based), and format (one-on-one versus group); the mentees' needs and characteristics; and the mentors' experience and commitment levels.Table 7 lists some common activities, but it is by no means exhaustive (Sipe and Roder 1999;Herrera 1999). (Freedman 1993;Sipe 1996):
Make activities fun as well as educational.
Focus on activities that promote mutual exchange, rather than on instruction for the mentee.
Plan activities that offer challenges.
Provide support and encouragement, but do not solve problems for the mentee.
# Intervention format
Most mentoring interventions have a one-on-one format.Usually, this format matches one mentor with one mentee.However, a mentor can also be matched with several mentees with whom he or she meets individually.The most common examples of the multiple one-on-one format are programs in which retired persons meet individually with several children each day of the week (Sipe and Roder 1999).The Friends of the Children program, based in Portland, Oregon, also uses this format.Their mentors-called "friends"-are paired with up to eight children with whom they meet individually several times a week (Woo 1999).
# Make activities fun as well as educational.
Practitioners must carefully balance the desire to achieve high staffing levels with the need to select staff members who are qualified, dedicated, and able to make a long-term commitment.
Mentoring can also be done in a group setting.This format most often matches one mentor with a group of young people.The groups typically include about four or five children, but they can range from two to 20 or 30 youths.Some group programs match two or more mentors with a group of participants.Assigning multiple mentors to a group may have several advantages.It reduces the mentor-to-mentee ratio, allowing for more personal attention for mentees.It allows mentoring programs to reach greater numbers of young people.And it reduces the problems that occur when a mentor is unable to attend a session-if one mentor cannot attend, the group can still meet with the other mentor(s).We should note, however, that very little research has been done on group programs, so we do not know if this format produces effective relationships or if youths derive the same benefits from a group format that they do in a one-on-one program (Sipe and Roder 1999).
# Building on others' experience
Identifying existing interventions on which to model your effort can prevent your having to reinvent the wheel.If you know of a mentoring program that had positive effects, try to replicate it.You may want to tailor an intervention to your community, but be cautious in changing key implementation elements, as you may alter the outcome.The Additional Resources section on page 194 may help you find ideas for your intervention.
# Select Staff Appropriate for Your Intervention
Mentoring interventions typically require a large staff.Many volunteers are needed to serve as mentors, and administrative staff are needed to train and support the mentors.Practitioners must carefully balance the desire to achieve high staffing levels with the need to select staff members who are qualified, dedicated, and able to make a long-term commitment.
# Recruiting staff
Before you recruit volunteers or a paid staff, clearly define the qualifications required for each position.Indicate the skills and characteristics that mentors and other staff members should possess.Put in writing the specific types of activities to be performed and the time commitment expected (NWREL 1998).
The Big Brothers/Big Sisters program, for instance, requires its professional case managers to screen applicants, make and supervise matches, and close matches when eligibility requirements are no longer met or either party can no longer participate fully in the mentoring relationship.They also advise mentors when difficult situations arise (Elliot 1997).
Decide where to look for potential staffers and volunteers.The required qualifications and the intervention's activities will help you determine where the best pool of candidates can be found. (Sipe 1996).
# Corporate involvement
Ask local businesses and corporations to support your program and help you recruit mentors.One common model of such a corporate partnership is the "adopt-a-school" program in which a business enlists employees as mentors (Herrera 1999).Businesses may also provide facilities for mentoring activities or sponsor field trips.Even if employers do not want to participate directly, they may be willing to give employees time off for mentoring (NMWG 1991).This is a very valuable contribution, as it allows individuals to mentor without affecting their personal or family time.More people may be willing to volunteer under these circumstances. (Ringwalt et al.1996).
Results from an evaluation of the SAGE program suggest that it can have a positive effect on violence-related behaviors and other health risk factors. |
Self-reports of study participants 18 months after the intervention indicated that SAGE participants carried a gun and sold illegal drugs less often than did participants in the second study group (summer jobs and JA only) or the control group.SAGE participants also experienced decreases in heavy drinking and injuring others with a weapon.At 30-month follow-up, positive effects were decreased, as is typical for prevention interventions.The authors note that the results of the study are limited, as decreases in violence and other risk behaviors were not observed at statistically significant levels (Flewelling et al.1999).
Career Beginnings is another program with corporate involvement.It is a multifaceted school-to-work initiative that targets disadvantaged high-school juniors and seniors who have average academic and attendance records and demonstrate commitment and motivation.Mentors support students in exploring college and career options through educational workshops, career-specific training, and quality summer work experiences.They also help guide students through the college admissions process or through the process of finding full-time employment.A 1990 evaluation of Career Beginnings compared youths who responded to follow-up interviews at one and two years after assignment with either the intervention group or the control group.3 Researchers found that Career Beginnings participants had a slightly higher rate of attendance than the control group.Intervention participants also had higher levels of college enrollment and higher educational aspirations than nonparticipants receiving comparable amounts of education and job-related services (Cave and Quint 1990;U.S. Dept.of Education 1993).
3 Although youths in the control group did not participate in Career Beginnings, they could receive other services from their schools or communities.
# Older adults as mentors
A survey of more than 700 mentoring programs found that approximately 5 percent recruited older adults and retirees as mentors (Sipe and Roder 1999).Evaluations have suggested that these intergenerational programs can produce positive, satisfying relationships that benefit both the youths and elders (Freedman 1988).A three-year evaluation of Across Ages revealed that a program of classroom instruction and parent workshops was more effective in preventing drug use when combined with intergenerational mentoring than when implemented alone.While both the mentoring and non-mentoring groups were more likely after the intervention to respond appropriately to peers' offers of drugs or alcohol, students in the Across Ages group also had a greater sense of self-worth and well-being and had fewer feelings of sadness and loneliness (LoSciuto et al.1996;Taylor et al.1999).Because of its promise for reducing risk factors and promoting protective factors, Across Ages has been selected by the Center for Substance Abuse Prevention as a model to be replicated in several sites across the United States.
Linking Lifetimes is another intergenerational mentoring program developed by Temple University's Center for Intergenerational Learning.A study conducted by Styles and Morrow (1992) examined the relationships that formed between youths and their mentors at four Linking Lifetimes demonstration sites.The mentees in the programs were youth offenders, teen mothers, and youths living in high-risk neighborhoods.They ranged in age from 12 to 17 years; mentors were 55 years and older.Of the 26 pairs studied, 17 were identified as being satisfied with the relationship.Specifically, members of satisfied pairs indicated that they had feelings of attachment, fondness, and commonality with one another; they felt committed to the relationship and wanted it to continue.Additionally, satisfied youths stated that they felt their mentor was a source of support.Satisfied mentors felt appreciated or believed they made a difference in their youths' lives.It is not clear from this study, however, whether the Linking Lifetimes program had an impact on youths' behaviors or attitudes.
# Intergenerational programs can produce positive, satisfying relationships that benefit both the youths and elders.
It takes a special person to be a mentor . . .practitioners must remember that mentoring is not suited for all volunteers.
# Criteria for staff and mentors
Mentors provide positive guidance and serve as role models.They act as teachers, confidants, friends, advocates, nurturers, and challengers.They devote many hours to their mentees and form lasting relationships with them.Clearly, it takes a special person to be a mentor, and practitioners must remember that mentoring is not suited for all volunteers.Other roles-such as support staff, tutors, or fundraisers-may be found for volunteers who do not have the qualifications or time needed for mentoring (Freedman 1993).
Although special criteria (to be discussed shortly) must be applied for mentors, all staff members-both volunteers and paid employees-should have the following qualities:
# Screening mentors
There are several ways to find out if a candidate has the qualifications and qualities you desire in a mentor.The most common screening tools are written applications, face-to-face interviews, reference checks (both personal and employment), and criminal background checks (Sipe and Roder 1999).If the mentor will spend time alone with a child, you should also conduct home visits (NMWG 1991).If mentors are going to transport children, their driving records should be checked.And in some school-based programs, mentors must have proof of health requirements, such as a test for tuberculosis (Weinberger 1992b).
# Train Staff and Mentors
The training required for intervention staff members will depend on their roles.For mentors, training content will depend on the activities to be conducted during mentoring sessions and the desired outcome of the overall intervention.
# Training for staff members
The individuals you select to recruit and screen mentors should be trained in how to effectively approach organizations, corporations, and individuals about mentoring, as well as how to interview and screen candidates.Recruiters should also learn how to tactfully turn down interested persons without alienating them.Even though someone is ill-suited for mentoring, he or she may be an ideal candidate for a support position.Staffers selected to support mentors should be trained in maintaining enthusiasm among volunteers, developing creative activities for the youths, and resolving conflicts between volunteers and participants. (NMWG 1991;Styles and Morrow 1992;Freedman 1993;Gallup 1998;NWREL 1998;Herrera 1999):
# Mentor training
Mentors must be patient and realize that the relationship will be one-sided initially.
Trust.An effective mentoring relationship is built on trust.Keys to gaining the trust of mentees include showing up for meetings and keeping promises.Patience and perseverance.Youths are likely to feel uncomfortable sharing intimate information.Some youths may be reluctant to talk about anything in the beginning.Mentors must be patient and realize that the relationship will be one-sided initially.Communication skills.Mentors must be able to share ideas with youths and suggest alternative behaviors and attitudes without sounding like they are passing judgment.And they must listen intently to mentees, while watching their body language and picking up on other cues that might indicate hidden feelings.Good communication skills will help develop the relationship and set a good example for mentees on how to interact with others.Problem-solving skills.Mentees often face difficult social and academic problems.Mentors should be trained in how to help their young people come up with solutions.
Self-esteem building.One of a mentor's roles is to help the mentee build self-esteem.Teach mentors how to guide their youths in setting initial goals that are attainable quickly and with relative ease.Early accomplishments will help mentees recognize their capabilities and develop pride in their achievements.As the relationship progresses, goals should become increasingly more challenging. - -Developmental stages.Mentors need to know about the developmental stages that children and adolescents go through.This will help them better understand mentees' behaviors and develop age-appropriate activities.Cultural and economic issues.Mentors should be informed about mentees' cultural and economic backgrounds so they can tailor activities to address the challenges mentees face in their families, neighborhoods, and schools.Because no two young people have identical backgrounds, some of this information should be provided to mentors individually when a match is made, rather than in a group training format.Provide mentors with a training manual with a summary of material covered in training sessions, additional resources such as whom to contact for help with difficult situations (e.g., case managers or a program director), and suggestions for activities (e.g., lists of appropriate events and field trips).Also include guidelines on appropriate mentor behavior; procedures for handling emergency situations such as injuries; and policies for confidentiality and liability, which should include mandates for reporting physical or sexual abuse and other life-threatening situations.
Plan supplemental training sessions throughout the intervention and offer mentors retraining as their mentees grow into different developmental stages (for example, when the mentee enters middle or high school).
# Resources for training
Small sponsoring organizations may not be able to provide complete training.Identify sources of technical assistance for training; for example, partner with a larger organization or with a university.
# Recruit Participants
Most mentoring programs are targeted to young people who lack positive adult role models or who have other risk factors for negative behaviors (Sipe and Roder 1999).But how do you find those young people?Sometimes they come to you.The Big Brothers/Big Sisters program, for example, has a waiting list and does not need to recruit.For most other programs, you'll need referrals from teachers or guidance counselors, community organizations that serve children, social service professionals, the local public housing authority, or the criminal justice system.You can also ask parents-through word of mouth or an organized communication campaign-to enroll their children in your program.
It is not enough, however, to simply locate children and adolescents in need.You must also make sure that the youths you recruit are going to be committed to the program.Make sure participants understand what will be expected of them.Also, make sure parents know what their child will be involved in and that they support participation.You can provide this information through-
written statements, interviews, home visits, and phone calls; - orientation meetings that describe the role of the mentor, mentee, and parents;
Emphasize the opportunities for new and exciting experiences that mentoring presents.
- a handbook for families and mentees.
# Provide incentives
Often, the experiences that mentoring relationships offerimproving academic performance, going to a movie, attending a sporting event, or simply having a trusted adult to rely on-are enough to interest young people in a mentoring program.However, if you are having difficulty recruiting intended participants, you may need to offer special incentives.For example, the Kansas City-based Ewing Marion Kauffman Foundation offered a monetary incentive to students who participated in Project Choice, a dropout-prevention program implemented in a local high school.If participants-who entered the program as freshmen-remained drug-free, avoided pregnancy, and completed high school on time, they received funds to cover their college tuition (Ewing Marion Kauffman Foundation 2000).
# Focus on the positive
Young people may be reluctant to take part in a mentoring program if it is positioned as an intervention or treatment for negative or problem behavior.Practitioners should emphasize the opportunities for new and exciting experiences that mentoring presents (NWREL 1998).
# Implement Your Intervention
The success of a mentoring intervention depends largely on the development of trusting, beneficial relationships between young people and adults (or in some cases, older adolescents).To help foster this type of relationship, practitioners should remember three key principles.
First, both the amount and quality of time are important.
Interactions between mentors and mentees must occur frequently enough to allow relationships to form.And mentors must be attentive to mentees during all interactions so they feel cared for and understood.
Second, sessions should occur regularly and consistently.Having a set schedule can help mentors improve their attendance rates (Tierney and Branch 1992) and give the young people something to look forward to.Sticking to the schedule helps build trust between the mentor and mentee.This point is extremely important-when a mentor misses meetings, the mentee may feel disappointed, angry, or let down (NMWG 1991).In a young person who is already at risk for academic problems, drug use, or violent behavior, these feelings can be highly destructive.
Finally, sessions should be face-to-face whenever possible.Not only does this type of interaction promote closeness, it allows mentors to notice important things about their mentees, such as body language, signs of physical abuse, or aspects of behavior or appearance that may be cause for concern (e.g., symptoms of depression, the appearance of gang-related tattoos, evidence of being in a fight).When circumstances prohibit a face-to-face meeting, mentors should call or write to their mentees, rather than let days or weeks pass without interaction.For example, one mentor in an intergenerational program wrote letters to his mentee while the youth was in a drug-treatment program (Styles and Morrow 1992).
# Match mentors with mentees
The matching of mentors with mentees can be done in a number of ways.Your approach to this process will depend on the intervention's goals and activities and on the preferences of the youths, their parents, and the mentors (Sipe 1996).Whatever criteria you choose, however, put them in writing and apply them uniformly.
# Common interests
Common interests are very important in a mentoring match (NWREL 1998).In fact, more than two-thirds of interventions in one survey matched mentors and participants according to their interests (Sipe and Roder 1999).Project RAISE (Raising Ambition Instills Self-Esteem), for example, has both mentors and students complete surveys to determine areas of interest and expectations; the results of those surveys guide staff in assigning pairs (Freedman 1993).Relationships in which the mentor and mentee agree on the types of activities they want to participate in tend to be most satisfying to both members of the pair (Sipe 1996).
# Gender and race
Some participants-and their parents-may prefer a match with a mentor of the same race or gender.This type of match may make parents and youths feel more comfortable and avoid cultural misunderstandings or misinterpretations (NWREL 1998).However, data have suggested that matching mentors and mentees of different races and genders may also result in satisfying relationships (Sipe 1996).While it is best to honor the preferences of mentees and their parents, practitioners may wish to discuss the potential benefits of a mixed-gender or cross-race match when mentoring activities would be significantly delayed by waiting for a mentor of the same gender or race (Sipe and Put matching criteria in writing and apply them uniformly.
schedules in order for meetings to be regular and consistent.
Natural and random matching Some practitioners let mentors and mentees form natural pairings.Workshops and social events allow mentors and participants to get to know one another and to develop their own matches.Another matching method is random assignment, in which no specific criteria are employed.
# Match the intervention's frequency, duration, and intensity to participants' needs
Mentoring relationships develop through many interactions over a long period of time.Mentors should meet with their youths for an hour or more each week for at least six months, the minimum length of time typically needed to establish a close, trusting relationship (Freedman 1993;Sipe 1996).Sipe and Roder (1999) found that half of the mentoring interventions in their survey required a one-year commitment.
Some mentoring programs require mentors to commit to a much longer relationship.The Friends of the Children program in Portland, Oregon, is a mentoring program that pairs high-risk children with full-time, paid "friends" who commit to relationships that last for a child's entire school career.Friends candidates must be able to meet with their youths on a consistent basis over many years and must have a bachelor's degree and experience working with children.Each candidate undergoes extensive background checks before being gender-matched with up to eight young people.Being a "friend" is viewed as a career.All friends receive benefits, including insurance and a 401(k) plan, and a modest monthly expense account (Hallman 1999).
Friends spend at least four hours each week with their children.Activities range from doing homework to going to the park or sharing dreams and ideas, but the overall goal of the activities is the same for all pairs-to teach problem-solving and conflictresolution skills, honesty, respect for self and others, hard work, and accountability (Friends 1999a(Friends , 1999b.
Friends of the Children is in its seventh year, so final results are still several years off.However, the Northwestern Regional Educational Laboratory has conducted a preliminary assessment of the program, and results are encouraging.Their study found that having a mentoring friend can lead to increased self-esteem, better attitudes, and improved communication skills.Additionally, most participants improved their academic performance.In fact, only 2 percent of participants failed to pass their grade in school.Children in the Friends program also avoided contact with the juvenile justice system, and most
# Mentoring relationships develop through many interactions over a long period of time.
Interventions in which the staff contacts mentors regularly report better quality matches.
# Supervise and support mentors
Sustaining the involvement of mentors is hard work.Mentoring programs must provide ongoing supervision of and support for volunteers to ensure that meetings are taking place regularly and to prevent mentors from becoming discouraged or suffering burnout.
Interventions in which the staff contacts mentors regularly report better quality matches (Sipe 1996).Most programs contact mentors once a month by phone (Sipe and Roder 1999).Some programs institute monthly or bi-monthly support meetings between mentors and staff, during which mentors can address concerns, frustrations, and difficulties.Other programs sponsor events such as picnics, parties, and conferences during which mentors receive gifts of appreciation, are recognized for jobs well done, and share success stories that illustrate how mentors are making a difference in young people's lives (Herrera 1999).
When planning your intervention, develop an infrastructure that can adequately support the mentors.The median ratio of mentors to staff was 20 to 1 in Sipe and Roder's survey (1999).If most of the mentors in your intervention are inexperienced, you may need a larger number of support staff (NWREL 1998).
# Encourage continued participation
The drop-out rate for mentoring interventions is fairly high. |
Some researchers have estimated that half of the relationships fail (Freedman 1993).Mentors must work to keep participants interested in the mentoring relationship.The following guidance for mentors can increase the likelihood that young people will stick with the program (Styles and Morrow 1993;Sipe 1996):
- Listen to the youths and respect their viewpoints.
Involve mentees in deciding how to spend time together.
Respect mentees' need for privacy; do not push them to share intimate information.
Be available to talk at any time. -necessary, change mentors to meet mentees' Change strategies and goals as mentees get older; if
# Monitor Progress and the Quality of Implementation
As with any intervention, monitoring is necessary to make sure your mentoring intervention is being implemented as planned (NMWG 1991).Establish mechanisms to assess the progress of and satisfaction with relationships.These mechanisms can include-
- asking mentors and mentees to sign in for meetings; - interviewing mentors, mentees, and parents; - having mentors log activities, accomplishments, and concerns.
If you find that a mentor or youth is frequently missing meetings, follow up with that individual to see if there are transportation problems or time conflicts.If a match is not working, even after considerable effort by the mentor and staff, try to reassign both members of the pair (U.S. Dept.of Education 1996).
# Evaluate Outcomes
When the intervention is complete, evaluate whether the overall goals and the goals of individual mentees have been met.Since one goal of any mentoring intervention is to form beneficial relationships, assess the quality of the relationships in your program.Determine how many relationships continued for the duration of the intervention, and ask both mentors and mentees how satisfied they were with their relationships.
Another typical goal of mentoring is to prevent or improve some kind of negative behavior, such as violence, drug use, or poor academic performance.Ask parents and teachers to assess changes in mentees' behaviors; you can also ask the young people themselves to identify any changes in the ways they think or act.Other ways to check the impact of your intervention include assessing dropout rates and checking school detention and suspension records to see if disciplinary actions decreased during the intervention.
Remember to compare the behaviors, attitudes, and academic performance of young people in the mentoring intervention with youths who did not participate in mentoring (i.e., a comparison group) to determine the significance of changes.If, for example, all middle-school students improved school performance and reduced delinquent behaviors during the period of your intervention, you cannot assume that mentoring caused those
To have the greatest impact, mentoring should be part of a concerted effort that involves several strategies.
changes in participants.They may have occurred without the intervention.Conversely, you may find that, although aggressive behaviors remained the same among participants, aggression increased among young people who did not take part in mentoring.Without a comparison group, you would not recognize the stable rate as significant.
# Maintain Results After Implementation
If your intervention achieved positive effects, you will, of course, want to sustain those effects.An important step in maintaining results is providing a supportive transition for mentees.This may be accomplished in a number of ways.Exit interviews between youths and staff, between mentors and staff, and between mentors and youths allow all three groups to discuss the benefits of the program and address concerns about what comes next for the youths.Recognition of mentees' accomplishments-through award ceremonies, banquets, and community or school newsletters-can motivate the young people to continue improving school performance, to avoid drugs or violence, and to seek out other positive relationships with adults.
It's helpful to link youths with other community services and activities, such as scouts and school or church groups, that can help fill any voids created by the end of their mentoring relationships.Assistance should be made available to mentees who have difficulty with the transition (NMWG 1991).
Because some pairings may want to continue their relationship in some capacity after the intervention has ended, practitioners should have in place a policy for future contact.Make sure mentors understand any liability issues that may apply if contact continues outside of the intervention's auspices.
# Link Mentoring with Other Strategies
The young people involved in mentoring interventions typically have several risk factors for adverse behaviors.Mentoring cannot overcome all of them-it is just one influence among many.To have the greatest impact, mentoring should be part of a concerted effort that involves several strategies, such as those discussed in previous sections of this sourcebook (Freedman 1993;Sipe 1996).
The Children at Risk (CAR) Program is a drug-and delinquency-prevention effort that combines strategies to offer comprehensive services for at-risk adolescents.These services include the assignment of case managers to participating families, tutoring and other educational activities, and police collaboration to reduce neighborhood crime.Mentoring is provided to about half of the youths in the program.Preliminary results of an outcome evaluation showed that, compared with a control group, CAR participants had almost half the number of contacts with the police and less than half the number of contacts with juvenile courts.A greater percentage of participants were promoted to the higher grade and had lower rates of chronic absenteeism.A full-scale case-control study is under way in high-risk neighborhoods in five cities to assess the effect of mentoring as well as intensive case management, family services, and educational incentives (Harrell 1996).
# Summary
Although the mentoring strategy appears promising for preventing youth violence and many other problems facing our nation's young people, there is very little scientific data to demonstrate whether, and under what circumstances, it is effective.More rigorous and systematic evaluations are still needed.In addition, research must address several key issues (Sipe 1996).
First, we must develop more effective ways of recruiting and screening mentors.The largest mentoring program-Big Brothers/Big Sisters-supports 75,000 matches nationwide, but it has almost as many young people waiting to be matched.Fewer than half of the adults who inquired about volunteering during a study of Big Brothers/Big Sisters actually applied to be mentors.Of those, only about one-third successfully completed the screening and matching process; for some, the process took months.
Additionally, mentoring efforts have traditionally been targeted to children in the early-to mid-adolescent years.We must determine how to design effective mentoring programs for teens and pre-adolescent children, as well.
Finally, there is little agreement about the financial resources needed to plan and implement a mentoring intervention.The Big Brothers/Big Sisters program estimates that it costs $1,000 to support a match for one year.But that cost may not be representative of all programs-researchers suspect the cost is somewhat less.In order to help communities assess the feasibility of mentoring, we must find a way to accurately estimate the costs of developing, supporting, and evaluating such an intervention.
# Save the Children
In cooperation with the National Mentoring Partnership and with funding from the Department of Justice, Save the Children has developed the National Mentoring Hotline, which houses a database of more than 1,500 mentoring interventions nationwide.An ad campaign, produced in partnership with the Ad Council, was launched in the fall of 1998 to publicize the hotline and attract potential volunteers.
# Youth Violence-A National Problem
Violent injury and death disproportionately affect children, adolescents, and young adults in the United States.Although rates for homicides have dropped in recent years, they are still unacceptably high.
# Fatal violence
Homicide is the second leading cause of death among young people ages 15 to 19.Among African American youths in that age group, homicide is the leading killer.From 1990 to 1999, nearly 34,000 young people ages 18 and younger were victims of homicide.That's an average of about 9 youths killed each day over the last decade.
Just as alarming as the number of young people dying from violence is the number of young people who are committing violent acts.In 1997, 1,700 youths under age 18 were implicated in 1,400 murders.Among the homicide offenders in 2000 whose age was know by authorities, approximately 48% were 24 or younger and 9% were younger than 18.
# Nonfatal violence
Violence does not have to be fatal to greatly affect individuals and communities.Violence-related injuries can leave emotional and physical scars that remain with victims long after the violent event has occurred.The rates of nonfatal victimization for rape, sexual assault, robbery, and aggravated assault are higher among people under age 25 than among other age groups.
Findings from the 1999 Youth Risk Behavior Survey (YRBS)-which is based on a nationally representative sample of students in grades 9 through 12-reveal that a significant portion of young people are involved in violent behavior.In the 30 days preceding the survey, weapon carrying was reported by 17.3 percent of students; 6.9 percent carried a weapon on school property.In the 12 months preceding the survey, 35.7 percent of students reported having been in a physical fight at least once and 4 percent reported being treated by a doctor or nurse for injuries sustained in a physical fight.Almost 9 percent of students reported being hit, slapped, or physically hurt on purpose by a boyfriend or girlfriend during the previous 12 months.
# Firearms and youth
In 1999, firearm-related homicides were the second leading cause of injury death among 15-to 19-year-olds and the third leading cause of injury death among 10-to 14-year-olds.Nearly 25 percent of all Americans who died from firearm injuries in 1999 were between ages 15 and 24.
In 1999, about 1 in 20 students participating in the YRBS reported carrying a firearm at least once in the 30 days before the survey.Although this figure represents a decline since the 1995 YRBS, it is still troubling.
# Deadly school violence
Preliminary results from a current CDC study indicate that between July 1, 1994, and June 30, 1999, 253 violent deaths occurred on school property, on the way to or from school, or at or on the way to or from a school-sponsored event.The majority of these incidents were homicides involving firearms.These violent deaths occurred in communities of all sizes, locales, income levels, and racial and ethnic make-up.
Preliminary results also show that, while the number of school-associated violent death events has decreased |
These recommendations update information on the vaccine and antiviral agents available for controlling influenza during the 1995-96 influenza season (superseding MMWR 1994;43(No.RR-9)1-13 and MMWR 1994;43(No.RR-15):1-10).The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 1995-96, b) side effects and adverse reactions, and c) the vaccination of pregnant women.#INTRODUCTION
Influenza A viruses are classified into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N).Three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) are recognized among influenza A viruses that have caused widespread human disease.Immunity to these antigens-especially to the hemagglutinin-reduces the likelihood of infection and lessens the severity of disease if infection occurs.Infection with a virus of one subtype confers little or no protection against viruses of other subtypes.Furthermore, over time, antigenic variation (antigenic drift) within a subtype may be so marked that infection or vaccination with one strain may not induce immunity to distantly related strains of the same subtype.Although influenza B viruses have shown more antigenic stability than influenza A viruses, antigenic variation does occur.For these reasons, major epidemics of respiratory disease caused by new variants of influenza continue to occur.The antigenic characteristics of circulating strains provide the basis for selecting the virus strains included in each year's vaccine.
Typical influenza illness is characterized by abrupt onset of fever, myalgia, sore throat, and nonproductive cough.Unlike other common respiratory illnesses, influenza can cause severe malaise lasting several days.More severe illness can result if either primary influenza pneumonia or secondary bacterial pneumonia occurs.During influenza epidemics, high attack rates of acute illness result in both increased numbers of visits to physicians' offices, walk-in clinics, and emergency rooms and increased hospitalizations for management of lower respiratory tract complications.
Elderly persons and persons with underlying health problems are at increased risk for complications of influenza.If they become ill with influenza, such members of high-risk groups (see Groups at Increased Risk for Influenza-Related Complications under Target Groups for Special Vaccination Programs) are more likely than the general population to require hospitalization.During major epidemics, hospitalization rates for persons at high risk may increase twofold to fivefold, depending on the age group.Previously healthy children and younger adults may also require hospitalization for influenza-related complications, but the relative increase in their hospitalization rates is less than for persons who belong to high-risk groups.
An increase in mortality further indicates the impact of influenza epidemics.Increased mortality results not only from influenza and pneumonia but also from cardiopulmonary and other chronic diseases that can be exacerbated by influenza.It is estimated that >20,000 influenza-associated deaths occurred during each of 10 different U.S. epidemics from 1972-73 to 1990-91, and >40,000 influenza-associated deaths occurred during each of three of these epidemics.More than 90% of the deaths attributed to pneumonia and influenza occurred among persons ≥65 years of age.
Because the proportion of elderly persons in the U.S. population is increasing and because age and its associated chronic diseases are risk factors for severe influenza illness, the number of deaths from influenza can be expected to increase unless control measures are implemented more vigorously.The number of persons <65 years of age at increased risk for influenza-related complications is also increasing.Better survival rates for organ-transplant recipients, the success of neonatal intensive-care units, and better management of diseases such as cystic fibrosis and acquired immunodeficiency syndrome (AIDS) result in a higher survival rate for younger persons at high risk.
# OPTIONS FOR THE CONTROL OF INFLUENZA
In the United States, two measures are available that can reduce the impact of influenza: immunoprophylaxis with inactivated (killed-virus) vaccine and chemoprophylaxis or therapy with an influenza-specific antiviral drug (amantadine or rimantadine).Vaccination of persons at high risk each year before the influenza season is currently the most effective measure for reducing the impact of influenza.Vaccination can be highly cost effective when it is a) directed at persons who are most likely to experience complications or who are at increased risk for exposure and b) administered to persons at high risk during hospitalizations or routine health-care visits before the influenza season, thus making special visits to physicians' offices or clinics unnecessary.When vaccine and epidemic strains of virus are well matched, achieving high vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) can reduce the risk for outbreaks by inducing herd immunity.
# INACTIVATED VACCINE FOR INFLUENZA A AND B
Each year's influenza vaccine contains three virus strains (usually two type A and one type B) representing the influenza viruses that are likely to circulate in the United States in the upcoming winter.The vaccine is made from highly purified, egg-grown viruses that have been made noninfectious (inactivated).Influenza vaccine rarely causes systemic or febrile reactions.Whole-virus, subvirion, and purified-surfaceantigen preparations are available.To minimize febrile reactions, only subvirion or purified-surface-antigen preparations should be used for children; any of the preparations may be used for adults.
Most vaccinated children and young adults develop high postvaccination hemagglutination-inhibition antibody titers.These antibody titers are protective against illness caused by strains similar to those in the vaccine or the related variants that may emerge during outbreak periods.Elderly persons and persons with certain chronic diseases may develop lower postvaccination antibody titers than healthy young adults and thus may remain susceptible to influenza-related upper respiratory tract infection.However, even if such persons develop influenza illness despite vaccination, the vaccine can be effective in preventing lower respiratory tract involvement or other secondary complications, thereby reducing the risk for hospitalization and death.
The effectiveness of influenza vaccine in preventing or attenuating illness varies, depending primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the virus strains included in the vaccine and those that circulate during the influenza season.When there is a good match between vaccine and circulating viruses, influenza vaccine has been shown to prevent illness in approximately 70% of healthy persons <65 years of age.In these circumstances, studies have also indicated that the effectiveness of influenza vaccine in preventing hospitalization for pneumonia and influenza among elderly persons living in settings other than nursing homes or similar chronic-care facilities ranges from 30%-70%.
Among elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and death.Studies of this population have indicated that the vaccine can be 50%-60% effective in preventing hospitalization and pneumonia and 80% effective in preventing death, even though efficacy in preventing influenza illness may often be in the range of 30%-40% among the frail elderly.Achieving a high rate of vaccination among nursing home residents can reduce the spread of infection in a facility, thus preventing disease through herd immunity.
# RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE
Influenza vaccine is strongly recommended for any person ≥6 months of age whobecause of age or underlying medical condition-is at increased risk for complications of influenza.Health-care workers and others (including household members) in close contact with persons in high-risk groups should also be vaccinated.In addition, influenza vaccine may be administered to any person who wishes to reduce the chance of becoming infected with influenza.The trivalent influenza vaccine prepared for the 1995-96 season will include A/Texas/36/91-like (H1N1), A/Johannesburg/33/94-like (H3N2), and B/Beijing/184/93-like hemagglutinin antigens.The actual influenza type B strain used by U.S. manufacturers is B/Harbin/07/94, which is antigenically equivalent to the B/Beijing/184/93 strain.Guidelines for the use of vaccine among certain patient populations follow.Dosage recommendations are also summarized (Table 1).
Although the current influenza vaccine can contain one or more of the antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines in the year following vaccination.Because the 1995-96 vaccine differs from the 1994-95 vaccine, supplies of 1994-95 vaccine should not be administered to provide protection for the 1995-96 influenza season.
Two doses administered at least 1 month apart may be required for satisfactory antibody responses among previously unvaccinated children <9 years of age; however, studies of vaccines similar to those being used currently have indicated little or no improvement in antibody response when a second dose is administered to adults during the same season.
During the past decade, data on influenza vaccine immunogenicity and side effects have been obtained for intramuscularly administered vaccine.Because recent influenza vaccines have not been adequately evaluated when administered by other routes, the intramuscular route is recommended.Adults and older children should be vaccinated in the deltoid muscle and infants and young children in the anterolateral aspect of the thigh.
# TARGET GROUPS FOR SPECIAL VACCINATION PROGRAMS
To maximize protection of high-risk persons, they and their close contacts should be targeted for organized vaccination programs.
# Groups at Increased Risk for Influenza-Related Complications:
- Persons ≥65 years of age 800) FLU-SHIELD. †Because of the lower potential for causing febrile reactions, only split-virus vaccines should be used for children.They may be labeled as "split," "subvirion," or "purified-surface-antigen" vaccine.Immunogenicity and side effects of split-and whole-virus vaccines are similar among adults when vaccines are administered at the recommended dosage. §The recommended site of vaccination is the deltoid muscle for adults and older children.The preferred site for infants and young children is the anterolateral aspect of the thigh. ¶Two doses administered at least 1 month apart are recommended for children <9 years of age who are receiving influenza vaccine for the first time.
# Groups that Can Transmit Influenza to Persons at High Risk
Persons who are clinically or subclinically infected and who care for or live with members of high-risk groups can transmit influenza virus to them.Some persons at high risk (e.g., the elderly, transplant recipients, and persons with AIDS) can have a low antibody response to influenza vaccine.Efforts to protect these members of highrisk groups against influenza might be improved by reducing the likelihood of influenza exposure from their caregivers.Therefore, the following groups should be vaccinated:
- physicians, nurses, and other personnel in both hospital and outpatient-care settings; - employees of nursing homes and chronic-care facilities who have contact with patients or residents;
- providers of home care to persons at high risk (e.g., visiting nurses and volunteer workers); and - household members (including children) of persons in high-risk groups.
# VACCINATION OF OTHER GROUPS General Population
Physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza.Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks.Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.
# Pregnant Women
Influenza-associated excess mortality among pregnant women has not been documented except during the pandemics of 1918-19 and 1957-58.However, additional case reports and limited studies suggest that women in the third trimester of pregnancy and early puerperium, including those women without underlying risk factors, might be at increased risk for serious complications from influenza.Health-care workers who provide care for pregnant women should consider administering influenza vaccine to all women who would be in the third trimester of pregnancy or early puerperium during the influenza season.Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy.Administration of influenza vaccine is considered safe at any stage of pregnancy.
# Persons Infected with Human Immunodeficiency Virus (HIV)
Limited information exists regarding the frequency and severity of influenza illness among HIV-infected persons, but reports suggest that symptoms might be prolonged and the risk for complications increased for some HIV-infected persons.Because influenza can result in serious illness and complications, vaccination is a prudent precaution and will result in protective antibody levels in many recipients.However, the antibody response to vaccine can be low in persons with advanced HIV-related illnesses; a booster dose of vaccine does not improve the immune response for these persons.
# Foreign Travelers
The risk for exposure to influenza during foreign travel varies, depending on season and destination.In the tropics, influenza can occur throughout the year; in the Southern Hemisphere, most activity occurs from April through September.Because of the short incubation period for influenza, exposure to the virus during travel can result in clinical illness that begins while traveling, an inconvenience or potential danger, especially for persons at increased risk for complications.Persons preparing to travel to the tropics at any time of year or to the Southern Hemisphere from April through September should review their influenza vaccination histories.If they were not vaccinated the previous fall or winter, they should consider influenza vaccination before travel.Persons in the high-risk categories should be especially encouraged to receive the most current vaccine.Persons at high risk who received the previous season's vaccine before travel should be revaccinated in the fall or winter with the current vaccine.
# PERSONS WHO SHOULD NOT BE VACCINATED
Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions).Use of an antiviral agent (i.e., amantadine or rimantadine) is an option for prevention of influenza A in such persons.However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications of influenza can benefit from vaccine after appropriate allergy evaluation and desensitization.Specific information about vaccine components can be found in package inserts for each manufacturer.
Adults with acute febrile illness usually should not be vaccinated until their symptoms have abated.However, minor illnesses with or without fever should not contraindicate the use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.
# SIDE EFFECTS AND ADVERSE REACTIONS
Because influenza vaccine contains only noninfectious viruses, it cannot cause influenza.Respiratory disease after vaccination represents coincidental illness unrelated to influenza vaccination.The most frequent side effect of vaccination reported by fewer than one third of vaccinees is soreness at the vaccination site that lasts for up to 2 days.In addition, two types of systemic reactions have occurred:
- Fever, malaise, myalgia, and other systemic symptoms occur infrequently and most often affect persons who have had no exposure to the influenza virus antigens in the vaccine (e.g., young children).These reactions begin 6-12 hours after vaccination and can persist for 1 or 2 days; - Immediate-presumably allergic-reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) occur rarely after influenza vaccination.These reactions probably result from hypersensitivity to some vaccine component; the majority of reactions are most likely related to residual egg protein.Although current influenza vaccines contain only a small quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy.Persons who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered.Persons with documented immunoglobulin E (IgE)mediated hypersensitivity to eggs-including those who have had occupational asthma or other allergic responses due to exposure to egg protein-might also be at increased risk for reactions from influenza vaccine, and similar consultation should be considered.The protocol for influenza vaccination developed by Murphy and Strunk may be considered for patients who have egg allergies and medical conditions that place them at increased risk for influenza-associated complications (Murphy and Strunk, 1985).
Hypersensitivity reactions to any vaccine component can occur.Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, most patients do not develop reactions to thimerosal when administered as a component of vaccines-even when patch or intradermal tests for thimerosal indicate hypersensitivity.When reported, hypersensitivity to thimerosal has usually consisted of local, delayed-type hypersensitivity reactions.
Unlike the 1976 swine influenza vaccine, subsequent vaccines prepared from other virus strains have not been clearly associated with an increased frequency of Guillain-Barré syndrome (GBS).However, a precise estimate of risk is difficult to determine for a rare condition such as GBS, which has an annual background incidence of only one to two cases per 100,000 adult population.Among persons who received the swine influenza vaccine, the rate of GBS that exceeded the background rate was slightly less than one case per 100,000 vaccinations.
An investigation of GBS cases in 1990-91 indicated no overall increase in frequency of GBS among persons who were administered influenza vaccine; a slight increase in GBS cases among vaccinated persons might have occurred in the age group 18-64 years, but not among persons ≥65 years of age.In contrast to the swine influenza vaccine, the epidemiologic features of the possible association of the 1990-91 vaccine with GBS were not as convincing.The rate of GBS cases after vaccination that was passively reported to the Vaccine Adverse Event Reporting System (VAERS) during 1993-94 was estimated to be approximately twice the average rate reported during other recent seasons (i.e., 1990-91, 1991-92, 1992-93 and 1994-95).The data currently available are not sufficient to determine whether this represents an actual risk.However, even if GBS were a true side effect, the very low estimated risk for GBS is less than that for severe influenza that could be prevented by vaccination.
Whereas the incidence of GBS in the general population is very low, persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history.Thus, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. |
Whether influenza vaccination might be causally associated with this risk for recurrence is not known.Although it would seem prudent to avoid a subsequent influenza vaccination in a person known to have developed GBS within 6 weeks of a previous influenza vaccination, for most persons with a history of GBS who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly immunization.
# SIMULTANEOUS ADMINISTRATION OF OTHER VACCINES, INCLUDING CHILDHOOD VACCINES
The target groups for influenza and pneumococcal vaccination overlap considerably.For persons at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly consider administering both pneumococcal and influenza vaccines concurrently.Both vaccines can be administered at the same time at different sites without increasing side effects.However, influenza vaccine is administered each year, whereas pneumococcal vaccine is not.Children at high risk for influenza-related complications can receive influenza vaccine at the same time they receive other routine vaccinations, including pertussis vaccine (DTP or DTaP).Because influenza vaccine can cause fever when administered to young children, DTaP might be preferable in those children ≥15 months of age who are receiving the fourth or fifth dose of pertussis vaccine.DTaP is not licensed for the initial three-dose series of pertussis vaccine.
# TIMING OF INFLUENZA VACCINATION ACTIVITIES
Beginning each September (when vaccine for the upcoming influenza season becomes available) persons at high risk who are seen by health-care providers for routine care or as a result of hospitalization should be offered influenza vaccine.Opportunities to vaccinate persons at high risk for complications of influenza should not be missed.
The optimal time for organized vaccination campaigns for persons in high-risk groups is usually the period from mid-October through mid-November.In the United States, influenza activity generally peaks between late December and early March.High levels of influenza activity infrequently occur in the contiguous 48 states before December.Administering vaccine too far in advance of the influenza season should be avoided in facilities such as nursing homes, because antibody levels might begin to decline within a few months of vaccination.Vaccination programs can be undertaken as soon as current vaccine is available if regional influenza activity is expected to begin earlier than December.
Children <9 years of age who have not been vaccinated previously should receive two doses of vaccine at least 1 month apart to maximize the likelihood of a satisfactory antibody response to all three vaccine antigens.The second dose should be administered before December, if possible.Vaccine should be offered to both children and adults up to and even after influenza virus activity is documented in a community.
# STRATEGIES FOR IMPLEMENTING INFLUENZA VACCINE RECOMMENDATIONS
Although rates of influenza vaccination have increased in recent years, surveys indicate that less than half of the high-risk population receives influenza vaccine each year.More effective strategies are needed for delivering vaccine to persons at high risk and to their health-care providers and household contacts.
Successful vaccination programs have combined education for health-care workers, publicity and education targeted toward potential recipients, a plan for identifying persons at high risk (usually by medical-record review), and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine.Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following paragraphs.
# Outpatient Clinics and Physicians' Offices
Staff in physicians' offices, clinics, health-maintenance organizations, and employee health clinics should be instructed to identify and label the medical records of patients who should receive vaccine.Vaccine should be offered during visits beginning in September and throughout the influenza season.The offer of vaccine and its receipt or refusal should be documented in the medical record.Patients in high-risk groups who do not have regularly scheduled visits during the fall should be reminded by mail or telephone of the need for vaccine.If possible, arrangements should be made to provide vaccine with minimal waiting time and at the lowest possible cost.
# Facilities Providing Episodic or Acute Care
Health-care providers in these settings (e.g., emergency rooms and walk-in clinics) should be familiar with influenza vaccine recommendations.They should offer vaccine to persons in high-risk groups or should provide written information on why, where, and how to obtain the vaccine.Written information should be available in language(s) appropriate for the population served by the facility.
# Nursing Homes and Other Residential Long-Term-Care Facilities
Vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians rather than by obtaining individual vaccination orders for each patient.Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility, and all residents should be vaccinated at one time, immediately preceding the influenza season.Residents admitted during the winter months after completion of the vaccination program should be vaccinated when they are admitted.
# Acute-Care Hospitals
All persons ≥65 years of age and younger persons (including children) with highrisk conditions who are hospitalized at any time from September through March should be offered and strongly encouraged to receive influenza vaccine before they are discharged.Household members and others with whom they will have contact should receive written information about why and where to obtain influenza vaccine.
# Outpatient Facilities Providing Continuing Care to Patients at High Risk
All patients should be offered vaccine before the beginning of the influenza season.Patients admitted to such programs (e.g., hemodialysis centers, hospital specialtycare clinics, and outpatient rehabilitation programs) during the winter months after the earlier vaccination program has been conducted should be vaccinated at the time of admission.Household members should receive written information regarding the need for vaccination and the places to obtain influenza vaccine.
# Visiting Nurses and Others Providing Home Care to Persons at High Risk
Nursing-care plans should identify patients in high-risk groups, and vaccine should be provided in the home if necessary.Caregivers and other persons in the household (including children) should be referred for vaccination.
# Facilities Providing Services to Persons ≥65 Years of Age
In these facilities (e.g., retirement communities and recreation centers), all unvaccinated residents/attendees should be offered vaccine on site before the influenza season.Education/publicity programs should also be provided; these programs should emphasize the need for influenza vaccine and provide specific information on how, where, and when to obtain it.
# Clinics and Others Providing Health Care for Travelers
Indications for influenza vaccination should be reviewed before travel, and vaccine should be offered if appropriate (see Foreign Travelers).
# Health-Care Workers
Administrators of all health-care facilities should arrange for influenza vaccine to be offered to all personnel before the influenza season.Personnel should be provided with appropriate educational materials and strongly encouraged to receive vaccine.Particular emphasis should be placed on vaccination of persons who care for members of high-risk groups (e.g., staff of intensive-care units , staff of medical/surgical units, and employees of nursing homes and chronic-care facilities).Using a mobile cart to take vaccine to hospital wards or other work sites and making vaccine available during night and weekend work shifts can enhance compliance, as can a follow-up campaign early in the course of a community outbreak.
# ANTIVIRAL AGENTS FOR INFLUENZA A
The two antiviral agents with specific activity against influenza A viruses are amantadine hydrochloride and rimantadine hydrochloride.These chemically related drugs interfere with the replication cycle of type A (but not type B) influenza viruses.When administered prophylactically to healthy adults or children before and throughout the epidemic period, both drugs are approximately 70%-90% effective in preventing illness caused by naturally occurring strains of type A influenza viruses.Because antiviral agents taken prophylactically can prevent illness but not subclinical infection, some persons who take these drugs can still develop immune responses that will protect them when they are exposed to antigenically related viruses in later years.
In otherwise healthy adults, amantadine and rimantadine can reduce the severity and duration of signs and symptoms of influenza A illness when administered within 48 hours of illness onset.Studies evaluating the efficacy of treatment for children with either amantadine or rimantadine are limited.Amantadine was approved for treatment and prophylaxis of all influenza type A virus infections in 1976.Although few placebo-controlled studies were conducted to determine the efficacy of amantadine treatment among children prior to approval, amantadine is indicated for treatment and prophylaxis of adults and children ≥1 year of age.Rimantadine was approved in 1993 for treatment and prophylaxis in adults but was approved only for prophylaxis in children.Further studies might provide the data needed to support future approval of rimantadine treatment in this age group.
As with all drugs, amantadine and rimantadine can cause adverse reactions in some persons.Such adverse reactions are rarely severe; however, for some categories of patients, severe adverse reactions are more likely to occur.Amantadine has been associated with a higher incidence of adverse central nervous system (CNS) reactions than rimantadine (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment).
# RECOMMENDATIONS FOR THE USE OF AMANTADINE AND RIMANTADINE Use as Prophylaxis
Chemoprophylaxis is not a substitute for vaccination.Recommendations for chemoprophylaxis are provided primarily to help health-care providers make decisions regarding persons who are at greatest risk for severe illness and complications if infected with influenza A virus.
When amantadine or rimantadine is administered as prophylaxis, factors such as cost, compliance, and potential side effects should be considered when determining the period of prophylaxis.To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community.However, to be most cost effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community.
# Persons at High Risk Vaccinated After Influenza A Activity Has Begun
Persons at high risk can still be vaccinated after an outbreak of influenza A has begun in a community.However, the development of antibodies in adults after vaccination can take as long as 2 weeks, during which time chemoprophylaxis should be considered.Children who receive influenza vaccine for the first time can require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 2 weeks after the second dose of vaccine has been received).Amantadine and rimantadine do not interfere with the antibody response to the vaccine.
# Persons Providing Care to Those at High Risk
To reduce the spread of virus to persons at high risk, chemoprophylaxis may be considered during community outbreaks for a) unvaccinated persons who have frequent contact with persons at high risk (e.g., household members, visiting nurses, and volunteer workers) and b) unvaccinated employees of hospitals, clinics, and chroniccare facilities.For those persons who cannot be vaccinated, chemoprophylaxis during the period of peak influenza activity may be considered.For those persons who receive vaccine at a time when influenza A is present in the community, chemoprophylaxis can be administered for 2 weeks after vaccination.Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that might not be controlled by the vaccine.
# Persons Who Have Immune Deficiency
Chemoprophylaxis might be indicated for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine.This category includes persons who have HIV infection, especially those who have advanced HIV disease.No data are available concerning possible interactions with other drugs used in the management of patients who have HIV infection.Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered.
# Persons for Whom Influenza Vaccine Is Contraindicated
Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated.Influenza vaccine may be contraindicated in persons who have severe anaphylactic hypersensitivity to egg protein or other vaccine components.
# Other Persons
Amantadine or rimantadine also can be administered prophylactically to anyone who wishes to avoid influenza A illness.The health-care provider and patient should make this decision on an individual basis.
# Use of Antivirals as Therapy
Amantadine and rimantadine can reduce the severity and shorten the duration of influenza A illness among healthy adults when administered within 48 hours of illness onset.Whether antiviral therapy will prevent complications of influenza type A among persons at high risk is unknown.Insufficient data exist to determine the efficacy of rimantadine treatment in children.Thus, rimantadine is currently approved only for prophylaxis in children, but it is not approved for treatment in this age group.Amantadine-and rimantadine-resistant influenza A viruses can emerge when either of these drugs is administered for treatment; amantadine-resistant strains are cross-resistant to rimantadine and vice versa.Both the frequency with which resistant viruses emerge and the extent of their transmission are unknown, but data indicate that amantadine-and rimantadine-resistant viruses are no more virulent or transmissible than amantadine-and rimantadine-sensitive viruses.
The screening of naturally occurring epidemic strains of influenza type A has rarely detected amantadine-and rimantadine-resistant viruses.Resistant viruses have most frequently been isolated from persons taking one of these drugs as therapy for influenza A infection.Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy.Persons who have influenza-like illness should avoid contact with uninfected persons as much as possible, regardless of whether they are being treated with amantadine or rimantadine.Persons who have influenza type A infection and who are treated with either drug can shed amantadine-or rimantadinesensitive viruses early in the course of treatment, but can later shed drug-resistant viruses, especially after 5-7 days of therapy.Such persons can benefit from therapy even when resistant viruses emerge; however, they also can transmit infection to other persons with whom they come in contact.Because of possible induction of amantadine or rimantadine resistance, treatment of persons who have influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms.Laboratory isolation of influenza viruses obtained from persons who are receiving amantadine or rimantadine should be reported to CDC through state health departments, and the isolates should be saved for antiviral sensitivity testing.
# Outbreak Control in Institutions
When confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus.Contingency planning is needed to ensure rapid administration of amantadine or rimantadine to residents.This planning should include preapproved medication orders or plans to obtain physicians' orders on short notice.When amantadine or rimantadine is used for outbreak control, the drug should be administered to all residents of the institution-regardless of whether they received influenza vaccine the previous fall.The drug should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak.The dose for each resident should be determined after consulting the dosage recommendations and precautions (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment) and the manufacturer's package insert.To reduce the spread of virus and to minimize disruption of patient care, chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk.Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not controlled by the vaccine.
Chemoprophylaxis also may be considered for controlling influenza A outbreaks in other closed or semi-closed settings (e.g., dormitories or other settings where persons live in close proximity).To reduce the spread of infection and the chances of prophylaxis failure due to transmission of drug-resistant virus, measures should be taken to reduce contact as much as possible between persons on chemoprophylaxis and those taking drug for treatment.
# CONSIDERATIONS FOR SELECTING AMANTADINE OR RIMANTADINE FOR CHEMOPROPHYLAXIS OR TREATMENT Side Effects/Toxicity
Despite the similarities between the two drugs, amantadine and rimantadine differ in their pharmacokinetic properties.More than 90% of amantadine is excreted unchanged, whereas approximately 75% of rimantadine is metabolized by the liver.However, both drugs and their metabolites are excreted by the kidney.
The pharmacokinetic differences between amantadine and rimantadine might explain differences in side effects.Although both drugs can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine compared with those taking rimantadine.In a 6-week study of prophylaxis in healthy adults, approximately 6% of participants taking rimantadine at a dose of 200 mg/day experienced at least one CNS symptom, compared with approximately 14% of those taking the same dose of amantadine and 4% of those taking placebo.The incidence of gastrointestinal side effects (e.g., nausea and anorexia) is approximately 3% among persons taking either drug, compared with 1%-2% among persons receiving the placebo.Side effects associated with both drugs are usually mild and cease soon after discontinuing the drug.Side effects can diminish or disappear after the first week despite continued drug ingestion.However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures).These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day.Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects, and recommendations for reduced dosages for these groups of patients have been made. |
Because rimantadine has only recently been approved for marketing, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently.Clinical trials of rimantadine have more commonly involved young, healthy persons.
Providers should review the package insert before using amantadine or rimantadine for any patient.The patient's age, weight, and renal function; the presence of other medical conditions; the indications for use of amantadine or rimantadine (i.e., prophylaxis or therapy); and the potential for interaction with other medications must be considered, and the dosage and duration of treatment must be adjusted appropriately.Modifications in dosage might be required for persons who have impaired renal or hepatic function, the elderly, children, and persons with a history of seizures.The following are guidelines for the use of amantadine and rimantadine in certain patient populations.Dosage recommendations are also summarized (Table 2).
# Persons Who Have Impaired Renal Function
# Amantadine
Amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion.Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency.A reduction in dosage is recommended for patients with creatinine clearance ≤50 mL/min.Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert.However, because recommended dosages based on creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully so that adverse reactions can be recognized promptly and either the dose can be further reduced or the drug can be discontinued, if necessary.Hemodialysis contributes little to drug clearance. *The drug package insert should be consulted for dosage recommendations for administering amantadine to persons with creatinine clearance ≤50 mL/min. †5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs. §Children ≥10 years of age who weigh 100 mg/day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. Elderly nursing-home residents should be administered only 100 mg/day of rimantadine.A reduction in dose to 100 mg/day should be considered for all persons ≥65 years of age if they experience possible side effects when taking 200 mg/day.NA=Not applicable.
# Rimantadine
The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration.Further studies are needed to determine the multiple-dose pharmacokinetics and the most appropriate dosages for these patients.
In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy controls of the same age.Hemodialysis did not contribute to drug clearance.In studies among persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher compared with control patients without renal disease who were the same weight, age, and sex.
A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance ≤10 mL/min.Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary.
# Persons ≥65 Years of Age
# Amantadine
Because renal function declines with increasing age, the daily dose for persons ≥65 years of age should not exceed 100 mg for prophylaxis or treatment.For some elderly persons, the dose should be further reduced.Studies suggest that because of their smaller average body size, elderly women are more likely than elderly men to experience side effects at a daily dose of 100 mg.
# Rimantadine
The incidence and severity of CNS side effects among elderly persons appear to be substantially lower among those taking rimantadine at a dose of 200 mg/day compared with elderly persons taking the same dose of amantadine.However, when rimantadine has been administered at a dosage of 200 mg/day to chronically ill elderly persons, they have had a higher incidence of CNS and gastrointestinal symptoms than healthy, younger persons taking rimantadine at the same dosage.After longterm administration of rimantadine at a dosage of 200 mg/day, serum rimantadine concentrations among elderly nursing-home residents have been two to four times greater than those reported in younger adults.
The dosage of rimantadine should be reduced to 100 mg/day for treatment or prophylaxis of elderly nursing-home residents.Although further studies are needed to determine the optimal dose for other elderly persons, a reduction in dosage to 100 mg/day should be considered for all persons ≥65 years of age if they experience signs and symptoms that might represent side effects when taking a dosage of 200 mg/day.children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, also is recommended.
# Drug Interactions
# Amantadine
Careful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants.
# Rimantadine
No clinically significant interactions between rimantadine and other drugs have been identified.For more detailed information concerning potential drug interactions for either drug, the package insert should be consulted.
# SOURCES OF INFORMATION ON INFLUENZA-CONTROL PROGRAMS
Information regarding influenza surveillance is available through the CDC Voice Information System (influenza update), telephone (404) 332-4551, or through the CDC Information Service on the Public Health Network electronic bulletin board.From October through May, the information is updated at least every other week.In addition, periodic updates about influenza are published in the weekly MMWR.State and local health departments should be consulted regarding availability of influenza vaccine, access to vaccination programs, and information about state or local influenza activity.
# Selected Bibliography
The following CDC staff members prepared this report:
# Persons Who Have Liver Disease
# Amantadine
No increase in adverse reactions to amantadine has been observed among persons with liver disease.
# Rimantadine
The safety and pharmacokinetics of rimantadine have only been evaluated after single-dose administration.In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations were observed after a single dose.However, in persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease.A dose reduction to 100 mg/day is recommended for persons with severe hepatic dysfunction.
# Persons Who Have Seizure Disorders
# Amantadine
An increased incidence of seizures has been reported in patients with a history of seizure disorders who have received amantadine.Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.
# Rimantadine
In clinical trials, seizures (or seizure-like activity) have been observed in a few persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine.The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated, because such persons have usually been excluded from participating in clinical trials of rimantadine.
# Children
# Amantadine
The use of amantadine in children <1 year of age has not been adequately evaluated.The FDA-approved dosage for children 1-9 years of age is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day.Although further studies to determine the optimal dosage for children are needed, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity.The approved dosage for children ≥10 years of age is 200 mg/day; however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable.
# Rimantadine
The use of rimantadine in children <1 year of age has not been adequately evaluated.In children 1-9 years of age, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day.The approved dosage for children ≥10 years of age is 200 mg/day (100 mg twice a day); however, for The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy.To receive an electronic copy on Friday of each week, send an e-mail message to lists@list.cdc.gov.The body content should read subscribe mmwr-toc.Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov.To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 783-3238.
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of this Division served as criteria managers.SRI International developed the basic information for consideration by NIOSH staff and consultants under contract CDC-99-74-31.#PREFACE
The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards.The National Institute for Occupational Safety and Health (NIOSH) evaluates all available research data and criteria and recommends standards for occupational exposure.The Secretary of Labor will weigh these recommendations along with other considerations, such as feasibility and means of implementation, in promulgating regulatory standards.
NIOSH will periodically review the recommended standards to ensure continuing protection of workers and will make successive reports as new research and epidemiologic studies are completed and as sampling and analytical methods are developed.
The contributions to this document on vinyl acetate by NIOSH staff, other Federal agencies or departments, the review consultants, the reviewers selected by the Society of the Plastics Industry, Inc., the American Academy of Occupational Medicine, the American Academy of Industrial Hygiene, and Robert B.
O'Connor, M.D., NIOSH consultant in occupational medicine, are gratefully acknowledged.
The views and conclusions expressed in this document, together with the recommendations for a standard, are those of NIOSH.They are not necessarily those of the consultants, the reviewers selected by professional societies, or other Federal agencies.However, all comments, whether or not incorporated, have been sent with the criteria document to the Occupational Safety and Health Administration for consideration in setting the standard.
The review consultants and the Federal agencies which received the document for review appear on pages v and v i .
# Acting Director, National Institute
for Occupational Safety and Health
# I. RECOMMENDATIONS FOR A VINYL ACETATE STANDARD
NIOSH recommends that employee exposure to vinyl acetate in the workplace be controlled by adherence to the following sections.
The recommended standard is designed to protect the health and provide for the safety of employees for up to a 10-hour workshift, 40-hour workweek, over a working lifetime.Compliance with all sections of the standard should prevent adverse effects of vinyl acetate on the health of workers and provide for their safety.
Sufficient technology exists to permit compliance with the recommended standard.Although NIOSH considers the workplace environmental limit to be a safe level based on current information, the employer should regard it as the upper boundary of exposure and make every effort to maintain exposures as low as possible.
The standard will be subject to review and revision as necessary.
Vinyl acetate, CH3COOCH=CH2, is a liquid at room temperature and is easily vaporized.Synonyms for vinyl acetate include: acetic acid, vinyl ester; acetic acid, ethenyl ester; vinyl A monomer; ethenyl ethanoate; and Vy Ac.Occupational exposure to vinyl acetate" is defined as exposure to airborne vinyl acetate at concentrations above one-half the recommended ceiling limit.Exposure to airborne vinyl acetate at concentrations at or below one-half the recommended ceiling limit will require adherence to the following Sections only: Sections 1(b), 2(a,c,d), 3,4,5,6,7, and 8(a,c).
The recommended standard is based on data indicating that vinyl acetate vapor at concentrations below 250 mg/cu m is a primary irritant to the upper respiratory tract and eyes, and that the liquid may irritate skin to the point of vesiculation.The irritations reported have all been reversible, and there are no known residual systemic effects.
# Section 1 -Environmental (Workplace Air) (a) Concentrations
Exposure to vinyl acetate in the workplace shall be controlled so that employees are not exposed at concentrations greater than 15 milligrams per cubic meter of air, or 4 parts per million parts of air, measured as a ceiling concentration in samples collected during any 15-minute period.
# (b) Sampling and Analysis
Workroom air samples shall be collected and analyzed as described in Appendix I, or by any other methods at least equivalent in accuracy, precision, and sensitivity.
# Section 2 -Medical
Medical surveillance shall be made available as outlined below to all employees subject to occupational exposure to vinyl acetate.
(a) Preplacement examinations shall include at least:
(1) Comprehensive medical and work histories, with special emphasis directed to evidence of any preexisting eye, respiratory, or skin disorders.
(2) Physical examination giving particular attention to the upper respiratory tract, eyes, and skin.
(3) A judgment of the employee's ability to use positive pressure air-supplied respirators.
(b) Periodic examinations shall be made available at least annually, except as otherwise determined by the responsible physician, and shall include:
(1) Interim medical and work histories.
(2) Physical examination as outlined in paragraph (a)(2) of this section.
(c) Applicants or employees found during examinations to have medical conditions that could be directly or indirectly aggravated by exposure to vinyl acetate, eg, chronic irritation of the respiratory tract, chronic inflammatory conditions of the skin, or chronic eye irritation, shall be counseled on the increased risk of impairment of their health from working with the compound.
(d) Pertinent medical records for all employees subject to exposure to vinyl acetate in the workplace shall be retained for at least 30 years after termination of employment.Records of environmental exposures applicable to an employee shall be included in that employee's medical records.These records shall be made available to the designated medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee or former employee.
# Section 3 -Labeling and Posting
All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading workers.Employees unable to read the labels and signs provided shall receive information regarding hazardous areas and shall be informed of the instructions printed on labels and signs.
(a) Labeling Each container of vinyl acetate shall carry, in a readily visible location, a label which bears the trade name of the product, if appropriate, and information on its known effects on human health.The name and pertinent information shall be arranged as in the example below.FIRST AID: In case of contact of liquid with eyes or skin, flush with copious amounts of water.Wash clothing before reuse.
# SPILL OR LEAK:
Contain the product within an area and flush with water spray.Vinyl acetate will float on water and create a fire hazard.
# FIREFIGHTING:
In case of fire, use foam, dry chemical, carbon dioxide, or water spray.
(b) Posting (1) The following warning sign shall be posted in readily visible locations at or near all entrances to areas where vinyl acetate is manufactured, used, or stored.
# VINYL ACETATE DANGER!EXTREMELY FLAMMABLE MAY POLYMERIZE VIOLENTLY IF HEATED MAY CAUSE SKIN AND EYE IRRITATION
Keep away from heat, sparks, and open flame.Use only with adequate ventilation.Avoid prolonged or repeated breathing of vapor.
If the use of respirators is permissible in accordance with Section 4 (c), the following statement shall be displayed in addition to the sign required in Section 3(b):
# RESPIRATORY PROTECTION REQUIRED IN THIS AREA Section 4 -Personal Protective Clothing and Equipment
Engineering controls shall be used when needed to keep concentrations of airborne vinyl acetate at or below the recommended ceiling limit and to minimize skin and eye contact.In addition, protective equipment and clothing shall be provided to employees when necessary.
(a) Eye Protection Employers shall provide chemical safety goggles or face shields (8-inch minimum) with goggles and shall ensure that employees wear this protective equipment during any operation in which there is the likelihood of exposure to liquid vinyl acetate.Eye protective devices shall be selected, used, and maintained in accordance with 29 CFR 1910.133.
# (b) Protective Clothing
Employees shall wear appropriate protective clothing, including gloves, aprons, suits, and boots, when needed, to prevent skin contact with liquid vinyl acetate.
(c) Respiratory Protection (1) The use of respirators to achieve compliance with the recommended exposure limit is permitted only: (A) During the time required to install or test the necessary engineering controls.
# (B)
During performance of nonroutine maintenance or repair activities, during work in confined spaces, or during emergencies when the concentration of airborne vinyl acetate may exceed the recommended environmental limit.
(2) When use of a respirator is permitted, it shall be selected and used in accordance with the following requirements :
(A) Employers shall establish and enforce respiratory protective programs meeting the requirements of CFR 1910.134.
(B) Employers shall provide respirators in accordance with Table 1-1 and shall ensure that employees use the respirators provided when necessary.The respiratory protective devices provided in conformance with Table 1-1 shall be those approved by NIOSH and the Mine Safety and Health Administration as specified under 30 CFR 11.
(C) Respirators specified for use in higher concentrations of airborne vinyl acetate may be used in atmospheres of lower concentrations.
(D) Employers shall ensure that respirators are adequately cleaned and maintained and that employees are instructed and drilled at least annually in the proper use and testing for leakage of respirators assigned to them.
(E) Respirators shall be easily accessible, and employees shall be informed of their locations.
Section 5 -Informing Employees of Hazards from Vinyl Acetate (a) All new and present employees working in areas where occupational exposure to vinyl acetate may reasonably be expected to occur shall be informed of the hazards of such employment, relevant symptoms of overexposure, appropriate emergency procedures, and conditions and precautions for the safe use and handling of vinyl acetate, including the information prescribed in paragraph (b) of this section.Employees shall be advised of the availability of this information.
(b) Employers shall institute a continuing education program, conducted by persons qualified by experience or training, to ensure that all employees have current knowledge of job hazards, proper maintenance, and cleanup methods.
The instructional program shall include oral and written descriptions of the general nature of the environmental and medical surveillance procedures and of the advantages to the employee of participating in these surveillance procedures.
(c) Required information shall be recorded on the "Material Safety Data Sheet" shown in Appendix II or on a similar form approved by the Occupational Safety and Health Administration, US Department of Labor.All electrical equipment shall meet the requirements of 29 CFR 1910 for hazardous locations.Ventilation systems, if used, shall be designed to prevent the accumulation or recirculation of vinyl acetate in the workplace environment and to effectively maintain safe levels of vinyl acetate in the breathing zones of employees.
Exhaust ventilation systems discharging to outside air shall conform with applicable local, state, and Federal air pollution regulations and shall not constitute a hazard to employees or to the general population.Ventilation systems shall be regularly maintained and cleaned to ensure effectiveness, which shall be verified by at least annual airflow measurements.Results of such airflow measurements shall be recorded and such records kept for at least 1 year.
# (b) Confined Spaces
(1) Entry into confined spaces, such as tanks, pits, and process vessels, shall be controlled by a permit system.Permits shall be signed by an authorized employer representative and shall certify that preparation of the confined space, precautionary measures, and personal protective equipment are adequate and that precautions have been taken to ensure that prescribed procedures will be followed.
(2) Confined spaces that have contained vinyl acetate shall be cleaned with water, purged with air, thoroughly ventilated, inspected, and tested for oxygen deficiency and for the presence of vinyl acetate and any other known or suspected contaminants.Every effort shall be made to prevent inadvertent release of vinyl acetate into confined spaces in which work is in progress.Vinyl acetate supply lines shall be disconnected or blocked off before and while such work is in progress.
(3) If the concentration of vinyl acetate in the confined space exceeds the recommended environmental limit, respiratory protective equipment is required for entry.
(4) No employee shall enter any confined space that does not have an entryway large enough to admit an employee wearing safety harness, lifeline, and appropriate respiratory equipment as specified in Section 4(c).
(5) Confined spaces shall be ventilated while work is in progress to keep the concentration of vinyl acetate at or below the recommended limit, to keep the concentration of other contaminants below dangerous levels, and to prevent oxygen deficiency.
(6) Anyone entering a confined space shall be kept under observation from the outside by another properly trained and protected worker.An additional supplied-air or self-contained breathing apparatus with safety harness and lifeline shall be located outside the confined space for emergency use.
The person entering the confined space shall maintain continuous communication with the standby worker.
# (c) Emergency Procedures
Emergency plans and procedures shall be developed for all work areas where there is a potential for exposure to vinyl acetate.They shall include those specified below and any others considered appropriate for a specific operation or process.Employees shall be instructed in the effective implementation of these plans and procedures.
(1) Plans shall be developed for obtaining emergency medical care and for the transportation of injured workers.
A sufficient number of employees shall be trained in first aid so that assistance is available immediately when necessary.
(2) Spills of vinyl acetate shall be cleaned up immediately.Spill areas shall be posted and secured.
All sources of ignition shall be eliminated.
Only authorized personnel, adequately protected and properly trained, shall be permitted to enter the area to shut off sources of vinyl acetate.
If sufficient drainage to suitable collection basins is available, the spilled liquid can be hosed away with large quantities of water.A water spray can be used to knock down vapors.Because vinyl acetate floats on water, spills shall not be allowed to enter public sewers or drains in amounts that could result in explosion or fire hazards.
(3) The collected runoff shall be either recovered or destroyed by chemical degradation or burning, in accordance with applicable Federal, state, and local regulations.
If a vacuum system is used to remove spilled vinyl acetate, there shall be no sources of ignition in the vicinity and appropriate flashback-prevention devices shall be provided and maintained in proper operating condition.
# (d) Storage
Vinyl acetate shall be stored at temperatures less than 100 F (37.8 C) in well-ventilated areas and kept away from ignition sources such as heat and direct sunlight.
No heating apparatus capable of exceeding 80% of the autoignition temperature of vinyl acetate (427 C) shall be used in vinyl acetate storage areas.The Federal standard for the storage and handling of flammable liquids is contained in 29 CFR 1910.106.
The storage of vinyl acetate in glass containers should be avoided.Vinyl acetate shall not be stored in the same areas as oxidizing agents or other incompatible chemicals.Containers of vinyl acetate shall be kept tightly closed when not in use and shall be stored so as to minimize accidental ruptures and spills.
(e) Handling and General Work Practices
(1) Before maintenance work is undertaken on equipment or systems, sources of vinyl acetate shall be disconnected and blocked off.
(2) Employees who experience skin contact with liquid vinyl acetate shall wash or shower to remove vinyl acetate from the skin.Contaminated clothing shall be removed and either cleaned before reuse or discarded.Uncleaned, contaminated clothing shall be stored in a container that is impervious to vinyl acetate.Personnel who clean contaminated clothing shall be informed of the hazards involved and be provided with guidelines on how to handle such clothing safely.
(3) Smoking and the carrying of matches, lighters, or other instruments of ignition shall be prohibited in all vinyl acetate work areas.
(4) Waste material contaminated with vinyl acetate shall be disposed of in ways that pose no hazard to employees.Disposal methods must conform with applicable local, state, and Federal regulations and must not constitute a hazard to the surrounding population or to the environment.Section 7 -Sanitation (a) The preparation, storage, dispensing (including vending machines), or consumption of food shall be prohibited in vinyl acetate work areas.
(b) Employees who handle vinyl acetate or equipment contaminated with vinyl acetate shall be instructed to wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities.
# Section 8 -Monitoring and Recordkeeping Requirements (a) Industrial Hygiene Surveys
Employers shall determine by industrial hygiene survey whether there is exposure to airborne vinyl acetate at concentrations greater than one-half the recommended ceiling limit.Records of these surveys, including the basis for any conclusion that concentrations of airborne vinyl acetate are at or below one-half the recommended limit, shall be kept.Surveys shall be repeated at least annually and as soon as possible after any process change likely to result in increased concentrations of airborne vinyl acetate in the workplace.If it is determined that concentrations of airborne vinyl acetate are above one-half of the recommended ceiling limit, the following requirements shall apply:
(b) Personal Monitoring (1) A program of personal monitoring shall be instituted to identify and measure, or permit calculation of, the exposure of each employee subject to exposure to vinyl acetate.
Source and area monitoring may be used to supplement personal monitoring.
(2) In all personal monitoring, samples representative of the exposure to vinyl acetate in the breathing zone of the employee shall be collected.
Procedures for sampling and analysis shall be in accordance with Section 1(b).
(3) For each determination of an occupational exposure concentration, a sufficient number of samples shall be collected to characterize employees1 exposures during each workshift.Variations in work and production schedules and in employee locations and job functions shall be considered when deciding upon collection schedules.
(4) Each operation in each work area shall be sampled at least once every 6 months or as otherwise indicated by a professional industrial hygienist. |
If an employee is found to be exposed to vinyl acetate at concentrations above the recommended ceiling limit, control measures shall be initiated, the employee shall be notified of the exposure and of the control measures being implemented, and the exposure of the employee shall be measured at least once every week.Such monitoring shall continue until two consecutive determinations, at least 1 week apart, indicate that the employee's exposure is no longer in excess of the recommended limit.At that point, semiannual monitoring may be resumed.
If such monitoring indicates that the employee's exposure no longer exceeds one-half of the recommended ceiling limit, personal monitoring may be discontinued.
# (c) Recordkeeping
Records of environmental monitoring for each employee shall be retained for at least 30 years after the individual's employment has ended.These records shall include the name of the employee being monitored, duties performed and job locations within the worksite, dates and times of measurements, sampling and analytical methods used, number, duration, and results of samples taken, concentrations of airborne vinyl acetate estimated from these samples, and the type of personal protection used, if any.Employees shall be able to obtain information on their own environmental exposures.
These records shall be made available upon request to designated representatives of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, and of the employee or former employee.
# II.INTRODUCTION
This report presents the criteria and the recommended standard based thereon that were prepared to meet the need for preventing impairment of health resulting from workplace exposure to vinyl acetate.The criteria document fulfills the responsibility of the Secretary of Health, Education, and Welfare under Section 20(a)(3) of the Occupational Safety and Health Act of 1970 to "...develop criteria dealing with toxic materials and harmful physical agents and substances which will describe exposure levels...at which no employee will suffer impaired health or functional capacities or diminished life expectancy as a result of his work experience."
After reviewing data and consulting with others, NIOSH formalized a system for the development of criteria on which standards can be established to protect the health and to provide for the safety of employees exposed to hazardous chemical and physical agents.The criteria and recommended standard should enable management and labor to develop better engineering controls resulting in more healthful work environments.
Simple compliance with the recommended standard should not be the final goal.
These criteria for a standard for vinyl acetate are part of a continuing series of criteria developed by NIOSH.
The proposed standard applies to workplace exposure arising from the processing, manufacture, use, storage, and handling of vinyl acetate.The standard was not designed for the populationat-large, and any extrapolation beyond occupational exposures is not warranted.It is intended to (1) protect against impairment of health by vinyl acetate, (2) be measurable by techniques that are valid, reproducible, and available to industry and government agencies, and (3) be attainable with existing technology.
During the development of the recommended standard for occupational exposure to vinyl acetate, it became apparent that there are deficiencies in available information on (1) effects on humans and animals exposed to vinyl acetate at low levels for extended periods, (2) possible carcinogenic, mutagenic, teratogenic, or reproductive effects of vinyl acetate on animals and humans, (3) the utility of the electroencephalograph in estimating the toxic potential of vinyl acetate, and (4) sensitive analytical methods and direct-reading monitoring devices for airborne vinyl acetate.
# III.BIOLOGIC EFFECTS OF EXPOSURE
# Extent of Exposure
Vinyl acetate, molecular formula CH3C00CH=CH2, is a colorless flammable liquid at room temperature.It has a vapor pressure of 100 mmHg at 21.5 C and a boiling point of 72.7 C. Its odor is at first pleasant but quickly becomes sharp and irritating .The threshold of odor detection for vinyl acetate has been reported to be as low as 1 mg/cu m (0.284 ppm) .Olfactory fatigue has occurred at 19.5 ppm (68.3 mg/cu m) .
Some salient physical and chemical properties of vinyl acetate are listed in Table XI-1 .Vinyl acetate is produced by a vapor-phase reaction between ethylene and acetic acid in the presence of a palladium catalyst or between acetylene and acetic acid in the presence of a zinc acetate catalyst .
In the United States, 1,481 and 1,606 million pounds of vinyl acetate were produced in 1976 and 1977, respectively .
Vinyl acetate is used primarily in polymerization processes, eg, to produce polyvinyl acetate, polyvinyl alcohol, and vinyl chloride-vinyl acetate copolymer .The polymers, usually made as emulsions, suspensions, solutions, or resins, are used to prepare adhesives, paints, paper coatings, and textile finishes .Low-molecular-weight polyvinyl acetate is used as a chewing gum base .
Vinyl acetate is extremely flammable and forms explosive mixtures at from 2.6 to 13.4% by volume in air .
Occupational exposure to vinyl acetate may occur in any work involving the production, storage, transport, or use of the chemical.
Occupations with potential exposure to vinyl acetate are listed in Table XI-2 .
NI0SH estimates that approximately 70,000 workers are potentially exposed to vinyl acetate in the United States.
# Historical Reports
The earliest report of vinyl acetate seems to have appeared in 1912 , At that time, it was a minor byproduct formed when acetylene and acetic acid were reacted to produce ethylidene diacetate.
During World War I, vinyl acetate was prepared and polymerized in Germany .
In the late 1920's, vinyl acetate production was commercialized; acetylene and acetic acid were reacted in the liquid phase using such catalysts as mercuric oxide .
The toxicity of vinyl acetate was evaluated in 1949 as part of a rangefinding study of 96 chemicals by Carpenter et al .
Sherman rats were exposed to the test substances for 4 hours to determine the nominal concentrations necessary to kill two to four of six exposed animals within 14 days.
For vinyl acetate, this concentration was 4,000 ppm (14,000 mg/cu m ) , causing the authors to classify it as a "moderate hazard."Before 1970, few industrial exposure studies had been conducted on vinyl compounds other than vinyl chloride.Research on the biologic effects of vinyl acetate and other vinyl compounds was accelerated after the carcinogenic hazard of vinyl chloride exposure became recognized.
# Effects on Humans
Much of the information on short-term effects of vinyl acetate on humans has come from controlled experimental exposures of volunteers and from one short-term study at a vinyl acetate production plant.
Gofmekler tested vinyl acetate on volunteers to determine threshold concentrations for olfactory perception, changes in light sensitivity of the eye, and ability to produce a conditioned-response change in the electrical activity of the brain.Vinyl acetate concentrations were determined by a colorimetric method reported to have a sensitivity of 0.025 Mg/ml of sample.
Odor determinations were made by 77 subjects, ranging from 20 to 65 years old .Each test concentration was administered for 2-3 hours and was repeated at an average interval of 3-5 days with each person during a 2-month period.
Light sensitivity was determined in 15 persons over a 3.5-month period .Subjects were placed in a dark room free of noise and other extraneous stimuli.
After their eyes became dark adapted, their ability to perceive a light stimulus from an ADM adaptometer was measured.
After 5-7 days of exposure to air to establish baseline data on light sensitivity, subjects were exposed to vinyl acetate at least three times at each concentration tested.Only those concentrations that produced a change in light sensitivity at least twice the mean error of the baseline values were considered effective.
To determine the concentration of vinyl acetate that could produce a conditioned response, two subjects inhaled vinyl acetate while their brain electrical activity was recorded on an electroencephalograph (EEG) .After 10-15 seconds of exposure, the vinyl acetate stimulus was reinforced by light, which caused a desynchronization in the EEG.Through association with the light (unconditioned stimulus), addition of vinyl acetate to the inspired air could become a conditioned stimulus, producing EEG desynchronization before the light was presented .Vinyl acetate exposures were conducted once a day at gradually decreasing concentrations to determine the lowest concentration that could produce this conditioned change in brain electrical activity.
Gofmekler found that the minimum perceptible concentration of vinyl acetate in odor detection tests was 1.0 mg/cu m (0.3 ppm), while 0.7 mg/cu m (0.2 ppm) was the maximum imperceptible concentration.The minimum active and maximum inactive concentrations for affecting light sensitivity of the eye were 0.77 and 0.60 mg/cu m (0.22 and 0.17 ppm), respectively.For production of a conditioned change in brain electrical activity, the minimum active concentration was 0.32 mg/cu m (0.09 ppm) and the maximum inactive concentration was 0.21 mg/cu m (0.06 ppm); apparently, vinyl acetate at these concentrations did not produce any observable unconditioned change in EEG patterns.The author concluded that the maximum acceptable concentration for occupational exposure to vinyl acetate should be 0.20 mg/cu m (0.06 ppm).However, this study presented no evidence that adverse effects resulted from exposure to vinyl acetate at the low concentrations that produced positive responses in these tests.
In 1968, investigators at the Mellon Institute described olfactory perception findings in nine volunteers exposed to vinyl acetate vapor at various concentrations for 2-minute periods.Each concentration was tested twice, and the concentrations were measured by gas chromatography; no other experimental details were provided.
The lowest concentration at which all subjects could detect an odor was 1.3 ppm (4.6 mg/cu m ) , and the highest concentration at which all subjects (with one questionable exception) could not detect an odor was 0.6 ppm (2.1 mg/cu m ) .
The investigators then determined the reactions of four volunteers exposed to vinyl acetate at higher concentrations for longer periods .
In experiments conducted on 4 consecutive days, from one to four of the subjects inhaled air containing vinyl acetate at various concentrations ranging from 19.5 to 71.5 ppm (68.3-250.3 mg/cu m) for 0.5-4 hours in a test chamber.Exposure information and the effects reported by each subject are shown in Table III-l. All subjects agreed that they could not work for 8 hours at the highest concentration tested, 71.5 ppm.
Although all subjects developed olfactory fatigue, the investigators noted that they returned to the chamber within 10 minutes after each test and reported that the odor was as strong as it had been at the beginning of the test, indicating rapid recovery from olfactory fatigue.
This report indicates that vinyl acetate can irritate the mucous membranes of the throat at concentrations as low as 19.5 ppm (68.3 mg/cu m) and can produce eye irritation at 71.5 ppm (250.3 mg/cu m ) .It also shows a wide variation in individual sensitivity; only one (B) of three subjects reported throat irritation at 19.5 ppm and another (C) did not report throat irritation at any concentration, although he did experience throat "dryness" at 71.5 ppm.
In 1969, El du Pont de Nemours and Company conducted an industrial hygiene survey of the vinyl acetate production area at its Niagara Falls plant .Air was sampled from the breathing zones of the workers with a midget impinger
# Epidemiologic Studies
The only available epidemiologic data on vinyl acetate resulted from a cross-sectional study.In 1969, Deese and Joyner described the effects of long-term exposure of chemical operators to vinyl acetate in three production units of a Gulf Coast chemical plant.
The study population consisted of 21 volunteers of the 26 operators then assigned to a vinyl acetate complex.The men ranged in age from 26 to 61 years (average 45.3 years) and had been employed in the vinyl acetate complex for an average of 15.2 years; 3 had been employed for less than 2 years, 12 for 2-20 years, and 6 for over 20 years.The control group, 21 operators from other production units not involved with vinyl acetate, was selected from participants in the company's multiphasic screening program, which included complete physical examinations, chest x-rays films, spirometry, electrocardiograms (ECG's), and analyses of blood and urine.The controls were closely matched in age with the vinyl acetate workers.Medical records were reviewed for the previous 5 years for all participants in the study, and the results of their most recent medical examinations were compared.The 21 exposed workers also answered a supplementary questionnaire designed to elicit their personal opinions regarding effects of exposure to vinyl acetate.
To characterize employee exposure to vinyl acetate, the authors collected 40 air samples at 3-6 sites in each of 3 production units during 2 sampling periods 1 month apart .Both 10-minute and 2-hour samples were collected in order to characterize average exposure and excursions.
Samples were analyzed for vinyl acetate by gas chromatography, and TWA exposures were calculated for the operators in each unit.
Results of these analyses showed vinyl acetate concentrations ranging from undetectable to 49.3 ppm (173 mg/cu m) , with a mean of 8.6 ppm (30 mg/cu m ) ; 83% of the samples showed concentrations of less than 10 ppm (35 mg/cu m) .TWA exposures for operators in the three process units were 8.2, 7.7, and 5.2 ppm (29, 27, and 18 mg/cu m ) .The authors assumed that these values were representative of the long-term exposure of workers in the study, since operating conditions, processes, and equipment in the plant had been unchanged for more than 5 years.They noted, however, that these values did not reflect high exposures that might occur during nonroutine operations.Vinyl acetate concentrations of 123.3-326.5 ppm (432-1,143 mg/cu m) were measured during one such operation, the opening of a hopper door to remove material, which required about 3 minutes to complete and was carried out an average of twice a day.The lowest concentrations of vinyl acetate, below 0.8 ppm (2.8 mg/cu m ) , were found in an "acoustically designed" control room equipped with a positive pressure ventilating system; the mean concentration inside each control room was lower than that of the general plant environs.
No major differences were found between the group exposed to vinyl acetate and the controls .A comparison of results of their most recent medical examinations showed some differences in mean blood chemistry values, but all mean values were within normal limits.The numbers of individual abnormalities in blood chemistry were similar in the two groups (12 in the vinyl acetate group and 9 in controls).Medical records for the two groups showed that the numbers of days lost due to illness during the last 5 years did not differ significantly; however, the number of episodes of absence was almost twice as high in the control group as in the exposed group.Vinyl acetate workers lost more time due to respiratory illness, but the authors attributed this excess to one worker with a recurrent upper respiratory infection; similarly, excess absenteeism from gastrointestinal illness in the exposed group was attributable to a single individual with an inflamed gall bladder.
In responses to the questionnaire, 13 of 21 vinyl acetate workers (61%) said they had never been bothered by vinyl acetate, 15 (71%) said it did not irritate their eyes, nose, or throat, and 18 (86%) reported no dermatitis .Two were "bothered" by the odor, and three specifically mentioned eye irritation.
Two workers reported upper respiratory tract irritation, specifically associated in one case with unplugging the hoppers, and one reported "a hurting in the chest" from breathing vinyl acetate at high concentrations.Skin effects noted by the workers included dryness of hands and irritation between the fingers; two workers reported that they had experienced skin rashes.The authors reported that there was no positive relationship between length of employment and responses to the questionnaire.
During air sampling, five subjects, including Deese and a laboratory analyst and one operator from each production unit, were asked to record the degrees of odor detection and irritation of the eyes and of the upper respiratory tract that they experienced .
Data from 12 sampling operations were reported; 1 sample contained vinyl acetate at a concentration of 21.6 ppm (75.6 mg/cu m) and the remainder ranged between 0.4 and 9.9 ppm (1.4-34.7 mg/cu m ) .
Three of three subjects exposed at 0.4 ppm (1.4 mg/cu m) reported detecting a slight odor of vinyl acetate .One of three subjects exposed at 7.6 ppm (26.6 mg/cu m) was unable to detect an odor, but all subjects detected the odor at higher concentrations; at 21.6 ppm (75.6 mg/cu m ) , all three exposed subjects agreed that the odor was marked.The authors noted that the three operators tended to be less sensitive to the odor of vinyl acetate than the two persons, one of whom was Deese, who had not been chronically exposed to odors of various chemicals.
Although Deese experienced slight eye irritation at 5.7 and 6.8 ppm (20.0 and 23.8 mg/cu m) , no other eye irritation was reported at concentrations below 10 ppm (35 mg/cu m) .However, all three subjects exposed at 21.6 ppm (75.6 mg/cu m) agreed that the eye irritation they experienced would be intolerable over a prolonged period.All three subjects also reported either hoarseness or cough at 21.6 ppm, but only Deese had upper respiratory tract irritation at lower concentrations, experiencing hoarseness at 4.2 and 5.7 ppm (14.7 and 20.0 mg/cu m ) .
The authors concluded that long-term exposure to vinyl acetate at concentrations of 5-10 ppm (18-35 mg/cu m) produced no serious chronic effects.
They noted that some subjects might be sensitive at concentrations of about 6 ppm (21 mg/cu m ) , but that concentrations up to 10 ppm (35 mg/cu m) were unlikely to produce irritation of the eyes or respiratory tract in most workers; however, concentrations above 20 ppm (70 mg/cu m) appeared to produce irritation in most persons. |
The authors also concluded that liquid vinyl acetate was not a serious skin or eye injurant provided prompt washing was carried out.Since this study was limited to a cross-sectional population of 21 of 26 vinyl acetate operators, no general conclusions can be drawn with respect to mortality or other chronic effects in human populations occupationally exposed to vinyl acetate.
No long-term (over 20 years) epidemiologic studies on vinyl acetate were found in the literature.
# Animal Toxicity
In 1968, the Mellon Institute, in an unpublished report , summarized the responses of rats, guinea pigs, mice, rabbits, and beagles to inhalation of various concentrations of vinyl acetate for 4 hours in a chamber monitored by gas chromatography.
Exposure concentrations or ranges were not fully reported.
The 4-hour LC50's for six male rats, six female rats, six male guinea pigs, six male mice, and four male rabbits were 3,987, 3,987, 6,215, 1,546, and 2,511 ppm (13,955,13,955,21,753,5,411, and 8,789 mg/cu m ) , respectively; no information was given on sublethal effects on any of these species.The one male dog exposed to vinyl acetate at 3,825 ppm (13,388 mg/cu m) for 4 hours survived.
The highest concentration at which no observable adverse effect was seen in a dog was 106 ppm (371 mg/cu m ) ; exposure at 240 ppm (840 mg/cu m) caused some blinking and reddening of the sclera.
In a similar investigation sponsored by the Union Carbide Corporation , three groups of rats were exposed to vinyl acetate at 1,000, 4,000, or 8,000 ppm (3,500, 14,000, or 28,000 mg/cu m) for 4, 2, and 2 hours, respectively.All rats survived the exposure at 1,000 ppm, three of six rats died "in two hours" at 4,000 ppm, and all of the rats exposed at 8,000 ppm died "in two hours."No sublethal effects were described.The authors also reported that the oral LD50 of vinyl acetate in rats was 2.92 g/kg and that the percutaneous LD50 (covered, 24-hour contact) in rabbits was greater than 5 ml/kg.
In addition, they found that "undiluted" vinyl acetate caused no reaction on the rabbit abdomen, but that 0.5 ml applied to the rabbit eye caused severe irritation or mild burns.
The test material contained hydroquinone as an inhibitor, but in concentrations that the authors thought to be innocuous.
In 1967, the Haskell Laboratory, in an unpublished report , noted the effects of vinyl acetate inhalation at 91-186 ppm (319-651 mg/cu m) on four dogs.
Dogs inhaled vinyl acetate at 91 ppm (319 mg/cu m) 6 hours/day, 5 days/week, for 6 weeks.Two and one-half weeks after this exposure ended, the same dogs were exposed to vinyl acetate at 79 ppm (277 mg/cu m) for 2 weeks and then at 186 ppm (651 mg/cu m) for 1 week.No circulatory abnormalities or evidence of disturbed metabolism were noted at any of these concentrations, but at 186 ppm eye irritation and tearing were apparent.
Microscopic and gross examination at autopsy showed no lesions that the pathologist attributed to vinyl acetate exposure.
In 1970, Gage presented the results of a short-term inhalation study of a number of industrial chemicals including vinyl acetate.Four groups of four male and four female Alderley Park specific-pathogen-free rats, weighing an average of 200 g, were exposed to vinyl acetate at 100, 250, 630, or 2,000 ppm (350, 875, 2,205, or 7,000 mg/cu m) for 6 hours/day, 5 days/week, for 3 weeks in chambers monitored by gas-liquid chromatography.Control rats were exposed to air alone.
Throughout the study the animals were observed for changes in body weight, clinical condition, and behavior.Urine samples were collected overnight after the last exposure day, for biochemical tests.The animals were then anesthetized with halothane, and blood was obtained by heart puncture, for hematologic tests.The organs were examined grossly, and fixed lung, liver, kidney, spleen, and adrenal tissues were examined microscopically.
Exposure to vinyl acetate at 2,000 ppm caused eye and nose irritation and respiratory difficulty, and these rats gained less weight than the controls .
Microscopic examination showed increased numbers of macrophages in their lungs, but no other microscopic or pathologic changes were reported.Female rats exposed at 630 or 250 ppm showed abnormally low weight gains.The results of urine and blood tests on rats exposed at 250 ppm were reported as "normal."
No signs of adverse effects were seen in rats exposed at 100 ppm.No abnormalities were apparent in the organs of rats exposed at 100, 250, or 630 ppm.Gage commented that vinyl acetate was the only unsaturated ester of a saturated carboxylic acid, among those tested, of sufficient volatility to exhibit what he termed "... typically... low toxicity, high concentrations producing irritation and narcosis."He recommended a "provisional occupational limit" of 50 ppm for vinyl acetate.
In a 1968 abstract, Goldstein et al reported the effects of inhaling vinyl acetate, alone and with acetic acid, on white mice of unspecified number, age, sex, weight, and strain.Gross and microscopic observations were made and toxic and lethal doses and cytochrome oxidase and succinic dehydrogenase activities of the pulmonary tissue were measured by unidentified methods.
Vinyl acetate alone produced a clinical picture of irritation, primarily of the respiratory system .
Microscopic examination revealed acute edematous-hemorrhagic or sero-fibrino-hemorrhagic inflamination, with or without foci of edematous or edematous-hemorrhagic pneumonia.Capillaries in the lung parenchyma, septa, and bronchial walls were dilated, and there were interstitial, subpleural, or parenchymal hemorrhagic foci scattered through the lungs.According to the authors, the experiment showed that vinyl acetate was about four times as toxic as acetic acid.They also noted that the risk of intoxication following industrial exposure to vinyl acetate was more than three times that following exposure to acetic acid.
No other details were presented.
Vinyl acetate acted rapidly after being inhaled by the mice, and most of the mortality from vinyl acetate (number of deaths not reported) occurred during the actual exposure.The activities of succinic dehydrogenase and of cytochrome oxidase in the lungs of animals that had inhaled vinyl acetate were lower than those in control animals; the activities of these two enzymes in the lungs of animals inhaling acetic acid were higher than those in the lungs of control animals.The microscopic lesions and enzyme activities produced by mixtures were similar to those produced by vinyl acetate alone, and the levels of "lethal concentrations" and "absolute toxicity" were reported to be quite similar for vinyl acetate with and without acetic acid.The authors did not define these terns.
The abstract stated that, since the biologic activity of vinyl acetate with acetic acid was greater than that expected from a simple additive effect, the combined action of the two compounds was synergistic.Because this abstract did not contain essential experimental data, its contribution toward establishing an occupational health standard for vinyl acetate is minimal, but the abstract suggested that mixed exposures to vinyl acetate and acetic acid, which could occur readily in the industrial environment, may be more hazardous than exposure to either chemical alone.
Bartenev , in 1957, investigated the effects of low concentrations of vinyl acetate on central nervous system (CNS) function and on recorded changes in reflex activity in the rabbit.The author's purpose was to establish the threshold concentrations that would elicit recordable changes in reflex activity.Using the methods of Lyublina and of Parfenov, the author monitored CNS activity by measuring two indices of the reflex activity of the rabbit foot: (1) the time for muscle tension reflex development to attain a value of 0.7 kg; (2) the muscle tension value when the reflex had been attained.
Six male rabbits, with body weights of 2,020-2,450 g, were exposed to vinyl acetate vapor at 125, 250, or 500 mg/cu m (35.5, 71, or 142 ppm) for 40 minutes.No significant changes were observed at 125 mg/cu m, but five of six rabbits exposed at 250 mg/cu m showed decreased times for development of target reflex muscle tension and decreased reflex strength.Three of the rabbits exposed at 500 mg/cu m exhibited sharp fluctuations in the excitability of the CNS that occurred much earlier than similar changes seen at 250 mg/cu m, accompanied by increased times for development of target reflex muscular tension and decreased reflex strength.
Bartenev also evaluated cerebral cortical activity in three rabbits by recording changes in the respiratory component of their reactions to electrical stimulation of the paw.
Two positive conditioned stimuli, the sound of a metronome and light from two flashlights, and a negative one, a dim light from another pair of flashlights, were presented to the rabbits twice before exposure, with 5 minutes between presentations, and twice during the 37 minutes when vinyl acetate vapor was being inhaled.
Exposure to vinyl acetate vapor at 25 mg/cu m (7.1 ppm) usually caused no marked effect on higher CNS activity, but, although it did not disturb differentiation, it clearly enhanced the reaction to the metronome when the stimuli were presented to one rabbit three times during an exposure.This rabbit exhibited the same phenomenon at higher concentrations.50 mg/cu m (14.2 ppm) caused different changes in the nervous activity of each rabbit, manifested particularly by uncertain differentiation between the two light stimuli.More profound changes occurred during exposure to vinyl acetate at 100 mg/cu m.
In this situation, the rabbits failed to respond to the sound stimulus after 20-26 minutes of exposure and to the strong light at the end of the exposure period.At that time, a paradoxical response to the weak light was present.Complete recovery of normal responsiveness to the various stimuli required 2-6 days.
Bartenev concluded that (1) the minimum (threshold) concentration of vinyl acetate vapor that affected the CNS of rabbits, determined by flexor reflex changes, was between 125 and 250 mg/cu m, (2) the threshold concentration of vinyl acetate vapor during a 37-minute exposure that altered the ability of rabbits to differentiate between qualitatively similar but quantitatively different visual stimuli was between 25 and 50 mg/cu m, and (3) inhalation of vinyl acetate at a concentration one-fifth of that causing changes in unconditioned reflex activity induced disturbances in conditioned reflex activity.
Goeva , in 1966, studied the acute and long-term effects of ingested vinyl acetate on mice and rats, including its influence on conditioned reflex development in rats.
In the first series of acute experiments, the oral median lethal dose, or LD50, of vinyl acetate for 50 white mice was determined to be 1,613 mg/kg; a majority of the mice died within 3-5 days.In the second short-term test, 20 mice were given oral doses of vinyl acetate of 300 mg/kg (about 0.2 of the median lethal dose) daily for 3 weeks.Each mouse received a total of about 6,000 mg of vinyl acetate.
Two animals died during the experiment.
At the end of the experiment, all surviving mice were given the median lethal dose (about 1,600 mg/kg), and 8 of the remaining 18 died; on these bases, the author concluded that vinyl acetate had moderate cumulative properties.
The long-term experiment on 30 albino rats lasted for 7 months and included one group of control rats and two experimental groups .
Rats ingested vinyl acetate in doses of 0.01 or 0.1 mg/kg with their drinking water.No information was given on the stability of vinyl acetate in water.The rats were observed or examined for: general appearance; body and organ weight changes; peripheral red blood cell counts and hemoglobin values; external gas exchange; liver function by Quick's test (excretion of hippuric acid after ingestion of sodium benzoate) and prothrombin time; blood cholinesterase activity; urinary protein, sugar, urobilin, and acetone; and, microscopically, for changes in the lungs, liver, kidneys, heart, spleen, and gastric and intestinal mucosa.
Experimental and control animals showed no appreciable differences in any of the parameters measured, ie, oral administration of vinyl acetate at 0.01 and 0.1 mg/kg produced no toxic effects in rats.It should be noted, however, that the acid environment of the stomach results in the rather rapid hydrolysis of vinyl acetate to acetic acid and acetaldehyde.
# Goeva
also determined the time required for acquisition of conditioned reflexes in rats that had previously ingested vinyl acetate at 0.01 or 0.1 mg/kg in their drinking water for 7 months.Rats that ingested vinyl acetate at 0.1 mg/kg exhibited fewer positive responses to the conditioned stimulus and took longer to acquire conditioned reflexes than controls; thus, the author considered this the threshold dose.No significant differences were observed in the acquisition of conditioned reflexes between control and experimental rats fed vinyl acetate at 0.01 mg/kg.Maltoni and Lefemine , in 1974, and Maltoni , in 1976, reported the results of a study involving 96 13-week-old Sprague-Dawley rats exposed to vinyl acetate vapor at 2,500 ppm (8,750 mg/cu m ) .The authors said this concentration appeared to be the "maximum possible dose for a chronic exposure" .
The rats were exposed for 4 hours/day, 5 days/week, for 52 weeks and observed for up to 83 weeks after exposure for tumorigenic effects.None of the rats exposed to vinyl acetate developed tumors; however, six controls developed a variety of tumors .No toxic effects from exposure to vinyl acetate were reported, but only 49 of 96 exposed animals (51%) survived at 26 weeks; 58 of 68 controls (85%) were alive at that time.
The authors did not discuss the reasons for this increased mortality in the rats exposed to vinyl acetate.
In 1976, Bartsch et al reported data comparing the mutagenicity of several olefinic compounds on two strains of Salmonella typhimurium, TA1530 and TA100, in a modified Ames test.Vinyl acetate served as the control substance.Vinyl acetate was combined with mouse liver fractions, with and without an NADPH-generating system, and S_^ typhimurium in a soft agar layer.No mutagenic effect was detectable with vinyl acetate.
# Metabolism
Filov , in 1959, discussed the fate of inhaled vinyl acetate in rabbits.The concentrations of inspired and expired vinyl acetate were measured polarographically, but the author did not specify the concentrations used.Blood was removed from the carotid artery periodically during exposure for polarographic analysis for vinyl acetate.
Filov reported that vinyl acetate tended to remain in the body after it was inhaled; 70% of the vinyl acetate administered was retained, and an equilibrium was established in the first few minutes after exposure began.Filov found no vinyl acetate in the blood, either during or after its inhalation, which suggested to him that vinyl acetate is rapidly metabolized when it enters the body through the lungs.
Filov also suggested that on hydrolysis vinyl acetate yields acetic acid, a normal body constituent, and vinyl alcohol, which should rapidly tautomerize to yield acetaldehyde, another normal body constituent.The rate of vinyl acetate hydrolysis in blood was investigated by determining its hydrolysis products in body fluids and the mode of their formation.Aqueous and physiologic solutions containing 380 pig of vinyl acetate were added to 2 ml samples of rat and human blood.
The mixtures were then analyzed spectrophotometrically at various time intervals for acetaldehyde.Amounts of acetaldehyde in 2 ml of blood ranged from 84 jug immediately after addition of vinyl acetate to 174 ¡ug 4.5 minutes after addition.
Filov calculated a theoretical yield of 194 /jg of acetaldehyde with complete hydrolysis and concluded that vinyl acetate hydrolyzes rapidly in the blood in vitro to produce acetaldehyde.
To identify the sites of hydrolysis of vinyl acetate in the blood, the author added 380 jug of vinyl acetate in physiologic solution to 2 ml samples of human or rat whole blood, plasma, or washed erythrocytes; the mixtures were held for 3 minutes and analyzed for acetaldehyde .
Whole human blood produced 175 jug of acetaldehyde, while plasma produced 178 jug, and washed cells produced none.In rat blood, 158-165 /ig of acetaldehyde were produced; 162-165 jug were produced in plasma, and washed rat erythrocytes produced about 70 ng of acetaldehyde, showing that hydrolysis occurred primarily due to plasma proteins and partially due to red cells.Incubation of blood plasmas from humans and rats at 62 C for 1 hour destroyed their abilities to hydrolyze vinyl acetate.
Acetaldehyde was detected in the blood of rats that had inhaled vinyl acetate vapor , Because of this finding, and because vinyl acetate was not detected in the blood, the true concentrations of acetaldehyde were measured in the blood of rats that had inhaled vinyl acetate or acetaldehyde until they assumed what was described as the lateral position; they were then decapitated, and blood was collected for acetaldehyde analysis.
The mean concentration of acetaldehyde in whole blood of seven rats inhaling vinyl acetate was 45.8 jug%; for seven rats inhaling acetaldehyde it was 30.4 A<g%, indicating that vinyl acetate is hydrolyzed rapidly in the blood, with formation of acetaldehyde.
Rostovskii et al reported that the rate constant for hydrolysis of vinyl acetate in aqueous alkali, 2.15 x 10*5 (- means to the power of), Is 370 times as high as that for its acid hydrolysis; the concentrations of acid or alkali studied were not reported.Filov's conclusion, that vinyl acetate is metabolized rapidly by enzymatic hydrolysis to acetaldehyde, is consistent with the information showing that vinyl acetate was rapidly hydrolyzed in aqueous alkali.
No information was presented in the Filov paper on the concentration of vinyl acetate inhaled or on the distribution of vinyl acetate and its metabolites in the organism, however.
The existence of nonspecific esterases in mammalian blood is well established .It is reasonable to assume that they are the probable basis for the hydrolysis of vinyl acetate observed by Filov , These enzymes have not been characterized with vinyl acetate as a substrate; however, Oi and Satomura , in 1967, found that vinyl acetate was the most easily hydrolyzed of the acetic acid esters tested with acetylesterase from the fungus Sclerotinia libertiana. |
Although Oi and Satomura primarily investigated the structure, function, and inhibition of acetylesterase, their results also were consistent with the finding of Filov that vinyl acetate may be rapidly hydrolyzed enzymatically.
In 1970, Boyland and Chasseaud reported the effect of vinyl acetate on glutathione (GSH) levels in rat liver.
Liquid vinyl acetate was administered intraperitoneally (ip) at a dose of 0.8 ml/kg (selected as about one-fourth the published LD50) to female Chester Beatty rats weighing 200-380 g. Forty-four control rats, weighing about the same as the experimental rats, were given arachis oil or 0.1 M orthophosphate buffer.
GSH assays were performed on homogenized liver samples from three and two experimental rats killed after 30 minutes and 2 hours, respectively; three control animals were killed after 2 hours for GSH assays.
The mean GSH level in control rat livers was 155 mg/100 g of liver .Mean GSH levels of the experimental rat livers, expressed as percentages of control values, were 77% after 30 minutes and 149% after 2 hours, ie, vinyl acetate produced an initial depression followed by an apparent elevation of rat liver GSH levels.The authors stated that a previous study had shown that vinyl acetate was a slowly reacting substrate for enzyme-catalyzed conjugation with GSH.Chasseaud , in 1973, also reported that vinyl acetate underwent enzyme-catalyzed conjugation with GSH.Boyland and Chasseaud concluded that if a compound is a good substrate for glutathione S-transferases, it will lower glutathione levels soon after administration to rats.Although the experiments of Filov indicate that vinyl acetate is rapidly hydrolyzed in blood, the experiments of Boyland and Chasseaud suggest that, following ip administration, vinyl acetate or its metabolites influence the metabolic activity of the liver.Tiunova and Rumyantsev , in 1975, published the results of a study of the inhalation exposure of male albino rats to vinyl acetate.Changes in the synchrony of the activity cycles of liver alanine-aminotransferase and aspartate-aminotransferase (transaminases) were determined over 5 months.The purpose of the study was to test the authors1 hypothesis that the desynchronization of fluctuations in enzyme activity during chronic exposures to a chemical stimulus would result in toxic effects, whereas maintenance of synchronization would result in compensation and adaptation.
Three groups of 10 rats each, weighing 120 g, kept in 0.47-cu m metal chambers, inhaled vinyl acetate at 2.4 ±0.2, 13.2 ±0.6, or 68.0 ±2.1 mg/cu m (0.68, 3.75, or 19.3 ppm) 24 hours/day for 4 months.The concentrations of vinyl acetate in the chambers were determined by gas chromatography.
Two unexposed groups, one maintained under colony conditions and one kept in chambers similar to those used for exposures, served as controls.
The activities of liver alanine-and aspartate-aminotranferase were determined (presumably in serum samples) in all five groups periodically throughout the 5 months (March-July).
In the colony controls, the activities of the two enzymes fluctuated synchronously; control animals placed in the chamber environment showed an altered rhythm of fluctuation, but the enzyme activities were still highly synchronous .Rank correlation coefficients for the activity of the two enzymes were 0.87 in the colony controls (P=0.01) and 0.81 in the chamber controls (P=0.05).Rats exposed to vinyl acetate at 2.4 mg/cu m also showed a change in the rhythm of fluctuation of enzyme activity, although synchrony was maintained.However, marked and unsynchronized changes developed in the activities of the two enzymes in rats exposed at 13.2 mg/cu m, and especially at 68 mg/cu m; other, undescribed, signs of intoxication were also reported in animals exposed at the latter concentration.Correlation coefficients were not given for the activities of the two enzymes in exposed animals.
The authors regarded the modification of the rhythm of fluctuation without loss of synchronization as an indication of adaptive change.
They concluded that these biologic rhythms could be used to distinguish adaptive from pathologic changes.
# Correlation of Exposure and Effect
Occupational exposure to vinyl acetate occurs primarily via inhalation of the vapor and contact of the liquid or vapor with the skin and eyes.
In humans, exposure to vinyl acetate vapor at lower concentrations (68.3-75.6 mg/cu m) has resulted in reversible eye and upper respiratory irritation .
Dermal exposure to the liquid may result in irritation of the skin .
Vinyl acetate was lethal to all (presumably six) rats exposed for 2 hours at 28,000 mg/cu m , and 4-hour LC50's for exposed rats, guinea pigs, mice, and rabbits ranged from 5,411 to 21,753 mg/cu m .No pathologic data were reported for the animals that died from these exposures .
The one beagle exposed to vinyl acetate at 13,388 mg/cu m and all of the rats exposed at 3,500 mg/cu m survived.Upper respiratory difficulty, eye and nose irritation, and increased macrophages in the lungs were noted in rats exposed at 7,000 mg/cu m periodically for 3 weeks , Deese and Joyner found that each of three persons exposed to vinyl acetate at 75.6 mg/cu m experienced hoarseness or coughing and eye irritation; one person became hoarse when exposed at about 15 mg/cu m (14.7).
Ocular effects have also been reported from contact with airborne vinyl acetate.Exposure to vinyl acetate at 840 mg/cu m caused some eye blinking and reddening of the sclerae in a dog ; 651 mg/cu m caused eye irritation and tearing in dogs ; and 0.5 ml of vinyl acetate caused severe irritation or mild burns when applied to a rabbit's eye .The lowest concentration that caused eye irritation in humans (one of three subjects) was 20.0 mg/cu m .
Two reports suggested that skin irritation can result in humans after dermal contact with (presumably liquid) vinyl acetate.One report noted that this irritation might result in blisters.Deese and Joyner reported that skin irritation or rash was noted by 3 of 21 vinyl acetate workers.
Union Carbide investigators reported that the dermal LD50 in rabbits was greater than 5 ml/kg in a 24-hour covered-skin contact test with liquid vinyl acetate, but they also stated that undiluted vinyl acetate on the skin of the shaved abdomen of a rabbit caused no reaction.
Vinyl acetate has not been characterized as a substrate for mammalian enzymes; however, it was the most easily hydrolyzed of the acetic acid esters tested with acetylesterase from the fungus Sclerotinia libertiana .This was consistent with the finding of Filov that vinyl acetate undergoes rapid enzymatic hydrolysis in vivo, producing end-products that are normal body constituents.
Evidence of possible adverse effects of vinyl acetate on the human nervous system is sparse.Gofmekler found that 0.32 mg/cu m was the minimum concentration of vinyl acetate capable of inducing EEG desynchronization as a conditioned response; 0.21 mg/cu m did not produce this effect.
Goeva found that rats given vinyl acetate in oral doses of 0.1 mg/kg for 7 months exhibited fewer positive responses to a conditioned stimulus and took longer to develop conditioned reflexes than either controls or rats fed 0.01 mg/kg of vinyl acetate.It is questionable whether these particular studies demonstrated adverse changes; so it does not now seem appropriate to conclude that vinyl acetate exposure in the work environment at these concentrations will induce biologically significant effects on the nervous system.
The readily identifiable odor of vinyl acetate appears to be one means by which workers are warned of its presence in the work environment.Determinations of the threshold of odor detection have given varying results.For example, Deese and Joyner reported that three of three subjects detected a marked odor of vinyl acetate at 75.6 mg/cu m; a "slight" odor was reported by all of three or four exposed at 14.7 and 1.4 mg/cu m.
In an experimental study , all of nine volunteers detected the odor of vinyl acetate at 4.6 mg/cu m, but, with one questionable exception, they did not detect its odor at 2.1 mg/cu m. Minimum perceptible (threshold) and maximum imperceptible concentrations for odor detection were determined by Gofmekler to be 1.0 and 0.7 mg/cu m, respectively.These findings indicate that the odor threshold of vinyl acetate probably ranges from 1.0 to 3.3 mg/cu m; their variability probably reflects differences in methods of determination, and possibly in the development by the test subjects of adaptation to the odor.While a noticeable odor of vinyl acetate may indicate a potential hazard, it is not quantitatively reliable.
Olfactory fatigue has also been observed during exposure to vinyl acetate.Vinyl acetate at 68.3-250.3 mg/cu m produced olfactory fatigue in all exposed volunteers .
Olfactory fatigue was complete in three of three persons exposed at 68.3 mg/cu m and in one of three at 119.7 mg/cu m after 3-116 minutes; two of three subjects at the latter concentration and four of four at 250.3 mg/cu m experienced partial olfactory fatigue.
The known effects of vinyl acetate on humans and animals are summarized in Tables III-2 and III-3.
# Carcinogenicity, Mutagenicity, Teratogenicity, and Effects on Reproduction
No specific data on the teratogenic or reproductive effects of vinyl acetate were found in the available literature.
No mutagenic effects were detectable in typhimurium strains TA1530 and TA100 exposed to vinyl acetate .In the single study on its carcinogenicity, 96 rats were exposed to vinyl acetate at 8,750 mg/cu m for 1 year and observed until the end of their lives.No evidence was found that vinyl acetate influenced tumor incidence.
Several compounds having structures similar to that of vinyl acetate, eg, vinyl chloride, vinyl bromide, vinylidene chloride, vinyl cyanide (acrylonitrile), and vinyl carbamate, have been shown to be carcinogenic or mutagenic , but there is no evidence to suggest that vinyl acetate induces similar irreversible processes.No other reports on the carcinogenic or mutagenic potential of vinyl acetate in humans or animals were found in the literature.
Vinyl acetate administered ip to rats at a dose of 0.8 ml/kg reduced liver glutathione levels initially .
This suggests that a fraction of the dose reached the liver and disturbed glutathione metabolism, perhaps by acting as a substrate for glutathione conjugase.No evidence from either in vitro or in vivo experiments indicates that an oxirane intermediate plays any role in vinyl acetate metabolism, although intermediates containing oxirane rings seem to be important in the metabolism of vinyl halides .Without further research, these aspects of vinyl acetate toxicity cannot be settled. considered air emissions of vinyl acetate from production facilities to be less significant than emissions from other processes surveyed and therefore did not recommend that the Environmental Protection Agency conduct further (in-depth) study of vinyl acetate air emissions.
Deese and Joyner , in the course of an epidemiologic study of vinyl acetate workers, reported industrial air sampling results.
"Short-term" samples were collected in a midget bubbler and an impinger in series, with toluene (near 5 C) as the collection medium, and "long-term" samples were collected similarly with standard Greenburg-Smith impingers; analyses were performed by gas chromatography.Deese (DE Deese, written communication, May 1978) indicated that the midget impinger samples were breathing-zone samples.The vinyl acetate concentration averaged about 8.6 ppm (30 mg/cu m ) , ranging from nondetectable to 49.3 pp m (173 mg/cu m ) .TWA concentrations in three production areas were reported as 8.2, 7.7, and 5.2 ppm (29, 27, and 18 mg/cu m) .
# Investigators for El du Pont de Nemours and Company
collected air samples in the breathing zones of workers In a vinyl acetate production area.Vinyl acetate was collected in midget impingers containing dimethylformamide and was analyzed by gas chromatography.Samples were collected during two separate periods in summer and winter.The reported TWA concentrations ranged from 0.4 to 4.9 ppm (1.4-17 mg/cu m) with no systematic seasonal variation.
# Sampling
Vinyl acetate has been collected by integrative sampling methods such as solid sorbent tubes and midget impingers and by grab-sampling methods, such as sampling bags .Ambient air samples have been collected in polyvinyl fluoride bags for analysis by gas chromatography or infrared absorption spectroscopy .Samples were collected with a 12-volt DC centrifugal blower, in 100-liter and 500-liter bags, requiring sampling periods of 2 minutes and 18-20 minutes, respectively.
Two possible disadvantages of this method were noted: contamination of sample by diffusion of bag material and loss of sample by sorption, decomposition, or permeation.An additional disadvantage of this method is that the large sampling bags and the associated pumps are not suitable for personal sampling.
Although often used, midget impingers may be inconvenient for personal sampling because it may be necessary to recharge them with collecting medium frequently (depending on its vapor pressure) and because they may interfere with the movements of the worker, especially when used in series.
Handling and transporting absorber solutions is difficult because of the possibility of spills and leaks.
Deese and Joyner used two standard Greenburg-Smith impingers in series or a "fritted glass midget impinger bubbler and a standard midget impinger" in series to collect vinyl acetate.The standard impinger series was used to collect 2-hour samples at a flowrate of 1.5 liters/minute.The midget impinger series was used to collect 10-minute samples at the same flowrate.The temperature of the toluene collecting medium was kept near 5 C with aqueous methanol and dry ice, and vacuum was provided by a portable constant-rate sampler or a sequential sampler.The mean collection efficiency for the first impinger of each series (midget or Greenburg-Smith) was 86.3% at 0 C; mean collection efficiency for the first absorber near 5 C was 84.2%.
Gas chromatography was used to analyze the samples.
Solid-sorbent devices are well suited for personal sampling; they are relatively small, and persons wearing them quickly adjust to their presence.They require less careful handling than liquid sorbents and are efficient and easy to use.Charcoal is a widely used general sorbent because it is nonpolar and has an affinity for organic vapors and gases.However, its collection and desorption efficiencies vary from batch to batch, so that it is necessary to determine the collection and desorption efficiencies for each batch.
Celanese Chemical Corporation investigators have developed a method that utilizes a low-flow air sampler pump in conjunction with a collection tube packed with Porapak Q to sample for vinyl acetate.Basically, an air sample is collected in the worker's breathing zone at a flowrate of 40-60 ml/minute; the sample passes through a 3-inch collector tube with a 1-inch backup tube, both packed with Porapak Q (50/80 mesh).The collector tube is removed from the pump connection and locked into the programmed thermal desorber, eg, Century PTD-132, and the sorbent in the collector tube is immediately convection-heated with purge gas, eg, air, drawn through the tube by a device similar to a large stainless steel syringe.After desorption, the "syringe" retains the analyte reconcentrated in a fixed 300-ml volume of purge gas.At any later time, replicate analytical size samples of this gas may be manually or automatically withdrawn from the "syringe" and injected into a gas chromatograph for analysis without sample dilution, since the syringe piston adjusts itself to maintain a constant sample concentration by compensating for the volume of sample withdrawn.
The sampling equipment is portable, automatic, and easy to use.
Desorption and analysis with a portable gas chromatograph can be performed by on-site (field) personnel, thereby minimizing both the chances of mixup of tubes during transportation to a laboratory and the typical transportation and laboratory delays.Desorption can also be performed at a site remote from that of sample collection.
NIOSH has proposed a solid-sorbent sampling method for vinyl acetate.It is recommended that the sampling rate and volume not exceed 0.1 liter/minute and 3.0 liters, respectively.Chromosorb 107 is the recommended sorbent.Vinyl acetate has been successfully collected by this method over the concentration range of 8.2-206 mg/cu m at a relative humidity of over 80%, but the method is known to be capable of collecting much smaller amounts of vinyl acetate (quantitative limit is 0.5 pig of vinyl acetate/300 mg of solid sorbent).This method, described in Appendix I, is the recommended sampling method.
# Chemical Analysis
Vinyl acetate has been determined by polarography , infrared absorption spectroscopy , bromometry , paper chromatography , colorimetry , and gas chromatography .
Horacek hydrolyzed vinyl acetate in an alkaline (LiOH) medium and determined the resulting acetaldehyde by polarography.The method was useful for concentrations of vinyl acetate of 0.01-1 mg/ml.The author stated that the method was simple, rapid, and sufficiently precise (not further defined), but interferences included aldehydes and many alkaline cations, eg, Na+, NH4+, K+, Cs+, Rb+, and Ba++.Filov also used a polarographic method to analyze for vinyl acetate, but he did not describe the method in detail.
Long-path infrared Fourier transform absorption spectroscopic analysis was used to measure vinyl acetate at concentrations ranging from 0.07 to 0.57 ppm (0.25-2.0 mg/cu m) .
Bokov et al used bromometry to determine vinyl acetate in air.This method was based on the addition of bromine across the double bond of vinyl acetate.The quantity of bromine consumed was indicative of the concentration of vinyl acetate.
Several colorimetric methods have been used for determination of small amounts of vinyl acetate in air.The complexation of mercuric acetate with vinyl acetate was the basis of one colorimetric method .Mercuric acetate was added to a solution containing vinyl acetate in ethyl alcohol; after 1 hour, diphenylcarbazide in ethanol was added to form a violet complex with the excess mercuric acetate.The sensitivity was reported as 0.05 mg/liter of sample.
To determine the concentration of vinyl acetate in air in the presence of aldehydes, Andronov and Yudina mixed a sample with hydroxylamine hydrochloride and ferric chloride and used phenolphthalein as the colorimetric agent.The sensitivity of this method was stated to be 1 ng in 3.5 ml.
Another colorimetric method was based on vinyl acetate's oxidation to formaldehyde by permanganate or periodic acid.Chromotropic acid was then used for colorimetric determination of the formaldehyde at 574 nm. |
Gofmekler mixed a sample of vinyl acetate with alkaline hydroxylamine to form acetohydroxyamino acid, which produced a color ranging from light yellow to purple in the presence of ferrous chloride.The sensitivity of the method was reported to be 0.025 jug/ml.
Horacek used paper chromatography to separate the hydroxamate derivatives of caprolactam, vinyl acetate, acrylic acid, and metacrylic acid esters.
The method was described as rapid and relatively sensitive; the amount of monomer in the aliquot was determined colorimetrically by adding a ferric salt.
Osokina and Erisman described an analytical method for vinyl acetate that involved reacting a salt of mercury with the vinyl acetate, followed by separation of the resulting mercury compound by paper chromatography.The addition of the mercury was found to proceed more rapidly in an alcoholic medium.
The minimum amounts of vinyl acetate detectable in various alcohols ranged from 0.3 to 1.0 jug.
The most widely used method for analyzing vinyl acetate is separation by gas-liquid chromatography with flame-ionization detection.
Analysis by gas chromatography generally involves either direct injection of a portion of the sample from a sampling container or injection of an aliquot of sample desorbed from a suitable sorption material.
The choice of column materials and operating parameters for vinyl acetate analysis depends on the relative retention times of the possibly interfering compounds.
West et al reported using a U-shaped 5-mm x 2-meter glass tube containing 20% beta,beta'-oxydipropionitrile on 30/60 mesh Chromosorb to measure vinyl acetate retention times at a column temperature of 53 C. In another retention behavior study of vinyl acetate, Germaine and Haken used a gas chromatograph with a 12-foot x 1/4-inch aluminum column packed with 10% methyl silicone polymer (SE-30) on 60/80 mesh, acid-washed, and silanized Celite 560 and operated at 150 C. Bollini et al used gas-liquid chromatography with flame-ionization detection to determine the amount of vinyl acetate monomer in a mixed aqueous suspension of polyvinyl acetate and butyl acrylate-vinyl acetate copolymer.They used a 1/8-inch x 6.6-foot steel column containing 10% polyphenylether OS-138 on Chromosorb W-AV (80/100 mesh) at 90 C. The authors' major criticism of this system was that the injection chamber of the chromatograph might become encrusted after approximately 10 injections.
To separate vinyl acetate from other organic compounds, Smith and Dahlen used a column of tetraamylsilane and dimethyldioctylsilane on 60/100 mesh Celite 545 at a column temperature of 95 C. Values obtained with this method had only a 0.4% error when compared with the known amounts of vinyl acetate used.
Deese and Joyner also used a gas chromatograph equipped with a flameionization detector to measure vinyl acetate concentrations.A 6-foot x 1/4-inch stainless steel column packed with 80/100 mesh Porapak Q was used at 200 C. Preliminary evaluation using known concentrations of vinyl acetate showed a 99.2% mean accuracy (range, 80.9-110.2%) with this method; it was stated to be accurate and reliable for the low concentrations (0.4-49.3 ppm) encountered in the study.
A 4-foot x 1/8-inch stainless steel column packed with Chromosorb 101, 80/100 mesh, has been used at 110 C for monitoring vinyl acetate in air by Celanese Chemical Corporation investigators .
May et al found Porapak Q to be a suitable packing in a pyrolysis gas chromatographic system for a 5% vinyl acetate-vinyl chloride copolymer.Two other reports noted that airborne vinyl acetate was analyzed by gas chromatography, but details of the analytical methodology were not presented.
NIOSH has proposed a method for analyzing vinyl acetate in workplace air samples by gas chromatography with flame-ionization detection.
Samples are collected on Chromosorb 107 and thermally desorbed with helium at 150 C. The desorbed vapors are injected onto a chromatographic column packed with 10% FFAP on 80/100 mesh Chromosorb W AW.This method has been found suitable for quantifying vinyl acetate in concentrations as low as 0.5 pig/300 mg of Chromosorb 107.
The pooled relative standard deviation of the sampling and analytical method was 8.1% for 50 samples over the concentration range of 8-200 mg/cu m. This method is described in detail in Appendix I.
There are a number of direct-reading devices that can be used to determine vinyl acetate in workplace air.
Combustible gas meters and colorimetric tubes, although they are not sensitive enough to determine vinyl acetate at concentrations as low as the recommended ceiling limit, may be useful for leak detection and other emergency situations.
NIOSH has evaluated nine commercially available, portable combustible gas meters.These instruments are not specific for vinyl acetate, but their utility for measuring concentrations of vinyl acetate can be enhanced by calibrating them under temperature and other conditions resembling as closely as possible those at the sampling site.
# Colorimetric tubes capable of semiquantitative measurements of vinyl acetate in air are manufactured by Draeger and by Gastec .
The Draeger tubes are sensitive to vinyl acetate at 50 ppm with 10 strokes of the pump, and the Gastec tubes can detect vinyl acetate at 10 ppm with a single stroke of the pump.
This sensitivity can be increased by increasing the number of strokes, down to about 5 ppm, the minimum detection limit for these devices.Ethyl acetate and other esters of acetic acid will interfere.
NIOSH has also evaluated several portable, direct-reading analyzers.At least three of these are suitable for determination of vinyl acetate concentrations at or below the recommended occupational exposure limit.The Wilks-Miran infrared analyzer is capable of detecting vinyl acetate down to about 0.02 ppm .
The Century organic vapor analyzer is capable of detection over the range of 1-10,000 ppm, depending on the scale selected .The photoionization meter produced by HNU Systems, Inc, can detect vinyl acetate, as well as many other gases and vapors, over the concentration range of 0.1-2,000 ppm, using energy sources of 10.2 and 9.5 electron volts (eV) .Although none of these devices is specific for vinyl acetate, the HNU photoionization meter with 9.5-eV energy source will discriminate out all compounds with ionization potentials above 9.5 eV; this includes most potential interferences, eg, ethyl acetate (10.11 eV), methane (12.6 eV), vinyl chloride (9.996 eV), acetic acid (10.36 eV), ethylene (10.5 eV), acrylonitrile (10.91 eV), and acetonitrile (12.2 eV) .NIOSH recommends a gas chromatographic method with flame-ionization detection for analysis of vinyl acetate in workplace air.
The recommended method is described in detail in Appendix I .This method has the advantage of permitting analysis by a quick instrumental method either on-site or in a laboratory remote from the site of sample collection.It is efficient and economical, since sampling tubes may be reused after analysis is completed.Host potential interferences can be eliminated by altering chromatographic conditions.Although this analytical method has not yet been approved or validated by NIOSH, it shows promise of being suitable for determination of vinyl acetate in workplace air at the concentrations required by the recommended standard, with acceptable precision and accuracy.
# Hazard Control By Process and Design Engineering (a) Ventilation
Engineering design of operations and process equipment involving vinyl acetate should be oriented toward controlling inhalation and skin and eye contact with the liquid or vapor.Properly designed and maintained ventilation systems should prevent dispersal of vinyl acetate into the workroom atmosphere and the accumulation of vinyl acetate on surfaces.These goals can be met with properly constructed and maintained closed systems.
If closed systems are not feasible, local exhaust ventilation systems should be provided at potential contamination sources to direct airflow away from the employees' breathing zones.
These systems should be designed to remove the vapor with proper allowance for makeup air and should prevent mere recirculation of contaminated air.Guidance for design of such systems can be found in Industrial Ventilation-A Manual of Recommended Practice , in Fundamentals Governing the Design and Operation of Local Exhaust Systems (ANSI Z9. , and in NIOSH's Recommended Industrial Ventilation Guidelines .
Ventilation systems require regular inspection and maintenance to ensure effective operation.
Inspections should include measurements of system function, eg, airflow at collection hoods, static pressure at branch ducts, or pressure drop across filters and fans.
Whenever measurements indicate unacceptable functional decrements in a system, the equipment should be inspected more closely and immediately repaired or otherwise restored to an acceptable state of function.
A water or oil manometer can provide a convenient, continuous method for evaluating airflow.The manometer should be marked to indicate design airflows.
The continued effectiveness of vapor control systems should be evaluated by sampling and analyzing air in the general workroom, in operators' breathing zones, and around potential contamination sources whenever the ventilation system or work operations or processes are changed.
Ventilation systems, as well as all other equipment in vinyl acetate manufacture or use facilities, must be designed and operated in a manner cognizant of the high flammability of this compound.Electrical motors and other electrical components must be explosion-proof.
Moving parts of the system, eg, fan blades, must be constructed of nonsparking materials.
# (b) Storage and Handling Areas
Manufacturing, processing, storage, and transfer equipment must be constructed of materials resistant to corrosion by vinyl acetate.
One vinyl acetate manufacturer recommends carbon steel, lined carbon steel, or aluminum and has noted that brass, bronze, or lead compounds are not acceptable construction materials .Small samples should be stored in brown bottles .Storage in outdoor or detached bulk storage areas is preferable to indoor storage.
Bulk storage areas must be diked to contain any spills, and sump pumps in these areas must be explosion-proof.Storage and manufacturing areas must be constructed so that spilled or leaked vinyl acetate does not run into sanitary sewers, where it may present an explosion or fire hazard.Facilities in which large quantities of vinyl acetate are processed or stored should be protected by automatic sprinkler or deluge systems .
Vinyl acetate storage areas should be separated from areas containing oxidizing and polymerization-initiating compounds.Vinyl acetate should also contain a suitable polymerization inhibitor, such as hydroquinone or diphenylamine, when stored .Any recommendations of the manufacturer regarding the necessity for the presence of dissolved oxygen should be followed .
The storage of vinyl acetate poses certain problems related to vent size, diking, and separation distances, which, in turn depend on other variables, such as tank size or design.Storage areas should therefore be designed in consultation with qualified fire protection engineers .
Loading and unloading operations are particularly hazardous because of the high flammability hazard associated with vinyl acetate.
Moving liquids, especially bulk liquids, produce buildups of static electricity.These must be controlled by bonding and grounding barge, railroad car, and tank truck terminals.
# V. WORK PRACTICES
# Storage, Handling, and Use
Vinyl acetate is extremely flammable and potentially explosive; its flashpoint has been reported as -5.5 C (22 F) , and the explosive limits, in air by volume, have been reported as 2.6-13.4% .Other pertinent physical and chemical properties are listed in .The maximum safe storage period depends on the amount and type of inhibitor added .Vinyl acetate has been found to react with certain desiccants such as silica gel and alumina gel .When desiccants are used, they should be tested for reactivity with vinyl acetate.
During the transfer of vinyl acetate from metal tanks or containers to other metallic vessels, the two vessels must be bonded and grounded to prevent the buildup of static electricity and possible spark generation.Failure to do so has caused explosion resulting in fatal injuries .
Inert gas purging of enclosed containers should be performed during transfer operations to prevent formation of explosive mixtures of air and vinyl acetate.Pressurized air should never be used for emptying vessels containing vinyl acetate .
Containers used to transport vinyl acetate should bear labels warning of the possibility of irritation to skin, eyes, and respiratory tract and providing information on the proper storage and handling of vinyl acetate.
DOT regulations require that vinyl acetate be tagged with a label classifying it as a flammable liquid (49 CFR 172).
Metal drums and other containers of vinyl acetate should be opened only with nonsparking tools.Fittings should never be struck with anything that may cause a spark .When containers have been emptied, all openings should be closed tightly .Vessels to be discarded should be steamed to remove traces of vinyl acetate and rendered impossible to reuse by crushing or piercing.
# Maintenance of Equipment
The duties of maintenance and repair workers pose special problems with regard to the evaluation of their potential exposure to vinyl acetate.
Often the very circumstances that require the maintenance or repair work, and under which work must be done, will negate some of the normal control procedures.Therefore, these activities should be very carefully supervised.Maintenance and repair workers should use and wear appropriate protective equipment and clothing and should follow standard operating procedures or directives provided along with required special work permits (see below).They should be trained to recognize and control the hazards to which they may be subjected.
All tank maintenance and repair work should be performed under a permit system or its equivalent.Immediately before such work begins, the air in the tank should be tested.If the concentration of vinyl acetate vapor is found to be at or below the recommended ceiling limit, a work permit authorizing the maintenance and repair work should be issued, and the work should be started as soon as all potential vinyl acetate sources have been blocked and the work area has been posted with signs saying that work is in progress.If the concentration of vinyl acetate vapor is found to be above the recommended limit, the tank should be steamed to remove residual vinyl acetate .The tank should then be cooled, preferably by rinsing with water and draining, and purged with fresh air.A work permit should not be issued until tests show that the vinyl acetate concentration in the tank is below the recommended limit.
If the work is interrupted before completion, the tank air should be retested and a new work permit issued before work is resumed.
The tank atmosphere should be tested frequently while the maintenance and repair work is in progress.If the vinyl acetate vapor concentrations are ever found to exceed the environmental limit, the work permit should be revoked and all work should stop until the concentration of vinyl acetate is reduced to the recommended limit or below and a new permit is issued.Tanks, equipment, pumps, lines, and valves should be drained and rinsed with water or purged with an inert gas before they are opened and repaired; workers performing this task should use proper protective equipment and avoid contact with any liquid draining or dripping from the equipment.Tanks should be steamed and kept above the boiling point of vinyl acetate (72.7 C) until residual vinyl acetate vapor has been removed; volatilized vinyl acetate in the steam effluent should not be allowed to contaminate the surrounding areas.
Tank entrances should be large enough to admit a person wearing a safety harness, life line, and respirator in case of emergency.
An appropriately equipped worker should be stationed outside the tank to keep the workers in the tank under observation at all times.
Tank cleaners or repair workers overcome by vapor should be moved to fresh air immediately, and artificial respiration should be applied if breathing has stopped.A physician should be summoned at once.
Exterior repair work should be allowed only after areas are determined to present no hazard from vinyl acetate vapor.
All spark-or flame-producing operations in the vinyl acetate work area must be rigidly controlled by a permit system or its equivalent.All outside welding or burning on tanks or equipment that have contained vinyl acetate should be done only after the containers have been completely purged with steam or filled with inert gas.Purging should continue while repair work is in progress .
# General Housekeeping
Areas where spills of vinyl acetate have occurred should be posted to prevent entry by nonessential employees and promptly cleaned by means that will minimize inhalation of, or contact with, vinyl acetate.Large spills should first be contained, then flushed with water into an appropriate drainage system where vinyl acetate can be safely stored and either recovered or destroyed.Supervisors should emphasize to employees the need for prompt cleanup of spills, prompt repair of equipment and leaks, proper storage of materials, and proper functioning of dikes and deluge systems.All collected vinyl acetate should be recycled into the process or disposed of in a manner that meets applicable local, state, and Federal regulations.
# Emergency Procedures
Specific procedures should be designed for the handling of emergencies involving vinyl acetate, and employees should be trained in these procedures.Complete written procedures for emergencies, revised and updated when necessary, should be readily available to all employees assigned to vinyl acetate work areas.Emergency procedures should provide for transportation of injured personnel to hospitals and should provide for instructions explaining the location, use, and maintenance of first-aid equipment, firefighting equipment, emergency showers, and eyewash fountains.Emergency drills should be held at least annually.All emergency plans should be designed to minimize personal injury.
Properly maintained safety showers and eyewash fountains should be located in or near all areas where exposure to liquid vinyl acetate may occur.
In case of dermal contact with vinyl acetate, the affected area should be flushed promptly with water.In case of ocular contact with vinyl acetate, eyes should be flushed immediately and thoroughly with water at low pressure.Exposed employees should then be taken promptly to the nearest medical facility to determine the need for further treatment.Employees should be made fully aware of these procedures.
For firefighting, carbon dioxide, foam, or dry chemical extinguishers or a spray of water should be used .Use of a stream of water should be avoided to prevent splashing and spreading of fire.Automatic sprinklers and hose lines with spray nozzles should be available for fire control. |
Appropriate firefighting equipment should also be readily available.It should be noted that vinyl acetate floats on water and that the heat of burning vinyl acetate may initiate violent polymerization which could spread fire .
# Respiratory Protection
Engineering and administrative controls, along with good work practices, are the preferred means of keeping vinyl acetate concentrations within the permissible exposure limits.However, respirators may be needed to adequately protect employees in some situations, such as emergencies, during nonroutine maintenance, during the time necessary to install and test engineering controls, and during the time necessary to evaluate the impact of a process change on workplace air.
Employers should provide each employee in these situations with appropriate respiratory protective equipment in accordance with Table 1-1, and ensure that a respiratory protection program is established and observed.Guidelines for such a program are found in 29 CFR 1910.134.
Cleanliness and maintenance of respirators should be emphasized.The interior of the facepiece should not be contaminated.Detailed information on respirator selection and usage may be obtained from the Respiratory Protective Devices Manual .Nelson and Harder evaluated the service life of organic vapor cartridges in a vinyl acetate atmosphere by determining the time necessary for 10% of a vinyl acetate influent (3,500 mg/cu m) to break through the cartridge.The flowrate was 53.3 liters/minute, the relative humidity was 50%, the temperature was 20-22 C, and the cartridge contained 26.25 g of activated carbon.
Breakthrough time was 81.1 minutes.Because the concentration tested was so great, this study suggests that organic vapor cartridges provide adequate protection at the concentrations at which they are recommended for use in Table 1-1 (up to 1,400 mg/cu m ) .
# Other Protective Equipment
The employer must provide all employees occupationally exposed to vinyl acetate with gloves and safety glasses with side shields or goggles and must ensure that they are worn when needed.Long-sleeved cotton coveralls may be provided and worn to minimize skin contact.Disposable coveralls may be used.Fabrics that generate static electricity should be avoided.In areas where liquid vinyl acetate is handled, suits or aprons and boots impervious to penetration by vinyl acetate should also be provided and worn.Gloves should be constructed of materials resistant to penetration by vinyl acetate.
No test data on glove materials were found; one vinyl acetate manufacturer provides neoprene gloves , and others have recommended "rubber" .
Other personal protective equipment should be provided, used, and maintained as specified in 29 CFR 1910.132-137.Proper protective clothing requires a snug, but comfortable, fit around the neck, wrists, and ankles.The protective equipment and clothing should be cleaned or replaced regularly.Personal protective equipment should be kept in suitable, designated containers or lockers when not in use.
# Sanitation and Personal Hygiene
Plant facilities should be maintained in accordance with sanitation requirements listed in 29 CFR 1910.141.
Contaminated clothing should be discarded or cleaned by laundering before reuse.Clothing to be reused should be stored in a container that is impervious to vinyl acetate.
Personnel who clean such clothing should be informed of the attendant hazards.
Good personal hygiene, including washing hands thoroughly before using toilet facilities, eating, drinking, or smoking, is important to prevent ocular, respiratory, and dermal irritation.
# VI.DEVELOPMENT OF STANDARD
# Basis for Previous Standards
A Threshold Limit Value (TLV) of 10 ppm or 30 mg/cu m (sic) was recommended by the Threshold Limits Committee of the American Conference of Governmental Industrial Hygienists (ACGIH) in 1969 and adopted in 1971 , A Short-Term Exposure Limit (STEL) or 20 ppm or 60 mg/cu m (sic) was recommended in 1976 .The Documentation of Threshold Limit Values noted 4-hour LC50 values in rats, mice, and rabbits of 4,000, 1,550, and 2,500 ppm, respectively.
No evidence of circulatory abnormalities or evidence of altered metabolism was noted in dogs exposed 6 hours/day to vinyl acetate for about 11 weeks at average concentrations of from 91 to 186 ppm.The documentation stated that Gage had found rats unaffected by repeated exposures at 100 ppm and had recommended 50 ppm as a working standard.The documentation also noted a report of 15 years' industrial experience with 21 vinyl acetate chemical operators in whom hoarseness and coughing ("slight irritation") were observed at around 22 ppm.
The medical records and multiphasic examinations were stated to have revealed no evidence of chronic effects from concentrations of 5-10 ppm.
The Threshold Limits Committee recommended a TLV of 10 ppm, citing the evidence that irritation may be experienced at around 20 ppm but not at 10 ppm and in the light of evidence that neither acute nor chronic effects occur from repeated daily exposures for many years .
According to an International Labor Office (ILO) report , Australia, Belgium, Finland, the Netherlands, Sweden, and Switzerland have maximum allowable concentrations (MAC's) for vinyl acetate of 10 ppm, or 30 mg/cu m (sic).The MAC for vinyl acetate in the USSR, Poland, and Yugoslavia is 10 mg/cu m (2.8 ppm).The Rumanian limits consist of average and maximum vinyl acetate concentrations of 50 and 100 mg/cu m (14 and 28 ppm), respectively.The ILO report noted that MAC's or ceiling values are used because timeweighted averages (TWA's) should not be applied to fast-acting substances, eg, irritants and narcotics, or to substances that are particularly toxic.
There is no current US Federal occupational standard for vinyl acetate.
Basis for the Recommended Standard (a) Permissible Exposure Limits Exposures to vinyl acetate in the workplace have produced mainly reversible irritation of the upper respiratory tract and eyes, sometimes accompanied by skin irritation .The available literature indicates that vinyl acetate typically produces only minor irritation and produces only minor irritation and produces only minor, perhaps inconsequential, changes in internal organs .No evidence was found of long-term systemic, carcinogenic, mutagenic, or teratogenic or other reproductive effects in humans or experimental animals.
Three of three persons exposed to vinyl acetate for short periods at 75.6 mg/cu m had upper respiratory tract irritation (hoarseness or cough); one of four exposed at 14.7 mg/cu m experienced hoarseness; and one of three exposed at 20.0 mg/cu m reported eye irritation .
All of these symptoms were reversible.Volunteers exposed to vinyl acetate at less than 1 mg/cu m showed changes in ocular light sensitivity and desynchronization of the EEG as a conditioned response , but there are no indications that these changes were signs of potentially adverse CNS effects.
All of the rats (presumably six) exposed for 2 hours to vinyl acetate at 28.000 mg/cu m died .Four-hour LC50's for rats, guinea pigs, mice, and rabbits exposed to vinyl acetate ranged from about 5,400 to 21,750 mg/cu m .A beagle exposed to vinyl acetate at 13,388 mg/cu m and all rats exposed at 3,500 mg/cu m survived.Rats exposed to vinyl acetate at 7.000 mg/cu m for 6 hours/day, 5 days/week, for 3 weeks exhibited respiratory difficulty, eye and nose irritation, and increased numbers of macrophages in the lungs ; examination at autopsy showed no visible abnormalities.Dogs exposed to vinyl acetate for 4 hours at 840 mg/cu m demonstrated eye blinking and reddening of the sclerae , and those exposed at 651 mg/cu m for 1 week had eye irritation and tearing .No other adverse effects were reported in the dogs.
There is very little information available on the long-term effects of vinyl acetate on humans or animals.Among 21 production workers exposed to vinyl acetate at an average of 30.1 mg/cu m (range, undetectable to 172.6 mg/cu m) for about 15 years, 3 stated that they had experienced skin effects, and there were 6 reports of eye, nose, or throat irritation ; no chronic effects were found.Rats exposed 4 hours/day, 5 days/week, for 52 weeks to vinyl acetate at 8,750 mg/cu m and followed for up to 135 weeks did not develop tumors ; however, their mortality after 26 weeks of exposure was higher than that of unexposed control animals.Although there is some structural identity between vinyl acetate and other vinyl compounds that are known to induce cancer, there is currently no evidence to suggest that vinyl acetate is carcinogenic, mutagenic, or teratogenic, or that it causes reproductive effects in humans or animals.
In contrast to the vinyl halides, vinyl acetate contains an ester moiety.Vinyl acetate appears to be rapidly detoxified by esterases present in mammalian blood , ie, by a metabolic route that is not available to the vinyl halides.While it is conceivable that vinyl acetate is oxidized to a reactive oxirane, neither biochemical nor biologic evidence is available to indicate that this pathway plays a significant role in the biotransformation of vinyl acetate.
In the absence of retrospective epidemiologic studies of morbidity and mortality, and because there is no evidence that there are Chronic effects in humans resulting from long-term exposure , NIOSH concludes that the recommended environmental limit should be based on the reversible irritation that has been associated with workplace exposure to vinyl acetate.The lowest concentration reported to induce any irritant effect (hoarseness) was 15 mg/cu m .
Since the toxic action of vinyl acetate, on short-term exposure, is expressed largely by reversible irritation of the respiratory tract and eyes , a ceiling concentration limit is deemed more appropriate than a TWA concentration limit.While hoarseness was experienced by only one of four persons exposed at 15 mg/cu m and eye irritation by one of three at 20.0 mg/cu m , the permissible exposure limit for vinyl acetate should protect even the more sensitive workers from these possible adverse effects.Therefore, a ceiling limit of 15 mg/cu m (4 ppm), measured in a 15-minute sample, is recommended as the occupational exposure limit, pending the development of more definitive data.
# (b) Sampling and Analysis s
Personal sampling, using a low-flow air sampler pump, thermal desorption, and analysis by gas chromatography are recommended for the determination of vinyl acetate.
This method is described in detail in Appendix I. The sampling equipment is portable, automatic, easy to use, and relatively inexpensive.
Gas chromatography offers the necessary sensitivity, precision, and accuracy and can be used in either field or laboratory situations.
# (c) Medical Surveillance
Employees should be given preplacement medical examinations if occupational exposure to vinyl acetate may occur.Because vinyl acetate is an irritant to the upper respiratory tract, eyes, and possibly to the skin , attempts should be made to identify persons with preexisting upper respiratory, eye, and skin problems at the preplacement examination.Since there is no evidence that a chronic hazard may be associated with occupational exposure to vinyl acetate, chest roentgenograms are suggested only for preplacement examinations.
# (d) Personal Protective Equipment and Clothing
Several investigators have reported that vinyl acetate caused dermal and ocular irritation.Reports of dermal effects have mentioned that skin irritation, rash, or blisters resulted from exposure to liquid vinyl acetate and that blisters also occurred from contact with clothing wet with vinyl acetate .
Ocular effects from exposure to vinyl acetate included eye irritation or reddened sclerae .None of these reported effects were severe, and all were reversible.Clothing impervious to liquid vinyl acetate, eg, rubber , should be worn to prevent skin contact.This clothing should include boots, gloves, coveralls, and face shields (8-inch minimum) with goggles or safety glasses with side shields.Such clothing should be cleaned inside and out after each use.Emergency showers and eyewash fountains should be readily available in case of accidental contact of the skin or eyes with vinyl acetate.When existing engineering controls are not adequate to reduce concentrations of airborne vinyl acetate to or below the recommended environmental limit, appropriate respiratory protective devices should be used, pending corrective action.
(e) Informing Employees of Hazards Exposure to vinyl acetate may cause respiratory, ocular, or dermal irritation.The reported irritation has not been severe, but prolonged contact with vinyl acetate may cause blisters on the skin or significant irritation of the eyes .Employees who may be exposed to vinyl acetate should be advised of the possible adverse effects of such exposure, methods of preventing exposure, and environmental and medical monitoring and surveillance procedures used to detect hazards.The benefits to workers of participating in these environmental and medical monitoring procedures should be stressed.
# (f) Work Practices and Engineering Controls
To minimize respiratory contact with vinyl acetate, engineering controls, preferably process enclosure, should be used when needed to control emissions into the workplace atmosphere.
Engineering controls should include local exhaust ventilation for processes known to produce large amounts of airborne vinyl acetate.
All vinyl acetate containers should be kept tightly closed when not in use, and should be stored properly, ie, conform to the provisions of CFR 1910.106 for storage of flammable and combustible liquids; this action should prevent breaks, spills, or contact with sources of ignition.
Vinyl acetate forms flammable and explosive mixtures with air at temperatures of -5.5 C and above, and has explosive limits, in air by volume, from 2.6 to 13.4% , so that it should be kept away from heat, sparks, flames, peroxides, aldehydes, or other agents that might cause a fire or an explosion.
Vinyl acetate is incompatible with nonoxidizing mineral acids, sulfuric acid, nitric acid, ammonia, aliphatic amines, and alkanolamines.Spills or leaks should be attended to promptly.
Emergency showers or eyewash fountains should be available and used to clean affected areas in case of gross skin or eye contact with vinyl acetate.All employees, including maintenance and repair personnel, should be fully informed of all procedures, routine and emergency, that their specific jobs entail.
The residual vinyl acetate vapor in confined spaces may exceed the recommended environmental limit.To ensure that workers in confined spaces are adequately protected, entry into confined spaces that may contain vinyl acetate vapor should be controlled by a work permit system.Permits should be signed by an authorized employer representative, certifying that the following preventive and protective measures have been taken.The confined space should be cleaned with steam, purged with air, and thoroughly ventilated, inspected, and tested for oxygen deficiency and for vinyl acetate and other contaminants before it is entered.Ventilation should continue while workers are in the confined space.Personal protective equipment should be readily available to the employee entering a confined space.Another worker stationed outside, equipped with approved personal protective and rescue equipment, should observe and be in communication with the employee working in the confined space.
# (g) Monitoring and Recordkeeping Requirements
To minimize exposure of employees to vinyl acetate, employers should anlayze engineering controls, work practices, and sanitation procedures on a continuing basis to ensure that they are operating as effectively as possible.
To ensure that concentrations of airborne vinyl acetate in the workplace do not exceed the recommended environmental limit, employers should conduct an industrial hygiene survey at least annually and as soon as possible after any change likely to result in increased concentrations of airborne vinyl acetate.If such a survey shows that concentrations of vinyl acetate in the workplace are above one-half the recommended ceiling limit, a personal monitoring program should be instituted, and both industrial hygiene surveys and personal monitoring should be repeated every 6 months.If personal monitoring shows that an employee is exposed to vinyl acetate at concentrations above the recommended ceiling limit, control measures should be implemented, the employee should be notified of the exposure and of the control measures being taken, and a personal monitoring program should be instituted, monitoring should be conducted weekly until two consecutive samples show that the employee is no longer overexposed to vinyl acetate.
Pertinent environmental monitoring and medical records should be retained for 30 years after termination of employment involving exposure to vinyl acetate.
# VII.RESEARCH NEEDS Epidemiologic Studies
Only one very limited (cross-sectional) epidemiologic report on employees exposed to vinyl acetate has been found in the literature, so that further research is required to assess the effects of long-term occupational exposure to vinyl acetate.Long-term epidemiologic studies that assess the effects of vinyl acetate on the skin, eyes, respiratory system, and general metabolic processes should be performed.These studies should include medical histories, specific pulmonary function studies, and comparison of the morbidity and mortality of exposed populations with those of appropriate control populations.
It is essential that accompanying industrial hygiene surveys accurately determine actual exposures in terms of concentrations, durations, and frequencies.Concomitant exposures to other chemicals should also be considered.
# Experimental Studies
Studies of both short-and long-term exposures to airborne vinyl acetate at low concentrations should be conducted in at least two animal species.Additional toxicologic experiments should be conducted on a variety of species to characterize, both functionally and anatomically, the nature of any changes induced by vinyl acetate and its metabolites.These studies should simulate occupational exposure regimens, in both the exposure schedule and the routes of exposure (inhalation and skin contact).
The results of these studies should provide insights into human susceptibility to the effects of low-level exposure to vinyl acetate.Skin absorption of liquid vinyl acetate in humans should be studied.
Well-designed and controlled behavioral studies should be undertaken to determine whether vinyl acetate affects the CNS, as some studies on humans and animals have suggested.
Electroencephalographic analyses of humans exposed to vinyl acetate should be conducted to determine whether low concentrations can induce adverse neurologic effects, and animal experiments should be conducted to determine whether or not permanent effects on the CNS can result from exposure to vinyl acetate.
The metabolic fate of vinyl acetate as a function of the concentration and duration of inhalation, including possible oxirane (epoxide) formation and the influence of modifiers of metabolism should be studied.Vinyl acetate's possible role as a substrate for esterases and the possible covalent binding of vinyl acetate or its metabolites to macromolecules should also be quantitatively evaluated. |
# Carcinogenic, Mutagenic, Teratogenic, and Reproductive Studies
No human or animal studies have been found on the possible teratogenic or reproductive effects of vinyl acetate and, thus, this type of research should be performed.Only one study of mutagenesis using Si^_ typhimurium and one study of carcinogenesis in rats have been found.Although the results of these studies showed no mutagenic or carcinogenic potential for vinyl acetate, further studies in several species are recommended because of vinyl acetate's structural similarity to compounds known to induce cancer.
# Sampling and Analysis
Improved methods of sampling and analysis for vinyl acetate should be investigated.An accurate and precise sampling system for airborne vinyl acetate, as well as convenient, portable direct-monitoring devices, should be developed further.
# IX.APPENDIX I METHOD FOR SAMPLING AND ANALYSIS OF VINYL ACETATE IN AIR
This analytical method for vinyl acetate is adapted from NIOSH Method No.P&CAM 278 (classification E) .A Class E method is defined by NIOSH as "Proposed:
A new, unproved, or suggested method not previously used by industrial hygiene analysts but which gives promise of being suitable for the determination of a given substance."The proposed validation range is 8-210 mg/cu m in a 1.5-liter sample.Although the method has not yet been validated at 7 mg/cu m, which is one-half of the recommended ceiling limit, it shows promise of being usable for determining vinyl acetate at this concentration.
# Principle of the Method
A known volume of air is drawn through a tube containing a Chromosorb 107 to trap the vinyl acetate present.The vinyl acetate is thermally desorbed into a 300-ml chamber.An aliquot of the desorbed vapor is injected into a gas chromatograph.The area of the resulting peak is determined and compared with the areas obtained from the injection of standards. (c) The lowest quantifiable level was determined to be 0.5 pxg of vinyl acetate/300-mg bed of Chromosorb 107.At this loading the relative standard deviation of replicate samples was better than 10%.
# Range and Sensitivity
# Interferences (a)
When two or more substances are known or suspected to be present in the air sampled, such information should be transmitted with the sample, because the substances may interfere with the analysis of vinyl acetate.
(b) Any substance that has the same retention time as vinyl acetate at the operating conditions described in this method is an interference.Therefore, retention time data on single or multiple columns cannot be considered proof of chemical identity.
(c) If the possibility of interference exists, separation conditions, eg, column packing, temperature, carrier flow, or detector, must be changed to circumvent the problem.
# Precision and Accuracy
(a) The pooled relative standard deviation of the sampling and analytical method was 8.1%.This reflects the precision of sampling and analysis of 50 samples of vinyl acetate collected with calibrated personal sampling pumps from humid atmospheres (>80%) over the concentration range of 8-206 mg/cu m. The relative standard deviation of samples collected from atmospheres averaging 8.6 mg/cu m (range 8.2-9.0) was 9.5%, from atmospheres averaging 24.3 mg/cu m (range 18.6-39.2) was 8.0%, and from atmospheres averaging 181 mg/cu m (range 159-206) was 5.9%.
(b) The concentration of the sampled air was independently determined using a gas-phase infrared analyzer.The samples were collected from humid air and stored at room temperature.The determination averaged 7% high, 5% high, and 4% low when analyzed on days 1, 7, and 14, respectively.Thus, the - sample displayed a 0.8%/day storage loss when stored at room temperature.This loss can be attributed to the analyte degrading in the presence of water, because samples spiked with 18 pig of vinyl acetate in "dry" hexane gave 98% recovery when stored for 14 days at room temperature.
(c) The breakthrough volume and therefore the capacity of Chromosorb 107 for vinyl acetate decreased with increasing relative humidity.Under the most adverse conditions tested, 83% relative humidity, the breakthrough volume was found to be 4.0 liters when an atmosphere of vinyl acetate at 113 mg/cu m was sampled at 0.125 liter/minute.
# Advantages and Disadvantages of the Method
(a) The sampling device is small, portable, and involves no liquids.
(b) The samples are analyzed using a quick instrumental method and the sampling tubes can be reused after the analysis is completed. (d) The precision of the method is limited by the reproducibility of the pressure drop across the sampling tubes.Variations in pressure drop will affect the flowrate.The reported sample volume will be imprecise because the pump is usually calibrated for one tube only.
# (e)
The amount of sample that can be collected is limited by the capcity of the sampling device.When the amount of vinyl acetate found on the backup section exceeds 10% of the amount found on the front section, the possibility of sample loss exists.Migration from the front to the backup section is not a problem because the sections are separated and individually capped immediately after sampling.Apparatus (a) Personal sampling pump capable of accurate performance at 0.1 liter/minute.The pump must be calibrated with a representative sampling device in line, and the pump battery must be fully charged prior to being used.
(b) Chromosorb 107 sampling tubes.
Individual front and backup tubes (Century Systems Corporation "Flare" tubes or equivalent) are used.The front section is a stainless steel tube 7.3 cm long with a 6-mm outer diameter, a 4mm inner diameter, and a 45-degree flare at one end.The backup section is a chrome-plated nickel tube 3 cm long with a 6-mm outer diameter, a 4-mm inner diameter, a 45-degree flare at one end and a hose connection at the other end.Each tube has a permanent metal frit in the outlet end of the tube.The front section contains 300 mg of prewashed Chromosorb 107 held in place with a removable metal frit.
The backup section contains 50 mg of prewashed Chromosorb 107 held in place with a plug of silylated glass wool.
The sampling device is assembled by joining the front and backup sections with a nylon nut and fitting.A hollow nylon ferrule is placed between the two sections.
The pressure drop across the tubes must be less than 10 inches of water at a flowrate of 0.1 liter/minute.The Chromosorb 107 is washed in a Soxhlet extractor for 8 hours with water, 8 hours with methanol, and 8 hours with dichloromethane.The sorbent is then dried overnight in a vacuum oven.The tubes are loaded with sorbent and thermally purged for 2 minutes with helium at 150 C. After cooling in a closed container, the ends are capped.
(c) Thermal desorber equipped with thermostatted desorbing oven, 300-ml sample reservoir, and a 2-ml gas sampling loop (Century Systems Corporation Programmed Thermal Desorber or equivalent). Under these conditions, the capacity ratio for vinyl acetate should be 4.4.
(4) Thermal desorption of samples.Wipe off the tube and insert it in the desorbing oven.Desorb with helium at atmospheric pressure.
The helium is stored in the 10-liter gas bag.Desorbing with air chars the Chromosorb and renders it unsuitable for reuse.
(5) Injection.
Inject a 2-ml aliquot of the desorbed vapors into the gas-chromatographic column.Since the desorbed vapors are stored in a reservoir, as many as five replicate injections of each sample can be made. After satisfactory analysis is obtained, purge the thermal desorber with helium for 2 minutes.
Remove the tube from the desorbing oven, place it in a test tube and cap the test tube.When the tube is cool, remove it from the test tube and cap it with the plastic caps. (2) Preparation of standards.Pipet 1.00-ml aliquots of hexane into clean glass vials.Crimp the vials shut with an aluminum serum cap equipped with a Teflon-lined silicone rubber septum.Inject either 25, 10, 5, or 1 ul of freshly distilled vinyl acetate into each vial.These standard solutions are freshly prepared for each analysis.
(3) Loading the standard.Support a U-tube on a ring stand.
Using a short length of tubing, attach the outlet end of a clean front section of a sampling tube to a small pump.The inlet end of the clean front section is attached to the side of the U-tube that has the hose connection.Use the solvent-flush technique to withdraw a 2-pil aliquot of a standard solution.Turn on the pump and inject this 2-jul aliquot into the end of the U-tube farthest from the sampling tube.
Sweep enough air through the U-tube (2 minutes at 200 ml/minute, approximately five volume changes) to ensure that all the vinyl acetate is loaded on the sample tube.Stop the pump, remove the sample tube, cap both ends, and label.This tube now contains a known amount of vinyl acetate.
# I (4)
Standardization.Analyze each tube from subsection (d)(3) as in subsection (c) (3).The standard curve is obtained by plotting the amount of vinyl acetate loaded on a tube vs the peak area found.If conditions warrant, prepare standards at higher or lower concentrations.
# (e) Calculations
(1) The sample weight in jug is read from the standard curve.
(2) Blank corrections are not expected.If the analysis shows a blank correction is needed, the correction is: WF = Ws -Wb where:
WF = corrected amount (jug) on the front section of the sample tube.Ws = amount (ptg) found on the front section of the sample tube.Wb = amount (jug) found on the front section of the blank sample tube.
A similar procedure is followed for the backup sections.
The concentration, C, of vinyl acetate in the air sampled is expressed in mg/cu m, which is numerically equal to jug/liter.
# C = WF + WB
where: WF = corrected amount of vinyl acetate found on front section in jug.WB = corrected amount of vinyl acetate found on backup section in /ug.V = volume of air sampled in liters.The "materials" listed in Section II shall be those substances which are part of the hazardous product covered by the MSDS and individually meet any of the criteria defining a hazardous material.
Thus, one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, while a third component could be included both for its toxicity and its reactivity.Note that a MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients.Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature.Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known.
The "%" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole possible.The basis might be animal studies, analogy with similar products, or human experiences.Comments such as "yes" or "possible" are not helpful.Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation.
Eye Contact-some pain and mild transient irritation; no corneal scarring.
"Emergency and First Aid Procedures" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid.
Information in the "Notes to Physician" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed employees.
# (f) Section VI.Reactivity Data
The comments in Section VI relate to safe storage and handling of hazardous, unstable substances.It is particularly important to highlight instability or incompatibility to common substances or circumstances, such as water, direct sunlight, steel or copper piping, acids, alkalies, etc. "Hazardous Decomposition Products" shall include those products released under fire conditions.It must also include dangerous products produced by aging, such as peroxides in the case of some ethers.Where applicable, shelf life should also be indicated.
(g) Section VII.Spill or Leak Procedures Detailed procedures for cleanup and disposal should be listed with emphasis on precautions to be taken to protect employees assigned to cleanup detail.
Specific neutralizing chemicals or procedures should be described in detail.Disposal methods should be explicit including proper labeling of containers holding residues and ultimate disposal methods such as "sanitary landfill" or "incineration."Warnings such as "comply with local, state, and Federal antipollution ordinances" are proper but not sufficient.Specific procedures shall be identified.
(h) Section VIII.Special Protection Information Section VIII requires specific information.Statements such as "Yes," "No," or "If necessary" are not informative.Ventilation requirements should be specific as to type and preferred methods.Respirators shall be specified as to type and NIOSH or Mine Safety and Health Administration approval class, ie, "Supplied air," "Organic vapor canister," etc.Protective equipment must be specified as to type and materials of construction.
(i) Section IX.Special Precautions "Precautionary Statements" shall consist of the label statements selected for use on the container or placard.Additional information on any aspect of safety or health not covered in other sections should be inserted in Section IX.The lower block can contain references to published guides or in-house procedures for handling and storage.Department of Transportation markings and classifications and other freight, handling, or storage requirements and environmental controls can be noted.
(f) Vials, 1.5-ml, with aluminum serum cups equipped with Teflon-lined silicone rubber septa.
(g) Microliter syringes, 10-jul and convenient sizes for making standards.
(h) Pipette, 1,000-jul, with disposable plastic tips.
(i) U-tube, glass with at least one hose connection, approximately 75-ml internal volume.
(j) Pump capable of drawing 200 ml/minute through the front section of the sampling device.
(k) Gas bag, 10-liter volume for helium purge gas.
(1) Test tubes with close-fitting plastic caps.
(m) Ring stand with clamps.
# Reagents
Whenever possible, reagents used should be ACS Reagent Grade or better.All nondisposable glassware used for the laboratory analysis of vinyl acetate is washed with detergent and rinsed thoroughly with tapwater and distilled water. (1)
Immediately before sampling, remove the plastic caps from the inlet and outlet ends of the sampling tube.
(2) Connect the tube to the sampling pump using a short piece of flexible tubing.The backup section is positioned nearest the pump.
The sampling tube is kept vertical during sampling to prevent channeling through the device.
(3) Air being sampled must not pass through any hose or tubing before entering the sampling device.
(4) The temperature, pressure, and volume of air sampled is measured and reported.The volume sampled should not exceed 3 liters, sampled at a flowrate of 0.1 liter/minute or less.Record either the flowrate and sampling time or the initial and final stroke readings and the volumetric stroke factor.
(5) Immediately after sampling, disassemble the two sections, cap the sections with .plastic caps, and label the sections.
Do not use rubber caps.
(6) For every 10 samples taken, handle one sampling device in the same manner as the samples (uncap, disassemble, cap, label, and transport); however, do not sample any air through this device.Label this device as a blank.Typical operating conditions for the gas chromatograph are: (A) 33 ml/minute helium carrier gas flowrate (B) 40 ml/minute hydrogen flow to detector (C) 435 ml/minute airflow to detector (D) 160 C injector temperature (E) 160 C manifold (detector) temperature (F) 60 C oven temperature mixture.This may be indicated as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets.
Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50skin-rabbit,"
"75 ppm LC man," or "permissible exposure from 29 CFR 1910.1000," or, if not available, from other sources of publications such as the American Conference of Governmental Industrial Hygienists or the American National Standards Institute Inc. Flashpoint, shock sensitivity, or similar descriptive data may be used to indicate flammability, reactivity, or similar hazardous properties of the material.
# (c) Section III.Physical Data
The data in Section III should be for the total mixture and should include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor pressure, in conventional millimeters of mercury (mmHg); vapor density of gas or vapor (air = 1); solubility in water, in parts/hundred parts of water by weight; specific gravity (water = 1); percent volatiles (indicated if by weight or volume) at 70 F (21.1 C); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor.These data are useful for the control of toxic substances.
Boiling point, vapor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment.This information is also useful for design and deployment of adequate fire and spill containment equipment.
The appearance and odor may facilitate identification of substances stored in improperly marked containers, or when spilled.
# (d) Section IV.Fire and Explosion Data
Section IV should contain complete fire and explosion data for the product, including flashpoint and autoignition temperature in degrees Fahrenheit (Celsius in parentheses); flammable limits, in percent by volume in air; suitable extinguishing media or materials; special firefighting procedures; and unusual fire and explosion hazard information.If the product presents no fire hazard, insert "NO FIRE HAZARD" on the line labeled "Extinguishing Media."
# (e) Section V. Health Hazard Information
The "Health Hazard Data" should be a combined estimate of the hazard of the total product.This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard.Other data are acceptable, such as lowest LD50 if multiple components are involved. |
Under "Routes of Exposure," comments in each category should reflect the potential hazard from absorption by the route in question.
Comments should indicate the severity of the effect and the basis for the statement if |
# (b) Protective Clothing
In any operation where the worker may come into direct contact with liquid ethylene dichloride, protective clothing shall be worn.The clothing shall be both impervious and resistant to ethylene dichloride.
Gloves, boots, overshoes, and bib-type aprons that cover boot tops shall be provided when necessary.Impervious supplied-air hoods or suits shall be worn when entering confined spaces such as pits or tanks unless known to be safe.
In situations where heat stress is likely to occur, air-supplied suits shall be used.All protective clothing shall be well-aired and inspected for defects prior to reuse. (1)
Samples shall be collected at least quarterly in accordance with Appendix I for the evaluation of the work environment with respect to the recommended limit.
( In a few of these capsule formations, there was desquamated epithelium.The renal tubular epithelium was swollen, and the tubules and lumina had many damaged cells.
The straight portions of the epithelium were the most severely affected.
The liver showed individual or small groups of transparent cells and degenerative nuclear changes.There was considerable swelling of the reticuloendothelium, leukocytic infiltration, and moderate fatty degeneration.
The course of illness of the second worker (the 39-year-old man), who also died, followed a similar pattern with conspicuous jaundice and anuria. ---- Rats, guinea pigs, rabbits, and monkeys were exposed at 400 ppm ethylene dichloride 7 hours/day, 5 days/week for various periods.All female rats were killed by the 10th exposure and all males by the 40th exposure.All male guinea pigs were killed by the 10th exposure and all females by the 24th.One female and 2 male rabbits were exposed 165 times. From these considerations it would appear that a more realistic appraisal of the TWA exposures of the majority of workers is 10-15 ppm.
Crystallization
Ethylene dichloride was found in the milk of nursing women occupa tionally exposed at approximately 15.5 ppm for an unspecified time.
The concentrations of ethylene dichloride in the milk ranged from 0.54 to 0.64 mg %.Concentrations of about 14.5 ppm ethylene dichloride were found in the women's breath.
Eighteen hours after exposure, the concentrations of ethylene dichloride in milk samples and breath were found to be 0.195- Both male and female guinea pigs exposed at 100 ppm ethylene dichlo ride for as many as 162 7-hour exposures in 226 days had reduced growth rates and increased liver to body weight ratios compared to controls.
Lung, heart, kidney, spleen, and testes organ weight to body weight ratios were normal.
Cats similarly exposed also had reduced growth rates.
A summary of findings from animal exposures is presented in Table XII- A total of 30 breathing zone samples were taken in the center of the room and at points considered to have high concentrations of vapor.Twenty-five of the 30 measurements exceeded the maximum permissible concentration of 12.4 ppm (50 mg/cu m ) .The highest concentration of ethylene dichloride was found during its suction transfer from a carboy into the extractor.
During the 7-10 minutes required for this transfer operation, concentrations of 5.6 to 22.5 ppm (22.7-90.0 mg/cu m) were found.Ethylene dichloride vapor was also released during the discharge of brine into a sewer after it had been used for washing the ethylene dichloride extract.
Cetnarowicz reported ethylene dichloride concentrations in a petroleum refinery which used an extraction solvent containing 80% ethylene dichloride and 20% benzene to separate and purify mineral oils from paraffins.
The concentrations determined at 4 locations within the refinery ranged from 10 to 200 ppm (0.04-0.8 mg/liter).The results of 2-3 samples collected at each site are presented in Table III-l.
The measured benzene concentrations ranged from 10-25 jug/liter.The sampling and analytical methods used in this study were not given. In another study, Brzozowski Carbon disulfide was determined to be the best desorbent for ethylene dichloride collected in charcoal tubes.
# (c) Analysis
Several methods have been used to quantify ethylene dichloride in air samples.
The analytical methods can be divided into 2 broad categories:
( V.
# DEVELOPMENT OF STANDARD
# Basis for Previous Standards
The in order to avoid confusion about the word ''allowable" in the MAC concept.
The TLV was maintained at 75 ppm until 1952.At that time, the ACGIH changed the TLV back to 100 ppm.Again, no information was given about the reasons for the change.
The definition of TLV as a time-weighted average (TWA) was formulated in 1953 by the ACGIH.
The Under these conditions, it should not be necessary to comply with all of the provisions of this recommended standard.However, concern for worker health requires that protective measures be instituted below the enforceable limit to ensure that exposures stay below that limit.Therefore, environmental monitoring and recordkeeping is recommended for those work situations which involve exposure above one-half the recommended limit, to delineate work areas that do not require the expenditure of health resources for control of inhalation hazards.One-half the environmental limit has been chosen on the basis of professional judgment rather than on quantitative data that delineate nonhazardous areas from areas in which a hazard definitely exists.
# VI.WORK PRACTICES
The principal method for manufacturing ethylene dichloride is by reacting chlorine with ethylene. Other chlorinated ethanes may be co products of ethylene dichloride manufacture and caution must be taken to avoid exposure to these substances as well.
# EXTREME CAUTION MUST BE EXERCISED AT ALL TIMES WHEN USING CARBON DISULFIDE BECAUSE OF ITS HIGH TOXICITY AND FIRE AND EXPLOSION
# HAZARDS.IT CAN BE IGNITED BY HOT STEAM PIPES.ALL WORK WITH CARBON DISULFIDE MUST BE PERFORMED UNDER AN EXHAUST HOOD. (d) Typical chromatographic operating conditions:
(1) 50 ml/min (70 psig) helium carrier gas flow.
(2) 65 ml/min (24 psig) hydrogen gas flow to detector.
(3) 500 ml/min (50 psig) airflow to detector. |
Lead poisoning remains one of the most common and preventable pediatric environmental conditions even though the United States (US) has made great strides in reducing the number of children with elevated blood lead levels.One objective of Healthy People 2010 is to eliminate blood lead levels (BLLs) >10 µg/ dL among the nation's children.US children living in poorly maintained housing built before 1978 are at greatest risk for elevated BLLs because of their frequent exposure to lead-based paint and lead-contaminated house dust and soil.
The prevalence of elevated blood lead levels (i.e., BLLs >10 µg/dL) among newly resettled refugee children is substantially higher than the 2.2% prevalence for US children.
# Background:
New Hampshire requires blood lead screening of newly arrived refugee children aged 6 months to 16 years.Beginning in May 2004, 242 refugee children, predominately from Africa, were resettled to New Hampshire.Of these, 96 children were tested twice for BLLs.The first blood lead samples were collected within 90 days of the children's arrival, and the second samples were collected 3 to 6 months after their resettlement.Most of the children had initial capillary BLLs 10 µg/dL; as did 5 other children who were siblings of cases (range: 11 to 73 µg/dL).Eleven of the recently resettled families had at least one child with a BLL >20 µg/dL. Environmental investigations revealed moderate lead hazards within the residences of the children as well as lead-contaminated soil in play areas frequented by the children.The children with elevated BLLs also showed evidence of extreme chronic malnutrition.Health examinations before arriving in the US indicated that 16 (37.2%) of the children had severe growth retardation (Height per Age Z-score <2; or approximately the second percentile on the standard pediatric growth curve) and, of the 40 children for whom weight was measured, 10 (25%) had evidence of failure to gain weight or of loss of weight (Weight per Height Z-score <2; or approximately the second percentile on the standard pediatric growth curve).
# Recommendations: Primary Prevention of Elevated Blood Lead Levels
Ideally all children would live in lead-safe housing, especially those whose nutritional status and lack of knowledge about the dangers of lead place them at great risk for lead poisoning.However, we recommend the following to reduce the risk of lead exposure in refugee children: 2.Repeat BLL testing of all refugee children 6 months to 6 years 3 to 6 months after refugee children are placed in permanent residences and older children, if warranted, regardless of initial test results.
- Children who mouth or eat non-food items, especially soil, which is common among certain refugee populations, are at risk for lead poisoning, regardless of the age of their housing. -The New Hampshire case study demonstrates that although some children had elevated BLLs when they arrived in the US, the majority of the children did not.The follow-up screening which was conducted on average 60 to 90 days after the placement of the children in the state and in their permanent residences, revealed elevated BLLs that ranged from 11 to 72 µg/dL. - The refugee status for most of the children entitles them to Medicaid, WIC, and other social services for at least 8 months after their resettlement, regardless of family financial status. |
A goal of CDC's National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP) is to strengthen collaborative work across disease areas and integrate services that are provided by state and local programs- for prevention of HIV/AIDS, viral hepatitis, other sexually transmitted diseases (STDs), and tuberculosis (TB).A major barrier to achieving this goal is the lack of standardized data security and confidentiality procedures, which has often been cited as an obstacle for programs seeking to maximize use of data for public health action and provide integrated and comprehensive services.Maintaining confidentiality and security of public health data is a priority across all public health programs.However, policies vary and although disease-specific standards exist for CDC-funded HIV programs, similarly comprehensive CDC standards are lacking for viral hepatitis, STD, and TB prevention programs.Successful implementation of common data protections in state and local health departments with integrated programs suggest implementation of common data security and confidentiality policies is both reasonable and feasible.These programs have benefited from enhanced successful collaborations citing increased completeness of key data elements, collaborative analyses, and gains in program efficiencies as important benefits.Despite the potential benefits, however, policies have not been consistently implemented and the absence of common standards is frequently cited as impeding data sharing and use.Adoption of common practices for securing and protecting data will provide a critical foundation and be increasingly important for ensuring the appropriate sharing and use of data as programs begin to modify policies and increasingly use data for public health action.This document recommends standards for all NCHHSTP programs that, when adopted, will facilitate the secure collection, storage, and use of data while maintaining confidentiality.Designed to support the most desirable practices for enabling secure use of surveillance data for public health action and ensuring implementation of comprehensive evidencebased prevention services, the standards are based on 10 guiding principles that provide the foundation for the collection, storage, and use of these public health data.They address five areas: program policies and responsibilities, data collection and use, data sharing and release, physical security, and electronic data security.Intended for use by state and local health department disease programs to inform the development of policies and procedures, the standards are intentionally broad to allow for differences in public health activities and response across disease programs.The standards, and the guiding principles from which they are derived, are meant to serve as the foundation for more detailed policy development by programs and as a basis for determining if and where improvements are needed.The process includes seven main steps: designating an overall responsible party; performing a standards-based initial assessment of data security and confidentiality protections; developing and maintaining written data security policies and procedures based on assessment findings; developing and implementing training; developing data-sharing plans or agreements as needed; certification of adherence to standards; and#
S tandards to Facilitate Sharing and Use o f S urveillance Data fo r P ublic H ealth A c tio n
i f H i f i S ) r V 1 J H i i i i i l o )
# II.Introduction
The true value of surveillance is measured by its impact on public health action and practice.1 Public health agencies at all levels have broad authority to collect, store, and use personal health information to identify, report, and control health threats and to plan, implement, and evaluate public health programs and services.The public trusts that any personal or confidential information collected as part of public health activities will be held securely and confidentially and will be used for legitimate public health purposes.Although protections exist through various laws, policies and procedures, these protections vary across jurisdictions2-4 and sometimes even within public health organizations.5
A goal of CDC's National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP) is to strengthen collaborative work across disease areas and integrate services that are provided by programs for prevention of HIV/AIDS, viral hepatitis, other sexually transmitted diseases (STDs), and tuberculosis (TB).6 A major barrier to achieving this goal is the lack of standardized data security and confidentiality procedures, which has often been cited as an obstacle for programs seeking to maximize use of data for public health action and provide integrated and comprehensive services.7 Although disease-specific standards exist for CDC-funded HIV programs,8,9 similarly comprehensive CDC standards are lacking for viral hepatitis, STD, and TB prevention programs.
CDC established data security and confidentiality guidelines for CDC-funded HIV surveillance programs in state and local- health departments in 19988 and updated the guidelines in 2006.9
The guidelines emphasize the protection of surveillance data and prohibit HIV surveillance programs from sharing data with programs that lack equivalent data security and confidentiality protections.These restrictions on data sharing had the unintended consequence of inhibiting the ability of some local health departments to link clients to appropriate treatment and prevention services.7,1 0
In 2008, CDC published updated recommendations for programs providing partner services for HIV, syphilis, gonorrhea, and chlamydial infections.The document includes recommendations related to record keeping, data collection, data management, and data security that were based on previously published HIV surveillance guidelines.1 1 The partner services recommendations encourage data linkage and sharing between public health service-provision prevention programs and disease-reporting surveillance systems.The recommendations suggest that sharing of individual-level surveillance data can help facilitate the timely provision of partner services but also underscore the need for well-defined security and confidentiality policies and procedures.Despite the potential benefits, however, these have not been consistently implemented.
In addition, CDC cooperative agreements with TB programs require that policies and procedures must be in place to protect the confidentiality of all TB surveillance case reports and files.TB programs should also collaborate with HIV/AIDS programs to conduct at least annual TB and AIDS registry matches to ensure completeness of reporting of HIV and TB coinfected patients to both surveillance systems.However, this collaboration has been hampered by perceived differences in policies and procedures to protect HIV test results.
# This document does not
# III.A bout this D ocum ent
This document recommends standards for data security, confidentiality, and use across surveillance and program areas for HIV, viral hepatitis, STD, and TB prevention in state and local health jurisdictions.The standards support the most desirable practices for enabling secure use of data and ensuring comprehensive preventive services while being broad enough to allow for differences in public health activities by disease program.The standards address five areas: program policies and responsibilities, data collection and use, data sharing and release, physical security, and electronic data security.
The standards are based on 10 guiding principles that provide the foundation for the collection, storage, and use of surveillance data for public health action.The guiding principles are derived from existing CDC policies and guidelines, model and existing legislation, and from related work, including current security and confidentiality principles for NCHHSTP's HIV surveillance programs and practical application of ethics in public health surveillance.8,9,11,13-20 Similar principles have been proposed as part of a national strategy2 1 consistent with public health values22,23 to ensure the privacy and security of public health data at all levels.
The standards are intended to apply to public health programs funded by NCHHSTP (including those of state and local health departments and their contractors) that are responsible for collecting, storing, and using surveillance data and to any entities with which these programs share data.The standards address the use of both identifiable (i.e., personally identifiable information ) and nonidentifiable data and may include: data used for epidemiologic investigations; data used to link patients with partner services, appropriate treatment, interventions, and other health services; and data used for case management and program evaluation.Because the use of identifiable data requires a higher level of protection than the use of nonidentifiable data, the document includes specific standards for the sharing of identifiable data.Key definitions for data sharing, data release, data release agreement, data dissemination, and personally identifiable information are highlighted in the box above and additional terms are provided in the Glossary (Appendix A).
# IV.Using this D ocum ent
Active data stewardship involves developing proactive policies, procedures, and training to ensure that public health data are collected, stored, and used appropriately.To that end, policies related to the security and sharing of data should be reviewed regularly and changed as needed.The data standards and the guiding principles from which they are derived are meant to serve as the foundation for more detailed policy development by programs and as a basis for determining if and where improvements are needed.Key components of data security and confidentiality, sharing, and use policy development are outlined below.
Overall Responsible Party (ORP)-A high-ranking official should be identified to accept overall responsibility for implementing and enforcing data security, confidentiality and sharing standards.This official should have the authority to make decisions about program operations that might affect programs authorizing, accessing or using the data, and should serve as the contact for public health professionals regarding security and confidentiality policies and practices. Certification-Programs are required to self-certify their adherence to the standards for ensuring the security, confidentiality, and appropriate use of the data they collect, store, and share.The certification statement should:
# S a m p l e c h e c k lis ts fo r c o n d u c t i n g in itia l a n d c o m p r e h e n s i v e a s s e s s m e n t s a r e p r o v i d e d in A p p e n d i x B.
# Data Security and Confidentiality Policies and
Identify one or more persons as the ORP for ensuring adherence to the standards Attest to adherence to all standards, or explain any lapses If lapses, describe steps to meet the standards in the future Describe policies and procedures instituted to ensure continued adherence to the standards NCHHSTP will describe the certification process in applicable program announcements.NCHHSTP will conduct periodic reviews of the data security, confidentiality and sharing procedures of grant recipients during routine site visits and provide technical assistance as needed.
# A s u g g e s t e d f o r m a t fo r a c e r tific a tio n s t a t e m e n t is p r o v i d e d in A p p e n d i x D.
Periodic and Ongoing Reviews and Assessments-Programs should review their data security, confidentiality, and sharing policies and procedures at least annually or sooner if improved technologies or legislative/regulatory changes occur and revise as necessary.In addition, they should periodically assess whether other changes in personnel, programs, organizations, or priorities require changes in policies and procedures.For example, changes in federal standards for encryption could affect existing policies and procedures and require software updates or other revisions.
Programs should also review their data-sharing plans or agreements periodically in light of improved technologies and revise as necessary.Tracking the security and confidentiality training of staff members authorized to access data, including documenting and storing their signed confidentiality agreements, should also be part of ongoing assessment activities.
# V. Benefits, Risks, and Costs of Sharing Data and M aintaining Security and Confidentiality
There is a balance that must be maintained between protecting the individual and the public from disease and protecting individuals' confidentiality and right to privacy.Both are vital to enhancing the public's health and maintaining the public's trust.Programs that have and follow consistent guidelines for the collection, storage, and use of HIV, viral hepatitis, STD, and TB data may reassure individuals, and the public, that sharing data for public health action will not compromise confidentiality.
Adherence to harmonized standards for data security across programs will enhance the ability to share data without compromising confidentiality.As programs consider how best to meet these standards, it is helpful to consider the benefits, risks, and costs. Written policies should address procedures for the dissemination of nonidentifiable summary data to stakeholders and the public.Summary data should be disseminated in a manner that facilitates understanding by affected populations and illuminates the compounding impact of syndemics.
# S e e A p p e n d i x E fo r a s u g g e s t e d o u t li n e o f a p o l ic y fo r d a t a se c u r ity , c o n fid e n tia lity , s h a r in g a n d u se .
Since some aggregate data could be used to identify individuals, policies should usually restrict release of certain data elements to avoid a confidentiality breach.Wider public access and searchability of databases (e.g., death records and obituaries) increases the capability to re-identify other de-identified data.Consideration should be given to consulting with de-identification experts prior to release when in doubt.In some instances, the obligation to use the data to help members of demographic groups examine trends and burden of disease for public health planning might outweigh the risk of possible stigma that could be associated with some aggregate data.For example, the release of data showing high rates of alcohol and drug use in a small community, although potentially stigmatizing, must be weighed against the potential additional resource planning and allocation for drug and alcohol treatment services that could result from such a release. -----
# STANDARD 4.6 Ensure that documents with line lists or supporting notes contain the minimum amount of potentially identifiable information necessary and, if possible, that any potentially identifiable data are coded to prevent inadvertent release of PII.
To the extent possible, PII should not be removed from a secure location or accessed from an unsecure area.However, some public health activities (e.g., field investigations and service provision) require taking such information into unsecure areas.In these situations, the use of PII should be limited and appropriate security measures implemented.
# GUIDING QUESTIONS:
» Is access to public health notes and investigation information containing identifiable data limited to personnel requiring the information for an approved purpose?
» Are confidential data elements coded?
# ELECTRONIC DATA SECURITY
Implementation of electronic data security standards will be conducted in a rapidly evolving technological environment.While technology is changing, the following elements will remain important to consider when developing policies.
Access: Access to surveillance data needs to be planned in advance.Access groups can be set up in virtually all IT environments, which will allow the program to designate users with different levels and types of rights.Programs should specify who has access to various data, under what circumstances, and how the identity of users are authenticated.For example, they might stipulate that identifiable data should be accessed only from a properly secure network server rather than from local workstations.Isolated segments or domains can be implemented, which limits access to those in selected groups.They also might limit the times during which data can be accessed, restrict the copying or downloading of data, and set up other controls as needed.Due to the technical nature of these control measures, IT personnel should be involved in the initial assessment and both the formulation and implementation of electronic data security policies.
# A p p e n d i x G a ls o a d d r e s s e s e le c tr o n ic d a t a s e c u r ity issu e s.
Encryption and Backups: Although encryption may not be needed for data on a production registry or surveillance data system located within a secure area and separate from any networks, encryption is still recommended.Any data in such a registry or system do need to be encrypted before being transmitted or downloaded to approved locations and while being used in the field on laptops or similar devices.Although surveillance databases and other files with identifying information need to be backed up, back-up databases and files should be encrypted in accordance with federal encryption standards and stored in a secure location. Before any portable device containing sensitive data is removed from a secure area, the data must be encrypted.Methods used to sanitize a storage device must ensure that any data on the device cannot be retrieved by using "undelete" or data retrieval software.Hard drives, flash drives, or any other storage media of computers that once contained PII must be sanitized or physically destroyed before the computers are labeled as excess or surplus, reassigned to other staff members, or sent off-site for repair.This requirement also applies to copiers, printers, fax machines, or other equipment that contain internal storage devices. The faxing of identifiable information is allowed but should be avoided when possible (see Appendix F for guidelines on the use of facsimile machines).The sender of a fax cannot be certain that the fax will actually be received by the person for whom it was intended.Although encrypted fax machines are available, they would be needed at both ends of an encrypted fax transmission.
# GUIDING
When a fax is necessary, minimize inclusion of confidential information.
Take precautions (such as a telephone call) to ensure that the recipient is present to receive, and confirm receipt of, the fax.
# GUIDING QUESTIONS:
» Have all alternatives to faxing PII been explored? »Have confidential data items been kept to a minimum?
» Have steps been taken to ensure that a person is standing by to receive and confirm receipt of a fax containing PII?
» Have the steps in Appendix F been followed to ensure secure use of fax machines? |
control, compromise, unauthorized disclosure, unauthorized acquisition, unauthorized access, or any similar term referring to situations where persons other than authorized users and for an other than authorized purpose have access or potential access to personally identifiable information, whether physical or electronic.
Confidential information: Any private information about an identifiable person who has not given consent to make that information public.
Confidentiality: Protection of personal information collected by public health organizations.The right to such protection is based on the principle that personal information should not be released without the consent of the person involved except as necessary to protect public health.
Confidentiality agreement (or nondisclosure agreement): A contract between at least two parties that outlines confidential material, knowledge, or information that the parties wish to share with one another for certain purposes, but wish to restrict access to by third parties.It is a contract through which the parties agree not to further disclose information covered by the agreement.Disclosure: Occurs when identifiable information concerning an individual is made known to a third party.Disclosures may be a u t h o r i z e d (as when a person has consented to the information being so divulged), u n a u t h o r i z e d (as when information is intentionally revealed to a party not consented to by the person), or i n a d v e r t e n t (as when a tabulation or file is unintentionally made available to the public that reveals or can be used to reveal personal information).
Encryption: Manipulation or encoding of information so that only parties intended to view the information can do so.The most commonly available encryption systems involve public key and symmetric key cryptography.In general, for both public and symmetric systems, the larger the key, the more robust the protection.
Identifiable data or identifiable information: See P e r s o n a lly id e n tifia b le i n fo r m a tio n .Personal identifier: Information that allows the identity of a person to be determined with a specified degree of certainty.This could be a single piece of information or several pieces of data which, when taken together, may be used to identify an individual.Therefore, when assembling or releasing analysis data sets, it is important to determine which fields, either alone or in combination, could be used to identify a person and which controls provide an acceptable level of security.Syndemic: Synergist interaction of two or more conditions that contribute to an excess burden of disease in a population.
Virtual private network (VPN): Network of computers that uses encryption to scramble all data sent through the internet-making the network "virtually" private.
# Periodic A ssessm en t Checklist
This checklist can be used to guide the periodic assessment of a program's compliance with the Standards for Data Security and Confidentiality.
For the answer to be "yes" to a question with multiple parts, all boxes must be checked.For each "No" response, provide additional information describing how the program intends to achieve compliance with that standard. |
depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Approximately one third of the world's population is infected with Mycobacterium tuberculosis (1), and despite an overall decline in tuberculosis (TB) cases in the United States, TB continues to pose substantial social, public health, and economic costs.In 2003, approximately 15,000 new cases of TB were reported in the United States (2), and an estimated 9-14 million persons have latent TB infection with attendant risk of future disease (3).
The laboratory is an essential part of the diagnosis, treatment, prevention, and control of TB (4).Delays in laboratory confirmation of TB and reporting of drug-susceptibility results can lead to delays in initiation of therapy, prolonged infectiousness, inappropriate therapy, and missed opportunities to prevent transmission (5,6).In the early 1990s, such delays contributed to the resurgence of TB and the emergence of multidrug-resistant TB (MDR TB) in the United States (5,6).
In response to the threat of MDR TB, CDC increased funding to strengthen public health laboratories and placed emphasis on providing prompt and reliable laboratory results (5,7).Since the early 1990s, public health laboratories have made substantial strides in improving test performance (7)(8)(9).These improvements contributed to the resumption of the decline of the incidence of TB in the United States and a decrease in MDR TB cases (10,11) since the mid-1990s.April 15, 2005 Nevertheless, TB outbreaks still occur and MDR TB continues to spread.For TB to be eliminated in the United States, further improvements in laboratory services are needed, and these advances need to be translated into improvements in the treatment, prevention, and control of TB (11).
Prompted by an Institute of Medicine (IOM) report (4) and by the growing need for high-quality, cost-effective TB laboratory services in a time of declining case rates and shifting public health priorities, the Association of Public Health Laboratories (APHL) and CDC commissioned the APHL Task Force on the Future of TB Laboratory Services in 2002.The Task Force includes representatives from APHL, CDC, public health laboratories, clinical laboratories, and the National Tuberculosis Controllers Association (NTCA).
The Task Force's primary goal was to develop a framework to improve TB control by promoting optimal use of laboratory services and effective information tracking and reporting.The Task Force defined concerns critical to laboratorians performing TB testing, public health officials, TB-control officials, and health-care providers and created benchmarks and outcome measures to promote delivery of prompt, highquality, state-of-the-art laboratory services.This report summarizes the recommendations of the Task Force and describes in greater detail specific actions and performance measures to guide development and implementation of an integrated system for providing TB laboratory services.This report also provides information on the scientific basis of the recommendations.
# Background
The increased incidence in TB cases during the mid-1980searly 1990s prompted an acceleration of TB-control efforts and focused attention on the role of the mycobacteriology laboratory in supporting patient management and TBcontrol efforts (4)(5)(6).Altogether, TB-related costs approach $1 billion each year in the United States (12).In addition, human immunodeficiency virus (HIV) infection is one of the greatest risk factors for development of TB (13).Prompt and reliable laboratory test results are critical for HIV-infected TB patients because of differences in the clinical analysis and more rapid course of the disease (14).
Since 1995, CDC has provided approximately $8 million/ year to state and local public health laboratories to improve TB laboratory services (7) and has placed increased emphasis on reliable and prompt results (5,7).The latter included efforts to reduce the delays associated with laboratory testing for M. tuberculosis, to improve communication between laboratorians and health-care providers, and to maintain a trained workforce.Recommendations developed during the mid-1990s for TB laboratory services (9,15,16) remain valid and include
- prompt delivery of specimens to the laboratory; - use of rapid, state-of-the-art methods (e.g., fluorescence microscopy, liquid media, and rapid identification methods); - reporting of smear results to health-care providers within 1 day; - reporting of culture identification of M. tuberculosis complex within 21 days; - reporting of drug-susceptibility test results within 30 days; and - reporting of all positive test results to the specimen submitter within 1 working day from the date of report.Reports demonstrate that during the 1990s, the emphasis on rapid diagnosis and other improvements in laboratory services contributed substantially to the resumption in the decline of the incidence of TB and the decrease in MDR TB cases nationwide (4,10).TB incidence is limited in certain areas of the United States, but other regions, especially those with substantial immigrant populations, still have high caseloads (4,17).Regardless of caseloads and incidence, effective TB treatment and control require prompt and reliable laboratory services.
Laboratory confirmation of a TB case often depends on a network of laboratories providing testing for diagnosis, treatment, and monitoring of therapy outcomes (18)(19)(20).However, information is limited regarding the capabilities, capacities, and interactions of the approximately 2,000 TB laboratories at state and local levels and in the private and public sectors.For example, all 50 state public health laboratories perform a level of TB testing and usually serve as the major referral and reference laboratories for culture identification and M. tuberculosis drug-susceptibility testing (7,8); in addition, certain medical centers and commercial laboratories provide advanced TB testing services (21,22).However, the precise contribution of each to TB laboratory services within a jurisdiction is unknown.Approximately 80% of initial TB laboratory testing (e.g., smear and culture inoculation) is performed in the private sector, whereas >50% of species identification and drug-susceptibility testing is conducted in public health laboratories (21).
Within a network of laboratories, referring specimens or isolates to other laboratories for testing is common and often involves both the private and public sectors (18)(19)(20)(22)(23)(24)(25)(26).Referral of specimens and cultures can lead to delays in testing, reporting, and treatment initiation for TB patients with smear-positive or smear-negative/culture-positive results (24).
Reimbursement models also complicate this process because they might contradict the common practice in which a specimen from a patient with a smear-positive result identified at a local site is referred to a full-service laboratory for culture.The complexities of TB testing and referral underscores the need for an integrated system that emphasizes efficient flow of specimens and information between public health and private-sector laboratorians, clinicians, and TB-control officials.
# Challenges
Improving TB laboratory services and developing a new, integrated approach is complicated by concerns regarding funding, communication, turnaround times, technology, workforce competence, information management systems, and maintaining proficiency standards.
# Funding
Because TB laboratory services are provided by both public and private laboratories and supported through a combination of private-sector dollars, Medicare and Medicaid payments, and local, state, and federal funds (4,7,12), the actual cost of providing these services is difficult to estimate.Levels of local, state, and federal funding for TB laboratories have remained constant or have decreased during recent years, and federal funding levels for state public health laboratories to improve TB testing have remained constant at approximately $8 million/year since 1995 (5,7).
# Communication
Delays in referring specimens and reporting information can lead to delays in diagnosis, disease treatment and control, and surveillance activities (7,(24)(25)(26).To optimize TB diagnostic, treatment, and control activities, the flow of specimens and information among laboratorians, clinicians, and TBcontrol officials should be efficient and well-coordinated.This will require increased communication and coordination among state public health laboratories, clinical laboratories, clinicians, and TB-control programs.Advances in information technology promise to speed the flow of information among key persons, thereby enhancing disease reporting and epidemiologic analysis of disease trends.However, resources to develop and install modern, integrated, compatible, electronic information systems are limited (27).
# Turnaround Times
Rapid detection, species identification, and testing for drug resistance are necessary to control TB among patients and populations.After CDC recommendations were published in 1993 (15), the majority of public and private laboratories began using the recommended rapid methods (7)(8)(9)22,23,28).However, approximately one third of laboratories have had difficulty meeting the recommended turnaround times, particularly for drug-susceptibility testing (7,28).A recent California study determined that 1) lengthy specimen transport times and the practice of conducting periodic, as opposed to daily, TB testing were major causes of delay in TB reporting; 2) delays varied by test type and by the type of laboratory performing testing; and 3) laboratory TB-test reporting often failed to conform to national guidelines and California regulations (24).A direct correlation existed between reporting delays and treatment initiation (24).
# Technology
Certain technologic advances (e.g., nucleic acid amplification testing , fluorescence in situ hybridization, or fluorescence high-performance liquid chromatography of mycolic acids) can contribute substantially to TB treatment and control by providing faster laboratory results (29,30).Such rapid methods will be needed to meet the Healthy People 2010 objective 14-14 of 2 days of average turnaround time for laboratories to confirm and report 75% of cultureconfirmed TB cases (31).However, no well-validated testing algorithms are available to guide programs in adopting or using these new technologies in laboratory and program settings with varying TB incidence, although general recommendations exist for use of NAAT to detect M. tuberculosis (32).
# Workforce Competence
The United States is experiencing laboratory workforce shortages ranging from 8% to >20% in different parts of the country, and expertise is being lost as increasing numbers of experienced staff reach retirement age (33).Multiple training programs for clinical laboratory scientists have closed.In the face of worker shortages, vacant positions are sometimes filled by staff who lack training in complex laboratory science.
# Information Management Systems
Operation of a modern laboratory requires integrating an information management system into the majority of laboratory activities, including inventory management, specimen tracking, test-result reporting, and information sharing with clinicians and public health officials.State-of-the-art laboratory information management systems are available that can improve the quality and organization of laboratory data and speed the flow of information to those who have a need to know.However, the majority of laboratories have either not yet implemented such systems, or they use systems that are not fully compatible with information management programs of TB-control officials or clinicians.
# Maintaining Proficiency Standards
As TB incidence declines and as correspondingly fewer cases are detected and fewer specimens tested, maintaining proficiency in TB-control activities will become more difficult (19,20).In addition, TB-control activities will become more expensive because of the loss of economies of scale.Recognizing this, IOM recommended that TB elimination activities be regionalized to provide better access to and more efficient use of clinical, epidemiologic, and other technical services (4).The concept of regionalizing laboratory services was further developed in a consultant's report (7), included as an appendix in the IOM report (4), which recommended that these matters be considered by a special committee of APHL.During initial deliberations, the Task Force made three observations: 1) regionalization was too simplistic as a generic solution to meet the TB-testing needs of diverse populations across the United States; 2) service models emphasizing coordination and collaboration among laboratories within and between jurisdictions were needed; and 3) principles, benchmarks, and outcome measures were required to guide development of TB laboratory systems.
# Process
APHL convened the Task Force in October 2002.Members represented public health programs from states with different population sizes and TB incidence, hospital and commercial laboratories, and CDC.The Task Force crafted a set of principles to guide development of benchmarks, which were specific actions considered essential to improving laboratory TB services and capable of being assessed by outcome measures.
An overview of Task Force activities was presented in December 2002 at the National Conference on Laboratory Aspects of Tuberculosis in San Francisco, California.Conference attendees, including laboratory administrators, bench laboratorians, clinicians, and TB-control officials, expressed support for the Task Force and its mission, as evidenced by discussion questions and conference evaluations.In February 2003, a summary of Task Force activities and preliminary benchmarks were presented to the federal Advisory Council for the Elimination of Tuberculosis (ACET).During a subsequent meeting, Task Force members evaluated models of network collaboration to further develop and refine the benchmarks and outcome indicators.
Preliminary Task Force recommendations were presented to APHL and NTCA members at their respective annual meetings in June 2003.In February 2004, ACET voted to formally endorse and support the APHL Task Force report, and in May 2004, APHL published the report (34).The recommendations are being presented also to other key stakeholders (e.g., the American Society for Microbiology and the American Thoracic Society ) to garner their input and support.
# Recommendations Overall Goal
The Task Force recommendations are intended to improve TB control through the optimal use of laboratory services and effective reporting and tracking of information.
# Guiding Principles
- TB elimination is a public health imperative.
- Effective TB control depends on an integrated system that includes clinicians, laboratorians, and TB-control officials.
# Organization of Laboratory Services
Provision of laboratory services is a jurisdictional concern because of reporting requirements and legal, programmatic, and financial factors, and because the need for laboratory services varies substantially among the diverse state and local treatment and control programs.Within each jurisdiction, laboratorians and TB-control officials should work together to determine how to maximize resources to obtain prompt, reliable test results.
# Recommended Benchmarks To Improve Laboratory TB Services and TB Control
Implementation of the following actions and base performance measures will require new, more effective partnerships among clinicians, TB-control officials, and public health and clinical laboratorians.
# Capacity and Capability Assessment
Ongoing assessment of available TB laboratory services should be performed to determine the status and capacity of services and to identify unmet needs, obstacles to obtaining laboratory services, and opportunities for improvement.Although data are intended primarily for local use, they might also improve understanding of laboratory capacity and capability for TB testing nationally.A standardized assessment tool should be developed to ensure data are collected consistently.A list of key information to be collected is provided (Box 1).
# Cost Analysis
An assessment of the actual costs of providing TB laboratory services should be performed.Because the cost of identifying individual cases increases as the number of cases declines, the cost of services probably will vary from one jurisdiction to another.A standardized cost-assessment tool should be developed to facilitate comparison of data nationally and across regions.
Cost assessment should include expenditures incurred by laboratories, public and private health-care providers, and TBcontrol programs to 1) provide optimal specimen transport and referral systems; 2) obtain laboratory testing services that meet recommended turnaround times; 3) implement new TBtest technologies in public and private laboratories, as appropriate; 4) provide training for laboratorians and health-care providers; and 5) optimize use of conventional and electronic communication systems, including computers and laboratory information management systems, to facilitate prompt flow of information among laboratorians, clinicians, and TBcontrol officials.
- Identify all laboratories providing TB testing services.
- For each in-state and out-of-state laboratory, document -name, location, organization, director, and contact information; -for whom service is provided (e.g., customers or constituency); -levels (i.e., types) of services provided; -laboratory workload and testing capacities; -compliance with recommended biosafety practices and facility design;- -participation in appropriate proficiency-testing programs; -systems and processes used for specimen referral and transport; -current laboratory testing algorithms and turnaround times; -rules for reporting results and providing isolates to customers; -ability to rapidly detect and guide treatment of multidrug-resistant (MDR) TB cases; and -the availability of a suitable workforce.
# Strategic Planning
A strategic plan for implementing and maintaining a systems approach to TB control should be developed.Resources, recommended testing algorithms for different patient populations, and guidelines should be developed to help each jurisdiction select the appropriate level of services for each public health system.The strategic plan should define action steps and assign responsibility for action item completion.The strategic plan should use a systems approach and involve all partners to ensure development, implementation, and ongoing assessment and improvement of a laboratory network that provides critical capabilities (Box 2).
# Outcome Measures
The following outcome measures should be used to assess improvements in laboratory services and in overall TBcontrol programs.A checklist of key performance indicators is included (Box 3).
# TB Incidence
Improvements in laboratory services should facilitate progress toward elimination of TB and the accomplishment of Healthy People 2010 objective 14-11, which calls for a rate of less than one case per 100,000 persons (31)
# BOX 2.Developing a strategic plan for tuberculosis (TB) laboratory services BOX 3.Performance indicators for assessing tuberculosis (TB) laboratory services
The jurisdictional strategic plan should define action steps, assign responsibility for action item completion, and measure progress by using the following key indicators.
- TB incidence: Monitor laboratory contribution to TB treatment and control within the jurisdiction.culosis (RVCT); 2) the percentage of pulmonary or laryngeal TB cases among persons aged >12 years for whom a sputum culture was done and the data entered in the RVCT; and 3) the percentage of culture-positive TB cases with drugsusceptibility results entered in the RVCT.
# Treatment Initiation
All patients with newly diagnosed, highly infectious TB (i.e., patients with positive acid-fast bacilli smear test results) should be started on appropriate treatment within 2 days of specimen collection.Progress toward this goal should be evaluated by monitoring 1) the percentage of initial diagnostic specimens for which the date of the report of positive results of AFB-smear microscopy to the health-care provider is within 1 day of the date of specimen collection (35), and 2) the average time to report the results.
# AFB-Smear, Culture, and Drug-Susceptibility Testing
Progress toward the goal of having all laboratories performing and reporting TB testing within the network in accordance with CDC recommendations (15,16) should be evaluated. |
Evaluation should include, at a minimum, monitoring the percentage of laboratories using recommended methods for their level of service and the percentage of laboratories meeting expedited turnaround times for reporting results and referring specimens or isolates for additional testing.
# Specimen and Isolate Referral
Written procedures for referring specimens and cultures and for reporting results should be available.Performance of the referral system should be monitored for time of specimen transport, tracking of specimens and information, and time of reporting results to submitting laboratories and health-care providers.
# Incorporation of Rapid-Testing Methods
Progress toward accomplishing Healthy People 2010 objective 14-14 (31), which sets a 2-day target for average laboratory turnaround time to confirm and report >75% of culture-confirmed TB cases, should be evaluated by monitoring the percentage of suspected TB patients for whom a rapid test is performed, the average turnaround time for reporting the results of a rapid test, and the percentage of newly diagnosed, culture-positive TB patients for whom the objective is met.
# Written Procedures for Interaction with TB-Control Partners
The laboratory should have a document of understanding that includes written procedures for service provision and com-munication between the laboratory and TB-control partners, including public health agencies, health-care providers, and state TB-control officials.The document should be monitored for completeness and should include detailed standard operating procedures for
- specimen submission (e.g., sample collection, transport, and submission guidelines; standard submission forms; specimen quality guidelines; and recommendations for generating reminders for serial specimen submission); - determining appropriateness of testing requests, including guidelines for evaluating testing requests, communicating with requestors, and requesting additional information or specimens; - results notification, including how and to whom test results (i.e., smear, culture identification, and drugsusceptibility) should be reported; - billing for services; and - evaluating service provision and communication processes.
# Efficient and Complete Flow of Information
To monitor development of an integrated system that ensures prompt, complete, and accurate communication, the following factors should be evaluated:
- number and percentage of mycobacteriology laboratories in a program area (measured by enrollment in a College of American Pathologists or Clinical Laboratory Improvement Act proficiency-testing program) that are participating in the laboratory system and those that are able to share data electronically; - number and percentage of TB clinicians who are aware of the integrated system, and number and percentage who participate in that system; - percentage of culture-positive TB cases reported to the TB-control program by the laboratory isolating the M. tuberculosis bacteria, and average time to report to the clinician and to the program; and - percentage of TB cases for which the TB-control program can identify the laboratory or laboratories at which initial and referred diagnostic testing were performed with respect to AFB-smear microscopy, culture identification, and drug-susceptibility testing.
# Isolate Recovery
The TB-control program should monitor the percentage of TB patients with culture-positive results for whom the program has obtained and archived an isolate.
# Measurement of Training Outcomes
The program should conduct periodic training needs assessments for laboratorians, clinicians, and TB-control officials, and should develop a plan for providing needed training.Training activities should be evaluated to determine which modifications in operations and performance improvements resulted from training.
# Models of Network Collaboration
Because the provision of laboratory services is a local concern, laboratorians and TB-control officials should work together to design a system to prioritize testing and maximize resources to obtain prompt, reliable test results.The following are examples of successful models for addressing certain aspects of a successful laboratory network:
- The California Bactec™ MGIT™ (Mycobacteria Growth Indicator Tube, produced by Becton, Dickinson and Company, Franklin Lakes, New Jersey) by-mail model uses an efficient specimen referral system to balance the need for rapid AFB-smear microscopy testing with the cost of providing rapid liquid culture and drug-susceptibility testing. -The Michigan model illustrates steps in assessing needs, strategic planning, integrating private and public laboratories, and using state-of-the-art communications systems to improve the flow of information (36). -The New York Fast Track model (37) provides access to complex, state-of-the-art testing for all clinicians in a jurisdiction. -The North Dakota consolidation model centralizes testing in the state laboratory to address concerns of workforce competence and to maintain proficiency as the number of specimens to be tested declines (38). -The Washington State core laboratory model (39) ensures high-quality services by a cooperative plan of consolidating testing in selected laboratories that provide comprehensive TB testing. -The Wisconsin mycobacteriology laboratory program involves a network that encourages voluntary adherence to recommendations, oversight, and training through regular site visits, and team building through annual meetings (40).
# California's MGIT By-Mail Model
To address the need for rapid culture results while maintaining rapid turnaround times for smear microscopy, the California State Public Health Laboratory (CSPHL) implemented a program in which CSPHL provides Bactec MGIT tubes by mail to 10 rural public health laboratories.The laboratories process specimens for mycobacterial smear and culture on-site, decreasing the turnaround time for reporting of smear results.Processed specimens are inoculated onto solid and MGIT culture media.Solid media are incubated and examined locally, but the MGIT tubes are mailed to CSPHL for incubation.For positive MGIT cultures, identification is performed by rapid methods, including DNA probes and HPLC.Drug-susceptibility testing is performed by using the radiometric Bactec method.Advantages of this system include rapid availability of smear results locally, as well as access to state-of-the-art rapid methods for culture identification and drug-susceptibility testing that could not be made available at every local laboratory.
# Michigan's National Laboratory System Model
The National Laboratory System (NLS) model ( 36), originally created for biologic and chemical terrorism preparedness, is based on an integrated public-private laboratory system that uses standard methods and engages in joint planning and training activities.As one of four NLS pilot sites, Michigan applied this model to multiple public health concerns, including TB control.As part of the NLS process, Michigan's state laboratory convened partners (e.g., clinical microbiology laboratory staff, regional public health laboratory directors, county health department surveillance staff, infection-control specialists, physicians, physician assistants, and proficiency-testing providers) in focus groups to identify the steps necessary to build a statewide laboratory system to support response activities for public health emergencies.Two critical concerns were improving specimen transport and improving communications among partners.
In response to focus group discussions, the Michigan state laboratory is pilot-testing a statewide courier system for overnight delivery of specimens and AFB-positive broth cultures to the state TB facility for rapid testing.The goals are to provide 1) 24-hour turnaround times for AFB-smear results and rapid culture testing for laboratories that do not perform their own testing and 2) rapid AFB identification and susceptibility testing to laboratories that perform rapid culture but do not perform rapid identification tests.In addition, the state public health laboratory is 1) developing a statewide, Internetbased communication system, the Michigan Disease Surveillance System, to provide epidemiologic and laboratory information to health-care providers engaged in TB-related work; 2) providing training in the standardized epidemiologic and laboratory methods recommended by Healthy People 2010, APHL, CDC, and ACET; and 3) partnering with commercial laboratories and private health-care providers to expedite submission of first isolates from new TB patients for rapid susceptibility testing and molecular typing.
# New York State Fast Track Referral Model
The Fast Track model program for TB was initiated by the New York State Department of Health's Wadsworth Laboratory in 1993 to expedite testing for highly infectious TB patients (37).Approximately 165 laboratories within institutions in New York are enrolled in the program.These laboratories process specimens for AFB smear and culture at the local level to provide rapid smear results.Specimens from patients whose smear is AFB-positive, who have a negative smear but radiologic indications and clinical TB symptoms, or who are suspected of having infection with MDR TB are fast-tracked to the state public health laboratory for rapid NAAT, liquid-and solid-media culture, and drugsusceptibility testing.
The Fast Track system provides equal access statewide to the latest rapid technology for detection and identification of TB, even for facilities that routinely see no or limited numbers of TB cases.Additionally, this system helps ensure that TB cases are reported rapidly by state laboratorians to health department TB-control programs and that isolates are captured into the public health system for fingerprinting analysis and outbreak investigation.
# North Dakota Consolidation Model
The incidence of TB in North Dakota has declined to less than one case per 100,000 state residents per year (2).Since 1993, the number of specimens sent to the state public health laboratory for testing has declined steadily; by 2000, the state laboratory received approximately 29 specimens per weeka number low enough to generate concerns about staff proficiency (19,20).In 2001, to address these concerns, the state public health laboratory developed a strategic plan for TB laboratory services (38).Elements of the plan included identifying medical centers that were using out-of-state commercial laboratories for TB testing, determining what services the state laboratory needed to provide to compete with private laboratories, and improving relations with private clinical laboratories in the state.
Beginning in 2001, state laboratorians implemented amplified direct testing with results available within 24 hours of specimen receipt, modified their processing and testing schedules to improve turnaround time, and met with staff in all North Dakota medical centers to improve communication.By educating partners in the state about the needs of the TBcontrol program and the services the state laboratory could provide, and by delivering reliable test results with rapid turnaround times, the state laboratory centralized all North Da-kota TB testing and increased its specimen volume to >45 specimens/week.Moreover, consolidating testing at the state level made test results readily available to TB program staff.
# Washington State Core Laboratory Model
The Washington state core laboratory model, which debuted in 1999, derived from an effort to coordinate delivery of laboratory services within the state in the midst of health-caresystem reforms (39).The model ensures that all laboratories have access to state-of-the-art TB testing by consolidating TB diagnostic testing in three specialty laboratories -the state public health laboratory and two urban hospital laboratories.All three have access to up-to-date technology, and they adhere to recommended safety and reporting requirements.
Hospital and clinical laboratories are encouraged to submit clinical TB specimens to one of the two core hospital laboratories.The state public health laboratory examines all clinical specimens submitted by county health departments, serves as the state TB reference laboratory, and maintains capacity to conduct molecular epidemiology studies of TB isolates.It also works with hospital and clinical laboratories that choose to provide limited, on-site TB diagnostic services to ensure that these laboratories meet national TB standards and are integrated into the new delivery system.This model has reduced the clinical workload at the state public health laboratory and simultaneously reduced turnaround times for reporting smear, culture, and drug-susceptibility test results (39).
Before initiating this system, state laboratorians evaluated the TB diagnostic capacity and expertise in the state and also examined alternative laboratory delivery systems for providing these services.The state public health laboratory 1) assembled a working group to evaluate possible causes of delays in reporting positive test results, 2) surveyed laboratories that provided TB testing to document the level of service provided and technology being used, 3) conducted on-site reviews of potential core specialty laboratories, and 4) hosted meetings throughout the state to gather input and buy-in from the laboratory community on the new approaches being considered.
# Wisconsin Mycobacteriology Laboratory Network Model
The Wisconsin Mycobacteriology Laboratory Network (WMLN) (40), sponsored by the Wisconsin State Laboratory of Hygiene (WSLH) and the state TB-control program, links clinical laboratories with the public health system.WMLN provides data sharing so that all TB-control partners receive regular reports on case counts, outbreaks, and resistance trends.Certain services (i.e., NAAT, HPLC, and TB identification and molecular genotyping) are centralized at WSLH.State laboratorians provide technical training to clinical laboratories, as well as serve as a repository for all TB isolates.The TB network also enhances preparedness for biologic terrorism, because clinical laboratories are prepared to process the TB testing provided by state laboratorians and provide personnel trained in Biosafety Level 3 practices for biologic-specimen processing in the event of a terrorist attack.
Development of the network began in 1997 with a survey of laboratorians, clinicians, and public health professionals to evaluate the role of all state laboratories in TB prevention and control.In 1998, a position paper was written by staff from the Wisconsin Tuberculosis Control Program to describe practices and make recommendations to achieve consistent, highquality testing in all laboratories performing TB testing.The recommendations addressed appropriate use of NAAT, laboratory safety, staff proficiency, problems with crosscontamination, and quality assurance.Beginning in 1999, network members promoted compliance with these recommendations through a series of site visits by WSLH staff and annual meetings with laboratory representatives from across Wisconsin.
# Dissemination and Implementation
The recommendations of the APHL Task Force on the Future of TB Laboratory Services have been approved by the APHL Board of Directors and endorsed by ACET.To ensure their widespread dissemination and implementation, key TBcontrol partners should take the following steps:
- - APHL and NTCA should build a stronger partnership and take advantage of opportunities to exchange information among their members at national, regional, and local meetings and training forums. -Clinicians, laboratorians, and public health authorities (including representatives of NTCA, APHL, and ATS) should work together to develop templates that are appropriate for high-and low-incidence regions and that include -recommendations for levels of service; -standardized laboratory education materials for clinicians, laboratory staff, public health personnel, and patients; -standardized laboratory requisitions (which might also be used to educate partners); -notification algorithms; -cost-assessment protocols; -process development (e.g., for analysis and improvement in turnaround time); and -quality oversight for optimal system performance.
# Research Needs
Continual improvement in the quality of laboratory services requires investment in and conduct of public healthrelated research, including 1) operational research to support science-and experience-based recommendations for laboratory services that provide for effective patient management and population-based TB control, 2) cost-benefit analysis for various types of services and technologies, and 3) collaborative technical research to develop and drive the implementation of innovative technologies.
# Conclusion
To eliminate TB in the United States, clinicians, TBcontrol officials, and public health officials need access to prompt and reliable TB laboratory services.Delayed laboratory confirmation of TB leads to delays in initiation of therapy, potentially inappropriate therapy, and missed opportunities to prevent transmission.Although provision of laboratory services is a jurisdictional matter and can be organized at the local, state, or regional level, any successful effort to provide prompt, reliable laboratory services should involve assessment and understanding of the structure, performance, and cost of the network of laboratory service providers and users; development of a referral and information network to ensure reliable testing and prompt flow of specimens and information; and use of quality-improvement principles to continually evaluate and improve the performance of the laboratory service network.
A systems approach is necessary to optimize laboratory TB testing and information exchange and to ensure that appropriate services are available in every program.Laboratorians, clinicians, public health officials, administrators, and funders should collaborate to ensure that health-care providers and TB-control officials have the information they need to treat TB patients, prevent TB transmission, and ultimately eliminate the disease in the United States.The full report of the APHL Task Force on the Future of TB Laboratory Services (34) provides additional information on the role of the public health laboratory in TB treatment and control, additional background on the Task Force processes, further guidance on developing a system for providing TB laboratory services, and steps for dissemination and implementation of the Task Force recommendations. |
Medical information systems may include Practice Management Software (PMS), Electronic Medical Records (EMR), and Personal Health Records (PHR).The phrase Electronic Health Records (EHR) sometimes is used to describe the combination of the latter two.These three types of software may be available as a suite or as separate products that can be linked, although the linkage of separate products sometimes is challenging.Software products may be designed to run on one - May be subject to temporary reduction in 24-hour service availability.#Introduction
# Introduction
HIV/AIDS clinical care has improved dramatically over the decades, given the availability of new medications and a better understanding of how best to use antiretrovirals and deliver primary care to persons living with HIV/AIDS.Positive change on such a massive scale, however, brings with it new demands on clinicians.
Along with innovations in HIV drug therapies, HIV/AIDS care has become more complex than ever before due to increasing comorbidities that are attributable to HIV treatment and the aging of the HIV-infected population in the United States.Patient needs also have expanded across a broad spectrum of medical, psychological, behavioral, and social issues.Notably, significant numbers of infected individuals are identified and enter care late in the course of their HIV disease, confronting clinicians with complex and immediate care challenges.
Since the early days of the epidemic, clinicians have received training in HIV/AIDS clinical care through the AIDS Education and Training Centers (AETCs) Program -the clinical training arm of the Ryan White HIV/ AIDS Program that is administered by the Health Resources and Services Administration (HRSA) and its HIV/AIDS Bureau (HAB).The AETC network trains approximately 150,000 health care providers each year during more than 18,000 training events.
The Guide for HIV/AIDS Clinical Care is a pillar of the Ryan White HIV/AIDS Program's mission to continuously improve HIV/AIDS clinical care.The Guide was first published in 1993 as a collaborative effort of several regional AETCs and was subsequently updated and expanded in 2006.The version before you incorporates many new insights, but the timetested format has been retained -easy access to crucial facts for a busy clinician.
The developers of the Guide strive to be responsive to how HIV/AIDS clinical care is provided today.
- With more routine HIV testing in medical settings, a large number of individuals are entering care via primary care sites that have relatively limited experience managing HIV/ AIDS disease.
- A notable proportion of HIV/AIDS primary care in the United States is provided by advanced practice nurses and physician assistants.
- Shortages in the health care work force are worsening.Experienced staff members are aging and retiring, a limited number of new clinicians are entering primary care and specializing in HIV/AIDS care, and fewer clinicians are available in geographic areas with limited resources.
As a result, front line primary care providers may be less familiar with management of HIV/ AIDS disease, as outlined in U.S. Department of Health and Human Services treatment guidelines (available at aidsinfo.nih.gov) and clinical practices presented in this Guide.
By presenting best practices in the clinical management of HIV/AIDS disease, the Guide can help us continue the remarkable advances in HIV/AIDS care that have made the Ryan White HIV/AIDS Program a model for health care delivery for our Nation and for the world.
# Background
Patients infected with HIV face a complex array of medical, psychological, and social challenges.A strong provider-patient relationship, the assistance of a multidisciplinary care team, and frequent office visits are key aspects of care.Through both the specific services they provide and their overall approach to patients, clinics can have a substantial impact on the quality of care for HIV-infected persons.For example, a patient-centered clinic environment in which education and supportive interventions are emphasized will greatly enhance patients' knowledge about HIV infection.Improving patients' skills in self-management will increase their participation in making health care decisions and provide a stimulus for more active involvement in their own care.
# Special Challenges of Caring for HIV-Infected Patients
Providers need to be mindful of several special issues, including the following:
- Many medical, psychological, and social challenges confront persons living with HIV.The delivery of effective care usually requires a strong provider-patient relationship, a multidisciplinary approach, and frequent office visits.
- The stigma associated with HIV/AIDS places a major psychosocial burden on patients.Stigma and discrimination must be addressed through strong confidentiality protections, emotional support, and cultural sensitivity.
- Underserved racial and ethnic groups are overrepresented among people with HIV.Efforts to understand and acknowledge the beliefs of patients from a variety of cultural backgrounds are necessary to establish trust between providers and patients.Cultural competency is imperative in the field of HIV care.
- Providers play a key role in the public health system's HIV prevention strategy.Disease reporting, partner notification, and risk assessment are important aspects of care.
Patients may see this as threatening and may need education and emotional support in order to participate in this process.
- Many patients have inaccurate information about HIV infection that can heighten their anxiety, sabotage treatment adherence, and interfere with prevention behaviors.Patients need assurance that HIV is a treatable disease and that, with successful treatment, they may live indefinitely.They also need to hear explicitly that HIV may be transmitted through sexual contact, injection drug use and other blood contact, and perinatal exposure, and that they can take specific measures to prevent transmission to others.
- Many patients need the support that only a peer can provide.Peer educators should be available to help patients navigate difficult health care systems, medication regimens, and lifestyle changes.
- HIV-infected patients need to have an active voice in their health care.Patient advisory groups can provide valuable program evaluation, which can be used to promote the patient-centered focus of the health care system.
These issues are discussed further in the sections that follow.
Section 1: The HIV Clinic: Providing Quality Care
# Components of HIV Care and Ways to Enhance Care
# Important Components of HIV Care
A first step in ensuring that patients are "engaged in care" is the establishment of systems that include mechanisms for coordination and communication of care.
- Clinics must offer a nonjudgmental and supportive environment, because of the sensitive nature of issues that must be discussed.
- A multidisciplinary approach, utilizing the special skills of nurses, pharmacists, nutritionists, social workers, case managers, and others is highly desirable to help address patient needs regarding housing, medical insurance, emotional support, financial benefits, substance abuse counseling, and legal issues.
- Providers and other clinic staff members should be prepared to conduct appropriate interventions and make timely referrals to community resources and institutions.
- The primary provider should coordinate the various aspects of health care, with close communication among providers across disciplines.
- Individual office visits should be long enough to allow time for thorough evaluation.
- Providers must be able to see patients as frequently as their medical and psychosocial needs require, and clinic scheduling should be flexible so that patients with acute problems can be seen quickly.
- A range of medical resources, including providers with subspecialty and laboratory expertise, needs to be established.Colocating services within testing and counseling sites or within HIV clinics is an excellent way to enhance patient compliance (see chapter Clinic Management).
- Patient education is a vital aspect of care that begins during the initial evaluation and continues throughout the course of care (see chapter Patient Education).
# Taking Steps to Enhance Care
Providing comprehensive care for HIVinfected patients requires a patient-centered focus, a multidisciplinary team, and a willingness to spend time on building relationships with patients.Providers should do the following:
- Make available self-management education to help patients identify problems, teach decision making techniques, and support patients to take appropriate actions to make necessary changes in their lives.
- Offer care in a patient-centered environment that allows the patient to actively participate in care decisions and provides patientspecific education.
- Encourage patients to learn all they can about their condition.
- Give accurate information regarding prognosis and the real hope that antiretroviral therapy provides.
- Foster an atmosphere of nonjudgment, trust, and openness.
- Anticipate that significant time will be required for patient education.
- Outline the range of clinic operations and state the expectations for provider-patient communication.Outline how appointments are scheduled and how prescription refill requests are managed.
- Arrange to see patients with acute problems quickly.Establish a triage system to provide efficient service delivery.
- Ensure that there are open lines of communication with all patients to receive and answer questions, assess treatment effectiveness, and manage side effects.
Section 1: The HIV Clinic: Providing Quality Care
# Helping Patients Cope with Emotional Issues
Patients coming to terms with HIV infection often experience a range of emotions, including anger, fear, shock, disbelief, sadness, and depression.Loss is a major issue for patients with HIV because health, employment, income, relationships with friends, lovers, and family, and hope all may be threatened.Many patients feel overwhelmed, and even patients who seem to be adjusting reasonably well can find it difficult to keep all of the many appointments that may be scheduled as they initiate care.Providers need to recognize that patients' emotional states affect their ability to solve problems and attend to important medical or social issues.Providers can do the following:
- Assess each patient's emotional state and the availability of friends and family for emotional support.Some patients will need counseling to help them decide whether to disclose their diagnosis to friends, family, or employers as well as support in dealing with HIV infection.Patients often feel hesitant about seeking emotional and practical support.
- Deliver important information in easily understood terms and in small amounts.
Reassess patient understanding of crucial information at subsequent visits, and repeat important information as necessary.
- Screen for anxiety, depression (including suicidal ideation), and substance use.
- Refer patients to community resources for crisis counseling, support groups, and, if appropriate, psychiatric treatment to help them achieve emotional stability.
- Assist patients in finding a case manager who can help them learn to navigate the health care system and reduce anxiety about keeping their lives in order.
- Assist patients in linking to social work services to assist with enrollment into medical insurance and to meet other social services needs, such as housing, food, child care, and substance abuse treatment.
# Helping Patients Develop Self-Management Skills
Self-management support is defined by the Institute of Medicine as the systematic provision of education and supportive interventions by health care staff to increase patients' skills and confidence in managing their health problems, including regular assessment of progress and setbacks, goal setting, and help with problem solving.
It can be viewed as a portfolio of techniques and tools to help patients choose healthy behaviors, and as a fundamental shift of the provider-patient relationship toward a collaborative partnership.
After patients have come to terms with their HIV infection, they are ready to embark upon the lifelong process of caring for themselves.Patient self-management involves adopting new health behaviors and requires changes that will occur as a progression of motivational skills.Motivation is defined as the "probability" that a person will enter into, continue, and adhere to a specific change strategy.Patients will feel empowered as they gain the skills and confidence to be active participants in their care.
Providers need to do the following:
- Create an atmosphere conducive to learning these self-management skills, including but not limited to the following areas:
- Problem solving - Adopt a team approach to health care with the patient as the central team player (patient-centered care).
- Incorporate problem-solving skills into all education efforts.
- Allow the patient time to set small obtainable goals as "first steps" in selfmanagement.
- Realize that many appointments with multiple members of the health care team may be necessary before a patient has all the necessary skills.
# Helping Patients Make Positive Changes in Health Care Behaviors
Regardless of whether a patient is new to care or has been in care for many years, the burden of a chronic disease is wearing.Positive change in behavior needs to be an ongoing focus of patient-centered care.After patients have selfmanagement skills, they still need help setting action plans for their health care.The provider needs to help patients adopt realistic action plans by:
- Realizing that new health behaviors require motivation and occur as a progression of learned skills
- Bolstering patients' self-confidence by adopting action plans that:
- Are realistic
- Are something that patients find of value (i.e., something they want to do)
- Are reasonable (it is better to underestimate and exceed the goal than to overestimate and fail)
- Are action-specific, with small, obtainable goals
# Peer Educators and Patient Advisory Groups
Patients need to be active participants in making decisions regarding their health care.Peer educators and patient advisory groups can help patients become more involved in their care.
In order to best support patients, it is helpful to have peer educators available for them during initial and subsequent visits.This helps to decrease patient anxiety and promotes a patient-centered atmosphere.Providers need to realize that peer educators:
- Are trained, HIV-infected individuals who provide a unique approach to client-centered care
- Attend clinical sessions and provide referrals for one-on-one counseling and support to the patients - Are "seasoned clients" who have a desire to help patients in their care
- Work under the same confidentiality guidelines as all other staff members Another valuable tool for patient-centered care is the use of a patient advisory group (PAG).The PAG is the voice of the people that the clinic serves.The HIV program will listen to this group's suggestions and use them to improve patient satisfaction and clinic functionality.The PAG's role could involve identifying clinic problems, recommending changes in the care delivery system, and discussing new treatment approaches.A successful PAG does the following:
- Provides comprehensive, individualized client-based education to all active patients
- Encourages clients to actively participate in treatment decisions and to involve family members and others who comprise their support system
- Designates members who facilitate meetings, promote upcoming meetings, coordinate Section 1: The HIV Clinic: Providing Quality Care speakers, and provide feedback to clinic staff and management
- Allows members to serve as cofacilitators, choose topics of discussion, set meeting guidelines, and invite new members
- Fulfills requirements of grants and other funding streams to have enhanced patient involvement
# Stigma and Discrimination
Stigma is founded on fear and misinformation.Theodore de Bruyn observed that stigma is associated with HIV/AIDS because, "It is a life-threatening disease; people are afraid of contracting HIV; it is associated with behaviors that are considered deviant; a belief that HIV/AIDS has been contracted due to unacceptable lifestyle choices; and, some believe it is the result of a moral fault which deserves punishment."
Stigma can adversely affect how patients are perceived by others and how they view themselves.The stigma associated with HIV/ AIDS is such that individuals known to be or suspected of being infected with HIV may be excluded from community activities and suffer isolation or abandonment.Some patients may feel ambivalent about seeking medical care if, by doing so, they risk disclosing their condition.Others may have learned from experience to expect rejection and therefore may not trust care providers.It is essential for providers to be supportive of patients who are dealing with the burden of stigma.
# Stigma of Fear of Contagion
Unfortunately, patients and their families are often unaware that routine household contact with a person with HIV poses no risk of contagion.They should be educated about that, and also taught what to do in situations that do pose risk, such as when bleeding occurs.Clinic staff members must model behavior in this area.For example, gloves should be worn only as appropriate during physical examinations and as consistent with universal precautions.There should not be separate facilities or special procedures for HIV-infected patients.
# Stigma Associated with Being Gay, Lesbian, Bisexual, or Transgender
Demonstrating respect and providing excellent care to patients with various cultural backgrounds, beliefs, and sexual orientations are central to medical professionalism.Providers should approach patients in an open and nonjudgmental fashion and be familiar with medical management issues unique to these populations, such as appropriate screening for sexually transmitted infections for men who have sex with men (MSM) and hormonal treatment for transgender patients.Clinic staff members also must be respectful and supportive; having a staff that is familiar with lesbian, gay, bisexual, and transgender (LGBT) cultures is a natural way to create a welcoming environment.Providers and social workers should be aware of community agencies with resources available to people who are lesbian, gay, or transgender.In addition, providers and clinic staff members should be aware of special legal issues that affect these populations.For example, designating a durable power of attorney for medical decision making can be particularly important in states that do not recognize same-sex partners as legal next of kin.
Section 1: The HIV Clinic: Providing Quality Care
# Other Special Cultural Issues
African-Americans, Hispanics, and some immigrant groups are disproportionately affected by HIV, and many people of color with HIV infection have major socioeconomic problems such as poverty, homelessness, lack of medical insurance, lack of acculturation, and undocumented immigration status.All these obstacles can make accessing health care difficult and attending to health problems less of a priority for the individual.A patient's cultural background influences healthrelated beliefs and behaviors, and personal or historical adverse experiences may make some patients distrustful of medical care.In addition, some patients' distrust of medical research can impede their willingness to access new drug therapies.Culturally competent communication between provider and patient may substantially affect adherence with therapies. |
For all these reasons, providers should do the following:
- Carefully explore what each patient believes about his or her health, what would be appropriate treatment, and who should be involved in medical decision making.
- Use professional interpreters to help overcome language barriers.
- Use case managers and peer educators to help bridge social barriers.The team of peer educators should be culturally diverse in order to be effective with all minority groups.
# Confidentiality and Disclosure
Confidentiality of medical information is always mandatory, but the stakes are particularly high for patients infected with HIV, who risk losing medical insurance, employment, and the support of friends or family if their diagnosis is disclosed inappropriately.Although people with HIV infection are protected against discrimination under provisions of the Americans with Disabilities Act, discrimination can be difficult to prove, and there are strict time limits after which charges of discrimination can no longer be made.
# Protecting Patient Confidentiality
Adherence to the Health Insurance Portability and Accountability Act (HIPAA) regulations is an important aspect of protecting patient confidentiality.Personnel policies should reinforce measures such as requirements that papers and computer screens containing patient-identifying information not be left unattended and should include provisions for documenting whether phone messages can be left for the patient, and if so, with whom.
# Helping Patients Disclose Their HIV Status
Patients who have a support network function better than those who are isolated.However, patients' fears of disclosure are often well founded, and providers must find a balance between accepting patients' unwillingness to disclose their HIV status and the need to develop support networks.Patients may find support groups or individual psychotherapy sessions beneficial in deciding when to disclose, and to whom.
The sex and needle-sharing partners of people with HIV need to be informed about their possible exposure to HIV.Local health departments can either assist patients in making these disclosures or provide anonymous partner notification for them.
A patient-centered clinic staff can help patients with disclosure.For example, they could encourage patients to bring their partners to one of their clinic or counselor appointments in order to disclose their HIV serostatus in the context of the clinic visit.This could allow the health care professional to answer the partners' questions and would provide a neutral environment for the disclosure discussion.Risk of intimate-partner violence should be assessed.
Section 1: The HIV Clinic: Providing Quality Care
# Public Health Role of Providers in the HIV Epidemic
Primary care providers must consider their public health role in curbing the spread of HIV.The incidence of HIV remains unacceptably high, and may be increasing in some populations, especially in communities with relaxed adherence to safer sex recommendations.
All AIDS diagnoses and, in some states, all positive HIV test results must be reported to the state health department.State laws vary in reporting requirements and subsequent notification of potentially exposed individuals (see the National HIV/AIDS Clinicians' Consultation Center Compendium of State HIV Testing Laws at www.nccc.ucsf.edu/), but the name of the source contact is never divulged to the person being notified.Providers should become familiar with the laws of their jurisdiction by contacting their health department. (The Association of State and Territorial Health Officers provides links to all state health departments at www.astho.org.)Providers are required to do the following:
- Inform patients that their AIDS diagnosis or positive HIV status (depending on individual state requirements) must be reported to the state health department, tell them whether partner notification is required, and explain what they should expect regarding efforts that must be made by the patient, provider, or health department to notify sex partners or individuals who may have been exposed to HIV through their needle sharing.Assure them that their names are always kept confidential and are never given to potentially exposed individuals by the health department.
- Carefully assess patients' risk-taking behaviors, educate them regarding HIV transmission, and perform screening for sexually transmitted infections. (See chapters Preventing HIV Transmission/ Prevention with Positives, Initial History, Initial Physical Examination, and Initial and Interim Laboratory and Other Tests.) -Provide counseling to encourage safer sexual practices and make referrals to drug rehabilitation or needle exchange centers as indicated. (See chapter Preventing HIV Transmission/Prevention with Positives.)
- Provide information about the role of antiretroviral therapy in reducing the risk of HIV transmission.
Section 1: The HIV Clinic: Providing Quality Care
# Clinic Management
Jonathan A. Cohn, MD HIV outpatient care is unique in that it combines two very different approaches to patient care: long-term health care for individuals with a chronic condition, and the vital public health service of reducing transmission of an infectious disease.Thus, chronic treatment and retention in care are important for both individuals and public health.
HIV services often are provided to persons who have challenges in regard to participation in their own health because of discrimination, poverty, active substance use, or mental health disorders.The context of HIV care still is one of persistent stigma regarding HIV infection itself and discrimination against racial, ethnic, and sexual minorities who constitute the groups with the highest HIV prevalence and incidence.At the same time, funding streams from federal, state, and local governments create opportunities for treatment of uninsured and underinsured individuals and provide resources for creating innovative, effective programs.Treatment guidelines, operations research data, and technical support are available to assist in designing, operating, and improving service programs.
# Patient Recruitment into Clinic
The persons who were easy to recruit and retain in care are already enrolled; the more challenging patients await recruitment.The U.S. Centers for Disease Control and Prevention (CDC) estimates that up to 25% of HIV-infected persons in the United States are not aware of their HIV infection, so there is still much work to be done to diagnose those individuals and link them to care.For newly diagnosed patients, studies show that there often is a substantial delay in attendance at an initial HIV care visit, with only 20-40% of them accessing care within 6 months of diagnosis (Mugavero, 2008).However, for the clinics, the numbers of newly diagnosed patients who present for care is substantial.A recent survey of 15 HIV programs across the country (median of 1,300 active patients each year) showed that a median of 250 (range 60-730) new patients were enrolled in each clinic each year (Yehia, 2008).
To facilitate linkage to care, every HIV clinic should 1) be linked to agencies that provide HIV testing and services for persons with HIV, and 2) make clinic access easy and comfortable for the clients of those outside services.Many HIV clinics establish referral linkages with community HIV counseling and testing services (CTS), AIDS service organizations (ASOs), sexually transmitted infection (STI) treatment facilities, family planning agencies, drug treatment facilities, local health departments, regional HIV/AIDS hotlines, and local hospitals and emergency rooms.Many clinics also offer free confidential or anonymous CTS using state or federal funding.Clinic personnel should build personal relationships with agencies that may provide referrals, invite staff of community agencies to visit the clinic, or hold open houses.Providers from ASOs, such as case managers, can be invited to accompany patients on clinic visits.Referring agencies must know what services the clinic provides and which patients it serves, as well as those it cannot serve.
Various approaches may help facilitate the patient's entry into care.A randomized study showed that using case managers to increase linkage of newly diagnosed persons to care can be effective: 78% of patients who had case management that focused on the initial clinic appointment kept an appointment within 6 months, whereas only 60% of patients without case management kept an appointment in the time frame (Mugavero, 2008).
Section 1: The HIV Clinic:
Providing Quality Care
Frequently, there is a delay of several weeks for a new appointment with an HIV clinician.Model programs have been established nationwide to improve linkage to HIV care.For example, the HIV/AIDS clinic at the University of Alabama at Birmingham offers new patients an orientation visit in the HIV program within 5 days of their request for a new patient appointment.In this clinic, an HIV program staff member initiates a welcoming interaction during the patient's first phone call requesting an appointment and invites the patient to an orientation visit.
During that visit, a psychosocial assessment is performed, specimens are taken for baseline laboratory tests, any immediate health issues are addressed, and referrals for mental health or substance use disorder care are initiated, if indicated.The orientation visit is used to give patients information on how to use the clinic effectively, provide other on-site nonmedical services, and start processes to access health insurance or AIDS Drug Assistance Program (ADAP) services as needed.The full initial medical visit is scheduled for a later date.In a nonrandomized comparison, the no-show rate at that clinic dropped from 31% to 19% with that approach (Mugavero, 2008).
Success in linking newly diagnosed persons to care may be enhanced through the participation of HIV-infected consumers as peer advocates (see chapter Supporting Patients in Care).Either volunteer or paid peer advocates can meet newly diagnosed patients who have been referred to the clinic, help familiarize them with the clinic services and staff, and help them adjust to both the fact of their HIV infection and their role as a chronic care patient.Groups for newly diagnosed persons co-led by a peer advocate and a professional as well as one-on-one interactions with patients within or outside the clinic (e.g., through a buddy system) can help newly diagnosed persons succeed in the clinic.In clinics that use peers, particular attention must be paid to confidentiality issues.The peers must be trained and supervised (see below), and the patients must agree to participate with peers, either individually or in groups.
Clinics differ in terms of the characteristics of people living in their catchment area and in regard to the levels of expertise of clinic staff members.Some successful clinics target a narrow but underserved population and concentrate on meeting the needs of that population.The environment and services offered by the clinic may be tailored to the patient population.For example, a youthfriendly clinic may differ in these respects from one targeting the working poor.
# Retaining Patients in Care
Retaining patients in care is an ongoing challenge (see chapter Supporting Patients in Care).Among the 15 surveyed HIV clinics mentioned above, the median no-show rate for appointments was 28% (range 8-40%).For new patients, the range was 5-54% and for returning patients it was 2-40%.Across all the clinics there was a median annual loss-tofollow-up rate of 15% (range 5-25%).A number of approaches may help patients maintain continuous care in the clinic (Yehia, 2008).
- Respect and cultural competence:
Respecting patients and providing them with effective care builds trust and keeps them coming back.New clinic attendees may have strong feelings related to HIV infection (e.g., fear of death) or how they acquired it (e.g., issues of shame or of secrecy).They may lack trust in medical care (from prior personal experiences or from historic events such as the Tuskegee syphilis experiments) or in current treatments (e.g., "Everyone I knew who took AZT died…").Some patients believe that HIV was created in government laboratories to target African-Americans and may or may not believe that the clinic staff is part of the conspiracy.It is important that all staff members be trained to anticipate, recognize, Section 1: The HIV Clinic: Providing Quality Care and work with issues such as these.Patients may experience obstacles to care when there are cultural differences or language barriers between themselves and the staff members.Diversity among health care staff can further improve the experience of ethnic minority patients.
- Welcoming staff attitude: Providers must know the target population and build a system that will make patients feel welcome.
Patients always should be made to feel that they came to the right place (even in cases in which they must be referred on to another provider or clinic).Patients should receive understanding and support, even if they arrive at the clinic without the required managed care referral form (at least for the first few visits).
Many clinics funded through the Ryan White Care Act (RWCA) employ patient advocates, persons from the target community who may or may not be HIV infected.Advocates directly assist patients in navigating the clinical care system and help patients ask questions or make their needs known to the clinic staff.Advocates or peer support persons can be instrumental in helping patients build self-esteem and acquire new habits that will enable them to use health care services in a proactive manner.It is very helpful for patients to be able to forge a personal connection with at least one staff member.
- Welcoming environment: Physically comfortable waiting and examination areas, with linguistically and culturally appropriate decoration and reading material, are important for patient retention.A clinic that serves parents or children should make available toys or children's books.
- Orientation to clinic systems and rules: New patients need a brief description of clinic staff and services, routine and emergency procedures, prescription refill procedures, and after-hours follow-up.They must understand requirements for referrals from managed care providers, and new patients may need help with fulfilling such requirements.Patients also must be oriented to what is expected of them (e.g., arriving on time, calling to cancel or reschedule appointments) and the consequences of not fulfilling their responsibilities (e.g., clinic rules regarding late arrivals).A handout or pamphlet with this information can be very helpful.Patients need to know how to determine the insurance coverage and other benefits for which they may qualify, and how to find out their options if their insurance coverage changes.
- Peer support: Many programs have HIVinfected staff members who provide specific peer-support services.Patients who have had unpleasant experiences seeking medical care in the past, or those who are not used to engaging in medical care, may get better support from another consumer than from a nonpeer staff member.Youth especially may trust information from peers more so than from adult professional staff members.
Peer advocates may work in this role part time or full time, as either volunteers or paid staff.Often they work specifically to make new or recently returned patients comfortable in the clinic.Some programs designate consumers as peer navigators, emphasizing their role in helping new patients, or patients returning after being lost to care, in finding their way through the health care system and support systems.Peers are especially helpful when they model good health behaviors, including adherence with appointments and medications and with avoiding unsafe sex or other HIV transmission activities.In some cases, peers have been the basis of a successful program, but in other cases peers model poor health behaviors and themselves become ill.Peers need to adhere to confidentiality rules Section 1: The HIV Clinic: Providing Quality Care and good work habits and need to provide accurate information to other clinic staff.
Effective selection, training, and supervision of peers are extremely important.
- Systems to support attendance: Patients should receive appointment reminders about 48 hours before each appointment.Reminders typically are given by phone or mail, although text messaging or other form of electronic communication may be more useful in some settings.It also may be effective to have a staff member contact patients who have missed appointments to find out what prevented them from attending, offer to reschedule, and try to eliminate barriers to clinic attendance.
Clinic sessions should be scheduled at times that are convenient for the patients.For example, mid-to-late afternoon is best for school-age children, occasional evenings or weekends are good for working people.
For patients with transportation problems, ASOs and other community organizations may have funding available (e.g., doorto-door taxi service for selected patients, van service, vouchers for use on public transportation).Addressing other barriers may require a coordinated effort by the clinic staff, case manager, and others.
Some programs have a policy detailing their interventions following one or more missed visits: usually one or more phone calls comes first, then a letter to the last known address, and as a last measure, some programs will dispatch personnel to visit the last known address in an attempt to reconnect with a patient who is lost to follow-up.These efforts are more successful when patients are asked for current telephone, address, and other contact information at every clinic visit.Staff members must know to whom a patient has disclosed his or her status; in verbal and written correspondence, staff members must avoid unintended disclosure of the patient's HIV infection.
It is important to document movement of patients to other locations (including correctional facilities) or other care providers whenever the information is known so that these patients are considered transferred rather than lost.Some states provide public lists of incarcerated persons; larger programs may use those lists to find patients who have been missing for some time.
HIV programs can be aggressive in trying to connect with patients who are missing, but also must respect explicit decisions by competent persons to change providers or to forgo medical care.
- Outreach encounters to promote participation in care: A study of seven sites across the United States, funded by the U.S. Health Resources and Services Administration (HRSA), found that outreach by health care professionals increased clinic attendance and that frequent outreach by any program staff member increased adherence with antiretroviral therapy (see "References," below).Outreach by medical professionals included efforts by physicians, nurses, or physician assistants to meet patients outside the HIV clinic setting, often in another part of a medical facility such as an inpatient unit.These encounters were the most expensive type of outreach, but the most effective in engaging new patients in care.Encounters with medical professionals did not increase adherence with medications, however. |
Other types of outreach, either face-to-face or otherwise (by phone, email, or postal service), by professional, nonprofessional, or paraprofessional staff members, increased adherence with medications, but not with clinic attendance.More frequent encounters of this type were associated with greater Section 1: The HIV Clinic: Providing Quality Care improvements in adherence.The results of the study suggest that initial face-to-face contact with medical providers is important for establishing trust that enables new patients to engage in care, and that frequent encounters with other staff members is important for maintaining patients on medications.
# Special Population: Women of Color
A 2008 report commissioned by HRSA collected data from the published literature, key informant interviews, and a consultation meeting with RWCA-funded providers to provide information on barriers and effective interventions to assist women of color in succeeding with HIV care.Three central themes were extracted from these varied inputs:
1.development of a responsive care environment that incorporates respect, cultural competency, and flexibility to meet women's needs; 2.incorporation of peers into the care system as trained and paid participants in the care teams; and 3.addressing women's needs through care coordination, flexibility, health system navigation, and better coordination and communication between medical and social service providers.HRSA funded a number of clinical sites to test different methodologies applying these principles through the Special Programs of National Significance mechanism; these projects are ongoing and results are not yet available.
# Models of Care
- Chronic Care Model Popular in recent years, the chronic care model refers to a mechanism for providing patient-centered care using a variety of staff personnel and interventions to maximize desired health outcomes.This approach has been most highly developed for diabetes care, but it can apply equally well to a wide range of chronic illnesses.In this model, patient training in self-care is key.In contrast to the tradition of teaching patients the pathophysiology of their health condition in lay terms, with this model, training involves focused skills building so that patients can better monitor their health status, use their discretionary medications, and know when and how to contact the professionals for assistance.Frequent contact between patient and clinical staff, both faceto-face and through other means, both in clinics and in the community, usually are involved.Care is directed toward panels of patients, not just individual patients.Program-wide monitoring of process and outcome variables, such as frequency and results of CD4 cell counts and plasma HIV RNA levels, informs the practice as a whole as well as the quality of care for individuals.These interventions have been shown to improve outcomes, but do not necessarily reduce costs because the staff time required can be substantial.
# Medical Home Model
The concepts of the chronic care model have been modified to create the model of the patient's "medical home," which may involve a primary care provider but also may involve a specialist who cares for the most prominent or demanding of a patient's health problems.The chronic care model is limited to treatment of one health condition whereas the medical home model supplements such targeted care (e.g., HIV-specific care) with coordination of the other health services the patient may need.HIV programs often act as the primary care provider, especially for patients who do not have insurance and therefore have limited access to other providers.Many HIV clinics have the capacity to better organize and implement a chronic care approach and to better coordinate services across other specialties and providers in order to be a true medical home.
Section 1: The HIV Clinic:
Providing Quality Care
# Clinical Services Needed for HIV Care
Optimal array of services provided by an HIV clinic At a minimum, HIV medical care providers need to offer confirmation of HIV infection, education, recommendations, and management regarding antiretroviral therapy; prevention, diagnosis, and management of HIV-related opportunistic diseases and treatment-related complications; screening and referral for common comorbidities, and linkages to other general health services.Most patients will need additional primary care and specialty health care and support services; it is often more effective and more convenient when these are available on-site rather than by referral.For health interventions to be successful, many patients will need assistance with health behavior change.
The services ideally provided by the HIV clinic include those on the list that follows.Detailed information on most of these topics is available in other chapters in this manual.These standards are derived from the primary care guidelines of the HIV Medicine Association of the Infectious Disease Society of America (HIVMA/IDSA), the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, the DHHS Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, the CDC guidelines on prevention services in HIV care programs, as well as U.S. Public Health Service Prevention Task Force and American Cancer Society recommendations (see "References," below).
- Age-appropriate immunizations including HIV-specific indications for some: pneumococcal vaccine, influenza vaccine, hepatitis A and B vaccines, tetanus-adult diphtheria and tetanus-adult diphtheriaacellular pertussuis vaccines, and human papillomavirus vaccine.
- Screening for sexually transmitted infections (syphilis, gonorrhea, chlamydia) at enrollment and periodically.
- Assessment of ongoing sexual or drug-use behaviors associated with HIV transmission, and counseling or other interventions to reduce transmission behaviors.
Interventions regarding sexual transmission behaviors should be linked with family planning.
- General health screening for hypertension, diabetes, dyslipidemia, and cardiovascular risks, and cervical, breast, colon, and prostate cancer.The role of screening for anal cancer remains controversial because of limited data on effective management of anal dysplasia.
- Care of common general medical illnesses including hypertension, dyslipidemia, uncomplicated diabetes, obesity, asthma, and chronic obstructive pulmonary disease.Care of a wider range of disorders, such as congestive heart failure and chronic kidney disease will vary by practice.
- Evaluation and care of common comorbidities including hepatitis B and C infection and latent and active tuberculosis (TB).Treatment of active TB, including directly observed therapy, often is provided by public health agencies; treatment of hepatitis may require referral to a specialist.
- Provision or linkage to oral health care, nutritional services, and other medical specialties including ophthalmology, dermatology, oncology, and others.
- Provision or linkage to HIV care for pregnant women, adolescents, and infected or perinatally exposed infants.
- Behavior change for general health issues including smoking cessation and other unhealthy substance use, diet for weight control, and exercise.
Section 1: The HIV Clinic: Providing Quality Care
- Behavioral health services for adaptation to the illness, mental health disorders, and substance use disorders including unhealthy alcohol use.
- Provision or linkage to social support services, including community-based case management.
- Additionally, clinics should have a system in place to protect the safety of their employees in regard to occupational HIV exposure (see chapter Occupational Postexposure Prophylaxis).
Resources required in providing comprehensive HIV care Other individual providers or small clinics may be eligible for Part B reimbursement for medical care of uninsured persons, by working with local case management agencies.
- Personnel: For patients who are selfsufficient or can access community-based services on their own, a lone provider potentially can deliver comprehensive HIV care.In most circumstances, however, patient care needs are met more effectively when multiple team members are available at the clinical site.
- Facilities: In addition to the usual office layout, other facilities are useful.An examination room suitable for gynecologic examinations is important.An apparatus for pulse oximetry is very useful in assessing patients with respiratory symptoms.Easy access to facilities for collecting venous blood, urine, and stool specimens should be available.On-site access to rapid tests that do not require Clinical Laboratory Improvement Amendments (CLIA) certification may be useful, such as urine pregnancy tests, fingerstick blood glucose tests, and perhaps the rapid HIV antibody screening tests.Laboratory certification to perform urine analysis and microscopic examination of vaginal fluid specimens is very useful.Refrigeration to maintain vaccines and material for tuberculin skin testing is necessary.Refrigeration also enables the clinic to provide patients with on-site injection of medications required once a week or less frequently.
- Training and technical assistance: Patients look to nontechnical staff to corroborate information given by physicians and midlevel providers.Further, patients expect
# Implementing interdisciplinary care in the clinic
It is not enough to have staff members from many disciplines on the payroll; rather, systems that allow staff members to function as a team must be created.Training with followup by supervisors is essential.Specific tasks for each staff member need to be assigned (see Table 1).Ideally, members of the staff can meet for a few minutes prior to each clinic session to anticipate special needs and allocate personnel resources.Some clinics place a checklist on each chart at each visit to indicate which team members a patient is meant to see that day and to confirm that all intended interactions have occurred.
The team's potential can be best utilized if there is a regular opportunity to meet and discuss patients outside clinic sessions, in multidisciplinary team meetings.When all members participate, the discussions can range from the selection of antiretroviral regimens for a patient to addressing the patient's adherence issues or chronic mental illness.Services for infected and affected family members also can be coordinated at these meetings.
Section 1: The HIV Clinic: Providing Quality Care
# Table 1.Clinic Personnel Responsibilities
Tasks prior to a clinic visit
- Remind every patient of appointments via phone call or mail. -Review charts to list items to address during the visit.
# Tasks during a clinic visit
- Verify patient's current contact information and current insurance status. -Orient new patients.
- Assist with insurance gaps (e.g., teaching about need for referrals, help with insurance application or ADAP). -Assess other barriers to care and psychosocial needs. -Assess medication adherence.
- Teach and provide behavior change counseling about medications and self-care. -Assess ongoing transmission behaviors.
- Teach and provide behavior change counseling about transmission behaviors. -Educate about clinical trial opportunities (if applicable). -Make referrals for psychosocial services.
- Make referrals/appointments for medical, dental, mental health care.
# Tasks following clinic sessions
- Make follow-up calls regarding new medication regimens or referrals. -Call or mail correspondence to patients who missed their visits. -Help patients overcome barriers to clinic attendance. -Extract patient data and enter it into the information system (not necessary with electronic medical records).
# Support Services and Linkages Needed for HIV Care Case management and support services enhance clinical care
It is a rare clinic that has the funding, personnel, and expertise to address all of its patients' psychosocial issues.Most patients need services from an array of agencies.Case managers assist patients in accessing the range of services and entitlements that can help them succeed in treatment.This may include helping patients apply for insurance; access support groups; access supplemental food, housing, homemaker and other concrete services; and access mental health and substance abuse services.Excellent case managers also help motivate patients.
Case managers should perform periodic assessments of clients' needs and update their comprehensive care plans at least every 6 months.Home visits can be very useful as part of the assessment.Some case managers or their agencies will provide certain direct services themselves; these may include shortterm counseling, transportation for clinic visits, accompanying patients to clinic visits, and providing financial assistance for specific emergencies.
Close coordination between clinic staff and case management is important for avoiding duplication of efforts and services.Periodic case conferences between clinic staff and case managers are ideal.Written communication, for example, when sharing case management care plans, can be useful.Case management agencies and clinical sites need to obtain written consent from patients to share the information that allows coordination.
# Creating useful linkages with community-based services
Clinics can develop relationships with community-based case managers or directly with providers of specific services, such as mental health, substance abuse, or housing Section 1: The HIV Clinic: Providing Quality Care services.Personal contact between staff members of clinics and outside agencies is important for establishing the relationship, and ongoing contacts are necessary for coordination.Community organizations often are pleased to give in-service education to clinic staff personnel in order to streamline the referral process.Clinics should make their expectations clear to community-based agencies.Clinics can function as advocates to ensure that their patients receive the attention and services for which they were referred.Periodic interdisciplinary meetings of clinic staff with representatives of community-based agencies, including case managers, are very useful.
# Consumer involvement in HIV clinical care
Many clinics have created patient (consumer) advisory groups to participate in planning and quality management.The role these groups take depends on the specific clinic; some advisory boards educate themselves about clinic issues and provide expert input to clinic processes.Other boards act more as social event or support groups.See chapter Supporting Patients in Care for further information.
# Enhancements to increase the HIV clinic's effectiveness: information and support
Clinics can enable patients to better care for themselves by providing them with information about HIV and by helping to build a community among them.
Much information is available for patients, including publications on medications, side effects, and adherence.Many clinics display HIV-related education materials, including information on safer sex practices and birth control; many also provide male and female condoms with instructions about their use.In some clinics, a separate area for educational materials may help clients maintain confidentiality.Free educational materials are available from federal and state HIV websites, and the pharmaceutical industry also produces some excellent materials.
Many ASOs and clinics host support groups for interested patients.Participation must be voluntary, and only patients who are comfortable with revealing their status to other patients will be willing to participate.Some support groups target specific populations.Groups may be more effective if an experienced counselor or mental health provider leads them.
Some clinics hold classes on HIV and adherence.Other clinics provide periodic symposia to keep patients up-to-date on treatment advances.Clinics serving pregnant women and parents may include classes on birth preparation and parenting.For clinics that have a community advisory board, the board can be the organizing force for these community updates.Both public grants and funds from the pharmaceutical industry may be used to support these events.
Some youth-oriented clinics arrange social events and outings for their patients.Programs for children or mothers may provide support services for both infected and affected children, ranging from formal psychological care to supportive recreational activities after school or during school breaks.
Section 1: The HIV Clinic: Providing Quality Care desktop computer in a small practice or on a computer server that can be accessed by many users simultaneously, or they may be based on the Internet and managed by the vendor.In all instances, backup of the data and maintenance of confidentiality and compliance with Health Insurance Portability and Accountability Act (HIPAA) rules and other laws are necessary.
PMS refers to software used principally for scheduling and billing; it includes information on patient demographics, insurance or payer, attendance with appointments, diagnoses, and sometimes other information.This is very useful in tracking clinic productivity and patient adherence with visits, and in developing an overview of a patient population and understanding the finances of a practice.PMS software can provide data regarding some quality measures, because services such as vaccinations and procedures performed within the practice can be tracked easily.
EMR refers to software used for clinical care, as a substitute for or supplement to a paper medical record.Providers enter their notes into these systems, and clinic staff document procedures and interventions performed in the office.With many systems, prescriptions may be written within the system and sent to pharmacies electronically or by fax, diagnostic tests may be ordered, and test results may be sent electronically into the EMR for clinician review and action.Paper documents often can be scanned into the system so that hard copies of outside reports can be included in the medical record.EMRs that substitute for paper records can reduce issues of storage, retrieval, and access to paper charts once the transition is complete.
EHR refers to software that the patients can access to see part or all of their medical record.These systems are designed to empower patients as members of their health care team, to provide detailed information to them, and to promote interaction between the consumer and provider.
# Potential advantages of EMR, PHR, and EHR
In an era of transformation of the U.S. health care system, much is said about the potential of these software products to increase efficiency and reduce errors.While this potential is real, substantial effort and investment is required to deploy and maintain systems that are useful to clinicians, administrators, and payers.An EMR for a small office or one that is deployed only in an HIV program can be managed fairly easily, and some products developed specifically for HIV care are available.An EMR for a large organization, such as a multispecialty group, is more complex and requires much more planning, training, maintenance, and sometimes customization to meet the needs of all the users.Success in EMR implementation is greater when the users are involved in the selection and implementation of the system, although it will never be possible to satisfy all users with one product.Commercially available systems run on servers for large organizations may provide options for customization; however, customization greatly increases the cost and complexity of installing the software updates that are likely to be required.
EMRs may be text based (such as the system used by the Veterans Health Administration) or data based.Text-based systems are often quicker to learn; however data-based systems may provide more information for quality and program management and reporting needs and may be more useful for billing functions. |
Some EMR software packages are available at no cost (such as the Veterans Health Administration system and other opensource software) whereas others are available commercially and are maintained by vendors.
Once fully implemented, EMRs are expected to improve quality by improving communication and coordination among clinicians, reminding clinicians about standards of care and the timing of health maintenance or monitoring, Section 1: The HIV Clinic:
Providing Quality Care avoiding errors associated with handwritten notes or prescriptions, documenting prescriptions, and providing warnings on potential drug interactions or hazards associated with specific diagnoses.EMRs are expected to lower costs by reducing the expense of maintaining paper records and by reducing duplication by sharing prescriptions, test orders, and test results among all users.EMRs can provide both process and outcome data for quality improvement activities (see chapter Quality Improvement), and data for Ryan White grantee reports.They also may make it easier for practices to fulfill and document adherence with the standards of payers.
Medicare and other payers are currently offering incentives for specific uses of EMRs, for example when at least 75% of prescriptions are sent electronically (because this is thought to reduce prescription errors) and for other types of "meaningful use" that are thought to improve the organization of care and adherence with clinical care standards.
# Cautions regarding EMR, PHR, and EHR
These software packages are complex entities that require substantial staff time and effort, hardware purchase and maintenance, training, and modifications in workflow.EMRs are not simply replacements for paper records; effective use involves changes in the work habits of clinicians.Successful implementation of an EMR system requires working with the end users as the system is developed so that reasonable compromises and accommodations can be made.Choices must be made regarding both the software and the hardware to be used (e.g., a laptop computer used by a single clinician in multiple examination rooms versus a fixed desktop computer in each room).An EMR system that must share data with another system such as a hospital EMR or a laboratory reporting system can be very complex and require substantial investment of time and money, even when the different software systems use compatible data standards.Effective implementation often occurs over the course of years.Implementation of EMR systems is not a panacea and will not solve all health care system problems, but use of EMRs is likely to be a necessity for functioning in the evolving systems of health care finance and reimbursement.
# Ensuring that patients receive necessary services at clinics without EMRs
At clinics in which paper charts are in use, forms, checklists, and flow sheets can be designed to remind providers of care standards, simplify data collection, and serve other purposes as well.Sample forms for initial and follow-up visits are posted on the HRSA HIV/AIDS Bureau (HAB) website (www.hab.hrsa.gov).They include reminders regarding clinical standards, reminders of services required for billing levels, checklists built around definitions used by Ryan White HIV/AIDS Program grantees for reporting to HRSA, and other data for quality management.These instruments often can be used to generate reports to individual providers.Staff members may find it challenging to adjust to using new forms; however, using checklists often saves time by listing required elements of the visit and by reducing the amount of writing.Including representatives from clinical, data, and quality management staffs in the process of designing forms increases the acceptability of new forms or procedures.
# Effective Management of HIV Programs
Managing a program with all the components described in this chapter is challenging.
To enhance communication and advance the clinic's objectives, staff meetings are important.Smaller organizations may include the entire staff at monthly meetings, whereas larger organizations may have staff meetings less often, such as on a quarterly basis.Some larger organizations find it useful to have a monthly interdisciplinary meeting of program leadership, with representation of the different Section 1: The HIV Clinic: Providing Quality Care disciplines or program components, such as nursing or clinical care, psychosocial support, data and quality management, behavioral health, research, finance, administration, satellite services, and consumers.These coordinating meetings provide an opportunity for personnel from each discipline to update others on current activities, challenges, successes, and initiatives.They also provide a regular forum for updates on fulfilling grant-related work plan tasks and reviews of financial reports.Minutes of the meetings, which include decisions taken and assignments made, should be prepared and circulated to participants; minutes should be reviewed at the subsequent meeting and reports on assigned tasks should be delivered.These larger organizations also may have monthly meetings by discipline, for example, comprising the nursing or clinical staff, to transmit information from the larger meeting and to coordinate the discipline-specific activities.In smaller programs, quality management may be part of staff monthly meetings whereas in larger programs it is more practical to have a separate quality management committee (see chapter Quality Improvement).
HIV programs often are contained within larger health organizations, and may be outliers with regard to the patients they serve and other features.It is important for program leadership to build and maintain support within the host institution.Where applicable, this may involve reminding the host institution of the grant or other funding the program generates.HIV programs often are on the forefront of innovative health care delivery, for example, in adopting quality management approaches and using other data to assist program management, incorporating EMR and PHR systems, implementing interdisciplinary care that integrates medical care with behavioral health, using a chronic care model or providing a medical home for patients, and linking with communitybased programs.An important task for HIV program leadership is making the host institution feel proud and supportive of the HIV program itself.Section 1: The HIV Clinic: Providing Quality Care Quality Improvement "Quality of care is the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge."
# Suggested Resources
(Institute of Medicine, 1990) "All health care organizations, professional groups, and private and public purchasers should pursue six major aims; specifically, health care should be safe, effective, patient-centered, timely, efficient, and equitable."
(Institute of Medicine, 2001) Bruce D. Agins, MD, MPH Quality Improvement: Raising the Bar Quality improvement (QI) has become a standard of practice for HIV programs in the United States.Quality management is included in contractual requirements for Ryan White-funded programs and has been integrated into training programs.Many clinicians have learned the basics of quality management, and may be participating in or even leading improvement efforts in their clinics.
Moving beyond the basics, however, remains a challenge for clinicians who have limited time to participate in activities not related to direct patient care.Yet, focusing on quality can reveal important phenomena in the clinic of which the leadership is unaware or may point out factors that explain why problems have not been easily resolved.
Increasingly, QI work in the HIV field is associated with important health outcomes such as HIV viral load suppression, retention in care, and reductions in costly service utilization such as hospitalizations and emergency department visits.Simple subanalyses of basic performance data may reveal disparities in how care is being provided to different patient groups in the clinic, for example, according to age, gender, or race/ethnicity.At the same time, advances in health information technology have made it easier to generate data for performance measurement, and for performing the simple analyses that can be used for improvement activities.
This chapter will quickly review the basics of QI; an appendix at the end of the chapter illustrates concepts with examples of more advanced improvement work.Chapter Health Resources and Services Administration HIV/AIDS Bureau Performance Measures in this manual presents a national quality initiative developed by the U.S. Health Resources and Services Administration (HRSA) HIV/AIDS Bureau (HAB) for Ryan White HIV/AIDS Program-funded clinics; HRSA's Performance Measures can be incorporated into the quality improvement programs of local clinics, and establishment of an HIV-specific quality management program is itself a HRSA performance measure.
The fundamental concepts of QI have evolved over the past century to include the following:
- QI provides an opportunity to solve problems that are part of the system and not dependent on one individual.
- Improving problematic processes within the health care delivery system will lead to improvements in outcomes.
- Focusing on performance measurement and improvement usually stimulates employees to maximize their performance.
- Leadership is key to the success of improvement work, and clinicians have the opportunity to provide this leadership through championing best outcomes for patient care.
Section 1: The HIV Clinic: Providing Quality Care
- Team-based problem-solving techniques lead to better care and promote a positive working environment.
- Consumers play a pivotal role in providing the "end-user" perception of the quality of the services delivered; their active participation in the quality management program strengthens improvement work and leads to better results.
In addition, documentation of QI activities helps to demonstrate institution-wide compliance with accreditation responsibilities and funding requirements, while often giving the clinic or institution an advantage when competing for alliances with purchasers.Data generated from the clinic's QI program showing improvements over time demonstrate to constituents that the program is successful and help to justify its funding.
Finally, monitoring systems that are dependent on single individuals will not last when these key players leave the clinic or are absent for long periods, whereas a fully functioning QI program that involves staff working in teams with a clearly defined infrastructure will keep going when even the most dynamic individuals depart.
# Introduction to Quality Improvement
QI includes regular measurement of care processes and outcomes to analyze the performance of the system of care.It involves the implementation of solutions to improve care and the monitoring of their effectiveness, with the goal of achieving optimal health outcomes for patients.Ongoing cycles of change and remeasurement are implemented to test and try different ideas to determine which practices result in improved care.QI activities in clinics can range from a single team focusing on improving one aspect of care to a comprehensive QI program with many teams working on a wide variety of improvement projects, with a well-established plan and an oversight committee.
The methods of QI are based on core principles that are readily translated into a practical approach and integrated into the clinical care delivery system (see Table 1).Successful implementation of QI involves actions at two levels: the QI activities and the HIV program processes that provide the structural backbone for them.
# Table 1.Core Principles of Quality Improvement
- Focus on the customer: improvement activities result in improved patient health - Measurement: collect and use data to improve care - Emphasis on systems of care: improve processes that link to desired outcomes - Involvement of participants: encourage direct participation in teams by those individuals who implement the processes being evaluated Section 1: The HIV Clinic: Providing Quality Care
# Measurement and Management Are Not Sufficient
Although it is the bedrock for improving care, measurement alone is not sufficient to improve quality.A common pitfall in implementing QI programs is to rely solely upon performance data, the medical or program director's interpretation of it, and one person's decisions about how to make changes.Successful improvements occur most often when staff members from the systems being assessed work together in teams.When they are engaged in the process, staff members are more likely to generate ideas for improvement and to accept changes.Staff review of improvement charts (see Figure 1, below) generates pride and a sense of accomplishment based on members' participation in the QI work.These charts may be posted on bulletin boards in common areas of clinics so that everyone can view them.
# Key Components of a Quality Plan
The key elements of a quality plan include a quality statement that describes the purpose, priorities, and goals of the QI program; a description of the organizational systems needed to implement the program, including committee structure and functions, definitions of accountability, roles and responsibilities, the process for obtaining consumer input, core measures, and data collection processes; and a description of how the plan will be evaluated.For further information, see New York State Department of Health AIDS Institute HIVQUAL Group Learning Guide (see "References," below).
# QI Personnel
The size of the clinic will determine who participates in quality-of-care activities.In small HIV clinics with a primary care provider, case manager, nurse, and support staff, most of the staff members are involved in all aspects of QI work.Larger institutions usually establish an HIV Quality Committee that includes senior management of the HIV clinic, designated QI staff if there are any, and other key players who work in the clinic.A member of this committee represents the group in the agency-wide QI committee.The Quality Committee identifies the priorities for improvement or agrees to pursue the priorities identified by staff members or patients in the clinic.The Quality Committee also charters improvement teams and identifies potential members who are key stakeholders in the process under investigation.In a small clinic that has only a handful of staff members, all clinic personnel may participate in the quality management program and in QI activities, although perhaps in a less formal way than in larger clinics.
# Team Membership and Responsibilities
Teams are formed to address the specific care processes or systems that are targeted for improvement.Team members should be selected to represent the different functions involved in these processes or to represent the components of the system under focus.The size of a team varies according to the size of the clinic and the process under study.In small clinics, the few dedicated HIV program staff members may constitute the project teams, with added representation from different departments as needed (such as from the laboratory, or from other medical disciplines).In larger clinics, teams often include 6-10 members.Membership should include representatives from the different groups in the clinic who are involved in the care process.In addition to the clinical and case management staff, scheduling clerks and medical records personnel often are important participants, especially when follow-up appointments and documentation are important components of the care process or have been identified as areas that need to be improved.
Section 1: The HIV Clinic:
Providing Quality Care
Involving consumers in QI project teams enhances the work of the team.Consumers who are involved in the clinic's community advisory board often are natural leaders and have a good grasp of clinic processes.Their feedback on the experience of care delivery can reveal areas that need improvement.They know the bottlenecks and can inform the staff how long a clinic visit lasts, whether assessments truly occurred, and whether behavioral interventions are effective.Their ideas about what improves care often diverge significantly from those generated by providers and may not even be recognized unless they participate directly in discussions about the system.
Teams are expected to analyze clinical processes, identify areas of change, implement tests of the changes, review data assessing the change, and ultimately make recommendations about which improvements should be adopted in the clinic.
As the project team conducts its work and gains experience, it will become more independent and assume more responsibility for ongoing measurement, data collection, and implementation of steps toward improvement.It should disband when implementation has resulted in sustainable results.
# Data Collection
# Selecting Indicators
Indicators are measurable aspects of care that can help to evaluate the extent to which a facility provides a certain element of care.Indicators should be based on standards or guidelines, meet the primary goals of QI, and reflect priorities specific to the community and the clinic.In addition, they should represent processes where changes are feasible.For example, in HIV clinics where the population consists of a large number of women, indicators may include rates of routine cervical cancer screening, rates of preconception counseling, or other aspects of care specific to women.In clinics that care for a high volume of patients who have been treated with antiretroviral therapy (ART) for a long time, indicators may focus on rates of virologic suppression, screening for adverse effects of antiretroviral medications, and resistance testing.Some indicators should be selected by soliciting input from patients who attend the clinic (see
# Developing and Measuring Indicators
Three major activities constitute the process of indicator development:
- Defining the measurement population - Defining the measures - Developing the data collection plan
The measurement population is defined by determining factors such as the location of care being studied, whether both men and women are eligible, the applicability of the indicator to various age groups, whether any clinical conditions are necessary to determine whether the indicator is applicable, and whether the patient must have been in treatment or visited the clinic more than once.
After the population is defined, the measure needs to be defined.The measure should be objective and should address specific aspects of quality care.It also should have a straightforward, dichotomous answer.For each measure, specific criteria must be developed to define the "yes" response and the "no" response (see Table 3).This often involves deciding the time period during which an activity has been performed.For example, an indicator that measures viral load monitoring must include the frequency with which that test should be performed.One simple way to construct this measure would be to ask, "Was viral load measured within the past 6 months?"Several indicators should be measured simultaneously, whether abstracted from medical records or analyzed through administrative databases.Indicators reflecting different aspects of patient management should be selected, as should those involving different populations.Indicators also should be selected to evaluate various components of the health care system, such as the components of the chronic disease model. |
The data collection plan includes determining the source of information (e.g., whether medical records or an electronic database will be used), how the data will be recorded, who will record the data, and how a data sample will be selected.A representative sample will allow inferences to be made about the overall clinic population based on observations of the smaller sample.Some form of random sampling should be used, either by using a random numbers table or by selecting every Section 1: The HIV Clinic:
Providing Quality Care nth record from the list of eligible patients.
A common pitfall at this point is to think of the measurement sample as a research project.
For the purposes of QI, a sample needs only to be current, representative, and readily obtained (i.e., sample size calculations and the achievement of statistically significant results are not necessary).
# Analyzing and Displaying Data
Data should be reviewed and distributed to all members of the team and others involved in the care process under evaluation.When possible, data should be displayed in graphic format.After data from multiple time periods have been collected (e.g., percentage of patients screened for latent TB), a simple line graph (run chart) can be constructed with each point representing a performance rate (percentage) for a given period of time.This usually is the simplest and most effective way to show performance data (see Figure 1).
# Identifying Targets and Implementing Improvements
After the project team has reviewed the data, it must decide where opportunities for improvement exist.The first step in this process is to investigate the care process in greater detail.Several techniques are used to accomplish this goal.The simplest is brainstorming, in which key stakeholders offer their suggestions as to which processes are the best candidates for change.Another easy method is flowcharting, in which the group breaks down the process into its components to identify how it is coordinated and how its parts fit together.A fishbone diagram, or cause-and-effect diagram, may aid in exploring and displaying the causes of a particular problem (Figures 2 and 3).It often helps for staff members to consider factors potentially influencing a process that are not obvious, and to help sort out those factors that are external to the clinic and those that are internal.Then, the areas that would be most likely to benefit from improvement are selected for change (see Figure 4) and tested in the Plan-Do-Study-Act (PDSA) cycle (see Figure 5).See "Appendix," below, for examples of QI projects conducted in HIV clinics.Medical nurse takes patient into the exam room.
# Patient in system?
Nurse asks for patient's name and searches the database for his/her le.
Nurse asks patient to complete paperwork for new clients and return it to the front desk.
Ask patient to be seated in the waiting room.
Etc.
# YES NO
Oval shape shows beginning to ending step in a process.
Rectangle depicts particular step or task.
Arrow shows direction of process ow.
Diamond indicates a decision point. After a change to a particular step of the process has been selected, a test of the change can be quickly implemented and evaluated.
A limited implementation of the proposed change can be tested -perhaps with just a few subsequent patients, or those attending on the following day, or those seen by a particular clinician.If the small change does not work, another change can be selected and implemented quickly.If the change is feasible and improvement is noted, it can be adopted more widely, before formal remeasurement occurs, and a regular period of remeasurement can be adopted.If the change was not successful, then another one can be chosen and tested.Occasionally, multiple changes may be tested simultaneously or on different days of the week.
Section 1: The HIV Clinic: Providing Quality Care
Often teams become caught up in following a rigid series of steps.Many different approaches to QI exist and can be implemented successfully.However, sometimes just stepping back to refocus on the three basic questions of the model for improvement presented by Langley et al. (see "Suggested Resources," below) can effectively guide QI activities.These are as follows:
- What do we want to accomplish?
- How do we know that a change will result in an improvement -in other words what measure will we use to demonstrate whether our improvements worked?
- What kinds of changes can we test that will result in an improvement?
Establishing Systems to Support QI
The key to sustaining QI in the clinic is development of an infrastructure that supports ongoing QI activities.The central components of this infrastructure include the following:
- A QI plan with goals and a process to prioritize these goals
- A work plan that clearly defines steps, sets timeframes for completion, and identifies responsible parties
- An organizational framework that displays clear lines of accountability for QI in the organization
- Commitment of senior management staff to support the program, allocate resources, and celebrate its successes
- Creation of a culture that supports quality in the program and that values the activities of QI as part of the regular work of the clinic (see Table 4)
- Patient participation, to share experiential knowledge and inform QI program development
- Establishment of a formal QI committee to oversee quality activities, monitor the quality plan, and evaluate its effectiveness The regular, ongoing work of the QI committee, supported by the clinic leadership, constitutes the backbone of the infrastructure that supports ongoing QI activities.The committee oversees the dynamic process of planning, implementation, and evaluation that involves the following:
- Analysis of data from the QI projects - Solicitation of feedback from participating staff and from patients
- Decision-making based on the information from its analysis These contribute to sustaining the QI program and its activities in the clinic.
Section 1: The HIV Clinic: Providing Quality Care
# Sustaining Improvements
Sustainability is probably the biggest challenge that clinics face in the field of QI.All too often, improvements do not last after initial projects are completed, because the structure and culture to support QI is not present or is not supported.The challenge of sustainability therefore is twofold: to maintain the successes of QI work and its clinical outcomes, and to maintain the systems of QI and to keep the QI program vital.By asking questions about how care systems can be improved and how QI activities are progressing, clinicians play an important role in both catalyzing and supporting QI activities.
# Appendix: Case Examples of Quality Management Initiatives
Using QI to Improve ART
# Management and Virologic Suppression
In one community health center, nearly 10% of patients on antiretroviral therapy (ART) were not virologically suppressed.The clinic had adopted a strategy of developing a specific ART management plan for each patient being treated.Review of the charts of the 45 patients not suppressed showed that only 40% had a plan in the chart.Only 20% had a plan that was executed.Improvement goals were set for each step, to increase from 40% to 90% for documentation and from 20% to 75% for execution.Over the course of a 4-month period, clinicians and support staff were educated about the plan and decision-support tools were created, including an algorithm showing key decision points for plan development and execution with corresponding prompts in the clinic database.Visit forms were revised to incorporate data fields specific to the ART plans.Reminders also were created.All changes were implemented through small tests of change with formal indicator remeasurement in 6 months; this showed that 100% of patients had a plan in their charts and that 71% of them had it executed.Continued monitoring showed a dip in performance 4 months later to 88% and 60%, respectively, but with gains restored 3 months subsequently to 100% and 65%, respectively.Vigilance and reaffirmation of the main steps have been keys to maintaining performance.The fields are now being added to the new clinic electronic medical record (EMR) system with automatic prompts based on changes in viral load values.
Another clinic focused QI efforts directly on improving rates of virologic suppression.Data on the HIV viral loads of each specific provider were generated to show comparative rates as a stimulus for improved performance on the part of individual providers.ART regimens were reviewed for their appropriateness, and renewed education about antiretroviral drug combinations and resistance monitoring was introduced.The clinicians reviewed their own patient lists each day.Patients who were not virologically controlled were contacted by phone by the clinician or a nurse.Nurses eventually were assigned directly to the primary care team to facilitate communication with patients and ensure that specific issues raised during phone conversations were addressed during clinic visits.Adherence problems were particularly common, and were addressed through these multiple contacts.Reasons for adherence lapses were identified, which allowed for more effective targeting of service interventions with specific patients, including substance use and mental health service referrals, regimen switching, and targeted adherence interventions.The individual providers improved their patients' rates of virologic suppression from 45% to 62%.Review of suppression rates also showed that a subset of patients remained controlled and did not require quarterly monitoring.A Section 1: The HIV Clinic: Providing Quality Care decrease in visit frequency was possible for this group, reducing overutilization of services and unnecessary costs.
# Using QI to Eliminate Disparities
The quality committee in another clinic wanted to determine whether the clinic's performance was consistent across all patient groups and arranged to have the clinic's patient data sorted by race, ethnicity, and primary language spoken.This revealed that data about race, ethnicity, and language spoken were not recorded in a high proportion of patient records.The team invited patients from their community advisory board to attend a staff meeting where a fishbone diagram was developed to identify potential causes of the poor collection rates of these patient data.Potential reasons were identified in all categories: equipment, patients, procedures, and staff (see Figure 3).A flow chart was developed to identify the sequential steps of data collection.A training program for intake staff was developed, resulting in an improvement in collection of these data to 85%.Subsequent analysis showed that only 54% of African-American patients and 68% of Latino patients had suppressed HIV RNA whereas white patients had a suppression rate of 75%.A focus group with Spanish-speaking patients revealed that these patients were not getting enough information about medication and its side effects.The QI team decided to aim for an improvement in virologic suppression rates to 75%.A number of changes were implemented and tested throughout the clinic including the addition of peer adherence counseling, using teach-back by non-physician staff to facilitate adherence problem-solving, along with medication reconciliation.With these new interventions, virologic suppression rates improved to 71% for African-Americans, 80% for Latinos, and 81% for whites.With ongoing QI activities, suppression rates have subsequently increased for all groups and the gap has narrowed.Ongoing changes aim to narrow the gap even further. -www.asq.org (American Society for Quality)
# Suggested Resources
- www.mytapestry.com (contains many links to other websites)
- www.ahrq.gov (Agency for Healthcare Research and Quality)
- www.jcaho.org (Joint Commission on Accreditation of Healthcare Organizations)
- www.nahq.org (National Association of Healthcare Quality)
- Group 2 measures are important measures for a robust clinical management program and should be seriously considered.
- Group 3 measures represent areas of care that are considered "best practice," but may lack written clinical guidelines or rely on data that are difficult to collect.
The Medical Case Management Performance Measures target all clients, and focus on two key issues: care plans and medical visits.Medical case management programs are encouraged to utilize the core clinical performance measures as appropriate.
The Oral Health Performance Measures target all clients.The measures are intended for use by programs providing direct oral health services.
The AIDS Drug Assistance Program (ADAP) Measures are intended for use by the ADAP.Four measures are included and target all clients, regardless of age.
The Systems-Level Performance Measures address aspects of access and entry to care and may be utilized by any system or network.
The Pediatric Performance Measures (not reproduced here) address a range of clinical, social, and system issues for programs that serve pediatric clients.
Section 1: The HIV Clinic: Providing Quality Care GROUP 3 continued
# MAC Prophylaxis
Percentage of clients with HIV infection with CD4 count of <50 cells/µL who were prescribed Mycobacterium avium complex prophylaxis in the measurement year Section 1: The HIV Clinic: Providing Quality Care
# HIV Care in Correctional Settings
Minda Dwyer, ANP-C; Douglas G. Fish, MD; Abigail V. Gallucci, BS; Sarah J. Walker, MS
# Background
Caring for HIV-infected patients who are incarcerated is a complex and challenging task.For many of these patients, the prison health service provides their first opportunity for access to consistent health care.This chapter will discuss some of the issues relevant to the HIV-infected population in correctional settings.
# Jail vs. Prison Settings
It is important to note the distinction between "jail" and "prison" custodial settings.These terms are often used interchangeably, but doing so can create confusion for health care providers, as the services that an inmate receives while incarcerated may differ greatly according to the type of facility (NYSDOH, 2008).Jails are locally operated, or managed, institutions that detain individuals who typically are serving short sentences of 1 year or less.They also hold individuals who are awaiting arraignment, trial, or sentencing, or those who have violated terms of their parole (Harrison and Beck, 2006).Because inmates who are detained in jail settings have shorter confinement terms, providers often face time constraints in establishing longerterm treatment plans for chronic conditions such as HIV/AIDS, and for substance use and mental health problems.Opportunities for inmate education also may be more limited.In addition, because jail inmates often are released within days, weeks, or months after initial confinement, establishing continuity of health care may be challenging for providers and administrators (Okie, 2007).
Prisons, in contrast, are operated by state governments or the Federal Bureau of Prisons.Prisons generally detain people who have been convicted of state or federal felonies and are sentenced to terms of longer than 1 year (Harrison and Beck, 2006).The nature of a person's crime, namely a state or federal offense, will dictate the type of prison in which he or she will be detained.The length of sentences for inmates in state or federal custody is longer than those for persons serving time in jail, and prison inmates typically have a firm release date in advance.As a result, HIV-infected inmates released from prison may be more likely to have treatment and discharge plans in place (NYSDOH, 2008).
Note that these characteristics may differ from prison to prison and jail to jail.
# Epidemiology
Inmates continue to be disproportionately affected by the epidemic, with the estimated overall rate of AIDS among prison inmates at more than 2.5 times the rate in the United States general population.In 2006, there were 21,980 HIV-infected inmates in prisons, according to the latest report from the Bureau of Justice Statistics, and there are many more in jails.With the advent of effective combination antiretroviral therapy (ART), AIDS-related mortality as a percent of total deaths in state prisons decreased significantly between 1995 and 2006, from 34.2% to 4.6% (Maruschak, 2006).
Often, behaviors that lead to incarceration also put inmates at high risk of becoming infected with HIV, hepatitis C virus (HCV), and other infectious pathogens.These risk factors may include unsafe substance use behaviors, such as sharing syringes and other injection equipment, and high-risk sexual Section 1: The HIV Clinic:
Providing Quality Care practices, such as having multiple sex partners or unprotected sex.Many inmates also may have conditions that increase the risk of HIV transmission or acquisition, such as untreated sexually transmitted infections (STIs).
The prevalences of chronic viral hepatitis and tuberculosis are much higher among incarcerated persons than among the general public.Depending on the prison system, 13% to 54% of inmates are infected with HCV (Cassidy, 2003).The incidence is 10 times higher among inmates than among noninmates and is 33% higher among women than among men (Nerenberg et al.,2002).The Centers for Disease Control and Prevention (CDC) recommends that all incoming inmates be screened for HCV, and those who are infected should be evaluated for liver damage and the need for treatment (Cassidy, 2003).Chronic hepatitis B virus (HBV) infection and tuberculosis also are substantially more common among the incarcerated population than among the general public.The presence of any of these conditions should prompt HIV testing (Nicodemus and Paris, 2002).
# Incarcerated Women
Women account for almost 7% of the prison population in the United States (West and Sobol, 2009).The HIV epidemic in the United States increasingly affects women of color, and this trend is reflected in HIV rates among the incarcerated.In terms of total numbers, there are more males than females with HIV/ AIDS in state and federal prisons nationally (19,809 and 2,135, respectively).However, the percentage of female inmates with known HIV infection in these settings is higher than that for incarcerated males (2.4% and 1.6 percent, respectively) (Maruschak, 2006).
In many cases, incarcerated women are low-income and have limited education and sporadic employment histories.Compared with men, they are less likely to be incarcerated for a violent crime, and more likely to be incarcerated for a drug or property offense.Women's property crimes often are the result of poverty and substance-use histories (National Institute of Corrections, 2003).
Numerous studies have shown that the behaviors that lead to incarceration also put women at increased risk of HIV infection. |
Risk factors that are present in abundance among female inmates include the following:
- History of childhood sexual abuse and neglect
- History of sex work, with increased frequency of forced, unprotected sex
- High rates of STIs
- High rates of mental illness
- History of injection drug use (IDU) or sex partners with IDU history
- Poverty Among all women entering a correctional facility, 10% are pregnant (De Groot and Cu Uvin, 2005).These women should be offered HIV testing, and HIV-infected pregnant women should be offered combination ART immediately to prevent perinatal HIV transmission.Many incarcerated women will receive their first gynecologic care in prison.Because the incidence of cervical cancer is higher among women with HIV, referrals for colposcopy should be made for any HIV-infected woman with an abnormal Papanicolaou test result.
# Testing and Prevention
The correctional facility is an ideal location for identifying individuals already infected with HIV, HCV, or HBV, and for education interventions that are geared to prevent infection among those at highest risk of these acquiring diseases.For many adults, the prison or jail setting is a rare potential point of contact with the health care system, making it an important avenue for HIV testing and linkage to care.
Section 1: The HIV Clinic: Providing Quality Care
Inmates commonly are hesitant to be tested for HIV because they fear a positive diagnosis and because of the potential stigma involved.They often lack accurate information about HIV, including awareness of behaviors that may have put them at risk and knowledge of means for protecting themselves from becoming infected.Health care providers in correctional settings are in a key position to evaluate inmates for HIV risk factors, to offer HIV testing, and to educate and counsel this high-risk group about HIV.
HIV testing policies in correctional facilities vary from state to state and among local, state, and federal penal institutions.Depending on the setting, policies may require testing of inmates upon entry, upon release, or both, but more than 50% of state prison systems do not require HIV testing at any point.Some prisons may do HIV testing based on clinical indication or risk exposure during incarceration, and this may be voluntary or mandatory.Most prison systems do provide HIV testing for inmates who request it.See Table 1 for an overview of the circumstances under which inmates in state prisons were tested for HIV in (Maruschak, 2006.
In high-risk settings such as correctional facilities, routine, voluntary HIV testing has been shown to be cost-effective and clinically advantageous (Paltiel et al.,2005).The CDC supports universal opt-out HIV screening in prisons and jails and has produced the HIV Testing Implementation Guidance for Correctional Settings (www.cdc.gov/correctionalhealth/default.htm).This document serves as a guide for individual institutions in determining and establishing the most appropriate testing strategy for their settings, presents the components of such a testing program, and explains obstacles that may be encountered in the implementation process.It also provides information regarding the following:
- Background statistics on HIV in correctional facilities
- Inmate privacy and confidentiality
- Opt-out HIV screening in correctional medical clinics
- HIV testing procedures
- HIV case reporting
Testing inmates for HIV prior to their release is a critical aspect not only of individuals' own health care needs but also of preventing transmission of HIV to others.Knowledge of their HIV status affects people's HIV risk behaviors: Studies have shown that, after learning they are infected with HIV, many persons take measures to reduce the risk of transmitting HIV to others.
# Risk-Reduction Education
Given the high HIV seroprevalence among inmates, the reentry of inmates into the community presents a danger of spreading HIV and other infectious diseases, and it is a public health concern.Thus, inmates need adequate HIV prevention counseling before release, both to protect themselves and to decrease the likelihood of infecting others in their communities with HIV (Gaiter and Doll, 1996).The World Health Organization (WHO) has stated: "All inmates and correctional staff and officers should be provided with education concerning transmission, prevention, treatment, and management of HIV infection.
For inmates, this information should be provided at intake and updated regularly thereafter."
Risk-reduction counseling addresses specific ways the inmate can reduce the risk of becoming infected with HIV.If an inmate is already HIV infected, the goal of counseling is to reduce the risk of infecting others or becoming infected with a drug-resistant strain of HIV.
Education should focus on the use of latex barriers with all sexual activity.Condoms and Section 1: The HIV Clinic: Providing Quality Care dental dams are not available in most jails and prisons; nonetheless, the inmate should receive education regarding their proper use.The state prisons systems that provide condoms to inmates are those of Vermont and Mississippi.
The larger metropolitan jails in New York City, such as Riker's Island, as well as those in Los Angeles, San Francisco, Philadelphia, and Washington, also provide condoms.Within the systems that allow condoms, inmates' ability to obtain them may be restricted (e.g., limited to one per week or available only via medical prescriptions or dispensing machines) (Sylla, 2007); see chapter Preventing HIV Transmission/Prevention with Positives.
No correctional system in the United States provides clean injection needles as a part of a prevention program (Sylla, 2007).However, inmates with a history of IDU should be educated about the risks of sharing needles and injection equipment, specifically the high risk of transmitting or acquiring HIV, HCV, and HBV.Inmates also should be counseled about the risks of sharing needles and other "sharps," such as those used for tattooing or body piercing.Substance abuse treatment should be provided when appropriate.
Recovery from addiction often is a chronic process and relapses are common.In addition to substance abuse treatment, risk-reduction strategies should include planning for support after release from the correctional setting.For example, prior to release, inmates should be provided with information about needle exchange or clean needle access programs in their communities.These programs have proved to be quite effective in decreasing the rate of parenteral HIV transmission (CDC, 1999).
Furthermore, overdose prevention should be discussed with inmates leaving correctional systems.Using heroin after a period of abstinence, such as during incarceration, hospitalization, or drug treatment, is a major risk factor for overdose.Former inmates are at highest risk of overdose within the first 2 weeks after release (NYSDOH, 2008).
Overdose risk is heightened when someone has a significant medical condition, such as HIV infection (Catania, 2007).The literature documents an increased number of correctional systems that consider including naloxone (Narcan) prescriptions in prerelease planning for inmates with a history of opiate addiction (Wakeman et al.,2009).Naloxone is a prescription medicine that reverses an overdose by blocking heroin (or other opioids) in the brain for 30-90 minutes (NYSDOH, 2008).
# Antiretroviral Therapy in Correctional Facilities
In correctional facilities, as in any setting, a consideration of HIV treatment must begin with educating the patient about the risks and benefits of treatment and the need to fully adhere to the entire regimen, and with an assessment of the patient's motivation to take ART (see chapter Antiretroviral Therapy).
Correctional facilities have two main methodologies for dispensing medications to those who are on ART.Each has advantages and disadvantages that can impact treatment adherence.These are directly observed therapy (DOT) and keep-on-person (KOP).
# Directly Observed Therapy
DOT is the system in which the inmate goes to the medical unit or pharmacy for all medication doses ; dosing is observed by staff members.This system offers the advantage of more frequent interaction between the patient and the health care team, allowing for earlier identification of side effects and other issues.
In general, patients have better medication adherence in this system, resulting in better control of HIV.For some inmates, however, the need for frequent visits to the medical unit or pharmacy may be a barrier to receiving proper treatment, particularly if they are housed at Section 1: The HIV Clinic: Providing Quality Care a distance from the medical unit.Another disadvantage of DOT is the potential loss of confidentiality, as many inmates feel that the frequency of dosing and the large number of pills they may take will reveal clues that they are HIV infected.In addition, this system puts inmates in a passive role in terms of medication treatment and does not foster selfsufficiency.
# Keep-on-Person
KOP is the system that allows inmates to keep their medications in their cells and take them independently.Monthly supplies are obtained at the medical unit or pharmacy.This system offers greater privacy and confidentiality regarding HIV status.It also allows inmates to develop self-sufficiency in managing medications, which may facilitate improved adherence upon release.However, as the KOP system involves less interaction with medical staff, problems with adherence can be more difficult to identify (Ruby, 2000).Problems with refills also can occur.For example, inmates usually must initiate the process for obtaining a refill.They may be told that a refill request was made too early or too late, which can result in delays in dispensing medications, and ultimately, treatment interruptions.In addition, many facilities do not have on-site pharmacies, but rely on local pharmacies, or a regional or central pharmacy in the state; this may further delay refills (NYSDOH, 2008).
In a study comparing DOT in HIV-infected inmates with KOP in nonincarcerated HIVinfected patients receiving ART as part of a clinical trial, a higher percentage of DOT patients achieved undetectable viral loads compared with the KOP patients (85% vs. 50%) over a 48-week period (Fischl, 2001).
# Adherence
Adherence is one of the most important factors in determining the success or failure of ART.For the HIV-infected inmate starting ART, a number of issues can affect medication adherence.These include patientrelated factors, factors related to systems of care (including the medication dispensing systems described above), and medicationrelated factors.The following are suggestions for supporting adherence to ART. (Also see chapter Adherence.)
# Patient-Related Factors
- Correct misconceptions about HIV and ART that are common among inmates and could affect adherence adversely.Inmates should be educated about the disease process and the role of the medications, along with the risks and benefits of taking ART.
- Use teaching tools that are appropriate in terms of language and reading level.
Illiteracy and low-level reading ability are common among inmates.Diagrams and videos may be more effective than readingintensive material in some cases.Basic HIV education prior to initiation of ART should include the following topics:
- How the medications work
- Consequences of nonadherence
- Names and dosages of all medications
- Potential side effects and strategies for managing them
- Encourage participation in peer support groups.These can be effective ways to foster self-esteem, empower inmates to come to terms with a positive diagnosis, allay fears and correct misconceptions about HIV disease, and aid adherence.Upon release, telephone hotlines may be available to provide follow-up support and linkages to community services.To the extent possible, family and friends should be included in the education process.
- Provide alcohol and substance abuse treatment before, or while, initiating ART.Without appropriate treatment during incarceration, linkages to supports, and Section 1: The HIV Clinic: Providing Quality Care follow-up treatment upon discharge, inmates are more likely to resume highrisk behaviors that may interfere with adherence to ART.In 2004, nearly one third of inmates in state facilities and one fourth of inmates in the federal system committed their offenses under the influence of drugs (Mumola and Karberg, 2006).
- Use mental health consultation to identify inmates with psychiatric needs.Treatment for underlying mental health disorders should precede or take place concurrently with the initiation of ART to ensure successful adherence.Depression and other psychiatric illnesses are more prevalent among inmates than among the general population (James and Glaze, 2006).
# Factors Related to Systems of Care
- Educate the facility's security staff about the importance of timely medication dosing, and communicate with other facilities in advance of a transfer; this can eliminate or reduce the frequency of missed doses.
- Schedule frequent follow-up medical visits in the early weeks after ART is initiated; these can make the difference in whether or not patients "stay the course."
# Medication-Related Factors
- Aggressively monitor and treat side effects.The most common barrier to proper adherence to ART is side effects from the medications.Inmates should be educated in advance about potential adverse events and urged to observe and report them.
In the first weeks after starting a new ART regimen, patients should be assessed frequently for side effects.For treating gastrointestinal toxicities, antiemetics and antidiarrheals should be available on an as-needed basis.As with all patients on ART, inmates should have appropriate laboratory monitoring.
- Be aware of food requirements.Various food requirements must be considered carefully when administering ART.That can be especially challenging in the correctional environment, particularly in facilities that do not allow inmates to self-administer medications.Make arrangements with prison authorities to provide food when inmates are taking medications that require administration with food.
- Avoid complex regimens and regimens with large pill burdens, if possible.Simple regimens with fewer pills appear to help improve adherence.
- Avoid drug-drug interactions.Some antiretroviral medications have clinically significant interactions with other drugs (e.g., methadone, oral contraceptives, cardiac medications, antacids).These interactions may cause failure of either the antiretroviral drug or the other medication, or they may cause additional toxicity.Consult an HIV specialist or pharmacist for information on drug interactions.
- Question patients about medication adherence at each appointment.
- ART regimens need to fit into each patient's schedule and lifestyle.This becomes a bigger issue when an inmate is close to Section 1: The HIV Clinic: Providing Quality Care release.Education about HIV management, including ART adherence, should begin well before the inmate is discharged back to the community.
# Transition to Community Care
It is estimated that 630,000 individuals are released from jails and prisons in the United States each year (Bonczar, 2003;Travis, 2005), and many of these individuals are HIV infected.Many will have difficulty managing even the most basic elements for successful reintegration into their communities.Inmates living with HIV face many challenges when reentering the community, such as finding stable housing, employment, adequate medication supply, follow-up medical care, and psychiatric and substance use treatment services (Hammett et al.,1997).
Ideally, the discharge process at the correctional facility will maximize the likelihood that the releasee will have continuous medical care.At the time of discharge from the correctional facility, all HIV-infected inmates should have a discharge plan that addresses the following:
- Housing - Health insurance - 30-day supply of HIV medications - Follow-up appointments for medical care and, if necessary, psychiatric and substance abuse care
As discussed, inmates in prisons generally serve longer sentences than do those incarcerated in jails, and they have a release date that is known in advance.Thus, HIVinfected inmates in prisons may be more likely than HIV-infected inmates in jails to have treatment and discharge plans in place before their release.However, because the extent of discharge planning resources varies among correctional systems of care, it is important for care providers to discuss the scope of services their clients received while incarcerated to learn of any service gaps upon reentry to the community (NYSDOH, 2008).
The need to find housing often is the greatest challenge for an HIV-infected inmate leaving a correctional facility.In many correctional systems, inmates must document a physical address at which they intend to reside in order to be released.However, problems with housing availability, stability, and location can create significant stressors for an HIV-infected releasee and can compromise the likelihood that he or she will access HIV health care and adhere to an HIV medication regimen (NYSDOH, 2008).
# Medication Continuity Issues
HIV-infected individuals leaving correctional settings have a variety of experiences with ARV medication continuity.A short confinement period, for example, can prevent the development of a solid transitional plan.Jail inmates may be released without their medications and have no choice but to call or walk into community health centers or clinics for their medications and ongoing care.Being released from jail after business hours, such as on a Friday night, can result in treatment interruptions over the weekend (NYSDOH, 2008).Depending on the state system, HIV-infected inmates leaving prison are more likely than jail releasees to have a medication supply in hand when they reenter the community.For example, in the New York State Department of Correctional Services, inmates will leave prison with a 30-day supply of HIV medications as well as a prescription for another 30-day supply (NYSDOH, 2008).
For some individuals, interruptions in treatment occur during their time in jail or prison.For example, many inmates choose not to disclose their HIV infection while they are incarcerated.Particularly if the sentence is short, an inmate may feel it better not to mention HIV status and instead plan to resume taking medications upon release.Such Section 1: The HIV Clinic: Providing Quality Care treatment interruptions can result in adverse health outcomes (NYSDOH, 2008).
It is important that clinic staff and community-based organizations develop the capacity to work with clients in real time as they present for care in order to help them maintain continuity with their medications.
# Strategies for Supporting Inmates upon Release
- A clear way to support clients is to intervene immediately and directly upon their release, such as by meeting them as they step off a bus or exit a facility.
- Engage clients by: - Provide material assistance by giving clients something tangible such as a meal ticket, condoms, bleach kit, or hygiene kit.
- Provide information and referrals to shortterm and survival services for clients to help improve their immediate situation.
- If possible, accompany clients to support them in obtaining short-term and survival services such as health care, food, shelter, and clothing. |
- Respond to emergency situations.
- Support clients in meeting parole or probation requirements to avoid reincarceration.Based on their individual histories, anticipate circumstances that may result in them breaking parole.For example, if a client confides that he or she has anxiety regarding meeting the parole officer, initiate and practice role plays to better prepare the client for this encounter.
- Be culturally competent.
- Link to services (e.g., medical care, mental health, substance use, domestic violence).
- Diversify clinic staffing, and use a multidisciplinary approach, including peer support.
- Think outside the box! (NYSDOH, 2008)
A number of HIV education resources for inmates and correctional health care providers are cited on the Albany Medical College website at www.amc.edu/patient/hiv/ index.htm (go to the section on correctional education).
Section 1: The HIV Clinic: Providing Quality Care
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# Patient Education
# Background
Informed and empowered patients are better able to achieve healthy outcomes as a result of improved communication and development of trust with their care providers.HIV patient education provides patients with knowledge about HIV infection, including prevention, treatment, and other aspects of care, along with tools that enable them to participate more actively in decisions regarding their medical care.Given the complexity and the rapid evolution of HIV information, education and skills-building should be an ongoing activity and a key aspect of the clinical care of HIV patients.This chapter provides a brief review of the areas that should be addressed in patient education and discusses some strategies for integrating patient education into HIV care; additional information on patient education is found in many other chapters, particularly Supporting Patients in Care, Preventing HIV Transmission/Prevention with Positives, Smoking Cessation, and Adherence, as well as in the "Patient Education" sections found at the end of most of the clinical chapters.
# S: Subjective
A newly diagnosed patient presents to clinic after being referred from a testing center in the community.The patient received the positive HIV test results more than a year ago, but has not been ready to seek care until now.The patient feared hearing that he/she was "going to die."Now, he/she is ready to consider facing this "terminal" illness.The patient received some information about HIV infection at the testing center, but that was months ago.
# O: Objective
See chapters Initial History, Initial Physical Examination, and Initial and Interim Laboratory and Other Tests for information on the initial clinic evaluation.
# A/P: Assessment and Plan
The patient will need extensive information and education about HIV infection in general, his/her individual health status and prognosis, and the support and care systems that are available.Below are some suggestions about specific areas to review with a new patient.
# Topics for Patient Education
Patient education should cover the following topics:
- What is HIV?
- How is HIV transmitted?
# Patient Educators
In most clinics, a number of different personnel may take on the responsibilities of providing health education to patients.They may include primary care providers, nurses, social workers, case managers, and pharmacists.Some clinics have designated health educators whose role is to provide this type of support for patients.Even when a formal health educator is available, a collaborative, multidisciplinary approach to patient education serves both patients and providers optimally.However, it is important to ensure that patient education messages are coordinated and that patients are receiving consistent information.
Patient education must be provided in a language and at a literacy level appropriate for the patient.Patient education should be conducted in the patient's primary language, if possible; otherwise, skilled medical interpreters should be involved.
# Conducting Patient Education
Rarely are patients able to absorb all of the necessary information in a single session.Attention and comprehension levels are optimal during the first 15-20 minutes of a visit, after which an individual's ability to absorb and retain information declines.Therefore, clinics should consider strategies to integrate brief patient education messages throughout the course of patient care and to engage patients in this process.Support groups, case managers, and peer educators can be invaluable in this process of engagement.
It is important to keep the medical information specific to the patient.Although there are some areas of education that should be considered for all patients (see above), patients should not be required to have a high level of understanding in each area.Patients should be given the opportunity to learn as much about an area as they would like, and should be encouraged to gain a working knowledge of the information that is necessary to keep them healthy and safe.Patients vary widely in terms of their interest level in mastering the details of their illness.For example, in the area of "What is HIV?"there may be some patients who want to know details about the basic science and immunologic impact of HIV.With this information, these patients might then want to take the lead in making treatment and care decisions for themselves, in consultation with their care providers.Other patients, however, would feel overwhelmed by this volume of information and involvement and may be best engaged in participating in their care by knowing how HIV is transmitted, how to keep themselves healthy, and how to access more information if they want it.Some patients would prefer for their care providers to "just tell them what to do" rather than take the lead in making their own treatment decisions.
There are a number of websites that provide HIV information for patients (see chapter Web-Based Resources).Many patients may prefer this form of self-education.Encourage patients to convey any information they discover to their care providers for further discussion.Reminding patients that they can be teachers as well as students can be a useful strategy for engaging patients in this process.
In addition, patients may learn of novel tools and information sources that could be useful to others.
Section 1: The HIV Clinic: Providing Quality Care
The following are some useful suggestions that providers can convey to their patients:
- Define your goals for each visit; please let your provider know your concerns and what you hope to learn in the course of the visit.
- Write down questions and concerns as they arise, and take that list with you to your appointments.
- Meet all the members of your care team and learn their areas of expertise and what they might be able to offer you.
- Ask about support groups and other peer groups that might be able to provide support/education.
- Review brochures and websites that provide additional information.
- Ask supportive friends or family members to accompany you to clinic visits.They may be able to obtain information that is helpful for their role in supporting your health or reminding you of information discussed at visits.
# Section 2: Testing and Assessment
# Initial History
# Background
Conducting a thorough initial history and physical examination is important even if previous medical records are available.This is the best opportunity to get a complete picture of the patient's HIV disease status, comorbid conditions, and his or her physical and emotional condition, as well as to establish the basis for an ongoing relationship with the patient.Many of the conditions that put immunocompromised patients at risk of disease can be detected early, by means of a thorough assessment.
The information gathered through the initial history and physical examination will provide a comprehensive standardized database for the assessment and treatment of HIV-related problems, including acute intervention and ongoing supportive care.
This chapter includes essential topics to cover during the clinic intake and examples of questions that can be used to elicit important information (the questions should be tailored to the individual patient).This can be completed during the initial visit or divided over the course of two or three early visits.For essential aspects of the physical examination to cover in an initial clinic intake visit, see chapter Initial Physical Examination.
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection who had two or more medical visits in an HIV care setting in the measurement year
(Group 1 measure)
# Review of Systems
For each positive answer, ask about location, characteristics, duration of symptoms, exacerbating and alleviating factors, previous diagnostic workup, and treatments tried.
# Bruising or Bleeding
- Have you noticed easy bruising or prolonged bleeding after injury?
- Nosebleeds or bleeding gums?
# Initial Physical Examination Background
Many of the conditions that put immunocompromised patients at risk of disease can be detected early, by means of a thorough history and physical evaluation.
# S: Subjective
See chapter Initial History.
# O: Objective
Assess the patient's general appearance, affect, demeanor in answering questions, body language, and other relevant characteristics.Measure vital signs; perform a physical examination.
# HRSA HAB Core Clinical Performance Measures
Percentage of women with HIV infection who have a Pap screening in the measurement year (Group 2 measure)
# Vital Signs
(These measurements establish a baseline against which future measurements can be compared.)
# Vital Sign
Recommendation/Notes
- Height - Should be measured once.
- Weight - Record at each visit.
- Temperature - Record at each visit.
- Blood pressure - Record at each visit.The BP cuff size should be appropriate for the patient's arm circumference.
- Heart rate - Record at each visit.
- Respiratory rate - Record at each visit.
- Oxygen saturation - Record at each visit.
- Waist, hip circumferences
- Waist and hip circumference should be measured for comparison in case the patient later develops obesity or lipoaccumulation related to antiretroviral therapy (ART).
# Abdominal circumference:
102 cm (39") in men = abdominal obesity >88 cm (35") in women = abdominal obesity Waist-hip ratios: >0.95 in men = increased risk of coronary heart disease (CHD) >0.85 in women = increased risk of CHD
# Ears/Nose
- Examine ear canals and tympanic membranes.
- Visualize nasal turbinates.
- Palpate frontal and maxillary facial sinuses.
# Oral Cavity
- Good lighting is essential for this examination.
- Examine:
- Gingiva and teeth (note loss of teeth, decay, inflammation)
- Mucosal surfaces (with dentures removed) (note any lesions or discolorations)
- Posterior tongue - Tonsils (note absence or presence; any abnormality in tonsil size)
- Pharynx (note lesions, exudate) - Refer to oral health specialist for examination.
# Endocrine
- Check thyroid for enlargement, tenderness, nodules, and asymmetry.
# Section 2: Testing and Assessment
# Lymph Nodes
- Document site and characteristics of each palpable node.
Node Sites :
- Posterior cervical chain - Anterior cervical chain - Submandibular - Supraclavicular - Submental - Axillary - Epitrochlear - Inguinal - Femoral
# Characteristics:
- Size (two dimensions, in millimeters) - Consistency (hard, fluctuant, soft)
- Tenderness - Mobility
- Definition (discrete, matted)
- Symmetry
# Lungs
- Inspect, auscultate, and percuss.
- Note any abnormal sounds including crackles or wheezes (e.g., signs of infections, asthma, congestive heart failure). -Note any absence of air movement (e.g., pneumothorax, pleural effusion).
# Heart
- Examine for jugular venous distention (JVD).
- Palpate for point of maximal impulse (PMI).
- Note rate and rhythm, heart sounds, murmurs, extra heart sounds.
# Breasts
- Palpate for breast masses in both men and women.
- Check for symmetry, nipple discharge, dimpling, and masses.
# Abdomen
- View: examine for distention, obesity, undernutrition, vascular prominence, petechiae.
- Auscultate; note bowel sounds. -Percuss; record liver size.
- Palpate for hepatomegaly, splenomegaly, masses, tenderness or rebound tenderness.
# Genitals/Rectum
- Inspect the genitalia and perirectal area; note lesions, warts, etc.
- Look for discharges, ulcerative lesions, vesicles, or crusted lesions; take samples for diagnostic studies (e.g., for chlamydia, gonorrhea, herpes simplex virus, syphilis, chancroid, as appropriate).
# Female Patients
- Perform speculum examination; note any lesions on vaginal walls or cervix.
- Obtain a Papanicolaou (Pap) test.
- Obtain endocervical swab for gonorrhea and chlamydia, and a posterior pool swab for wet mount evaluation for trichomoniasis, candidiasis, and bacterial vaginosis. -Consider anal Pap test, especially if the patient has a history of an abnormal cervical Pap test or genital warts (perform before introduction of lubricant).- - Bimanual examination; note size of uterus and ovaries, shape, and any tenderness or pelvic pain.
- Rectal examination (e.g., for anorectal lesions, warts) and evaluation of posterior uterine abnormalities. -Note nail changes (clubbing, cyanosis, thickening, discoloration). -Assess for pedal or leg edema.
# Habitus
- Look carefully for signs of lipoatrophy or lipohypertrophy, wasting, or obesity.
- Subcutaneous fat loss (face, extremities, buttocks).
- Central fat accumulation (neck, dorsocervical area, breasts, abdomen).
# Skin
- Examine the entire body, including scalp, axillae, palms, soles of feet, and pubic and perianal areas.
- Describe all lesions (e.g., size, borders, color, symmetry/ asymmetry, distribution, raised/ flat, induration, and encrustation).
- Note evidence of folliculitis, seborrheic dermatitis, psoriasis, Kaposi sarcoma, fungal infections, prurigo nodularis, etc. -Note any tattoos and or body piercings.
# Neurologic
- Assess the following:
- Mental status, including orientation, registration, recent and remote memory, and ability to calculate (serial subtraction) - Cranial nerves - Peripheral sensory examination, including pinprick, temperature, and vibratory stimuli - Extremity strength and gait to discern myopathy, neuropathy, and cerebellar disease - Fine motor skills such as rapid alternating movements (often abnormal in dementia) - Deep tendon and plantar reflexes
# Psychiatric
- Assess the patient's general mood (e.g., depressed, anxious, hypertalkative). -Note verbal content (e.g., whether the patient answers questions appropriately; unusual or odd content).
- Note inappropriate or unusual behavior, such as extremes of denial, hostility, or compulsiveness. -See section Neuropsychiatric Disorders for more complete information on common pathologies.
- If the possibility of an emergency situation exists (e.g., potential suicide or violence), refer to crisis mental health services for immediate evaluation.
Section 2: Testing and Assessment
# A/P: Assessment and Plan
After completing the initial history and physical examination, do the following:
- Enter the information garnered through the history and physical examination into the patient's chart or database.
- Continue to develop the problem list, assessment, and plan for patient care.
- Complete follow-up or laboratory studies suggested by the history and physical examination. (See chapter Initial and Interim Laboratory and Other Tests.)
- Prescribe opportunistic infection prophylaxis as appropriate. (See chapter Opportunistic Infection Prophylaxis.)
- Arrange for any appropriate vaccinations.
(See chapter Immunizations for HIV-Infected Adults and Adolescents.)
- Refer for dental, nutrition, and social services, as well as case management and mental health care, as appropriate.
- Refer for any additional specialty care needs identified in the history or physical examination.
- Make follow-up appointment with health care provider.
- Answer the patient's questions.
# Patient Education
A very important aspect of caring for HIVinfected individuals is educating patients about HIV infection, including goals of care and ways of achieving those goals.
# Interim History and Physical Examination Background
This chapter shows the suggested frequency and follow-up intervals of the history and physical examination for monitoring HIVinfected patients, as well as specific areas to assess in an ongoing manner.With this information, the clinician can track disease progression and formulate and maintain an appropriate care plan.Note that information gathered in the history or physical examination may call for additional directed explorations.
It is important to document new or ongoing symptoms and functional limitations at each visit.This information is particularly useful when outside agencies must determine the patient's disability status. (See chapter Karnofsky Performance Scale.)
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection who had two or more medical visits in an HIV care setting in the measurement year.
(Group 1 measure)
Percentage of women with HIV infection who have a Pap screening in the measurement year.
(Group 2 measure) The CDC disease staging system (most recently revised in 1993) assesses the severity of HIV disease by CD4 cell counts and by the presence of specific HIV-related conditions.The definition of AIDS includes all HIV-infected individuals with CD4 counts of <200 cells/µL (or CD4 percentage <14%) as well as those with certain HIV-related conditions and symptoms. |
Although the fine points of the classification system rarely are used in the routine clinical management of HIVinfected patients, a working knowledge of the staging criteria (in particular, the definition of AIDS) is useful in patient care.In addition, the CDC system is used in clinical and epidemiologic research.
In contrast to the CDC system, the WHO Clinical Staging and Disease Classification System (revised in 2007) can be used readily in resource-constrained settings without access to CD4 cell count measurements or other diagnostic and laboratory testing methods.The WHO system classifies HIV disease on the basis of clinical manifestations that can be recognized and treated by clinicians in diverse settings, including resource-constrained settings, and by clinicians with varying levels of HIV expertise and training.
# S: Subjective
When a patient presents with a diagnosis of HIV infection, review the patient's history to elicit and document any HIV-related illnesses or symptoms (see chapter Initial History).
# O: Objective
Perform a complete physical examination and appropriate laboratory studies (see chapters Initial Physical Examination and Initial and Interim Laboratory and Other Tests).
# A: Assessment
Confirm HIV infection and perform staging.
# P: Plan
Evaluate symptoms, history, physical examination results, and laboratory results, and make a staging classification according to the CDC or WHO criteria (see below).
# CDC Classification System for HIV Infection
The CDC categorization of HIV/AIDS is based on the lowest documented CD4 cell count and on previously diagnosed HIV-related conditions (see Table 1).For example, if a patient had a condition that once met the criteria for category B but now is asymptomatic, the patient would remain in category B. Additionally, categorization is based on specific conditions, as indicated below.Patients in categories A3, B3, and C1-C3 are considered to have AIDS.
# WHO Clinical Staging of HIV/AIDS and Case Definition
The clinical staging and case definition of HIV for resource-constrained settings were developed by the WHO in 1990 andrevised in 2007.Staging is based on clinical findings that guide the diagnosis, evaluation, and management of HIV/AIDS, and it does not require a CD4 cell count.This staging system is used in many countries to determine eligibility for antiretroviral therapy, particularly in settings in which CD4 testing is not available.Clinical stages are categorized as 1 through 4, progressing from primary HIV infection to advanced HIV/AIDS (see Table 2).These stages are defined by specific clinical conditions or symptoms.For the purpose of the WHO staging system, adolescents and adults are defined as individuals aged ≥15 years. In persons with untreated HIV infection, the CD4 count declines by approximately 50-80 cells/µL per year, on average.The pattern of decline may be slow and steady, or the CD4 count may level off for an extended period of time (as in long-term nonprogressors) and then decrease.Although it takes an average of 10 years for a newly infected person to progress to AIDS, there is great variation among patients.For some patients, disease progression occurs within a couple of years.For others, it takes more than 20 years, and a small number of patients appear to maintain high CD4 counts and undetectable HIV RNA levels without ART (aviremic or "elite" controllers).
Among asymptomatic individuals, the CD4 count typically is the major factor that guides the decision to initiate therapy, though the trend in recent years has been to treat willing individuals even at very high CD4 levels.Clinical status, viral load, pregnancy, comorbidities, and patient adherence to medications are among the other factors that should be taken into consideration (see chapters Risk of HIV Progression/Indications for ART and Antiretroviral Therapy).
Prophylaxis against opportunistic infections is based on CD4 count, and sometimes on 1).
# Viral Load Monitoring
The HIV-1 viral load measurement indicates the number of copies of HIV-1 RNA per milliliter of plasma.Although HIV ultimately resides within cells, the plasma measurement is an accurate reflection of the burden of infection and the magnitude of viral replication.It is used to assess the risk of disease progression and can help guide initiation of therapy.It is critical in monitoring virologic response to ART.
There are several commercially available HIV-1 viral load assays and numerous institution-specific assays.The range of detectable virus differs somewhat with each test, but the lowest level of detection generally is 40-75 copies/ mL. A viral load below this "undetectable" level indicates the inability of the assay to detect HIV in the plasma, but does not indicate absence or clearance of the virus from the body.The highest levels of detection of the viral load assays typically are between 500,000 copies/mL and 750,000 copies/mL. Viral loads higher than these levels are reported, for example, as >500,000 copies/mL. Note that commercially available assays may not detect HIV-2, and they do not accurately quantify it.
After initial infection with HIV, the viral load quickly peaks to very high levels, usually >100,000 copies/mL (see chapter Primary HIV Infection).During the period of acute infection, when HIV antibody testing may indicate negative results, the viral load test may be used to detect HIV infection (however, most viral load assays are not diagnostic tests, so the HIV antibody assay should be repeated in 4-6 weeks to confirm the HIV diagnosis).Generally, 3-6 months after primary infection, the viral load declines and then levels off, remaining in a steady state.Among patients who are not taking ARV medications, a small number maintain a low or even undetectable viral load (aviremic or "elite" controllers), but the vast majority of those patients have relatively high HIV RNA levels.
Higher plasma viral loads are associated with increased risk of progression to symptomatic disease and AIDS; they also are associated with higher risk of HIV transmission (see chapter Risk of HIV Progression/Indications for ART).Although the CD4 cell count is more predictive of clinical disease progression than the HIV RNA level, and is the major factor in determining when to initiate ART for asymptomatic patients, the viral load can play a role (for example, if the viral load is very high).
Once a patient has started ART, the viral load is used to monitor the response to therapy.A key goal of ART is to achieve a viral load that is below the level of detection (e.g., 200 copies/ mL. If the viral load does not reduce to an undetectable level (or at least <200 copies/ mL), or if it rebounds after suppression, virologic failure has occurred, and possible causes should be investigated (e.g., poor ARV adherence, resistance to ARVs, or reduced drug exposure).
The HIV viral load should be checked at least twice at baseline, before the patient starts an ART regimen.Follow-up viral load measurement should be performed at regular intervals, depending on the patient's clinical situation (see Table 1).For stable patients, viral load usually should be monitored every 3-4 months; for highly adherent and stable patients with suppressed viral loads for at least several years, some experts monitor every 6 months.With new therapy or changes in therapy, significant change in viral load or CD4 count, or declining clinical status, the viral load should be measured at more frequent intervals.
Viral loads, like CD4 counts, are affected by laboratory variation, assay fluctuations, and patient variables such as acute illness and recent vaccinations.Variations of <0.5 log 10 copies/mL (threefold) usually are not clinically significant.Viral load results that are inconsistent with previous trends should be repeated, and treatment decisions usually should be based on two or more similar values.Recent illnesses or vaccinations can transiently increase viral load.If a patient has had a recent illness or vaccination, the viral load measurement should be deferred for 4 weeks, if possible.
# Patient Education
- The CD4 cell count is the best indicator for gauging the strength of the immune system and for determining whether a person is at risk of infection with certain organisms.The higher the CD4 count, the stronger the immune system.
- CD4 counts are variable.Caution patients not to pin emotions and hopes to a single laboratory result.A change of <30% may not be significant.
- The HIV viral load is the best indicator of the level of HIV activity in the patient's body.
- The CD4 count and HIV viral load are used to help determine when to initiate therapy.
- The goal of therapy is to suppress the viral load to below the level of detectability by laboratory tests.An undetectable viral load does not mean HIV has been completely eradicated or that the patient is not infectious to others.
- For most patients on effective ART, the CD4 count will rise as the virus is suppressed.This indicates an improvement in the immune system.
- In stable patients, the CD4 count and HIV viral load usually should be monitored every 3-4 months.
# References
# Risk of HIV Progression/ Indications for ART Background
The CD4 cell count and HIV viral load (RNA level) are closely linked to HIV-related illness and mortality, and are the laboratory measures that are followed in clinical practice.They are the primary markers that give prognostic information on disease progression and on response to antiretroviral therapy (ART) (see chapter CD4 and Viral Load Monitoring).However, it is increasingly recognized that a number of other factors are involved in HIV disease progression.These include individual HIV-specific immune responses, immune activation, viral factors, host genetics, and age.The role of these factors and their interplay are complex and incompletely understood.
# CD4 Count
The CD4 count (and CD4 percentage) marks the degree of immunocompromise.The CD4 count is used to stage the patient's disease progression, determine the risk of opportunistic illnesses, and assess prognosis (see chapter CD4 Monitoring and Viral Load Testing).The CD4 count also guides decision making about the timing of ART initiation, helps in determining the need for prophylaxis against opportunistic infections, and helps in formulating differential diagnoses for symptomatic patients (see Table 1, Figure 1, and chapters CD4 and Viral Load Monitoring and Opportunistic Infection Prophylaxis).
Persons with HIV infection are at increased risk of complications at lower CD4 counts.A CD4 count of <200 cells/µL (or CD4 percentage of <14%) indicates severe immunosuppression, and is an AIDS-defining condition.Persons with CD4 counts below this level are at greater risk of a number of opportunistic illnesses and death, increasingly so at lower CD4 counts (see Table 1).In asymptomatic individuals, CD4 count has typically been the main indicator of need for ART.It is well established that ART is extremely effective at reducing HIV-related illness in persons with lower CD4 counts.In recent years, accumulating data have suggested that ART may be beneficial even for persons with higher pretreatment CD4 counts.
Randomized trials have shown that starting ART for asymptomatic patients with pretreatment CD4 counts of 200-350 cells/µL results in decreased morbidity and mortality compared with starting therapy for persons with CD4 counts of 350 cells/ µL, data from randomized controlled studies showing benefit of ART are not available, but several cohort studies have found decreased rates of complications and death among persons who initiated ART at CD4 counts of 350-500 cells/µL, compared with persons who initiated treatment at lower CD4 counts.Additionally, some (though not all) observational evidence suggests a mortality benefit of ART even among persons with pretreatment CD4 counts of >500 cells/µL. These cohort studies are complemented by a number of investigations that demonstrate ongoing and adverse effects of HIV and associated inflammation on various organ systems.
These lines of evidence, along with the demonstrations of the impact of ART in decreasing HIV transmission, and the availability of ARVs that generally are safe, tolerable, and effective, support the rationale for earlier initiation of treatment.Many experts favor treatment of all HIV-infected individuals, regardless of CD4 count.The current U.S. Department of Health and Human Services (DHHS) adult and adolescent treatment guidelines recommend starting ART for all willing asymptomatic patients whose CD4 counts are 500 cells/µL, whereas the other half consider ART for those patients to be optional (see Table 2 and chapter Antiretroviral Therapy).
# Other Factors Associated with HIV Progression
Although the CD4 count and HIV viral load are the most important predictors of HIV progression, it is increasingly recognized that a number of other factors, and likely others that remain unknown, contribute to disease progression in HIV infection.
# Viral factors
Variations in the HIV genome have been associated with an altered rate of disease progression.For example, deletions in the nef gene have been associated with a slow rate of progression.On the other hand, virus that uses the CXCR4 protein as a coreceptor for entry (termed X4 virus or syncytia-inducing virus) has been associated with accelerated progression.As another example, drugresistance mutations may affect how efficiently the virus replicates (viral fitness).Patients who have virus with decreased fitness have slower immune deterioration than those with wildtype virus.
# Host immune factors
Host genetic factors have been shown to alter the rate of HIV progression.Various human leukocyte antigen (HLA) alleles have been associated with faster or slower progression rates.Genetic polymorphisms also play a role.For example, CCR5 is a chemokine receptor that can serve as a coreceptor for HIV entry into the CD4 cell.A naturally occurring variant allele for CCR5 has a 32 base pair deletion.Individuals who are heterozygous for this allele have slower progression of HIV disease.
Increased immune activation and elevated markers of inflammation, such as IL-6 and D-dimer, also have been associated with risk of disease progression and death.They also may be involved in the ongoing damage seen in a number of end organs.Although T-cell activation and levels of inflammation decrease with ART, they often do not return to normal.
# Age
Several studies have shown a higher risk of morbidity and mortality in older patients.When followed from seroconversion, older patients demonstrate faster disease progression compared with younger patients (see Table 2).Older patients also are found to have a less robust increase in the CD4 count in response to ART.These observations have led to the recommendation to consider age as a factor in determining when to initiate therapy in the European AIDS Clinical Society (EACS) guidelines.
# Patient Education
- The CD4 cell count and HIV viral load are the two markers that provide information on the degree of current immunocompromise and the risk of disease progression.
- The lower the CD4 count, the higher the risk of AIDS-related illness.
- In asymptomatic persons, CD4 count is the major indicator for initiation of antiretroviral therapy.
- A low HIV viral load is associated with slower immune deterioration; a high viral load is associated with quicker immune deterioration.
- Older individuals may have a poorer response to therapy; earlier initiation of therapy may be considered for older patients.
# References
# Primary HIV Infection Background
Primary HIV infection refers to the very early stages of HIV infection, or the interval from initial infection to the time that antibody to HIV is detectable.During this stage of HIV infection, patients typically have symptoms of acute HIV seroconversion illness, very high HIV RNA levels (>100,000 copies/mL), and negative or indeterminate HIV antibody test results.
Diagnosing patients with primary HIV infection is a clinical challenge.The symptoms of primary HIV are nonspecific, and although many patients seek medical care for symptoms of HIV seroconversion illness, the diagnosis commonly is missed at initial presentation.The difficulties involve recognizing the clinical presentation of acute HIV infection and testing patients appropriately.In HIV treatment facilities, clinicians generally do not see patients with primary HIV infection unless they are referred with the diagnosis already established.In other health care settings, clinicians may not be familiar with the signs and symptoms of acute HIV infection and often do not consider this diagnosis.Despite the difficulties, recognizing primary HIV infection in symptomatic patients is essential.Early diagnosis provides an opportunity for early linkage to HIV care and may decrease future HIV transmission by newly identified patients, who are particularly infectious during early untreated HIV infection.
After infection with HIV, it takes a median of 25 days before the HIV antibody test indicates positive results; in some individuals, it may be several months before seroconversion occurs.Persons with known exposures to HIV, whether occupational or not, should be monitored closely beginning at about 3 weeks after exposure (routine monitoring at 6 weeks, 3 months, and 6 months after exposure to HIV is likely to result in delayed diagnosis of HIV infection).For information on postexposure prophylaxis, see chapters Nonoccupational Postexposure Prophylaxis and Occupational Postexposure Prophylaxis.
# S: Subjective
Approximately two thirds of patients infected with HIV develop symptoms of acute HIV infection, a condition known as acute retroviral syndrome.Symptoms typically appear 2-6 weeks after exposure to HIV and generally include several of the following:
- Fever (present in 80-90%)
- Rash, often erythematous and maculopapular
- Fatigue
- Pharyngitis (with or without exudate)
- Generalized lymphadenopathy
# Laboratory
The initial laboratory work should include the following:
- CD4 cell count and HIV viral load.
- A baseline HIV genotype test for all patients with primary HIV infection, even those who do not choose to start antiretroviral treatment (ART).In some cities in the United States and Europe, 6-16% of infected individuals have acquired HIV virus strains with mutations that confer resistance to antiretroviral medications.These resistance mutations may be identified by early resistance testing, but may not be detectable later. (See chapter Resistance Testing.)
- Patients diagnosed on the basis of HIV RNA should have an HIV antibody test repeated in 4-6 weeks to confirm seroconversion and HIV infection.
# Treatment
It is reasonable to consider starting ART for patients with acute HIV infection, because some limited evidence suggests that treatment initiated during primary HIV infection may preserve HIV-specific immune function that would otherwise be lost as the infection progresses.However, it is not clear whether initiating early treatment yields long-term immunologic, virologic, or clinical benefits. |
The potential advantages of ART for primary infection must be weighed against the Section 2: Testing and Assessment possibility of short-and long-term toxicities, the possibility of developing drug resistance, and the adherence challenges associated with starting ART quickly for newly diagnosed patients.These issues are complex, and consultation with an HIV expert or referral to a clinical trial is recommended.Issues concerning the possible treatment of primary HIV infection are reviewed in the U.S.
# Department of Health and Human Services
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
For pregnant women with acute or recent HIV, the risk of perinatal HIV transmission is very high; thus, ART should be started as early as possible to try to prevent infection of the infant (see chapter Reducing Maternal-Infant HIV Transmission).
For patients who opt to start therapy during primary HIV infection, the choice of agents and the recommendations for monitoring are the same as those for the treatment of patients with chronic HIV infection (see chapter Antiretroviral Therapy).The initial goal of therapy in primary HIV infection is to suppress the HIV viral load to undetectable levels.
# Patient Education
- Patients with primary HIV infection need support and counseling, as do all newly diagnosed patients.
- Intensive education about HIV infection, the course of disease progression, prognosis, and the risks and benefits of ART must be undertaken.
# Rapid HIV Testing
Background About 1.5 million people are thought to be living with HIV in the United States, and it has been estimated that about 20% of these individuals are unaware of their HIV serostatus.Almost 56,000 new HIV infections occur in the United States each year.It is important to identify persons who are infected with HIV, in order both to link them to health care services and to reduce the risk that they will unknowingly transmit HIV to others.
The U.S. Centers for Disease Control and Prevention recommends routine voluntary HIV screening for all adults, adolescents, and pregnant women.Nevertheless, many people are reluctant to be tested.Rapid HIV testing is one tool that makes it much easier for individuals to be tested for HIV and to obtain their test results promptly and reliably.Results of standard HIV tests typically are not available until about 1 week after the test, and clients are required to return for a second visit in order to obtain their results.Because of this, many people do not return to learn their results.With rapid HIV testing, clients can be tested and receive their results during a single visit.Rapid testing can allow immediate referrals to engage patients in medical care; it also makes possible referrals for urgent treatment, such as for pregnant women, and allows quick decisions to be made in a number of clinical situations, such as assessment for postexposure prophylaxis.
# Clients and Settings for Rapid Testing
Rapid HIV testing is recommended for use in settings in which the availability of rapid HIV test results would influence medical care immediately, or as a routine screening tool in settings where HIV prevalence is high or clients are not likely to return for the results of HIV tests.These settings include labor and delivery facilities (to allow intervention to reduce the risk of perinatal HIV transmission in women with undocumented or unknown HIV status), prenatal care facilities for women who present late in pregnancy, hospital emergency departments, urgent care and acute care clinics, sexually transmitted infection clinics, drug treatment clinics, hospitals, and other clinical care or testing sites.Rapid HIV testing is being implemented in employee health departments at hospitals as part of evaluation for and provision of postexposure prophylaxis.In addition, rapid testing is becoming common in nonclinical settings in high-risk jurisdictions such as jails and mobile health service vans, and in community outreach programs.
# Rapid HIV Tests
The U.S. Food and Drug Administration (FDA) has approved six rapid tests for use in the United States (Table 1).Federal regulations under the Clinical Laboratory Improvement Amendments (CLIA) program categorize tests as waived, moderate complexity, or high complexity.Four rapid tests are approved as CLIA-waived tests, meaning that they may be performed at the point of care after appropriate staff training and with procedures in place to insure quality control.These tests use whole blood or oral fluid and require a few simple steps to perform.Other rapid tests are "nonwaived" tests and must be performed in laboratories.Results for rapid tests performed at the point of care are available in less than 30 minutes; results for those done in a laboratory should be available within 1 hour.
# Interpreting Rapid Test Results
All FDA-approved rapid tests are highly sensitive and specific, as shown in
# Section 2: Testing and Assessment
The positive predictive value of a single positive rapid HIV test result depends on the specificity of the test and the HIV prevalence in the community.The high specificity of the rapid tests (Table 1) means that, if a test result is positive, the likelihood that a client is truly HIV infected depends on the local HIV prevalence.In a population with a high HIV prevalence, a positive rapid test result is likely a true positive, but in a population with a low HIV prevalence, that result has a greater chance of being a false positive.For this reason, every positive rapid HIV test result is considered a preliminary result and must be confirmed by either Western blot or immunofluorescence assay (IFA), just as a positive standard ELISA result must be confirmed in this way.
# Information for the Client
# Educating the Client Before Testing
It is important to offer rapid HIV testing as part of a health screening, to educate clients about HIV infection and about the test, and to give them an opportunity to ask questions and to decline testing.The provider should reassure clients that the rapid HIV test is just as accurate as the standard HIV test.The provider should emphasize that a second test always is performed in order to confirm a positive rapid test result.When possible, rapid testing should be made available during a regular office visit so that clients do not face additional waiting time.
# Giving Reactive (Preliminary Positive) Rapid Test Results
# Example of simple language to use outside labor and delivery settings
The following wording is suggested when the client's rapid test result is positive: "Your preliminary test result was positive, but we won't know for sure if you are infected with HIV until we get the results from your confirmatory test.In the meantime, you should take precautions to avoid transmitting the virus.This means protecting sex partners from possible exposure (using condoms, for example), not sharing injection drug needles or syringes, and so forth."
Emphasize the importance of a confirmatory test, arrange for the confirmatory test to be performed as soon as possible, and schedule a return visit for the patient to receive the test result.
# Language to use in labor and delivery settings
The following wording is suggested when the client's rapid test result is positive:
"Your preliminary HIV screening result was positive.You may have HIV infection.We need to do a second (or confirmatory) test, but it is important to start medication to reduce the risk of passing HIV to your baby while we wait for the result.It is important to delay breast-feeding until we have the second test result."
# Follow-Up for Results of Confirmatory Tests
Clinical sites that offer rapid HIV testing should have a protocol for conveying the results of confirmatory HIV tests to clients.Rapid testing sites should either provide this service in-house or have mechanisms in place for referring clients to community-based HIV services.For example, when women have preliminary positive results on tests done during labor and delivery, confirmatory test results may be sent to their obstetrician, but often may be sent to the local health department.These women should be given appointments specifically for receiving their confirmatory test results.Clinicians should be familiar with community resources for referring clients with positive rapid test results.All clients with confirmed positive HIV test results should be referred for HIV care; testing sites should establish reliable referral pathways to qualified HIV care providers.
# Patient Education
In general settings and in situations not involving labor and delivery, advise patients of the following:
- Rapid HIV testing is an important component of health screening.Learning early that they have HIV infection can help patients better maintain their health.
- Knowing that they have HIV infection can help patients take precautions to prevent transmission of HIV to others.
- Patients can refuse an HIV test, and it will not affect the care they receive.
- The results from the rapid tests are available at the same visit, usually in less than 1 hour.
- The rapid test is very accurate -as accurate as the standard HIV test.
- If the rapid test result is positive, a second, confirmatory test always is done in order to provide assurance that the rapid test result was accurate.
- It is important that patients return for the results of the confirmatory test.
- If a patient's rapid test result is negative, that patient almost certainly does not have HIV infection, but the test may not detect recent infection.
- Test results are kept confidential.However, if a confirmatory test result is positive, most state laws require that information to be reported to the health department.
- There are clinics and other resources to help patients obtain more information as well as counseling, care, or treatment.The provider should provide specific referrals to these.
# Resistance Testing Background
Genotype and phenotype testing for resistance currently is commercially available for all nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) that have been approved by the U.S. Food and Drug Administration (FDA).In addition, standardized genotype testing is commercially available for raltegravir (an integrase inhibitor) and enfuvirtide (a fusion inhibitor).Resistance tests for CCR5 antagonists are not commercially available.
Neither genotype nor phenotype predicts which antiretroviral (ARV) drugs will be active in a particular patient, only ARVs that are not likely to be active.Nevertheless, studies comparing the use of resistance testing with expert opinion alone have shown that resistance testing can improve virologic control of HIV.Resistance testing is used to guide subsequent treatment for patients whose antiretroviral therapy (ART) is failing and for those whose viral load is not completely suppressed after starting therapy.It also is used to select an initial regimen that is likely to be effective for patients who have never been treated, and it is recommended for all patients with HIV infection (both acute and chronic) upon entry into care, whether or not ART is to be initiated.In addition, resistance testing is recommended for pregnant women who are not on ART and for those who are on ART but have a detectable HIV viral load.
# Genotype Tests
Genotype testing works by amplifying and sequencing HIV taken from a patient to look for mutations in the HIV reverse transcriptase, protease, integrase, or envelope genes that are known to correlate with clinical resistance to ARV drugs.Genotype tests generally can detect mutations in plasma samples with HIV RNA levels of >1,000 copies/mL, but sometimes are successful with viral loads of 500-1,000 copies/mL. Species representing 20% or more of the amplified product usually can be detected by current techniques, but minor species may not be detected.Resistance mutations that developed in the past during treatment with certain ARV medications may be archived as minor species and become invisible to genotype testing (as early as 4-6 weeks) after the drug is discontinued.These resistance mutations may reemerge and cause drug failure, however, if the previous drug is used again.By contrast, mutations acquired at the time of infection (from a transmitted virus that was already resistant) appear to persist for years, although the duration is not known precisely and may vary by mutation.
A genotype test takes 1-2 weeks to complete.The results are reported as a list of the mutations detected; most reports also include an interpretation that indicates the drug resistance likely to be conferred by those mutations (see "Modifying Factors," below, for a discussion of the limitations of resistance testing).
Note that the standard genotype tests detect mutations that may affect reverse transcriptase inhibitors and PIs; a specific genotype for the integrase inhibitor (or fusion inhibitor) class must be ordered if there is concern for resistance to this class.Also, there are no commercially available tests for resistance to CCR5 antagonists.For patients with virologic failure while taking a CCR5 antagonist, a coreceptor tropism assay should be considered (though the result does not rule out the possibility of resistance to CCR5 antagonists).
Genotype results must be interpreted carefully.Because mutations can become invisible to the genotype testing process when the selective pressure of a drug is removed, a thorough
# Choosing Between Genotype and Phenotype
Genotype testing is faster and cheaper than phenotype testing, and it can detect emerging resistance, that is, virus with a mixture of strains of which some may be sensitive and some may be resistant to a given drug, as long as they are present in sufficient quantity.tor, obtain specific genotypic testing for resistance to these to determine whether to continue them.
# Suboptimal suppression or viral load
- Determine role of resistance: identify active drugs for new regimen.
# Pregnant women
- Genotype or phenotype, depending on treatment history (as above)
- Before initiation of ART or prophylaxis.
- For all on ART with detectable HIV RNA levels.
- Optimize the selection of active drugs for ARV regimen.
# Not Usually Recommended
After discontinuation (>4 weeks) of ARVs - Assist in selecting optimal regimen to achieve maximal viral suppression.
- Drug-resistance mutations may decrease in number and become undetectable on assays.
Plasma viral load 500 but <1,000 copies/mL, testing may fail but can be considered.
by complex interactions of mutations that, by themselves, would not be predictive.In some cases, results of the genotype and the phenotype may be discordant; in these cases consultation with an expert is recommended.
# Recommendations for Resistance Testing
An overview of when genotype and phenotype testing is and is not recommended is presented in Table 1.
Section 2: Testing and Assessment
# Antiretroviral-Naive Patients
With treatment-naive patients, resistance testing may reveal resistance mutations that were acquired at the time of infection, through infection with a strain of HIV that had already developed ARV resistance.Current guidelines recommend genotype testing for recently infected patients and for ARV-naive, chronically infected patients before initiation of therapy.It is important to test as early as possible in the course of HIV infection, to increase the likelihood of detecting transmitted mutations.The rationale for resistance testing in ARV-naive patients is twofold: 1) The prevalence of primary resistance is substantial, particularly in locations with a high prevalence of persons taking ART; and 2) Unknowingly starting a patient on ARV medications to which his or her virus is already resistant may risk failure of the initial regimen, rapid acquisition of additional resistance mutations, and curtailment of future treatment options.
# Limits of Resistance Testing
As discussed above, drug-resistant HIV evolves in response to selective pressure applied by the ARV drugs in the patient's system.Specific resistance mutations develop in response to the pressure exerted by specific drugs (M184V, for example, evolves in response to lamivudine or emtricitabine).The presence of viral resistance suggests that a particular drug (and drugs with similar resistance patterns, or cross-resistance) is unlikely to be successful in suppressing viral replication.
In contrast, the absence of resistance to a drug on a genotype or phenotype test does not necessarily indicate that the drug will be effective, particularly if that drug (or drugs sharing cross-resistance) has been used previously.If a particular drug is discontinued, the viral strains harboring the mutations that confer resistance to that drug may decrease below the threshold of detection by the resistance assay, so the resistance test may not reveal certain resistance mutations.In such situations, minority populations of resistant viruses may exist in reservoirs and may emerge rapidly under selective pressure if that drug is restarted, or if drugs with similar or overlapping resistance patterns are used.The implications of archived mutations are twofold: 1) Resistance tests are most reliable while the patient is still taking the failing regimen; and 2) Resistance testing should be interpreted in the context of both the drugs that the patient was taking at the time of the test and the drugs that the patient had been exposed to previously (i.e., the patient's ARV history).In addition, it is important to review any previous resistance tests, which may show resistance mutations that were not revealed on subsequent testing.
# Resistance Testing in Patients with Virologic Failure
As discussed in the chapter Antiretroviral Therapy, factors other than resistance may cause failure of ART; these include nonadherence, drug-drug interactions, and malabsorption.Therefore, before assuming drug failure, it is important to assess the causes of ARV regimen failure.If resistance is suspected, resistance testing should be done while the patient is taking the failing regimen, for the reasons noted above.
Section 2: Testing and Assessment
# Patient Education
- Advise patients of the following:
- Resistance testing can improve the likelihood of virologic control of HIV.
- Most treatment guidelines recommend resistance testing in certain circumstances.
- Both genotype and phenotype testing can detect resistance only if it exists in at least 20% of the viral species present in a patient (known as the dominant species).
Minor species may harbor resistance that remains undetected by either test.
- In general, a patient's viral load must be at least 1,000 copies/mL for either test to be reliable, although samples with >500 copies/mL sometimes can be analyzed. |
- Resistance tests are most reliable when performed while a patient is still taking a failing regimen, or within 4 weeks after stopping.
- Neither test predicts which drugs will be active in a particular patient, only drugs that are not likely to be active.
Section 2: Testing and Assessment
# Karnofsky Performance Scale Background
The Karnofsky Performance Scale is an assessment tool intended to assist clinicians and caretakers in gauging a patient's functional status and ability to carry out activities of daily living.
It is important to assess a patient's performance on a regular basis, especially as the effects of HIV progress.Documentation of Karnofsky scores over time may be very useful in following a patient's course of illness, and can help a disabled patient in his/her application for disability benefits.It also is used for some research applications.
# Occupational Postexposure Prophylaxis Background
Health care workers (HCWs) and other employees in medical, public safety, sanitation, and laboratory settings are at risk of occupational exposure to HIV.Although avoiding exposure to HIV is the only reliable way of preventing HIV infection, postexposure prophylaxis (PEP), can reduce the risk of HIV infection in exposed HCWs.PEP is defined as antiretroviral (ARV) therapy that is initiated soon after exposure to HIV with the intention of preventing HIV infection.This chapter examines the general issues involved with PEP in occupational settings.The information is based on the U.S. Public Health Service (USPHS) guidelines for PEP (see "References," below).For information on PEP for nonoccupational HIV exposures (such as sexual exposure), see chapter Nonoccupational Postexposure Prophylaxis.Note that other bloodborne pathogens, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV), also may be transmitted through occupational exposure; it is important to consider these potential infections when assessing occupational exposures.For information on the management of occupational exposures to HBV and HCV, refer to the 2001 USPHS PEP guidelines (see "References," below).In addition, the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline) is available for telephone consultation at 888- .
The risk of HIV infection after exposure depends on several factors that are related to the exposure itself and to the source patient (see below).To make sound PEP recommendations, the clinician must assess the risk of HIV infection from the particular exposure.After this assessment, the clinician and the exposed worker must discuss the possible benefit of PEP (given the risk of HIV transmission from the injury) in relation to the willingness of the exposed worker to adhere to a 28-day course of ARV medicines, the potential toxicity of the regimen, and drug interactions.HCWs who are pregnant at the time of their exposure must weigh the risk of fetal exposure to HIV against the potential teratogenic and other risks of the ARV drugs (it should be noted that pregnancy is not a contraindication to PEP, and that a number of ARVs are recommended for use during pregnancy, based on safety and efficacy data (see chapter Reducing Maternal-Infant HIV Transmission).The efficacy of PEP is related to the specific PEP regimen, the timing of PEP, and the exposed worker's level of adherence to the PEP regimen.PEP is most likely to be effective if it is started within hours of an exposure, and outcomes may be compromised as the time from exposure increases.Nevertheless, it may be reasonable to offer PEP up to 72 hours after exposure.Although the optimal duration of PEP is not known; studies support ARV treatment for 28 days.
In the work setting, HIV infection may occur through percutaneous injuries (e.g., needlesticks) or mucocutaneous exposures (e.g., mucous membrane or nonintact skin exposure to blood or other potentially infectious body fluids).The risk of HIV seroconversion after occupational exposure with an HIV-contaminated hollow-bore needle is best described as 0.3%, on average.Another way of describing this to an exposed HCW is that, without PEP, HIV transmission occurs about once in 300 instances of needlestick from a known HIV-infected source patient.In a retrospective casecontrol study of HCWs with percutaneous exposure to HIV, the following exposure and source patient factors were associated with an increased risk of HIV transmission: The factor described as "terminal AIDS in the source patient" is considered a surrogate for a source patient with a high HIV viral load (this study was done prior to the routine use of HIV viral load assays); high HIV viral load is known to be a substantial risk factor for HIV transmission.
Compared with percutaneous injury, exposure of infectious body fluids to mucous membranes (e.g., eye or mouth) or to skin with an obvious impairment of integrity (e.g., abrasion or wound) typically involves a lower risk of HIV transmission (the transmission risk for mucous membrane exposure to HIV is approximately 1 in 1,000, and less than 1 in 1,000 for cutaneous exposure).However, mucocutaneous exposures that involve large volumes of blood or other infectious fluid from an HIV-infected patient with a high HIV RNA level or prolonged duration of contact are considered increased-risk exposures.
# S: Subjective
An HCW reports possible exposure to HIV through a needlestick injury or mucocutaneous exposure.
Ideally, the HCW immediately decontaminated the injured or exposed skin with soap and water, or flushed the exposed mucous membranes with copious amounts of water or saline.The HCW should report the exposure immediately to appropriate authorities in the health care institution (e.g., the institution's needlestick hotline).
Take a thorough history of the specific exposure, including the type of exposure, the type and amount of body fluid involved, the point of entry or exposure, the time it occurred, the HIV status of the source patient (if known), and HIV risk factors of the source patient (if HIV status is not known). - Perform a baseline HIV antibody test.
# A: Assessment
- Test for other infections transmitted through occupational exposure, particularly hepatitis B (HBV surface antigen, surface antibody, core antibody), and hepatitis C (HCV antibody).
- Obtain complete blood count (CBC), creatinine and estimated glomerular filtration rate (GFR), and hepatic transaminases at baseline, before treatment with ARV medications.
- For women who may be pregnant, perform a pregnancy test.
(The institution should perform appropriate testing of the source patient testing for bloodborne pathogens if the patient's status is unknown.)
# Treatment
Consult
# Addendum: Workplace Obligations
- The health care institution has certain obligations to an exposed employee.- The institution should do the following:
- Evaluate the circumstances of the exposure, the type of fluid, and possible entry points.
- Evaluate the source patient.
- Perform baseline HIV antibody testing of the exposed HCW.
- Counsel the exposed HCW about the possible risks and benefits of PEP.
# Section 3: Health Maintenance and Disease Prevention
- Offer or recommend PEP as soon as possible after the exposure, preferably within the first several hours.
- Counsel the HCW about avoiding secondary transmission to others (safer sex and other risk-reduction practices, as indicated).
- Support and maintain the confidentiality of the HCW.
- For an HCW who is taking PEP, monitor for medication toxicity and adherence, and check for drug-drug interactions with other medications the HCW may be taking.
- Repeat HIV testing at 6 weeks, 3 months, and 6 months.
# Patient Education
- Persons who have possible exposures to HIV in the work setting should contact the PEP service of their employer or a qualified medical provider as soon as possible after the exposure, or they should go to an emergency department.Although PEP may be effective if it is started within 72 hours of exposure, the sooner medications are initiated, the better the chance for preventing HIV transmission.
- PEP medications should be taken as directed for the full 28-day course.Adherence to PEP medications is essential for successful treatment.
- PEP recipients should be advised to contact their providers if they experience uncomfortable side effects.Providers may prescribe medications to alleviate the side effects, or they may prescribe different PEP medications.
- Until HIV infection has been ruled out, exposed workers should be advised to use latex barriers to prevent transmission of HIV to their sex partners.
- Exposed HCWs should be counseled about the symptoms of primary HIV infection and instructed to contact their care providers immediately if symptoms develop.
# Nonoccupational Postexposure Prophylaxis Background
Although avoiding exposure to HIV is the only reliable way of preventing HIV infection, postexposure prophylaxis (PEP) can decrease the risk of infection after exposure to HIV.Antiretroviral (ARV) therapy is an important prophylactic intervention for appropriate persons with nonoccupational exposures (e.g., sexual contact; sharing of injection drug needles or other equipment) as well as those with occupational exposures (e.g., needlesticks).The U.S. Department of Health and Human Services (DHHS) has developed recommendations for nonoccupational PEP (nPEP) based on data from animal models, perinatal clinical trials, and observational studies.Efficacy of nPEP remains hypothetical, and randomized clinical trials are not possible, but nPEP appears to be safe.
Overall, nPEP is more likely to be effective when the exposure is a single episode and nPEP is initiated in a timely manner.It is not appropriate for cases of multiple sexual exposures or injection drug use (IDU) exposures over time or for exposures that occurred >72 hours before starting nPEP treatment (see Figure 1).
The model for nPEP is derived in part from protocols for occupational PEP (e.g., in terms of risk stratification, pretreatment testing, timing of treatment, treatment regimens, and duration of treatment).However, the recommendations for PEP and nPEP are distinct and should not be confused. (For information on occupational PEP, see chapter Occupational Postexposure Prophylaxis.)One significant difference between the protocols is that nPEP protocols should include interventions to reduce the risk of HIV transmission.Although exposed individuals usually seek care because they are interested specifically in antiretroviral prophylaxis, the nPEP model takes advantage of a critical opportunity to provide risk-reduction counseling and education.
See chapter Occupational Postexposure Prophylaxis for further discussion of evaluating possible benefits and risks of PEP.
# S: Subjective
The patient reports potential exposure to HIV through a sexual encounter or the sharing of needles or other equipment for IDU.Take a thorough history of the specific sexual or drug-use activities, the time the exposure occurred, the HIV status of the source person (if known), and HIV risk factors of the source person (if HIV status is not known).In cases of sexual assault, evidence collection and specific paperwork may be required as well.
# O: Objective
Examine for trauma and for signs or symptoms of sexually transmitted infections (STIs), which may increase the risk of HIV transmission.In injection drug users, examine for abscesses and signs or symptoms of infection.For women who may be pregnant, perform a pregnancy test.
# Section 3: Health Maintenance and Disease Prevention
# A: Assessment
Assess for potential exposures to HIV and other bloodborne pathogens and for the presence of other STIs.The risk of HIV infection depends on the HIV status of the source and on the characteristics of the source (e.g., HIV viral load) and of the exposure (see Figure 1).The estimated risk of HIV exposure will determine whether nPEP should be offered.An algorithm for risk evaluation and treatment decisions is presented in Figure 1.
# P: Plan Laboratory Testing
- Perform a baseline HIV antibody test.
- Evaluate and test for other infections transmitted through sexual or IDU exposures, including chlamydia, gonorrhea, syphilis, herpes simplex virus infection, hepatitis B (HBV surface antigen, surface antibody, and core antibody), and hepatitis C (HCV antibody).
- Obtain complete blood count (CBC), liver function tests (LFTs), and creatinine and estimated glomerular filtration rate (GFR) at baseline before treatment with ARV medications.
# Treatment
Follow the algorithm in Figure 1 Once the decision is made to institute nPEP, do the following:
Begin ARV prophylaxis as soon as possible after the exposure, but always within 72 hours.Treatment should be continued for 28 days, unless the source person is determined to be HIV negative.
Provide counseling about the efficacy of nPEP, including the importance of protection against future HIV exposures, timely initiation of nPEP medications, and adherence to these medications for 28 days.
Counsel exposed patients to use latex barriers with their sexual partners until transmission of HIV infection has been ruled out.
Counsel patients, as appropriate, about ways to reduce risks of future exposure to HIV.
In cases of sexual assault, refer the patient to a rape counselor. Africa.In both studies, the ARV prophylaxis was given in conjunction with other riskreduction interventions, including counseling, condom provision, and STI testing and treatment.This and other studies will explore the efficacy and safety, and possible effects on risk of various types of PrEP and microbicides in different populations.The CDC has issued interim guidelines on the use of oral tenofovir-emtricitabine as PrEP in MSM (see "References," below); until more data are available, alternative approaches to PrEP should not be undertaken.
# Patient Education
- Persons who have possible exposures to HIV should contact a medical provider or go to an emergency room as soon as possible after the potential exposure has occurred.PEP may be effective if it is started within 72 hours of exposure, but the sooner medications are initiated, the better the chance for preventing HIV transmission.
- PEP medications should be taken as directed for a full 28-day course.Adherence to PEP medications is essential for successful treatment.
- If patients are experiencing uncomfortable adverse effects, they should contact their care provider.Providers may prescribe medications to alleviate the adverse effects or select other PEP medications.
- Until HIV infection has been ruled out, exposed persons should be advised to use latex barriers to prevent transmission of HIV to their sex partners.
- Exposed persons should be counseled about the symptoms of primary HIV infection and instructed to contact their care provider immediately if symptoms develop.
# Preventing HIV Transmission/ Prevention with Positives Background
Helping patients to reduce the risk of transmitting HIV to others is an important aspect of medical care for HIV-infected individuals.Most people with HIV infection want to prevent others from being infected with HIV, but they may practice sexual or injection drug behaviors that put others at risk of infection.Most HIV-infected patients also want to protect themselves from acquiring sexually transmitted infections (STIs) or bloodborne infections.This chapter offers recommendations for discussing HIV transmission and prevention with HIV-infected patients, with the goal of reducing HIV transmission.This aspect of care is often referred to as "prevention with positives" (PWP).
Taking responsibility for preventing HIV transmission is an important concern for most people with HIV, as well as for their health care providers.Multiple studies have shown that one third to three fourths of HIV medical providers do not ask their patients about sexual behavior or drug use.However, many HIV-infected individuals report that they want to discuss prevention with their health care providers.Each patient visit presents an opportunity to provide effective prevention interventions, even in busy clinical settings.
It is clear that information alone, especially on subjects such as sexual activity and drug use, cannot be expected to change patients' behavior.However, health care providers can help patients understand the transmission risk of certain types of behavior and help patients establish personal prevention strategies (sometimes based on a harm-reduction approach) for themselves and their partners.Some patients may have difficulty adhering to their safer sex goals.In these cases, referrals to mental health clinicians or other professional resources such as prevention case management may be helpful.
# Techniques for Brief, Effective Interventions by Providers
A number of strategies have been shown to be more effective than providing information alone.Effective and brief provider-initiated interventions include the following elements:
- Establish rapport and provide services in an understanding, nonjudgmental manner.Patient educators, nurses, peer counselors, social workers, and mental health providers may be effective in discussing prevention strategies with patients.
- Conduct a quick, detailed behavioral risk assessment:
1.See the key areas of risk assessment and intervention listed in Table 1, below.
2.Assess where the patient's risk behavior lies along the risk continuum (described in chapter Smoking Cessation).
Correct misinformation and answer questions.
4.Assess the patient's readiness for behavior change (see "Stages of Change model," below).
5.Screen for and treat STIs.
6.Supply medications, condoms, and lubricant as needed.
- Assess the patient's readiness for change and approach any high-risk behavior in a step-wise manner, recognizing when the patient is ready for next steps.Such interventions may be carried out for 5-10 minutes per visit over a series of visits.The "Stages of Change" model and appropriate strategies include the following:
1.Precontemplation: The patient is not ready to change; reassess at subsequent visits.
# Contemplation:
The patient is considering a change in the future; discuss and help the patient to identify concrete next steps, such as a date for initiating change.
# Preparation:
The patient is ready to change soon; discuss a concrete action plan and connect the patient with appropriate resources as needed.
4.Action: The patient is actively engaged in changing behavior; continue to discuss and address challenges; offer encouragement.
# Maintenance:
The patient has made behavioral changes; continue to discuss and address challenges, offer encouragement and congratulations.
# (Relapse):
The patient has relapsed to previous risky behaviors; recognize the triggers and difficulties the patient had with maintenance and offer support and encouragement to try again when the patient is ready.
- Customize messages, as each individual patient's needs are variable.
- Understand that patients often have competing priorities and pressures involving mental health needs, relationships, finances, housing, employment, and other issues that may result in risky sexual and drug-use behaviors.
# Examples of Prevention Intervention Programs with Demonstrated Efficacy in Treatment Settings
The U.S. - Partnership for Health: This intervention involves brief, 3-5 minute, one-on-one counseling sessions between the provider and the patient on self-protection, partnerprotection, and disclosure. |
The approach fea-tures loss-framed messages that emphasize the risks or negative consequences of risky behavior.The provider then helps the patient develop a plan for risk reduction.
- Positive Choice -Interactive Video Doctor: This program involves an approximately 24-minute session during which HIV-infected patients complete the Positive Choice risk assessment on a laptop computer while waiting for scheduled visits with their providers.Based on the riskassessment results, a video clip appears with the actor-portrayed Video Doctor who delivers interactive risk-reduction messages that are tailored to the patient's gender, risk profile, and readiness to change.The messages are delivered with motivational interviewing principles, using a patientcentered, empathetic and nonjudgmental approach.After the video session, the computer prints out an individualized educational sheet for the patient and an assessment sheet for the provider to use for follow-up.
# Summary of Prevention with Positives: Key Areas of Intervention
More detailed discussions of topics follow this table. - Assess the patient's level and circumstances of risk to target your intervention.
- Emphasize that nasal straws or sniffers (e.g., for cocaine) should not be shared.
- Assess the patient's readiness to quit or cut down on drug and alcohol use, and to separate it from sex. -Deliver messages tailored to the patient's readiness; for example, educate on the risks of harming oneself or other, facilitate a plan for harm reduction, or refer to rehabilitation/ detoxification programs and centers.
# Section 3: Health Maintenance and Disease Prevention
# Needle-Use Practices
Subjective/objective question to ask:
- Tell me about any needle sharing since your last clinic visit.
# Assessment and plan:
- After assessing the patient's risks and readiness, and if the patient is not ready for treatment (e.g., referral to detoxification programs or to buprenorphine and methadone programs for heroin users), the following messages for harm reduction can be offered:
- Use only sterile needles from pharmacies or needle exchange programs. (Provide informations about local needle exchange programs.Some are listed here: www.nasen.org.) -Never reuse or share needles, syringes, or drug preparation equipment because it leads not only to transmission of HIV, hepatitis B, and hepatitis C, but also to bacterial infections and abscesses. -Use new or disinfected cookers and new cotton filters to prepare drugs.
- Clean the skin with a new alcohol swab before injecting.
- If equipment must be reused, it should be cleaned properly with bleach or water.
- Safely dispose of syringes in a sharps container (which can be a clean detergent or other container), then take them to a needle exchange program or pharmacy for disposal.
# Mental Health Assessment
Mental illnesses such as bipolar disorder, depression, and posttraumatic stress disorder can increase the chances of risky sexual and drug-use behaviors.
# Antiretroviral Therapy (ART)
Lower levels of HIV in the blood (in particular, complete suppression of the HIV RNA through effective ART) have been associated with lower levels of HIV virus in genital secretions and with reductions in the rate of HIV transmission among serodiscordant couples.
Effective ART with virologic suppression appears to sharply reduce the risk of HIV transmission and is one important means of HIV prevention.However, it does not eliminate transmission risk.In some individuals, there can be substantial discrepancies between HIV RNA levels in the serum and the sexual fluids.
Be watchful for attitude shifts away from safer sexual and needle-sharing behaviors among patients who believe that ART protects them from transmitting HIV.
# Sexual Transmission and Prevention of HIV
Begin the education process by learning what the patient and his or her immediate family members (if the family is aware of the patient's HIV status) believe about HIV transmission.Also be sure the patient understands how the virus is not transmitted (e.g., via sharing plates and eating utensils or using the same bathrooms) to allay any unnecessary fear.
Advise the patient not to share toothbrushes, razors, douche equipment, or sex toys to avoid transmitting HIV via blood or sexual secretions.This also will help prevent the transmission of other bloodborne or sexually transmitted infections, including hepatitis C, from coinfected patients.The patient should not donate blood, plasma, tissue, organs, or semen because these can transmit HIV to the recipient.
There is no reason why a person with HIV cannot have an active, fulfilling, and intimate sex life.However, the patient must be counseled properly about the risk of transmission.This discussion between the provider and patient should be client centered.This means that the provider should let the patient guide the discussion, starting from the patient's current point of knowledge and practice, always addressing any presenting concerns the patient may have prior to proceeding with a discussion about sexual transmission and risk.The provider should ask open-end questions, in a nonjudgmental manner, to elicit information about the patient's relationships, sexual behaviors, and current means of reducing transmission risk.
It is important to recognize that not every patient seeks the complete elimination of risk (e.g., via abstinence) but rather a reduction in risk, chosen after the options are discussed with the provider.The clinician may help the patient select and practice behaviors that are likely to be less risky.There are many methods for reducing risk, including the following:
# Partner Notification
A good way to begin a discussion about HIV prevention and transmission is with an inquiry about any previous experiences disclosing to partners.The provider then can ask whether the patient currently has a need to disclose to one or more partners and whether he or she is ready and motivated to share information about HIV status.The provider should prompt patients to consider several questions about disclosure, including how they might approach the discussion, how their partners might react, what information they might offer their partners, whether partners are likely to keep their status confidential, and whether they have any concerns about personal safety (e.g., owing to fear of a violent reaction).If patients fear violence or retaliation or are not ready to share their status but want their partners to know, the provider may offer assistance with partner notification, for example through the local health department, in a confidential manner.As an alternative, patients may want the provider to talk with their partners, and that option can be offered as well.See the - Apply a drop of lubricant inside the condom (not more, because it increases the risk that the condom will come off).
- Use polyurethane condoms instead of latex because they conduct heat and may feel more natural.
- Use insertive (female) condoms, which are not as restrictive to the penis.
- Use specially designed condoms that do not restrict the top of the penis (e.g., Inspiral, Xtra Pleasure).
For patients who are unable or unwilling to use condoms, the following suggestions may help reduce HIV transmission risk:
- Use plenty of lubricant to reduce friction and microtrauma, which create portals of entry for the virus.
- Avoid spermicides that damage the vaginal or anorectal linings.
- Avoid douching products. -Avoid recreational drugs, especially methamphetamine, that impair the ability to maintain "safer" sexual behaviors.
- Avoid the use of drugs such as nitrates (poppers) that enhance blood flow to the genitals.
# Insertive (Female) Condom Use
The insertive "female" condom may be used for vaginal or anal intercourse.It is a thin polyurethane pouch with a flexible ring at the opening, and another unattached flexible ring that sits inside the pouch to keep it in position in the vagina (for use in the anus, the inner ring must be removed and discarded).
The female condom may be an option for women whose male partners will not use male condoms or for couples who do not like standard condoms.Female condoms are more expensive than male condoms, but may be procured at a lower cost at some health departments or Planned Parenthood clinics.They generally are less well known to patients and may be unacceptable to some women whose culture or religion prohibits or discourages touching one's own genitals.Note that the female condom cannot be used at the same time as a male condom.
Be sure the patient knows how to use the insertive condom before she or he needs it; after teaching, encourage practice when alone at home and unhurried.Women who have used the diaphragm, cervical cap, or contraceptive sponge may find it easy to use the female condom.Illustrated directions are included in each box of insertive condoms.
Instructions on the use of insertive condoms are provided in Table 3.
# Table 3.Instructions for Use of Insertive (Female) Condoms
Vaginal Intercourse
- Open the pouch by tearing at notched edge of packet, and take out the female condom.Be sure that the lubricant is evenly distributed on the inside by rubbing the outsides together. -Find a comfortable position, such as standing with one foot on a chair, sitting with knees apart, or squatting.Be sure the inner ring is inside, at the closed end of the pouch. -Hold the pouch with the open end hanging down.While holding the outside of the pouch, squeeze the inner ring with your thumb and middle finger.Still squeezing, spread the labia with your other hand and insert the closed end of the pouch into the vagina. -Now, put your fingers into the pouch itself, which should be inside the vagina, and push the inner ring and the pouch the rest of the way up into the vagina with your index finger.Check to see that the front side of the inner ring is just past the pubic bone.The back part of the inner ring should be up behind the cervix.The outer ring and about an inch of the pouch will be hanging outside the vagina. -Until you and your partner become comfortable using the female condom, use your hand to guide the penis into the vagina, keeping it inside the pouch.If, during intercourse, the outer ring is pushed inside the vagina, stop, remove the female condom, and start over with a new one.Extra lubricant on the penis or the inside of the female condom may help keep this from happening. -After intercourse, take out the condom by squeezing and twisting the outer ring to keep the semen inside the pouch.Throw away in a trash can; do not flush.Do not reuse. -More information is available on the Planned Parenthood website (www.plannedparenthood.com).
# Anal Intercourse
- Remove the inner ring and discard it.Put the female condom on the penis of the insertive partner and insert the condom with the penis, being careful not to push the outer ring into the rectum.The outer ring remains outside the anus, for ease of removal after ejaculation.
# Noninjection Drug Use and Prevention of HIV Transmission
Exposure to HIV through contaminated blood may occur with the use of noninjection drugs; for example, by sharing cocaine straws or sniffers through which cocaine is inhaled.These straws easily can penetrate fragile nasal mucosa and become contaminated with blood from one user before being used by another individual, who may then experience mucous membrane exposure or even a cut or break in the mucous membrane from the bloody object.Straws or sniffers should not be shared.
# Tattoo, Piercing, and Acupuncture Equipment
Patients should be aware of the risk of contamination of tattoo equipment, inks, and piercing equipment, and they should avoid situations wherein they might either transmit HIV or pick up other bloodborne pathogens.
Acupuncturists generally use sterile needles, but clients should verify that before using their services.
# Maternal-Infant HIV Transmission
HIV-infected women can have healthy pregnancies, with good health outcomes for both mother and baby.For this to occur, women must know their HIV status as early as possible, preferably before becoming pregnant, and must receive effective ART.
Although intervention to reduce the risk of perinatal infection is most effective if begun early in pregnancy, or preferably before pregnancy, it may be beneficial at any point in the pregnancy, even as late as during labor.
For further information, see chapter Reducing Maternal-Infant HIV Transmission.
Preexposure Prophylaxis (PrEP)
# Immunizations for HIV-Infected Adults and Adolescents Background
Immunocompromised individuals are at higher risk of acquiring many types of infections compared with immunocompetent people.Although HIV-infected persons could benefit greatly from immunization against preventable infections, little specific research on the effectiveness of immunizations in this population has been completed.In general, vaccines have better efficacy in HIV-infected patients when immune function is relatively well preserved, notably when the CD4 count is >200 cells/µL. Persons with advanced immunodeficiency may have an impaired humoral response, and may not respond to vaccines, or they may require supplemental doses to develop serologic evidence of protection.If possible, vaccines should be administered before the CD4 count decreases to 200-300 cells/µL (unless there is evidence of immunity).
Live vaccines generally should not be administered to individuals with HIV infection, particularly those with advanced immunodeficiency, unless the anticipated benefits of vaccination clearly outweigh the risks.
Administration of vaccines can be associated with a transient rise in plasma HIV RNA.
Recommendations about vaccination for patients with HIV infection are presented in Table 1.
# Table 1.Vaccine Recommendations
# Vaccine Type Recommendation
# Pneumococcal (polysaccharide)
- Recommended for all; consider revaccination 5 years after initial vaccination; some experts recommend vaccination every 5 years. -If CD4 count is <200 cells/µL, may be less effective; consider revaccination when CD4 count increases in response to ART.
# Hepatitis A Virus (HAV)
- Recommended, for persons with chronic liver disease, injection drug users, men who have sex with men, international travelers, and hemophiliacs.Consider for all, unless there is serologic evidence of previous disease. -Recommended (booster is recommended every 10 years in adults; or, if potential exposure , after 5 years). -To protect against pertussis, substitute single dose of Tdap for Td booster in all patients aged 19-65 who have not received Tdap previously.
# Measles, Mumps, Rubella (MMR)
- Live vaccine is contraindicated for use in patients with severe immunosuppression (CD4 count of <200 cells/µL). -Recommended for all nonimmune persons with CD4 counts ≥200 cells/µL.
# Varicella-Zoster (VZV)
- Live vaccine is contraindicated for use in patients with severe immunosuppression (CD4 count of <200 cells/µL). -Consider for HIV-infected, VZV-seronegative persons with CD4 counts ≥200 cells/µL. - If vaccination results in infection with attenuated virus, treat with acyclovir.
- Susceptible household contacts of susceptible HIV-infected individuals should be vaccinated. -Avoid exposure to VZV, if possible.If someone without immunity to VZV is exposed to VZV, administer varicella-zoster immune globulin (VZIG) as soon as possible (but within 96 hours). -Two doses (0, 3 months).
# Section 3: Health Maintenance and Disease Prevention
# Vaccine Type Recommendation
Human Papillomavirus (HPV)
- Two vaccines:
- Gardisil includes HPV strains 16 and 18 (oncogenic) and 6 and11 (wart causing)
- Cervarix: includes HPV strains 16 and 18 - Recommended for females aged 9-26.
- Gardasil vaccine approved for males aged 9-26.
- Not contraindicated for use in HIV-infected individuals, though no data are available regarding use in this group. -No data on efficacy in preventing anal dysplasia.
# Meningococcal
- Recommended if risk factor is present (e.g., college freshmen living in dormitory, military recruits, asplenia, complement component deficiency, travel to or residence in endemic area, occupational exposure).
Abbreviations: Ab = antibody; Ag = antigen; ART = antiretroviral therapy
# Immunizations for HIV-Infected Patients Traveling to Developing Countries
Routine vaccinations should be reviewed and updated before travel.All patients traveling to other countries should be evaluated for both routine and destination-specific immunizations and prophylaxes.Inactivated (killed) and recombinant vaccines (e.g., diphtheria-tetanus, rabies, hepatitis A, hepatitis B, Japanese encephalitis) should be used for HIV-infected persons just as they would be used for HIV-uninfected persons anticipating travel.For further information, see the U.S. Centers for Disease Control and Prevention (CDC) webpage (www.cdc.gov/travel/).Recommendations specific to HIV-infected travelers are located in "The Immunocompromised Traveler" under the section called "Special Needs Travelers."Select the "Traveler's Health" option for regional travel documents and information on outbreaks.
Decision making about immunization for the HIV-infected traveler should take into consideration the traveler's current CD4 cell count, history of an AIDS-defining illness, and clinical manifestations of symptomatic HIV.
In the CDC recommendations, asymptomatic HIV-infected persons with CD4 counts of 200-500 cells/µL are considered to have limited immune deficits, whereas patients with CD4 counts of >500 cells/µL are considered to have no immunologic compromise.For patients taking antiretroviral therapy, current CD4 counts rather than nadir counts should be used in deciding about immunizations.The CDC recommends that newly diagnosed, treatmentnaive patients with CD4 counts of <200 cells/µL delay travel until after immunologic reconstitution with antiretrovirals to minimize risk of infection and immune reconstitution illness during travel.
The following should be noted about specific vaccinations:
- Inactivated (killed), enhanced-potency polio and typhoid vaccines should be given instead of the live, attenuated forms.In adults aged >18, vaccinate 8 weeks before travel to allow time for the initial two doses of polio vaccine.
- Measles or measles, mumps, and rubella (MMR; omit if patient has evidence of immunity) should not be given to severely immunocompromised patients.Instead, immune globulin should be given to measles-susceptible, severely immunocompromised persons traveling to measles-endemic countries.
# Section 3: Health Maintenance and Disease Prevention
- Yellow fever vaccine is a live-virus vaccine with uncertain safety and efficacy for HIVinfected persons, and it should be avoided if possible.Travelers with asymptomatic HIV infection and relatively high CD4 counts who cannot avoid potential exposure to yellow fever should be offered the choice of vaccination.If travel to a zone with yellow fever is necessary and vaccination is not administered, patients should be advised about the risk of yellow fever, instructed about avoiding the bites of vector mosquitoes, and provided with a vaccination waiver letter (though travelers should be warned that not all countries accept waiver letters). |
- The influenza season in the Southern Hemisphere is April through September, but in the tropics, influenza is a year-round infection.Immunocompromised patients should be protected on the basis of influenza risk at the destination.HIV-infected patients should not be given live intranasal influenza vaccine.
# References
- Advisory Committee on Immunization Practices.
# Preventing Exposure to Opportunistic and Other Infections Background
Persons with HIV infection are more susceptible than others to certain infections.HIV-infected persons may come into contact with opportunistic pathogens in the course of various aspects of their daily activities.Pets, children, personal and sexual contacts, and food and water, as well as involvement in occupational tasks, recreation, hobbies, and other activities all potentially can expose an HIV-infected person to opportunistic pathogens, some of which are ubiquitous and cannot be avoided.Among the ubiquitous pathogens are Candida, Mycobacterium avium complex, Pneumocystis jiroveci pneumonia, and human herpesvirus 6 and 7.Exposure to other opportunistic pathogens may be minimized if patients are aware of the risks.
The following tables group opportunistic pathogens by type of exposure.Mechanisms of transmission and recommendations for avoidance are outlined.Note that a number of infections can be transmitted by several of these modes.
For information about vaccinations, see chapter Immunizations for HIV-Infected Adults and Adolescents; for opportunistic infection (OI) prophylaxis, see chapter Opportunistic Infection Prophylaxis.
# Topics:
- Water related
Pathogens - Hepatitis A (HAV) - Cryptosporidium - Shigella - Campylobacter - Amoeba - Giardia - Isospora - Microsporidia
# Transmission
- Infection occurs through drinking contaminated water or eating produce or other food that has been washed in contaminated water. -Water ingested accidentally during recreation also can make people sick.
# Recommended avoidance measures
- To decrease exposure from water in developing countries, take the following precautions:
- Do not drink tap water or use it to brush teeth.
- Avoid ice that is not made from bottled water.
- Avoid raw fruits or vegetables, as they may have been washed in tap water.
- Bring tap water to a rolling boil for at least 1 minute before consuming.If this is not possible, treatment with iodine or chlorine, especially if in conjunction with filtering, reduces risk of infection. -Additional recommendations, include the following:
- Avoid drinking untreated water.
- When choosing a home water filter, especially for filtering untreated water, be aware that not all filters remove the pathogens listed above. -Do not drink water from lakes or rivers.
- Avoid swimming in water that may be contaminated with stool.
- Avoid swallowing water during recreational activities (lakes, rivers, saltwater beaches, pools, hot tubs, and ornamental fountains may be contaminated with Cryptosporidium). -In the event of a cryptosporidiosis outbreak in the municipal water supply, boil tap water for at least 1 minute to eliminate risk of infection. -Cryptosporidium may be present in municipal water outside outbreak settings, though the magnitude of this risk is unknown.Some HIV-infected patients may chose to take precautions to decrease risk. -Be aware that bottled water may be contaminated with Cryptosporidium.
- See the discussion of travel-related topics, below.
# Section 3: Health Maintenance and Disease Prevention
# Food Associated
# Pathogens
- Toxoplasma - Salmonella, Shigella, Campylobacter (enteric infections)
- Listeria - Cryptosporidium - Other enteric pathogens
# Transmission
- Exposure may occur through eating or handling contaminated food.
# Recommended avoidance measures
- Always wash hands before preparing and consuming food.
- Wash hands, cutting boards, counters and utensils thoroughly after contact with uncooked foods. -Do not allow raw meat or eggs to come into contact with other foods.
- Wash produce thoroughly.
- Cook meat and poultry to an internal temperature of 165-170ºF. It is safest to confirm temperature with a thermometer.Meat that is no longer pink inside likely has reached a temperature of 165ºF. - Avoid raw or unpasteurized milk, including goat milk, and foods that contain unpasteurized milk or milk products. -Avoid foods that might contain raw egg (e.g., Hollandaise sauce, Caesar salad dressing, some mayonnaises, uncooked cake and cookie batter, eggnog, homemade ice cream).Pasteurized eggs can be used safely in recipes that call for raw egg. -Avoid eating raw or lightly steamed shellfish.
- Avoid eating raw seed sprouts, as these may be contaminated with enteric pathogens.
- Avoid foods from street vendors, especially in developing countries.
- Be aware that unpasteurized juices may be contaminated with Cryptosporidium.
- Rates of infection with Listeria are low, but HIV-infected people who are severely immunocompromised are at increased risk. -HIV-infected persons who wish to decrease their risk of listeriosis should take the following precautions:
- Avoid soft cheeses including feta, brie, camembert, blue-veined, and Mexicanstyle cheeses such as queso fresco unless they are clearly labeled as pasteurized.
Hard cheeses, processed cheeses, cream cheese, cottage cheese, and yogurt generally are safe. -Before eating leftover foods or ready-to-eat foods, such as hot dogs, cook them until they are steaming hot. -Avoid foods from deli counters, such as prepared meats, salads, and cheeses, or heat these foods until steaming hot before eating them. -Avoid refrigerated pâté, or heat until steaming hot.Canned or shelf-stable pâté generally is safe. -Avoid refrigerated smoked seafood, unless it is part of a cooked dish.Canned or shelf-stable smoked seafood generally is safe. -Also see information on travel-related infections, below.
# Environmental
# Pathogens
- Toxoplasma gondii
- Cryptosporidium - Coccidioides - Histoplasma capsulatum - Cryptococcus neoformans - Aspergillus
# Transmission
- Cryptosporidium and Toxoplasma may be present in soil and sands, and infection can occur through handling soil during gardening or playing in or cleaning sandboxes. -Infection with Coccidioides and Histoplasma occurs with inhalation of fungal spores that become airborne owing to disturbance of contaminated soil.
- Chlamydia - Gonorrhea - Trichomonas - Lymphogranuloma venereum (LGV) serovars of C. trachomatis - Cryptosporidium - Shigella - Campylobacter - Amoeba - Giardia - Isospora - Microsporidia
# Transmission
- Depending on the pathogen, infection may be transmitted by exchange of body fluids, by skin-skin contact, or by oral-fecal contact. -Sexually transmitted infections (STIs) can occur at genitals, rectum, or mouth, depending on sexual practices. -A number of enteric pathogens can be transmitted during sex (by oral-fecal contact).
# Recommended avoidance measures
- Male latex condoms, when used consistently and correctly:
- Are highly effective in preventing sexual transmission of HIV and many other STIs, including syphilis, chlamydia, gonorrhea, and trichomoniasis. -Decrease risk of acquiring HSV-2, HPV, CMV, HBV, and HCV.
- Do not prevent enteric pathogen exposure (which is via fecal-oral contact).
- HIV-infected persons should be screened for STIs at least annually.Those with highrisk partners or sexual practices should be screened more frequently. -To avoid infection with HSV, HIV-infected persons should avoid sexual contact when a partner has an overt herpetic lesion (genital or oral-labial), though HSV transmission also can occur during asymptomatic shedding. -The use of suppressive antiviral therapy by persons with genital herpes reduces HSV-2 transmission to susceptible partners, though the effectiveness of this approach in HIVinfected patients has not been evaluated. -The safety and effectiveness of the HPV vaccine in HIV-infected women and in men is being studied. -Patients who are CMV seronegative should be advised that CMV can be sexually transmitted. -To decrease risk of exposure to enteric pathogens during sex, patients can:
- Use barriers such as dental dams during oral-anal contact - Change condoms after anal sex - Wear latex gloves during digital-anal contact - Wash hands after sex
# Transmission
- Injection drug users are at risk of a host of infections, including viral hepatitis, skin and soft-tissue infections, infective endocarditis, and pulmonary infections. -Injection drug use also may put users at risk of acquiring TB and STIs.
- Infection may occur from contaminated drug-injection equipment (needles, syringes, water, and other preparation equipment). -Infection also may occur from the user's own skin or mouth bacteria, which can enter the bloodstream. -The drug itself, or an adulterating substance, may be contaminated.
# Recommended avoidance measures
- Injection drug users should be advised not to share needles or drug preparation equipment, and should be educated about needle exchange programs. -If receptive, injection drug users should be referred to substance abuse treatment programs. -Injection drug users should be educated about methods of reducing risk, including the following:
- If equipment is being reused, clean with bleach and water.
- Avoid dangerous injection sites such as groin and neck.
- Do not crush capsules or tablets in the mouth prior to injecting, as this may introduce harmful oral bacteria into the bloodstream. -Do not lick injection needles or syringes.
- Use boiled water for preparing drugs for injection; if not available, use tap water.
- Boil the drug before injecting.
- Use a new or disinfected "cooker," and a new filter to prepare drugs for injection.
- Always clean injection sites with alcohol before injecting. -Be aware that black tar heroin may be contaminated with Clostridium spores, which are not killed by heating the drug prior to use.
# Other Bloodborne
# Pathogens
# HIV - HCV - HBV - CMV
# Transmission
- Tattooing and body piercing - Reuse of medical equipment and transfusion of infected blood (primarily outside the United States) - Occupational exposures (e.g., needlesticks) of health care workers
# Recommended avoidance measures
- Persons considering tattooing or piercing should be educated about the potential risk of bloodborne pathogen transmission if proper infection control procedures are not followed. -When receiving a transfusion, HIV-infected patients who are seronegative for CMV should be administered only CMV antibody-negative or leukocyte-reduced cellular blood products in nonemergency situations. -Universal precautions always should be followed by health care workers.
# Section 3: Health Maintenance and Disease Prevention
# Pet and Animal Related
# Pathogens
- Toxoplasma - Cryptosporidium - Salmonella - Campylobacter - Shiga toxin-producing Escherichia coli - Bartonella - Leptospira - Brucella - Capnocytophaga - Cryptococcus - Mycobacterium avium and marinum - H. capsulatum
# Transmission
- For the most part, people with HIV infection can and should keep their pets.
- HIV-infected persons should be made aware of the potential risks posed by animals and of the avoidance measures for decreasing risks of infection. -Exposure may occur though a lick, a bite or a scratch, or through contact with a pet's stool.Some infections may be spread though contact with an animal's coat or skin. -Fleas may spread some infections to pet owners.
- Patients also may be exposed while performing occupational tasks that bring them into contact with animals (e.g., in pet stores, veterinary clinics, farms, and slaughterhouses).
# Recommended avoidance measures
- Always wash hands after handling animals, and after cleaning cages or aquariums.
- When acquiring a new pet, avoid animals <6 months of age (cats younger than 1 year) and those with diarrhea. -Stray animals may carry many infections and should be avoided.
- Avoid contact with animal stool.
- Avoid animals with diarrhea.
- Pets with diarrhea should be examined by a veterinarian and should have stool checked for Cryptosporidium, Salmonella, Campylobacter, and Shiga toxin-producing E. coli. -Wash any bites or scratches with soap and water, and seek medical attention.
- Animals should not be allowed to lick people in the mouth, or on any open cuts or wounds. -Cats may increase risk of Toxoplasma and Bartonella infection.
- To minimize risk of Toxoplasma exposure:
- Litter boxes should be cleaned daily, preferably by someone who is not HIV infected or pregnant. -If an HIV-infected person is cleaning a litter box, gloves should be used, and hands should be washed afterward. -Keep cats indoors and do not allow them to hunt.
- Do not feed cats raw or undercooked meat.
- In areas where histoplasmosis is endemic, avoid contact with bird droppings, including soil under bird roosting sites. -Always use gloves when cleaning aquariums to avoid contact with Mycobacterium marinum. -Avoid contact with reptiles (such as lizards, snakes, and turtles), as well as chicks and ducklings, as these may carry Salmonella. -Avoid exotic pets such as monkeys, ferrets, and other wild animals.
# Section 3: Health Maintenance and Disease Prevention
# Contact with Children
# Pathogens
- CMV - Cryptosporidium - Giardia - HAV - Influenza - VZV - Enteric pathogens
# Transmission
- HIV-infected persons who work as childcare providers, or who have children in daycare, may be exposed to opportunistic pathogens. -The poor personal hygiene habits of children facilitate spread of infection.
- Risks specific to the individual, given his/her immune status and medical history, should be discussed with a health care provider. -CMV infection may occur through contact with many body fluids, including stool, urine, and saliva. -Diapering may bring a person into contact with Cryptosporidium and other enteric pathogens. -In addition to opportunistic pathogens, childcare providers are exposed to other illnesses, carried by children, to which they may be more susceptible.
# Recommended avoidance measures
- Wash hands thoroughly after contact with stool or urine.
- Wash hands after diapering and disinfect changing station often.
- Wash hands after contact with saliva or objects covered with saliva, such as cups or pacifiers. -Ensure that the immunization status of HIV-infected persons is up to date, as appropriate for their immune status. -HIV-infected persons who are susceptible to VZV should avoid exposure to people with chickenpox or shingles. -VZV-susceptible household contacts of HIV-infected persons should be vaccinated against VZV if they are HIV negative, so that they will not transmit VZV to their HIVinfected contact.
# Travel Related
# Pathogens
- Enteric pathogens - Plasmodium species (malaria) - Yellow fever virus
# Dengue virus - Other geographically specific infections
# Transmission
- Travelers to developing countries are at risk of foodborne and waterborne infections.
- Malaria is transmitted by the bite of an infected female Anopheles mosquito.
- HIV-infected patients are at higher risk of severe malaria.
- Yellow fever and dengue fever are spread by mosquito bites.
# Section 3: Health Maintenance and Disease Prevention
# Travel Related
# Recommended avoidance measures
- Plan the travel itinerary, vaccinations, and prophylaxis in consultation with a health care provider experienced in travel medicine. -Discuss area-specific risks and avoidance measures with the healthcare provider. -The U.S. Centers for Disease Control and Prevention (CDC) Traveler's Health website has detailed information on most issues pertaining to infections in travelers (www.cdc.gov/travel). -Review and update routine vaccine history prior to travel. -Generally, live vaccines for HIV-infected persons should be avoided, with some exceptions:
- Measles vaccine is recommended for all nonimmune persons with CD4 counts of ≥200 cells/µL. Measles immune globulin should be considered for those with CD4 counts of <200 cells/µL who are traveling in measles-endemic areas. -Varicella vaccine can be considered for VZV-seronegative persons with CD4 counts of ≥200 cells/µL. - Yellow fever vaccination may be considered, see below.
- Inactivated (killed) enhanced potency polio and typhoid vaccines should be given instead of the live, attenuated forms. -Killed and recombinant vaccines including influenza, diphtheria-tetanus, rabies, HAV, HBV, Japanese encephalitis and meningococcal vaccines should be administered as they would be for HIV-uninfected persons preparing for travel. -The oral cholera vaccine (not available in the United States) is not recommended for most travelers by the CDC.Traveler's diarrhea:
- See sections on foodborne and waterborne infections (above) for risk reduction strategies. -Antimicrobial prophylaxis is not routinely recommended for HIV-infected persons traveling in developing countries. -Prophylaxis may be appropriate in select situations (for example, high risk of infection and short length of travel) - For those to whom prophylaxis is given, fluoroquinolones (such as ciprofloxacin 500 mg PO once daily) may be considered for nonpregnant patients. -HIV-infected patients traveling in developing countries should bring antibiotics to be used empirically in the event of developing diarrhea. -Appropriate regimens include:
- Ciprofloxacin 500 mg PO BID for 3-7 days - Azithromycin 500 mg PO once daily as an alternative, and for pregnant women - Antiperistaltic agents such as loperamide or diphenoxylate can be useful in the treatment of traveler's diarrhea. -Do not use antiperistaltic agents if high fever or blood in the stool is present.Stop use if symptoms persist >48 hours. -Seek medical care if diarrhea is severe, bloody, accompanied by fever and chills, leads to dehydration, or does not respond to empiric therapy.
# Section 3: Health Maintenance and Disease Prevention
Travel Related
# Recommended avoidance measures
Malaria:
- HIV-infected patients should be advised to avoid travel in malarious areas.
- If travel to a malarious area cannot be avoided, effective chemoprophylaxis should be given.Consult the CDC Traveler's Health website for specific information (www.cdc.gov/travel). -Be aware that some malaria prophylaxis medications may have drug-drug interactions with antiretrovirals. -Personal protection measures should be followed, including avoidance of peak biting times and use of insect repellants, protective clothing, and permethrin-soaked bed netting.Yellow fever:
- HIV-infected patients should be discouraged from visiting areas where yellow fever infection is a risk. -Vaccination may be considered in some HIV-infected persons with high CD4 counts who cannot avoid potential exposure, after discussion of risks and benefits. -Vaccine response may be poor, and serologic testing can be considered. -If vaccination is not administered, patients should be advised about the risk of yellow fever, instructed about avoiding the bites of vector mosquitoes, and provided with a vaccination waiver letter. -Personal protection measures should be followed, including avoidance of peak biting times and use of insect repellants, protective clothing, and permethrin-soaked bed netting.Other geographically specific opportunistic infections include visceral leishmaniasis, Penicillium marneffei infection, coccidiomycosis, histoplasmosis, and TB. |
# References
# Opportunistic Infection Prophylaxis Background
Prophylaxis against opportunistic infection (OI) is treatment given to HIV-infected individuals to prevent either a first episode of an OI (primary prophylaxis) or the recurrence of infection (secondary prophylaxis).Prophylaxis is recommended to prevent three important OIs: Pneumocystis jiroveci pneumonia (PCP), Mycobacterium avium complex (MAC), and toxoplasmosis.Prophylaxis also is recommended to prevent tuberculosis (TB) in patients with latent Mycobacterium tuberculosis infection (see chapter Latent Tuberculosis).In endemic regions, prophylaxis against Histoplasma capsulatum and Coccidioides species is advised.And in some situations, prophylaxis against other OIs may be reasonable; see the OI prevention recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) (reference below) for additional information.
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection and a CD4 count of <200 cells/µL who were prescribed Pneumocystis jiroveci pneumonia prophylaxis
(Group 1 measure)
Percentage of clients with HIV infection and a CD4 count of <50 cells/µL who were prescribed Mycobacterium avium complex prophylaxis within the measurement year (Group 3 measure)
# Pneumocystis jiroveci Pneumonia
Background PCP remains the most common lifethreatening infection among U.S. residents with advanced HIV disease.
# Primary Prophylaxis: Indications
- Prophylaxis should be administered to all HIV-infected patients with a CD4 count of 200 cells/µL in the presence of a CD4 percentage <14%, or a history of an AIDS-defining illness.
- For patients whose CD4 counts are declining toward 200 cells/µL, the CD4 count should be monitored closely.PCP prophylaxis should be considered for patients with a CD4 count of 200-250 cells/µL if laboratory monitoring will not be possible within 3 months.
# Prophylaxis Options: Recommended Regimens
- Trimethoprim-sulfamethoxazole (TMP-SMX) (also known as cotrimoxazole, Bactrim, and Septra) one double-strength tablet PO once daily (Note: This regimen also is effective in preventing toxoplasmosis.)
- TMP-SMX one single-strength tablet PO once daily (this lower-dose regimen may be better tolerated) (Note: This also is likely to be effective in preventing toxoplasmosis.)
# Prophylaxis Options: Alternative Regimens
Other options for prophylaxis include the following:
- TMP-SMX one double-strength tablet TIW (e.g., Monday, Wednesday, and Friday) (Note: This regimen also is likely to be effective in preventing toxoplasmosis.)
- Dapsone 100 mg PO once daily or 50 mg PO BID (Note: These regimens do not prevent toxoplasmosis.)
- Dapsone 50 mg PO once daily + pyrimethamine 50 mg PO once weekly + leucovorin 25 mg PO once weekly (Note: This regimen also is effective in reducing the risk of toxoplasmosis.)
- Warning: Glucose-6-phosphate dehydrogenase (G6PD) deficiency can increase the risk of hemolytic anemia or methemoglobinemia in patients receiving dapsone.Screen for G6PD deficiency before starting dapsone. (G6PD deficiency is found in approximately 10% of African-American males, and in 1-2% of males of Mediterranean, Indian, and Asian descent.)
- Aerosolized pentamidine 300 mg once per month, via Respirgard II nebulizer (Note: This regimen does not prevent toxoplasmosis.)
- Warning: Aerosolized pentamidine may increase the risk of extrapulmonary pneumocystosis, pneumothorax, and bronchospasm.It increases the risk of TB transmission to others if the patient has active pulmonary tubercular disease, unless ventilation (negative-pressurized facility with outside venting) is adequate.Do not use for patients in whom TB is suspected.The availability of treatment facilities offering aerosolized pentamidine may be limited.
- Atovaquone suspension 1,500 mg once daily (Note: This also is effective in reducing the risk of toxoplasmosis.)Atovaquone is more expensive than dapsone.
It should be taken with high-fat meals for optimal absorption.
- Atovaquone suspension 1,500 mg + pyrimethamine 25 mg + folinic acid 10 mg all taken PO once daily (Note: This regimen also is effective in reducing the risk of toxoplasmosis.)
# Secondary Prophylaxis Indications
Prophylaxis should be given to all patients with a history of PCP.
# Discontinuing Prophylaxis
Primary or secondary prophylaxis can be discontinued if the CD4 count has increased to >200 cells/µL for at least 3 months in response to effective antiretroviral therapy (ART), with the following cautions:
- If the patient had PCP in the past and the episode of PCP occurred at a CD4 count of >200 cells/µL, it may be prudent to continue PCP prophylaxis for life, regardless of how high the CD4 count rises as a consequence of ART.
- PCP prophylaxis should be reinitiated if the CD4 count decreases to <200 cells/µL or the patient meets other criteria as indicated above.
# Section 3: Health Maintenance and Disease Prevention
# Prophylaxis During Pregnancy
TMP-SMX is the recommended agent for use during pregnancy; dapsone may be used as an alternative.Some experts recommend high dose folate supplementation (e.g., 4 mg daily) for pregnant women receiving TMP-SMX, because TMP-SMX may worsen folate deficiency.Prophylaxis that includes pyrimethamine generally should be deferred until after pregnancy.During the first trimester, aerosolized pentamidine (which is not systemically absorbed) can be used if the potential teratogenicity of oral agents is a concern.
# Mycobacterium avium Complex
# Background
Mycobacterium avium complex (MAC) is common among patients with advanced HIV disease and it occurs in people with CD4 counts of <50 cells/µL.
# Primary Prophylaxis: Indications
Prophylaxis should be administered to all HIV-infected patients with CD4 counts of <50 cells/µL. Before starting prophylaxis, rule out active MAC infection by clinical assessment and, if warranted, by acid-fast bacilli (AFB) blood cultures (see chapter Mycobacterium avium Complex).Also rule out active TB prior to starting any rifabutin-containing regimen for MAC prophylaxis.Review the current drug regimen for medications that may interact with MAC prophylaxis.
# Secondary Prophylaxis
Patients should receive lifelong chronic maintenance therapy, unless immune reconstitution occurs in response to ART.See chapter Mycobacterium avium Complex.
# Discontinuing Prophylaxis
Primary prophylaxis for MAC can be discontinued in persons who have responded to effective ART with sustained increases in CD4 counts to >100 cells/µL for at least 3 months.Careful observation and monitoring are required, and prophylaxis should be restarted if the patient's CD4 count decreases to <50 cells/µL.
Secondary prophylaxis can be discontinued in patients who received at least 12 months of treatment for MAC, are asymptomatic, and have sustained (for at least 6 months) CD4 counts of >100 cells/µL on ART.Secondary prophylaxis should be reintroduced if the CD4 count decreases to <100 cells/µL.
# Prophylaxis During Pregnancy
Azithromycin is the prophylactic drug of - Warning: G6PD deficiency can increase the risk of hemolytic anemia or methemoglobinemia in patients receiving dapsone.Screen for G6PD deficiency before starting dapsone. (G6PD deficiency is found in approximately 10% of African-American males, and in 1-2% of males of Mediterranean, Indian, and Asian descent.)
- Atovaquone 1,500 mg PO once daily, with or without pyrimethamine 25 mg PO once daily + folinic acid 10 mg PO once daily; however, this alternative is quite expensive.
- Neither aerosolized pentamidine nor dapsone alone provides protection against TE.
# Secondary Prophylaxis
Patients should receive lifelong chronic maintenance therapy, unless immune reconstitution occurs in response to ART (see chapter Toxoplasmosis).
# Discontinuing Prophylaxis
Primary prophylaxis for TE can be discontinued in patients who have responded to effective ART with sustained CD4 counts of >200 cells/µL for at least 3 months.CD4 counts Section 3: Health Maintenance and Disease Prevention should be monitored carefully, and prophylaxis should be restarted in patients whose CD4 counts decrease to 200 cells/µL on ART.Secondary prophylaxis should be reintroduced if CD4 counts drop to <200 cells/µL.
# Prophylaxis During Pregnancy
TMP-SMX may be used as primary prophylaxis during pregnancy.Risks of TMP-SMX in the first trimester must be balanced against the risks of reactivated toxoplasmosis.Some experts recommend high dose folate supplementation (e.g., 4 mg daily) for pregnant women receiving TMP-SMX, because TMP-SMX may worsen folate deficiency.Pyrimethamine has been associated with birth defects in animal studies, but limited data in human studies have not shown an increased risk.Secondary prophylaxis generally should be provided using the same guidelines as for nonpregnant women.
# Histoplasmosis
# Background
Infection with Histoplasma capsulatum is common in several geographic areas including the Ohio and Mississippi River Valleys, as well as parts of Central and South America, Asia, and Africa.Symptomatic disease can occur via primary infection or reactivation of previously silent infection in the setting of waning cellular immunity.CD4 counts of ≤150 cells/µL, along with positive Histoplasma serology and environmental exposure, are associated with increased risk of symptomatic disease.Histoplasmosis can cause a range of clinical manifestations including respiratory, gastrointestinal, central nervous system (CNS), and cutaneous disease.
# Primary Prophylaxis: Indications
Prophylaxis can be considered for HIVinfected patients with CD4 counts of ≤150 cells/µL who are at high risk because of occupational exposure and for those who live in an area where histoplasmosis is highly endemic.HIV-infected patients with CD4 counts of ≤150 cells/µL should be educated to avoid exposure.
# Prophylaxis Options: Recommended Regimens
- Itraconazole 200 mg PO once daily (Note: Itraconazole has significant interactions with many drugs, including nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and maraviroc.Dosage adjustments may be required, and some combinations may be contraindicated; consult with a pharmacist or other specialist.)
# Secondary Prophylaxis
Patients with a history of severe disseminated disease or CNS infection and those who have relapsed despite receiving appropriate therapy should receive long-term suppressive therapy.
# Discontinuing Prophylaxis
Primary prophylaxis can be discontinued once CD4 counts are >150 cells/µL for at least 6 months.CD4 counts should be monitored carefully, and prophylaxis should be restarted for patients whose CD4 counts decrease to ≤150 cells/µL.
# Prophylaxis During Pregnancy
Azoles should not be used during the first trimester of pregnancy because of teratogenicity concerns.
# Coccidiomycosis
# Background
The Coccidioides species fungus is endemic to many arid regions.In the United States, it is found primarily in the Sonoran Desert in Arizona and the San Joaquin "Central" Valley in California, but also in areas of New Mexico, western Texas, Nevada, and Utah.It also is endemic to many arid regions in Central and South America.Immune response to Coccidioides species declines as CD4 counts decrease, and risk of developing symptomatic disease in endemic areas is increased when the CD4 count is ≤250 cells/µL. In HIV-infected patients, six syndromes have been described: focal pneumonia, diffuse pneumonia, cutaneous involvement, meningitis, liver or lymph node involvement, and positive serology without localized infection.
# Primary Prophylaxis: Indications
# Secondary Prophylaxis
Patients who have completed initial treatment for coccidiomycosis should be considered for lifelong chronic maintenance therapy.
# Discontinuing Prophylaxis
Primary prophylaxis can be discontinued once CD4 counts are ≥250 cells/µL for at least 6 months, but should be restarted if the CD4 count drops to <250 cells/µL.
Suppressive therapy should be continued lifelong for patients with a history of diffuse pulmonary, disseminated, or meningeal disease, as these patients are at high risk of relapse.Patients with focal coccidioidal pneumonia who have had good clinical response to antifungals can discontinue secondary prophylaxis once they have received 12 months of therapy, and have CD4 counts >250 cells/µL on ART.These patients should undergo close radiologic and serologic monitoring for recurrence.
# Prophylaxis During Pregnancy
Women who acquire coccidiomycosis in the second or third trimester of pregnancy are at increased risk of dissemination.Azoles should not be used during the first trimester of pregnancy because of teratogenicity concerns.
# Section 3: Health Maintenance and Disease Prevention
# Patient Education
- Discuss adverse effects of the selected medication(s) and how the patient should respond in the event of rashes, diarrhea, and other complications.
- Explain the purpose of each medication, and be sure that patients understand the dosage and frequency of administration.
- Reinforce the need to continue taking the medication indefinitely (potentially for life) to reduce the risk of the OI.
- OIs can occur despite prophylaxis.Instruct patients to contact their health care provider if they become ill.
# S: Subjective
Ask about symptoms of active TB, including fever, cough, and weight loss; see chapter Mycobacterium tuberculosis.HIV-infected persons who have no symptoms of active TB and have not been treated previously for active or latent TB are eligible for LTBI treatment.When patients do have symptoms that could represent active TB, active TB must be evaluated and ruled out by appropriate diagnostic methods before initiating treatment (see "Assessment," below).
Persons who have had bacillus Calmette-Guérin (BCG) vaccine can be evaluated by an IGRA (preferably) or by a TST with correct interpretation.Immigrants from many countries will have had childhood BCG vaccination.
Health care providers should ask about a history of potential exposure to TB, because that might indicate infection with drugresistant TB.Such risk may occur when the patient knows a source patient or when the exposure occurs in a setting with known drug resistance or in a location with ongoing TB transmission where others remain at risk of exposure.In general, all the licensed IGRA tests are considered interchangeable with the TST.
Use of an IGRA is preferred for persons with previous BCG exposure and for patient groups at risk of not returning for TST readings.The TST is preferred for children under 5 years of age.The cost of an IGRA is higher than the cost of a TST, and individual clinics should compare the total costs of both testing approaches, including the costs involved in TST protocols of recalling patients who miss visits, repeating TSTs, and treating persons with prior BCG exposure who may have falsepositive TST results.
# Tuberculin skin test
The TST is administered as an intradermal injection of 0.1 mL (5 tuberculin units) of purified protein derivative (PPD), which raises a wheal in the skin.This is sometimes referred to as the Mantoux test.Multiple-puncture tests such as tine tests and the use of other strengths of PPD are considered unreliable.Anergy testing is not routinely recommended because a randomized controlled study of HIV-infected patients in the United States did not show an advantage to treating anergic, tuberculinnegative persons.
PPD tests are not designed for reading by the patient; a trained health care worker must measure the area of induration (not erythema) 48-72 hours after the test is administered.Induration of 5 mm or more is considered a positive result for HIV-infected persons, other immunosuppressed persons, anyone with recent TB exposure, and anyone with fibrosis on chest X ray that is consistent with previous TB.For HIV-uninfected health care workers, 10 mm of induration is a positive result; in various other populations, either 10 mm or 15 mm of induration may be considered positive.Care providers at many large HIV clinics find it challenging to ensure that their patients return for the PPD reading.One randomized study found that offering incentives (e.g., a fast-food coupon) plus counseling was more effective than counseling alone in obtaining return visits for PPD readings.
# Interferon-gamma release assay
IGRA tests performed on peripheral blood samples are available in the United States from two manufacturers.Although the tests are expensive, results are obtained without the patient having to make a return visit to the clinic, and false-positive readings following BCG vaccination do not occur.Both IGRA tests use specific antigens from M. tuberculosis to stimulate the patient's lymphocytes and quantify the production of interferongamma in response.QuantiFERON-TB Gold (QFT-G) is performed by incubating a heparinized blood sample for 16-24 hours with the synthetic MTB antigens along with positive and negative controls.The incubation must begin within 12 hours, so the need for proximity to a laboratory that performs the test imposes limits on access.The laboratory calculates the amount of interferon-gamma Section 3: Health Maintenance and Disease Prevention produced by the patient's cells, providing a quantitative result and an interpretation (positive, negative, or indeterminate).The QuantiFERON-TB Gold In Tube (QFT-GIT) provides the clinician with three prepared tubes (three antigens in one tube and positive and negative controls) into which patient blood samples are placed; these tubes may be held for up to 16 hours at room temperature, incubated at 37°C for 16-24 hours, then centrifuged.After centrifugation, the same tubes can be held again at room temperature for up to 3 days or refrigerated for up to 4 weeks before they are analyzed.This provides much greater flexibility in sending specimens to distant or reference laboratories and it makes the technology useful for a much wider array of clinical sites.Again, quantitative results and an interpretation are provided.The T.SPOT TB (T-SPOT) test requires separation and processing of 4 aliquots of 250,000 peripheral blood mononuclear cells each, a step that requires a sophisticated laboratory setting.The number of cells that produce interferon in response to the two MTB antigens is compared with positive and negative controls; both a quantitative result and its interpretation (positive, negative, borderline, or indeterminate) are provided.Performing the test is very labor intensive, and it must take place within 8 hours of obtaining the sample (within 32 hours if using T-Cell Xtend reagent); thus T-SPOT is the least flexible of the three assays.
Limited data suggest that the QFT-GIT is the most specific test (lowest rate of false-positive results) and the T-SPOT is the most sensitive test (with the lowest rate of false-negative results).However, few studies have compared the IGRA assays, and there is no reliable "gold standard" for sensitivity or specificity for latent TB infection.Although these tests do not detect previous BCG exposure, they will yield positive results in all three TB-causing species of the Mycobacterium tuberculosis complex, M. tuberculosis, Mycobacterium bovis, and Mycobacterium africanum, and may yield positive results in persons with exposure to certain rare mycobacteria other than M. tuberculosis (Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium szulgai).
There is limited experience using IGRAs for persons with HIV infection and other immunosuppressed states.The overall frequency of positive and negative results is the same with QFT-GIT and TST.However, there is substantial discordance among HIV-infected patients: many with positive TST results will have negative IGRA results, and vice versa.No data are available to determine which test is more reliable.Indeterminate results with QFT-GIT are more frequent with patients who have lower CD4 lymphocyte counts. |
Some experts anticipate that the T-SPOT may be more consistent in persons with lower lymphocyte (including CD4 cell) counts because a fixed number of cells are used in the assay; however, lymphocyte function may be altered in any case.It appears that there are higher rates of positive results among HIV patients with the T-SPOT than with the other IGRAs.TSTs are known to yield false-negative results in persons with HIV-associated immunosuppression, yet despite this limitation, TSTs are recommended for use with all newly diagnosed HIV patients and for annual testing in certain patients.
# A: Assessment
A chest X ray should be obtained for all HIVinfected persons with positive TST or IGRA tests.Asymptomatic patients with negative chest X-ray results should be offered treatment for LTBI.Persons with symptoms consistent with pulmonary or extrapulmonary TB, and those with abnormal chest radiography, require further assessment.This assessment may include sending three separate sputum specimens collected on three consecutive days, or at least 8 hours apart, including at least one early morning specimen (using saline
# P: Plan
As with any treatment of TB, adherence to the regimen is required for success.Treatment regimens for LTBI in the United States and other high-income nations are presented in Table 1.
# Potential ARV Interactions
Rifampin and rifabutin have important interactions with certain antiretroviral drugs, and dosage adjustments or treatment modifications may be required.Rifampin reduces the blood levels of nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), the integrase inhibitor raltegravir, and the CCR5 antagonist maraviroc.Rifampin can be used by persons taking efavirenz although many experts recommend increasing the efavirenz dosage to 800 mg daily.Coadministration of rifampin and maraviroc is not recommended, but may be possible with appropriate dosage adjustment of maraviroc; consult with an expert.Rifampin should not be used with nevirapine, etravirine, or PIs. (In some cases, the adverse pharmacokinetic effect of rifampin on PIs may be overcome with large doses of ritonavir, but consultation with a specialist should be obtained before this approach is undertaken; rifampin should not be used in combination with ritonavir-boosted saquinavir because of high rates of hepatic toxicity.)
No data are available on the use of rifabutin for treatment of LTBI.Nevertheless, rifabutin may be considered in place of rifampin for patients taking antiretroviral combinations that include NNRTIs (other than efavirenz) or PIs (other than ritonavir alone).In these cases, the dosages of both rifabutin and the antiretroviral agent usually require adjustment. (See Table 3
# Other Drug Interactions
Rifampin decreases the blood concentrations of estrogens, anticonvulsants, hypoglycemic agents, and many other drugs.Review all medications a patient is taking before initiating rifampin and make adjustments as necessary.
(See Table 12: Clinically significant drug-drug interactions involving the rifamycins at www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm#tab12.)
# Pregnancy
HIV-infected pregnant women with positive LTBI test results and no evidence of active TB should receive standard prophylaxis as soon as possible, even during the first trimester.
The preferred prophylaxis during pregnancy is a 9-month isoniazid regimen (with pyridoxine, as above).Alternative agents, such as rifampin or rifabutin, should be used with caution because of limited experience.Neonates born to women who received rifampin during pregnancy should be given vitamin K (10 mg) to reduce the risk of hemorrhagic disease.Pyrazinamide generally is avoided during pregnancy because of lack of information regarding fetal effects.
# Patient Education
- Patients should know that TB bacteria in their bodies cannot be passed to others while the TB is latent.However, because they have HIV infection, the TB bacteria is more likely to make them sick at some point in the future.
- Treatment for LTBI will help kill the TB bacteria and reduce patients' chances of becoming sick with active TB.
- Patients must take all of their medicine, every day, to prevent the TB from spreading and making them sick.
- Advise patients to contact their health care provider immediately if they have adverse effects to the medication, such as rash or itching.Occasionally, INH can cause tingling or numbness in the hands or feet.The pyridoxine (vitamin B6) they are taking should help prevent that, but they should let their provider know if it occurs.
- Advise patients to avoid the use of alcohol while taking INH.The medicines for TB are processed by the liver and, when combined with alcohol, they easily can overload the liver.Acetaminophen (Tylenol) also is processed by the liver, so patients should keep their intake to a minimum. (Patients with hepatitis C, liver disease, or chronic alcohol use should not take more than 3 grams per day.)
- Tell patients that blood tests will be done regularly to make sure the liver is working well, so it is important to keep follow-up appointments.They should take all their medications, vitamins, and supplements with them to the clinic so that their health care provider can review them and make sure there are no drug interactions.
- If patients experience nausea, vomiting, poor appetite, or abdominal pain; if they notice their urine darkening or becoming cola colored; or if they notice their eyes or skin yellowing, they should contact the clinic immediately.These problems may indicate that the liver is being overwhelmed, and it is important to find out before permanent damage is done.
- Rifampin will cause sweat, tears, urine, and plastic contact lenses to turn orange.
- Rifampin can make birth control pills ineffective.Patients should use a backup method of contraception until treatment is complete.Condoms can help prevent HIV transmission and reduce the likelihood of pregnancy.
# Background
According to the U.S. Centers for Disease Control and Prevention, smoking prevalence among the general adult population in the United States is approximately 20%.Among HIV-infected persons, the prevalence of cigarette smoking appears to be two to three times greater than in the general population, with estimates ranging from 50% to 70%.
The health effects of cigarette smoking are extensive and have been well documented.There are approximately 400,000 smoking-related deaths annually in the United States.HIV-infected smokers appear to be at higher risk of a variety of tobacco-related conditions than HIV-uninfected smokers.These include lung cancer, head and neck cancers, cervical and anal cancers, oral candidiasis, and oral hairy leukoplakia.HIV-infected smokers who smoke are more likely to develop the conditions listed above, as well as bacterial pneumonia, Pneumocystis jiroveci pneumonia, other pulmonary conditions, and cardiovascular disease.Additionally, HIVinfected smokers have been shown to have a decreased immunologic and virologic response to antiretroviral therapy.Thus, for HIV-infected persons, even more so than for HIV-uninfected persons, clinicians should consider smoking cessation a health care priority.Although many care providers may feel that they can do little to affect the smoking behaviors of patients, evidence suggests that brief interventions by physicians are quite effective.Studies indicate that smoking cessation interventions as brief as 3 minutes in duration, when delivered by a physician, have a positive impact on abstinence rates of current smokers.Furthermore, studies have found that more than half of current HIV-infected smokers have expressed interest in, or have thought about, smoking cessation.Cigarettes are highly addictive; the U.S. Surgeon General has equated the addictive potential of cigarettes to that of heroin and cocaine.This is in part because nicotine stimulates the release of several neurotransmitters in the brain, including dopamine.Over time, chronic exposure to nicotine causes physiologic changes in the brain that contribute to the addictive potential of cigarettes.
Cigarette smoking involves dependence on more than a single chemical compound, however.It is a multidimensional behavior that has both physiologic and psychological components.Therefore, smoking cessation efforts often require a combined approach to be successful.
# Behavioral model for smoking cessation
Several behavioral models present a psychological framework for understanding individuals who are attempting to change behaviors.The transtheoretical model of health behavior change is one of the more frequently cited frameworks for understanding the stages of behavior change of smokers.According to this model, there are five phases of behavior change: precontemplation, contemplation, preparation, action, and maintenance.Using this framework, clinicians can devise interventions that are most appropriate for the patient's current stage on the continuum.
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection who received tobacco cessation counseling within the measurement year.
# Section 3: Health Maintenance and Disease Prevention
- Precontemplation: The individual does not expect to make any change in behavior within the next 6 months.At this stage, the individual is resistant to hearing or learning about health behavior change.
- Contemplation: The individual plans to make a behavior change within the next 6 months.This stage is characterized by ambivalence about smoking.
- Preparation: The individual anticipates making a behavior change within the next month.Individuals in this phase have made plans for taking action and intend to make a change.
- Action: The individual has made a significant change; in the case of smoking cessation, this means that the individual has quit completely.
- Maintenance: The individual attempts to prevent relapse.
Patients may move back and forth among these stages at various points during the process of smoking cessation.
# Cessation interventions in the clinic
As suggested above, brief smoking cessation interventions delivered by clinicians can significantly increase abstinence rates of current smokers.The U.S. Surgeon General has developed guidelines for clinicians to use during clinic visits to help patients who are interested in smoking cessation.These include use of the Five A's model, which provides a brief and structured framework for addressing smoking cessation in clinical settings (see Table 1).Incorporate questions about tobacco use when obtaining vital signs or when reviewing a patient's history.
- "Do you currently use tobacco?"
- "Do you currently smoke cigarettes?"
# ADVISE to quit
Using a clear, strong, and personalized message, urge every tobacco user to quit.
- "It is important for you to quit smoking now."
- "Quitting is the most important thing you can do to protect your health." - "I can help you quit."Also link smoking with something specific to the patient, such as secondhand exposure to children or partners, his/ her own lung, cardiovascular, or cancer risk, or the expense of cigarettes.
# ASSESS readiness to make a quit attempt
Determine whether the tobacco user is willing and ready to make a quit attempt within 30 days.
- "Are you willing to give quitting cigarettes a try?"
# ASSIST in the quit attempt
For the patient willing to quit, assist in developing a quit plan.Provide practical counseling, support, and supplementary materials.
- Have patient set a quit date and enlist the support of his/her family and friends. -Offer pharmacotherapy, as appropriate, including nicotine replacement. -Provide counseling that includes problem solving and skills building.
# Section 3: Health Maintenance and Disease Prevention
# Component Action Example
# ARRANGE for follow-up
Arrange for follow-up contacts beginning within the first week after the quit date.
- Contact patient via telephone or in person soon after the quit date.This can be done by the primary clinician or other trained staff members. -During the follow-up encounter, assess and identify any problems, review medication use and side effects, provide reminders about additional resources. -Congratulate patients on their successes.
- Help those with relapses assess problems with and barriers to quitting, and offer additional or different assistance. -For patients who report a relapse, help them identify the circumstances that led the relapse and assist them with recommitting to smoking abstinence.
# Pharmacologic interventions
In addition to counseling, the use of pharmacologic interventions such as nicotine replacement therapy and other adjuvant therapies should be considered.These therapies were developed for the general population, but current clinical guidelines suggest that they should be efficacious for HIV-infected smokers.
Clinicians should be aware of potential medication adverse effects (see Table 2).
# S: Subjective
- Ask all patients about their smoking status at every visit.This can be easily incorporated as part the initial intake when vital signs are obtained.
- Document smoking history, including the number of cigarettes smoked per day.
- If the patient is not ready to quit, use MI techniques to identify beliefs and barriers and to create ambivalence about smoking.
- For the smoker interested in quitting:
- Help identify triggers to smoking, and develop a quit plan.
- Assess for contraindications to pharmacologic smoking cessation treatments such as history of seizure disorders, sleep disturbances, mood disorders, and pregnancy.
- For patients who recently quit, congratulate them on their accomplishments and reinforce the benefits of continued cessation.
- For patients who recently relapsed, help them identify what led to the relapse and how to avoid relapses in the future.Assist them in getting back on track with a cessation program.
# O: Objective
During the physical examination, assess for evidence of smoking-related illnesses and the comorbid conditions that may be affected by smoking.At a minimum, measure blood pressure and oxygen saturation measurements and examine for oral lesions, abnormal breath sounds, and decreased peripheral perfusion.
# A/P: Assessment and Plan
Determine the smoker's readiness to change (see behavioral model for smoking cessation, above).For those smokers in the preparation or action stage, assist with implementing a quit plan.For those who are in the relapse stage, reinforce self-efficacy and encourage them to recommit to cessation.For those in the maintenance stage, congratulate them and reinforce the benefits of smoking cessation.
For patients willing to quit, offer resources and information that will help them to be successful in their quit attempt.Evidence suggests that the combination of counseling and medication is more effective than either intervention alone.Therefore, every effort should be made to combine counseling sessions with pharmacotherapy for patients who are motivated and ready to quit smoking.
Components of effective counseling include problem solving, skills training, and social support.Problem solving and skills training should focus on how to deal with triggers or urges that may lead to relapse.Examples include recognition of situations or events that may prompt a person to smoke (e.g., drinking alcohol, being around other cigarette smokers, situational stress) and means of reducing or coping with these situations.Social support interventions include providing reassurance that the patient has the ability to succeed with smoking cessation, communicating caring and concern, and encouraging the patient to talk about the quit process.
Offer medications, if there are no contraindications to pharmacologic interventions (see Table 2).All currently available over-the-counter and prescription medications have been shown to be effective.However, studies have shown that combination therapy may be more efficacious than monotherapy.The current tobacco cessation guidelines recommend the following combinations, all of which include nicotine preparations: long-term nicotine patch (>14 weeks) with ad lib use of nicotine gum or spray, nicotine patch with nicotine inhaler, and nicotine patch with sustained-release (SR) bupropion.
Both bupropion SR and varenicline may cause sleep disturbance, and varenicline may cause exacerbation of neuropsychiatric symptoms.For HIV-infected patients who take efavirenz as part of their antiretroviral therapy, concomitant use of either bupropion SR or varenicline may increase the possibility of these side effects.Additional research in this area is needed.
# Section 3: Health Maintenance and Disease Prevention
All patients who are actively quitting should have close follow-up, and they should be offered support.Research has shown that ongoing support during the quit phase results in higher abstinence rates.
Follow-up can include telephone calls or inperson evaluation.
For patients who recently quit or relapsed, continue to provide support and encouragement.Assist individuals who relapsed with the opportunity to continue with cessation plans.
Refer patients to smoking cessation groups, classes, and other resources.
# Patient Education
- For patients who have decided on pharmacologic interventions and for whom there are no contraindications, provide education regarding medication side effects, anticipated withdrawal symptoms, and strategies for managing withdrawal.
- Review and reinforce strategies in the event of relapse.
- For those who are not ready to quit, inform them of the consequences of continued smoking and remind them about the available resources.
# Suggested Resources:
- National Telephone Counseling and Quit Line (800-QUIT-NOW) (800-784-8669)
- American Cancer Society (www.cancer.org)
# Nutrition Background
Maintaining good nutritional status is important to support overall health and immune system function for people with HIV/AIDS.Many HIV-related conditions affect and are affected by the body's nutritional status.These include conditions related to HIV itself (e.g., opportunistic infections and other illnesses), comorbid conditions, and adverse effects of therapies.
Inadequate nutrition in people with HIV infection may result from many factors, including conditions such as nausea, vomiting, and anorexia (see chapter Nausea and Vomiting) that may prevent adequate intake of nutrients and medications; diarrheal infections (see chapter Diarrhea) that prevent absorption of nutrients and medications; poor oral health conditions that interfere with chewing or tasting food (see chapter Oral Health); systemic illnesses (including HIV itself) that create a catabolic state; and psychological conditions (such as depression) that impair patients' ability to nourish themselves.In addition, financial constraints may limit patients' access to nutritious food.
Evaluation and enhancement of patients' nutritional status may help correct or compensate for deficiencies (e.g., in the case of weight loss or nutrient deficits), may be a key treatment modality for certain conditions (e.g., dyslipidemia, hyperglycemia), and may help to maintain good health and immune function.This chapter focuses on the evaluation of patients with nutritional deficiencies, particularly weight loss, and on simple strategies for maintaining good nutrition in individuals with barriers to maintaining adequate weight.
It should be noted that obesity and overweight conditions are increasingly common in HIVinfected individuals; many of the principles described here also may be applied to the evaluation of overweight patients.Recommendations for weight reduction for HIV-infected patients are the same as for the general population and will not be discussed in detail; for overweight patients with lipohypertrophy, diabetes, dyslipidemia, or coronary artery disease, see the respective chapters on these conditions. |
Ideally, HIV-infected individuals will receive the services of HIV-experienced nutrition specialists, who may contribute to the patient care team in the following ways:
- Conducting routine screening to identify and treat nutritional problems - Preparing a tailored nutritional plan to optimize patients' nutritional status, immune status, and overall well-being
- Screening and developing interventions for growth problems in children
- Developing strategies to prevent loss of weight and lean body mass
- Adapting dietary recommendations to help reduce the risk of comorbid conditions such as diabetes and heart disease, or treating these complications
- Educating patients about how to modify their dietary habits to maximize the effectiveness of medical and pharmacologic treatments
- Tailoring nutritional recommendations to fit patients' lifestyles and financial resources
- Counseling patients to promote nutrition self-care using available resources Section 3: Health Maintenance and Disease Prevention
- Providing nutritional support to patients may help to do the following:
- Address common problems associated with HIV disease and its treatment (e.g., weight loss, wasting, fatigue, loss of appetite, adverse changes in taste, dental problems, gastrointestinal complaints)
- Treat chronic comorbid conditions (e.g., cardiovascular disease, hypertension, diabetes, cirrhosis)
- Improve quality of life
- Enhance immune responses, slow disease progression, and prolong life
# S: Subjective History
Identify nutrition risk factors at the start of care through interview, questionnaire, or both.Update the history at least annually.
The history should elicit signs and symptoms related to nutrition issues, indications regarding dietary habits, and symptoms that suggest nutritional deficiencies.
# Section 3: Health Maintenance and Disease Prevention
To develop a specific dietary history, ask about the following:
# Dietary History
# Usual Dietary Intake Factors That May Affect or Limit Intake
- Frequency of intake of foods providing key nutrients (e.g., dairy products, fortified or whole grains, fruits and vegetables, fluids, meat, eggs, beans) as well as those that perhaps should be limited (fast-food items, highly processed or salted products) - Usual meal patterns (number of times per day, snacks) and whether meals are prepared and eaten at home or eaten at restaurants or fast-food establishments - Specific information about nutritional supplements (e.g., vitamins, minerals, herbs, protein), including contents, amounts, formulation (pills, powders, drinks), cost, and overlap among products
- Amount of money available for food, or participation in food assistance programs (e.g., food stamps, food pantries) - Appetite, general well-being (e.g., fatigue, pain, depression) - Food allergies, intolerances - Problems with dentition, swallowing, heartburn, diarrhea, constipation - Coordination of foods and supplements with medications (HIV or other)
Elicit symptoms that may be related to nutritional deficiencies.
# Symptoms with Possible Relationship to Nutritional Deficiencies
- General symptoms (e.g., fatigue, decreased cognitive function, headache) - Behavioral changes (e.g., irritability, apathy, decreased responsiveness, anxiety, attention deficit) - Body habitus changes (e.g., loss or gain of fat) - Gastrointestinal symptoms (e.g., diarrhea, constipation, bloating)
- Changes in skin, nails, hair (e.g., dryness, breaking, thinning) - Muscle loss - Neurologic symptoms (e.g., weakness, sensory changes, gait abnormalities)
# O: Objective Physical Examination
Perform a careful physical examination, if possible with anthropometric and body composition testing as described below (Table 1).Compare current findings with past assessments and review at least every 6 months.
The physical examination should include the following:
- Vital signs, with orthostatic vital signs if dehydration is suspected
- Weight (compare with previous values) and body mass index (BMI)
- General appearance and gross nutritional status (e.g., obesity, cachexia, wasting)
- Body habitus: loss of subcutaneous fat in face, buttocks, arms and legs and/or increased fat in abdomen, breasts, back of neck, and upper back ("buffalo hump")
- Muscle mass at www.cdc.gov/growthcharts/. A variety of growth charts are available for children from specific ethnic groups (e.g., Chinese, Vietnamese, Thai), children with selected conditions affecting growth (e.g., Down syndrome), or those who are born prematurely.Percentiles for both height and weight should be recorded sequentially.
# Body Composition Testing
Body composition commonly is tested by bioelectrical impedance analysis (BIA) (Table 2) or skinfold thickness and circumference (Table 3).
# Table 2.Bioelectrical Impedance Analysis
BIA testing is the standard of care for adults but has not been well validated for children:
- BIA is useful for assessing disease progression or health maintenance, documenting response to treatment, and justifying the cost of nutritional supplements and AIDS-wasting medications. -The test is simple, noninvasive, and quick (<5 minutes).However, staff training and specialized software are required to interpret the results. -Perform BIA at baseline.Update every 6-12 months or more frequently if the patient is ill, has a decline in immune status, or has a weight change of 5-10%. -The BIA test reports the following:
- Body cell mass (BCM): the target component, reflecting cells in muscles, organs, and the circulation; losses may indicate AIDS wasting.BCM is recorded in pounds.Monitor for trends. -Fat: an index of energy stores; recorded in pounds and percentage.
- Phase angle: a measure of cellular integrity, an independent indicator of morbidity and mortality in HIV-infected patients.
# Table 3.Skinfold Thickness and Circumference Measures
Skinfold thickness and circumference measures can be used for adults and children in resource-limited settings, and for situations in which bioelectrical impedance analysis is not available.Circumference measures also can be used to monitor changes over time associated with lipodystrophy in adults.
- Skinfold thickness is measured with calipers.
- Circumference measures are taken at specific anatomical landmarks with nonstretchable tape.
- Techniques and protocols for taking anthropometric measurements can be found at www.cdc.gov/nchs/ data/nhanes/nhanes_03_04/BM.pdf.
# Laboratory Testing
Perform basic laboratory (blood) tests, including the following:
- Hemoglobin and/or hematocrit
# A: Assessment
Assess subjective information and objective findings to evaluate nutritional status.
# Identify Nutrition Concerns
Several factors may influence nutrition, including the following:
- Barriers to good nutrition (e.g., lack of knowledge or motivation for self-care, poor appetite, lack of money for food, lack of facilities for food storage and preparation)
- Lifestyle factors (e.g., smoking, substance abuse, frequent eating out, erratic eating patterns, hectic schedule, high stress)
- Physical problems affecting food and nutrient intake (e.g., poor appetite, nausea, fatigue, pain, weakness, mouth or throat pain, acid reflux, missing or decayed teeth, poorly fitting dentures, poor eyesight, constipation)
- Nutrient losses (e.g., owing to diarrhea, vomiting)
- Potential confounding factors (e.g., use of multiple overlapping or questionable supplements, eating disorders)
# Evaluate Dietary Intake
Assess the following diet-related issues:
- Expected excesses or deficiencies from dietary history or interview
# Evaluate Laboratory Findings
- Evidence of malnutrition (e.g., low iron or protein stores)
- Evidence of disease or risk of disease for which dietary treatment is indicated (e.g., high fasting glucose, hypertension, hyperlipidemia)
# Develop a Problem List
The following suggests a useful format for a nutrition-related problem list.Poor diet: poor food choices, bingeing, skipping meals, high sugar intake, high alcohol consumption, high intake of refined foods, low fruit and vegetable intake, insufficient protein, insufficient calcium, food allergies or intolerances that limit intake Comorbid conditions: diabetes, hypertension, cardiovascular disease, cancer, gastroesophageal reflux disease (GERD)
Medications: drug-drug or drug-nutrient interactions or difficulty coordinating medicines with meals Supplements: insufficient or excessive intakes, cost of supplements unaffordable, supplements with potential or unknown risks
# P: Plan
Develop a nutritional plan and provide practical nutrition education for common problems (see "Resources," below).
Evaluate and treat concurrent medical problems (e.g., diarrhea, nausea, infections, malignancies, depression, pain).For severe or persistent nutritional problems, or for specific needs, refer to a nutrition specialist for evaluation and treatment.
Common nutrition-related problems are presented in Table 5, along with simple management suggestions that may help resolve them and help patients maintain adequate nutrition.
# Table 5.Practical Interventions for Common Nutrition-Related Problems
# Problem Suggestions
Weight Loss (decrease in both body cell mass and fat)
- Early identification and ongoing monitoring are key.
- Identify and treat underlying risk factors.
- Try to add calories without adding "bulk":
- Fat (9 calories/gram): butter, margarine, avocado, cream, mayonnaise, salad dressing - Carbohydrate (4 calories/gram): jam, jelly, sugar, icing, gum drops - Protein (4 calories/gram): protein powders, cheese, nut butters, trail mix, powdered breakfast drinks, nonfat dry milk - Eat more frequently.
- Maximize good days.
- Use canned supplements (e.g., Ensure, Boost).
- For wasting or substantial weight loss, consider referral for therapies such as appetite stimulants or human growth hormone.
# Diarrhea
- Increase soluble fiber; decrease insoluble fiber.
- Replenish beneficial bacteria (e.g., with lactobacilli preparations).
- Avoid intestinal irritants and stimulants.
- Decrease dietary fat.
- Decrease or eliminate lactose.
- Increase fluids and provide electrolytes (sodium, potassium).
- Treat with pancreatic enzymes.
# Early Fullness
- Take small, frequent meals.
- Concentrate on solid foods, with liquids between meals.
- Eat lower-fat, lower-fiber foods.
- Wear loose-fitting clothing.
- Sit up while eating.
- Eat, walk, and eat again.
# Nausea
- Take small, frequent meals.
- Try dry snack foods.
- Avoid fried foods, very sweet foods, spicy foods, and foods with strong odors. -Try cool, clear beverages, popsicles.
- Try ginger-containing foods and drinks.
- Keep liquids to a minimum at meals.
# Section 3: Health Maintenance and Disease Prevention
Problem Suggestions
# Changes in Taste
- Eat a variety of foods, not only favorite foods.
- Try protein sources other than red meat.
- Marinate foods, use sauces.
- Use more and stronger seasonings.
- Try tart foods.
- Use sugar or salt to tone down the flavor of foods.
- Try a mouth rinse of 1 teaspoon of baking soda in 1 cup of warm water before eating.
# Loss of Appetite
- Rely on favorite foods.
- Ask family members and friends to prepare meals.
- Eat small, frequent meals.
- Keep snacks handy for nibbling.
- Eat before bedtime.
- Eat in a pleasant place, with other people.
- Make the most of good days.
- Try light exercise to stimulate appetite.
- Add extra calories without adding bulk.
- Consider appetite stimulants (e.g., megestrol, stimulants).
# Difficulty Chewing or Swallowing or Sore Mouth and Throat
- Choose soft, nutritious foods.
- Blend or puree foods (e.g., soup or stew, smoothies).
- Add cream sauces, butter, or gravy for lubrication.
- Sip liquids with foods.
- Use a straw or drink foods from a cup.
- Choose bland, low-acid foods.
- If hot foods cause pain, serve foods cold or at room temperature.
- Avoid alcohol and tobacco.
- Soothing lozenges or sprays may help.
# Food Insecurity
- Refer to social services for assistance with accessing resources such as food stamps, community meals, or a food pantry program. -Refer to a dietitian for assistance with low-cost food ideas.
- Use materials at www.cheapcooking.com/index.htm.
# Unbalanced Diet and Other Conditions Requiring Dietary Modification
- Refer to a dietitian for counseling and education.
# Nutrition Specialists
Whenever possible, nutritional services should be provided by a registered dietitian (RD) who is a qualified HIV care provider.In the United States, holding this status requires a nutrition degree from an accredited college, graduation from an approved internship or master's degree program, and maintenance with 75 continuing-education units every 5 years, including specific and ongoing HIV training.An RD with HIV/AIDS expertise in the United States can be located by going to www.eatright.org, clicking on "Find a Nutrition Professional," entering the patient's zip code or city, and selecting "HIV/AIDS" under areas
# Resources
The following online resources provide information, guidelines, and tools for providers and patients in managing issues related to nutrition and HIV:
# Antiretroviral Therapy
Susa Coffey, MD
# Background
Potent combination antiretroviral therapy (ART), typically consisting of three or more antiretroviral (ARV) drugs, has greatly improved the health and survival rates of HIV-infected patients in areas of the world with access to ARVs.More than 20 individual ARVs in six classes are available in the United States, in addition to several fixed-dose combination preparations.These can be combined to construct a number of effective regimens for initial and subsequent therapy.Although ART has its limitations (see below), it saves lives and improves immune system function, reduces the risk of many HIVrelated and "non-AIDS" complications, and reduces the risk of HIV transmission.Increasingly, several lines of evidence point to the benefit of ART even for patients with high CD4 counts.
Mortality and morbidity benefits of ART are particularly obvious in patients with relatively advanced immune suppression or with symptoms related to HIV infection.For asymptomatic patients with higher CD4 counts (e.g., >350 cells/µL), the question of when to initiate ART remains an area of research and debate.It is clear there is a spectrum of risk for adverse outcomes that increases as the CD4 count declines.In persons with CD4 counts of 350 cells/µL rather than 500 cells/µL, the limited data that are currently available (from cohort studies) are inconsistent on the question of whether initiation of ART results in better outcomes.A randomized clinical trial of earlier (>500 cells/µL) versus deferred (<350 cells/µL) treatment is under way, and the results of that study along with those from the cohort studies may help define an optimal threshold at which to initiate ART.
Meanwhile, in recent years, a growing body of evidence has demonstrated adverse effects of untreated HIV on many organ systems and aspects of functioning, even in persons with high or relatively high CD4 counts (>350-500 cells/µL).These include the following: Many of these effects appear to be mediated through persistent immune system activation and ongoing inflammation in various organ systems.ART with virologic suppression appears to reduce immune activation and protect against many of these morbidities, but it may not restore immune system function to normal and may not fully reverse disease processes.The beneficial effects of ART may be attenuated for patients who start ART with lower CD4 cell counts.Additionally, the risk of certain ARV-related adverse events may be greater for those who start ART at lower CD4 levels.
Although ART can confer substantial health benefits, it has significant limitations.ART does not cure HIV infection and it requires that multiple medications be taken for life (i.e., potentially many decades).It may cause a variety of adverse effects (some severe), is expensive, requires close adherence to be effective and to prevent the emergence of resistance, and sometimes fails (because of the patient's imperfect adherence or other factors).The failure of an ARV regimen when accompanied by drug resistance usually means that subsequent regimens are less likely to succeed.
In past years, many of the available ARVs presented challenges in the realms of adverse effects, pill quantity, dosing frequency, and durability.Given these limitations of ART, much attention was devoted to estimating the point at which the potential benefits of ART outweighed the potential risks of ART.Today, the newer ARV regimens, specifically those currently recommended by the U.S. Department of Health and Human Services (DHHS) for initial therapy, are for most patients, simple, tolerable, and effective.As a result of both the availability of ARV regimens that are less toxic and easier to administer, and the increasing appreciation of the adverse impacts of untreated HIV, the tipping point between the potential benefit and the potential risk of ART is shifting.Most HIV experts (as is reflected in the current DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents; see below) recommend earlier initiation of treatment, and many recommend ART for all willing individuals regardless of CD4 count, unless there are compelling reasons not to treat (see "When to Initiate Therapy: DHHS ARV Guidelines," below; also see the DHHS Guidelines for a full discussion of these issues).An expected additional benefit of earlier treatment is the likelihood that HIV transmission will be reduced.
Of course, in deciding when to start ART for the individual patient, practitioners must weigh the expected benefits of ART for that person (in terms of morbidity and mortality) against the possible risks of ART (e.g., toxicity, drug resistance, adverse drug interactions).
Although implementing and monitoring ART is complex, a number of guidelines from expert panels are available to help clinicians select effective regimens for particular patients.The DHHS keeps a repository of frequently updated recommendations on the use of ARV medications for adults and adolescents, pregnant women, and children.All clinicians who treat HIV-infected patients should be familiar with the most current versions of these treatment guidelines.They are available on the Internet at the AIDSinfo website (aidsinfo.nih.gov/guidelines/).The DHHS Guidelines are referenced frequently in this chapter.In some situations, ART may be needed relatively urgently.These include the following:
- AIDS-defining conditions
- Acute opportunistic infections
- Lower CD4 counts (e.g., <200 cells/µL)
- Rapidly declining CD4 counts (e.g., >100 cells/µL/year)
- Higher viral loads (e.g., >100,000 copies/mL)
# A: Assessment
Make the following basic decisions:
- The patient is or is not likely to benefit from ART at this time (i.e., do potential benefits outweigh the risks?).See the DHHS Guidelines noted above, which thoroughly address the issue, and note that many experts are increasingly concerned about the potential harm of untreated HIV infection, even in individuals with high CD4 cell counts.See chapters Risk of HIV Progression/ Indications for ART and CD4 Monitoring and Viral Load Testing.
- The patient is or is not willing to start ARVs at this time (the choice to accept or decline therapy ultimately lies with the patient).
If not, work with the patient on readiness issues, with more urgency if the CD4 count is low or the patient has symptoms or comorbidities that suggest treatment is needed.
- The patient is or is not likely to adhere to an ARV regimen (an adherence counselor, with or without a mental health clinician, may be able to assist with this assessment and should be called upon if available).
No patient should be automatically excluded from consideration for ART; the likelihood of adherence must be discussed and determined individually (see chapter Adherence). |
# P: Plan
After educating the patient about the purpose and logistics of the proposed regimen and assessing the patient's potential for adherence, ART can be initiated, changed, or postponed accordingly.
The primary goal of therapy is to reduce HIV-related morbidity and mortality through maximal and durable viral suppression; this includes improving immune function and reducing HIV-associated inflammation.Among the secondary goals are improving quality of life and reducing the risk of HIV transmission.
# Preparing the Patient for ART
Before starting ART, it is important to have a detailed discussion with patients about their readiness to commit to a medication regimen, the expected benefits and possible adverse effects, and required monitoring and follow-up visits.Patients must understand that the first treatment regimen offers the best opportunity for effective viral suppression and immune reconstitution, which are the primary goals of ART.
# Supporting Adherence
Numerous strategies have been tested for their effectiveness in supporting patients' adherence to the ART regimen.Successful approaches include extensive patient education, telephone contact with office staff members who can answer questions about adverse effects or other difficulties, family meetings, and peer support.Trust and accessibility appear to be important predictors of adherence, and some practitioners see the patient for two or three appointments before starting ART.
Compact regimens consisting of fewer pills and once-daily dosing often encourage adherence.Advise patients about potential adverse effects and at the same time let them know that many adverse effects may be treated or that substitutions often can be made for problematic ARVs.The choice to accept or decline ART ultimately lies with the patient (see chapter Adherence).
# Anticipating Difficulties
Choosing an initial regimen that fits the patient's lifestyle and that is likely to be tolerable, and easy to take, will improve the likelihood of long-term success with that regimen.If patients develop toxicities to one or more components of an initial regimen, substitutions typically can be made without limiting the success of the regimen.Close monitoring and "check-in" appointments allow these adjustments to be made under clinical supervision.Close monitoring also can help to identify medication toxicities that Section 4: Health Care Maintenance and Disease Prevention may limit treatment and to detect early signs of inadequate medication adherence; early intervention to treat adverse effects and to support adherence may increase the likelihood of treatment success.
# Considerations in Regimen Selection
Regimens should be selected with consideration of both patient factors and medication factors.The patient's schedule, adherence history, and self-defined goals of ART should be considered in selecting a regimen to which the patient will best adhere.The patient's comorbid conditions and potentially interacting medications should be evaluated for possible contraindications or synergism.The ARV history and all resistance profiles should be reviewed carefully so that a regimen that will be likely to achieve durable viral suppression can be chosen. Tables 14, 15ae, and 16a-b of the DHHS Guidelines).
The advantages and disadvantages of various drug classes and individual drugs recommended for use in initial therapy are reviewed in Table 6 of the DHHS Guidelines. 6 of the DHHS Guidelines).In the end, the regimen should be selected with the individual patient in mind because the only effective combination for that patient is the one that he or she is willing and able to take on a consistent basis.See the information on drug resistance and toxicities below as well as the full text of the DHHS Guidelines for more complete discussions.
# Use of Multiple Classes of Drugs
Salvage therapy for patients with ARVresistant HIV often comprises agents from three or more ARV classes; consult with an expert.
# Boosted Protease Inhibitors
Ritonavir is used at low doses in combination with most other PIs to enhance or "boost" the serum level and prolong the half-life of the PI.This strategy generally decreases the dosing frequency and the number of pills required, and it improves the activity of some PIs.Several currently used PIs require boosting with ritonavir, and some require ritonavir boosting to overcome certain interactions between PIs and other medications (e.g.,
# Preferred Starting Regimens
More than 20 ARVs in six drug classes have been approved for use in the United States by the U.S. Food and Drug Administration (FDA) (see Appendix B, Tables 1-6 and Tables 11-13 in the DHHS Guidelines).In recent years, an increasing number of fixed-dose combinations (FDCs) have become available to simplify dosing and reduce pill burden.
These include four NRTI combinations:
- Abacavir + lamivudine (Epzicom)
- Abacavir + lamivudine + zidovudine (Trizivir)
- Emtricitabine + tenofovir (Truvada)
- Lamivudine + zidovudine (Combivir)
One PI coformulation:
- Lopinavir + ritonavir (Kaletra)
And a one-pill-per-day formulation of two NRTIs and one NNRTI:
- Emtricitabine + tenofovir + efavirenz (Atripla)
Other FDCs are in development and may become available in coming years.
The DHHS Guidelines suggest "preferred" and "alternative" components for initial therapy (
# Once-Daily Regimens
The use of convenient and simplified dosing is an obvious strategy for improving adherence, particularly with the availability of coformulations that reduce pill burden (see "Preferred Starting Regimens," above).The DHHS Guidelines currently include three
# Follow-Up of Patients Starting ART
Patients who start a new ARV regimen ideally should be seen at least twice within the first month to allow for an assessment of their adherence to therapy and the tolerability and adverse effects of the regimen.
When patients have been on a new regimen for 2-8 weeks, clinicians should check the following:
- HIV viral load, to monitor initial virologic response to therapy, then every 4-8 weeks until the viral load is below the level of detection
- CD4 cell count
- CBC with platelets, especially for patients starting a zidovudine-containing regimen, to monitor for anemia
- LFTs, to monitor for hepatotoxicity (patients starting a nevirapine-containing regimen should be monitored closely for the first 18 weeks of treatment)
- Serum electrolytes, blood urea nitrogen, and creatinine (particularly for patients taking tenofovir)
- Fasting glucose and lipids (after 3-6 months)
For further information, and for recommendations about monitoring stable patients, see chapter Initial and Interim Laboratory and Other Tests.
# Regimen Failure
An ART regimen may fail for several reasons, including the following:
# Incomplete virologic response
- Viral load does not decline below the level of detection (i.e., <40-75 copies/mL) within 6 months of initiating therapy. (For some patients with multidrug resistance, it may not be possible to decrease plasma HIV viral load to undetectable levels, and stabilization of viral load below the previous baseline may be an appropriate goal of therapy.)
# Virologic rebound
- Virus is repeatedly detected in plasma after suppression to undetectable levels.Confirmatory testing is required to rule out "blips" of virus (isolated elevations in viral load of less than several hundred copies/ mL) that are not clinically significant and to ensure that the increase is not caused by infection, vaccination, or problems with test methodology.Note that some patients may have persistently detectable low-level viremia (<200 copies/mL); the clinical significance of this is not clear.
# Immunologic failure
- Despite virologic suppression on ART, the CD4 cell count shows an inadequate response or a persistent decline.
# Clinical progression
- Recurrent, persistent, or new HIV-related illness occurs after ≥3 months on ART.Note that new or recurrent symptoms of opportunistic illness occurring in the first weeks to months after starting ART, especially in patients with severe immunosuppression, may not reflect a failure of ART.Rather, these symptoms could be attributable to persistence of opportunistic infections that may require longer treatment, or they could be caused by an immune reconstitution inflammatory syndrome (see chapter Immune Reconstitution Inflammatory Syndrome).
# Responding to Apparent
Treatment Failure
# Suggestions for Changing an ARV Regimen for Suspected Drug Failure
The following recommendations are adapted from the DHHS Guidelines.
Distinguish between the need to change a regimen because of drug intolerance or inability to adhere to the regimen and the failure to achieve the goal of sustained viral suppression.In the event of intolerability, single agents usually can be changed without resistance testing.
In general, do not change a single drug or add a single active drug to a failing regimen; it is important to use at least two or, preferably, three fully active ARVs (e.g., ARVs selected on the basis of resistance testing or because they are from a drug class to which the patient's virus has not been exposed).If resistance testing (performed while the patient is taking the failing regimen) shows resistance to only one agent in a regimen, it may be possible to replace only that drug; however, consultation with an expert is recommended.
In general, the goal of ART is to suppress HIV RNA to undetectable levels, in order to improve or maintain immune function.This usually is possible even for patients with resistance to multiple drugs as new ARV agents and new classes of ARVs have become available.Nevertheless, some patients have limited options for new regimens that will achieve durable virologic suppression.In some of these cases, it may be reasonable to continue the same regimen if partial virologic suppression and clinical and immunologic stability are maintained.The risk of continuing patients on a partially suppressive regimen, however, is the emergence of additional resistance mutations.
# Special Situations for ART ART during acute or primary HIV infection
It is not yet known whether ART has a longterm benefit when started during primary HIV infection, though there are a number of theoretic reasons why early treatment may reduce the severity of immune system disruption, lessen both the short-term and
# Pregnant women
Combination ARV regimens are recommended for all women during pregnancy, regardless of CD4 count or HIV RNA level.The goal of ART for pregnant women is to reduce the risk of transmission to the infant and to treat HIV infection in the mother, through maximal virologic suppression.Obviously, the decision of whether to start ART during pregnancy is the choice of the woman, and her choice must be respected.
# Acute opportunistic infections
The presence of opportunistic infections is a strong signal of the need for ART and effective immune reconstitution.For some of these infections, ART is the primary therapy, and for others it is adjunctive.
Although ART
# HIV-associated nephropathy
ART is a primary treatment for HIVAN and should be started urgently for patients with suspected HIVAN.See chapter Renal Disease.
# Expert Consultation
The
# Patient Education
- Making the decision to start ART is rarely an emergency situation.Before starting patients on ART, health care providers must work with them to determine how important therapy would be for them, what goals of therapy are likely to be achieved, and which personal issues are pertinent for selecting the best regimen to fit their lifestyles.
- Providers should review the proposed drug regimen with their patients.Be sure patients understand the instructions about dosage, scheduling, food requirements or restrictions, drug storage, adverse effects, toxicities, and type of reactions that must be reported immediately, as well as remedies for common adverse effects.
- Providers should explain to patients that successful ART requires a commitment to taking the medications precisely as prescribed.There is a limited number of ARVs, and if they are taken incorrectly, the virus quickly can become resistant to the medications.This will mean even fewer choices and less effective treatment in the future.It also may mean that they could transmit resistant virus to a partner or, if they are pregnant, to an infant.
- Patients should know that HIV medications do not prevent transmission of infection to others.Safer-sex recommendations must be followed and other high-risk activities (e.g., needle sharing) must be carefully avoided to prevent the transmission of the virus to others (see chapter Preventing HIV Transmission/Prevention with Positives for more information).
- Recommend prevention measures such as using latex barriers during sex (safer sex) and not sharing needles or other drug-using equipment, even with other HIV-infected persons.
- Patients should know that, if their virus develops resistance to some ARVs and they pass that virus on to another person, HIV medications may not be effective for that person.If a patient's partner happens to have a drug-resistant strain of HIV, it is possible for the patient to become infected with a resistant virus in addition to the one he or she has already, and that may limit treatment options.
- HCV, HBV, and other sexually transmitted infections such as syphilis and gonorrhea can be transmitted between two HIVinfected partners.
- Patients should be advised to check with their provider before discontinuing ARVs.If ARVs must be discontinued, it is usually best to stop all ARVs at once.The exception to this recommendation may be NNRTIcontaining regimens; in this case, the NRTIs should be continued for about 1 week after discontinuation of the NNRTI, if possible.Even carefully managed interruptions can cause drug resistance mutations.Again, this will limit future treatment options, and it - Patients should be encouraged to advise their providers of all other medications that they take, including over-thecounter medications, herbal remedies and nutritional supplements.
- Discuss contingencies in the event the client is unable to take ARVs for a day or more (e.g., illness, severe adverse effects, hospitalization, or other unexpected circumstances).
# References
# Overview of Prevention of Perinatal HIV Transmission
In the absence of antiretroviral (ARV) prophylaxis or other interventions, the rate of perinatal HIV transmission in the United States ranges from 16% to 25%.Antiretroviral therapy (ART) is highly effective in reducing the risk of perinatal transmission of HIV, to as low as 1-2%.All pregnant women with HIV infection should be educated about the risks of perinatal HIV transmission and offered ART and other medical management to maintain or improve their own health and to reduce the risk of HIV transmission to their infants.
# HIV Education and Counseling of Pregnant Women
Educating pregnant women about the importance of HIV testing is a critical element in preventing perinatal HIV transmission.However, extensive pretest counseling is not essential.A woman must be told that HIV testing is a standard component of prenatal care, that her clinician recommends the tests, and that all pregnant women should be tested for HIV because knowing about HIV infection is important for their health and the health of their babies.Research has shown that a provider's strong endorsement of HIV testing is a major predictor of whether a woman receives an HIV test.Testing should be voluntary and free of coercion, and a woman should know that she can decline testing without the risk of being denied care.A woman's age, cultural background, educational level, and primary language may influence her knowledge about HIV transmission and her willingness to be tested; the clinician should consider these factors carefully when providing education and information.
The following minimum information should be provided through an educational session with a health care provider or through written or electronic media (e.g., brochures, videos):
- HIV is the virus that causes AIDS.Approximately 25% of women with HIV who are not treated will transmit the virus to their babies during pregnancy, during labor and delivery, or by breast-feeding.
- A woman could be at risk of HIV infection and not know it.
- ART is highly effective in protecting the infant from being infected with HIV and can improve the mother's health.
- HIV testing is recommended for all pregnant women.
- Women who decline testing will not be denied care.
Women should be told that test results are confidential to the extent allowed by law and that medical and other services are available for women with HIV infection.Reporting requirements for the specific state should be explained.
HIV testing should be performed as early in pregnancy as possible to allow for interventions to prevent transmission and for effective management of a woman's HIV infection, if the woman is found to be HIV seropositive.The CDC recommends repeat HIV testing in the third trimester for women who receive health care in jurisdictions with an elevated incidence of HIV or AIDS among women, as well as for women at high risk of acquiring HIV (e.g., a history of injection drug use, exchange of sex for money or drugs, multiple sex partners, or a partner known to be HIV infected Infant risk factors for HIV infection include premature birth, low birth weight, skin and mucous membrane lesions such as thrush, and breast-feeding.Breast-feeding increases the risk of HIV transmission by 5-20%.In the United States, where safe, affordable replacement feeding and clean water routinely are available, women with HIV should not breast-feed.However, some women with HIV will be under tremendous cultural and familial pressure to breast-feed and will need the clinician's ongoing support to use substitute formula.
Because many factors that affect the risk of perinatal HIV transmission may be modified, clinicians should educate pregnant women carefully about the importance of ARV prophylaxis and other strategies to reduce the risk of maternal-fetal transmission of HIV.
# Antiretroviral Therapy During Pregnancy
The goals of ART for the pregnant woman are the same as those for any person living with HIV:
- To suppress the level of HIV as low as possible for as long as possible
- To preserve and restore immune function
- To prolong life and improve quality of life An additional, and crucial, goal of ART for pregnant women is to reduce the risk The DHHS Perinatal HIV Guidelines Working Group recommends fully suppressive combination ART for all pregnant women, unless there are compelling reasons based on pregnancy-specific maternal and fetal safety issues to modify this approach.Key recommendations from the DHHS Perinatal ARV Guidelines include the following:
- Assess the woman's HIV disease status and make recommendations about initiating or altering an ARV regimen, as part of the initial evaluation.
- Recommend ARV prophylaxis to all pregnant women regardless of HIV viral load or CD4 count.
- Discuss known benefits and potential risks of ART. |
- Include ZDV as part of the antenatal ART regimen, unless there is severe toxicity or the woman is already on a fully suppressive regimen.
- If HIV RNA is >500-1,000 copies/mL, perform drug-resistance testing prior to starting or changing ART.
- Emphasize the importance of adherence to the regimen.
- Ensure that the woman has access to and coordination of services among perinatal, primary care, and HIV providers as well as mental health and drug abuse services and income support as needed.
A fundamental principle of the guidelines is that therapies of known benefit should not be withheld during pregnancy unless they may cause adverse effects to the woman, fetus, or infant, and these adverse effects outweigh the potential benefits.Thus, women should be advised of the potential risks and benefits of ART (to the woman, fetus, and infant) and of the limited long-term data on outcomes for infants with in utero exposure to ARVs, but treatment decisions should be guided by the woman's clinical, virologic, and immunologic status and by the goal of preventing perinatal transmission.Women should be educated and counseled on the importance of close adherence to the ART regimen (see chapter Adherence).
Drug-resistance testing should be conducted for all pregnant women before the initiation of therapy, and for women who are already on ART without fully suppressed HIV RNA.
All women receiving ARVs during pregnancy for prophylaxis or for treatment should receive a combination containing at least three agents, with the aim of viral suppression to undetectable levels (i.e., <40-75 copies/mL, depending on the assay
# ART Recommendations by Clinical Scenario
# Recommendations for ARV Chemoprophylaxis to Reduce Perinatal HIV Transmission
The DHHS Perinatal ARV Guidelines offer recommendations on ARV prophylaxis to reduce perinatal HIV transmission based on four clinical scenarios, categorized by whether the mother needs ART for her own health and by her ART status when she presents for care (see Table 6).
# HIV-infected pregnant women currently receiving ART
Women already receiving ART should, in general, continue to receive it during pregnancy if it is suppressing viral replication.
If the woman has detectable virus (e.g., >500-1,000 copies/mL) on therapy, HIV drugresistance testing should be performed, and the regimen should be optimized to maximize the likelihood of achieving virologic suppression.
Women presenting in the first trimester should be counseled about the risks and benefits of ART during this period.Discontinuation of therapy could lead to increased viral load and potential for transmission to the fetus.HIV-infected pregnant women not on ART who need ART solely to prevent perinatal transmission ART is recommended as perinatal prophylaxis with pregnant women for whom treatment is not required for their own health.This recommendation applies to all pregnant women regardless of viral load.Rates of transmission are very low among women with undetectable or low viral loads (<1,000 copies/ mL) but transmission has occurred at all RNA levels.ARV medications decrease the risk of transmission, including in women with low viral loads.Antenatal ART not only lowers maternal viral load but also provides the infant with preexposure prophylaxis during the birth process; the neonate also receives postexposure prophylaxis through neonatal ZDV.
Women should be counseled about the benefits of ART in preventing perinatal transmission.
Because the risk of teratogenic effects on the fetus is greatest during the first 10 weeks of gestation, the woman may wish to defer starting a regimen until after 12 weeks'
and Disease Prevention gestation.As discussed above, efavirenz should be avoided during the first trimester.
Consideration can be given to discontinuing ART in women who do not have indications for continued ART; see "Postpartum Follow-Up of HIV-Infected Women," below.
# HIV-infected pregnant women who previously have received ART or prophylaxis but are not currently receiving any ARV medications
In some instances, a pregnant woman has been on ART for prophylaxis during a previous pregnancy and subsequently discontinued the medication.ARV drug-resistance testing should be conducted prior to initiating ART.The regimen should be chosen on the basis of previous ART experience and the reasons for stopping and results of past and current resistance testing, with avoidance of drugs and combinations with teratogenic (e.g., efavirenz ) or adverse maternal effects.The selection of an ART regimen for women with advanced HIV disease or a history of extensive prior therapy can be challenging, and consultation with an HIV specialist is recommended.As discussed above, efavirenz should be avoided during the first trimester.
# Pharmacokinetic Considerations During Pregnancy
Physiologic changes that occur during pregnancy (e.g., prolonged gastrointestinal transit time, increase in body fat and water, and changes in cardiac, circulatory, hepatic, and renal function) may affect the kinetics of drug absorption, distribution, and elimination.Few pharmacokinetic studies have been conducted on levels of ARVs during pregnancy, but available data suggest that altered dosing for some PIs (e.g., lopinavir/ritonavir) may be required (see Table 5 of the Guidelines).
# Special Circumstances Hepatitis B coinfection
In selecting ARVs, providers must decide whether to concurrently treat HBV, using NRTIs that have activity against both HIV and HBV (i.e., lamivudine, emtricitabine, and tenofovir).Making these decisions is complicated, and consultation with an expert is recommended.Also see the relevant discussion in the DHHS Perinatal ARV Guidelines, and chapter Hepatitis B Infection in this manual.
HBV-infected pregnant women who are not immune to hepatitis A should be vaccinated.
Infants born to coinfected women should receive HBV immune globulin and start the HBV vaccine series within 12 hours after birth (with subsequent vaccine doses per usual protocol).
# Hepatitis C coinfection
Treatment for hepatitis C (HCV) is not recommended during pregnancy.
Recommendations for ART during pregnancy are the same for women who are coinfected with HCV as for those without HCV coinfection.
Coninfected pregnant women should be tested for immunity to hepatitis A and HBV; if not immune, they should be vaccinated.Infants born to coinfected women should be evaluated for HCV infection.
See the relevant discussion in the DHHS Perinatal ARV Guidelines, and chapter Hepatitis C Infection in this manual.
# Safety and Toxicity of Antiretroviral Medications During Pregnancy
Limited data are available on the safety of ARVs in pregnancy, particularly when ARVs are used in combination.The existing safety and toxicity information is derived from animal and human studies, clinical trials, registry data, and anecdotal experience.
# Intrapartum Management and Mode of Delivery
All pregnant women with HIV infection should receive the intrapartum and neonatal components of ZDV prophylaxis used in the PACTG 076 protocol, as outlined earlier.IV ZDV should be given to the woman during labor as a 1-hour loading dose of 2 mg/kg followed by a continuous infusion of 1 mg/ kg per hour until delivery.Women on ART should continue their regimen on schedule as much as possible during labor, except that women receiving ZDV or a ZDV-containing fixed-dose combination should be given IV ZDV, with other components continued PO.For women on a stavudine-containing regimen, the stavudine component should be discontinued while IV ZDV is being administered.
For women who have detectable viral load at the time of delivery, the addition of the single-dose nevirapine protocol (single dose to the woman during labor, single dose to the neonate) generally is not recommended in the United States, because clinical trials conducted to date, although small, have not shown benefit and there is a risk of nevirapine resistance.However, single-dose nevirapine may be considered in special circumstances for women with high HIV RNA levels, especially when a patient is not on ART and delivery is vaginal rather than via a scheduled cesarean delivery.If single-dose nevirapine is given, most specialists recommend also giving NRTIs (e.g., ZDV/3TC), and continuing the NRTIs for at least 7 days to decrease the risk of nevirapine resistance.
Studies conducted before the availability of viral load testing found that cesarean delivery performed before the onset of labor or rupture of membranes significantly reduced the risk of perinatal transmission.However, now that many HIV-infected pregnant women in the United States and other high-income settings are receiving potent combination ART, rates of HIV transmission rates are very low (about 1.2-1.5%, unadjusted for mode of delivery); it is difficult to determine whether delivery by cesarean section further decreases the risk of peripartum transmission.
For a woman with a viral load of 1,000 copies/mL at or near the time of delivery (this would apply to many women on ART for whom viral suppression has not been achieved by the time of delivery because of late entry into care, issues of adherence, or viral resistance), the DHHS Perinatal ARV Guidelines and the American The DHHS Perinatal ARV Guidelines outline four scenarios in which the clinician must decide whether cesarean delivery is needed (see Table 9 in the Guidelines).The data on the benefits of cesarean delivery are complex and must be considered alongside the increased risk to the mother after surgery.The clinician should consult an obstetric/HIV specialist to discuss specific situations.Infants should have a baseline complete blood count and should be monitored for anemia while they are taking ZDV.Pneumocystis jiroveci pneumonia (PCP) prophylaxis for HIV-exposed infants is recommended for infants with indeterminate HIV status starting at 6 weeks when the ZDV prophylaxis regimen is completed until they are determined to presumptively or definitively HIV seronegative.Initiation of PCP prophylaxis should be stopped or avoided altogether when HIV has been presumptively excluded.
Parents and family caregivers must be taught how to monitor the infant for signs of illness until an HIV diagnosis is made or ruled out.They also need to know that the infant's exposure to ARV agents in utero is an important part of the infant's medical history and should be shared with future health care providers.Although no enduring consequences of ARV exposure have been confirmed, the child may be at risk of longterm problems.
# Patient Education
- The clinician should provide the pregnant woman with the most current information on the risk of perinatal HIV transmission and the importance of ARV prophylaxis.
- The clinician and the patient should have a detailed discussion about whether she needs ART for her own health as well as about ARV regimens that would help her to decrease the risk of perinatal transmission.
- The clinician should review with the patient the critical importance of her adherence to ART regimens before prescribing a regimen.
- The clinician should review possible adverse effects of the ARVs and give the patient specific instructions about managing them if they are mild or seeking medical advice if they are more serious, such as ongoing fatigue, persistent nausea and vomiting, or signs of hyperglycemia.
- The clinician should explain the signs and symptoms of early labor to the patient and emphasize the importance of seeking medical care if she has signs and symptoms of early labor or premature rupture of membranes.
- Early in the third trimester, the clinician and the patient should discuss the risks and potential benefits of cesarean section based on her viral load and clinical status.
- Intrapartum management, including the use of intrapartum ZDV, should be discussed with the patient so that she knows to tell the delivery team about her HIV status when she presents in labor.
- The clinician should discuss infant feeding plans with the mother and reinforce that she should not breast-feed.The clinician may need to provide ongoing support for and Disease Prevention formula feeding.
- The clinician should discuss follow-up plans and make referrals for the patient and her infant.If possible, the woman should meet the pediatric HIV team before delivery or in the postpartum period.The importance of ARV prophylaxis and follow-up for the newborn should be emphasized.
# References
- The first task in caring for an HIV-infected woman who is pregnant or considering pregnancy is to provide counseling that will allow her to make informed reproductive choices.Taking a careful reproductive history and providing preconception counseling should be part of any woman's routine primary care.To make informed choices about pregnancy, the patient needs education and information about the risk of perinatal transmission of HIV, potential complications of pregnancy, continuation or modification (or possibly, initiation) of ART, and the support she will need to optimize maternal and fetal outcomes.See chapter Health Care of HIV-Infected Women Through the Life Cycle for a more detailed discussion of preconception evaluation.
If ART is indicated for the woman's own health, an appropriate regimen should be started before pregnancy, to attain a stable, maximally suppressed maternal viral load prior to conception.Antiretroviral (ARV) resistance testing should be performed before ART is initiated.Particular ARVs should be avoided, including those with increased risk of causing teratogenicity (e.g., efavirenz), hepatotoxicity (e.g., nevirapine), or metabolic complications such as lactic acidosis (e.g., didanosine and stavudine).See chapter Reducing Maternal-Infant HIV Transmission.It should be noted that most fetal organogenesis occurs in the early weeks of pregnancy, before most women know that they are pregnant.Thus, any medication with potential teratogenicity or fetal toxicity, whether an ARV or another drug, should not be administered to women who intend to become pregnant or may become pregnant.Certain medications (e.g., ribavirin) also should be avoided by male partners of women who may become pregnant.
Folate supplementation to reduce the risk of neural tube defects in the developing fetus should be started at least 1 month before conception, if possible, because the neural tube forms in the early weeks of pregnancy (see below).
# Evaluation and Counseling of Pregnant Women
All HIV-infected pregnant women should receive thorough education and counseling about perinatal transmission risks, strategies to reduce those risks, and potential effects of HIV infection or HIV treatment on the course or outcomes of pregnancy.
- The goals of therapy for pregnant women receiving ART, as for all persons being treated for HIV infection, are to suppress the HIV viral load maximally (preferably to undetectable levels) for as long as possible, to improve quality of life, to restore or preserve immune function, and, for pregnant women specifically, to reduce the risk of perinatal transmission as much as possible.
- Therapy-associated adverse effects, including hyperglycemia, anemia, and hepatic toxicity, may have a negative effect on maternal and fetal health outcomes.Pregnant women should be advised about possible ARV-related adverse effects and should be monitored regularly for these events.
- HIV-infected women should receive evaluation and appropriate prophylaxis for opportunistic infections (OIs), as well as the vaccinations indicated for persons with HIV infection (see below).
- Some medications, both ARVs and other drugs, may cause fetal anomalies or toxicity when taken during pregnancy.These should be avoided in pregnant women, unless the anticipated benefit outweighs the risk.Consult with an HIV or obstetric specialist, a pharmacist, or the drug labeling information before prescribing medications for pregnant women.
- Options for mode of delivery should be discussed early.The benefits and risks of vaginal vs. cesarean delivery are outlined in the perinatal guidelines.If the HIV viral load is >1,000 copies/mL at 36 weeks of pregnancy, a scheduled cesarean delivery at 38 weeks' gestation is recommended to further reduce the risk of transmission.
Other evaluation and support measures for pregnant women should include the following:
- Screening for other potential maternal health problems, such as diabetes and hypertension
# Comprehensive Care of Pregnant Women with HIV Infection
Comprehensive care is important for pregnant women with HIV infection to achieve a healthy pregnancy and delivery.A multidisciplinary approach is the most effective way to address the medical, psychological, social, and practical challenges.For example, while her medical care is being managed by her obstetrician and an HIV specialist, the pregnant woman may need help from a social worker to find appropriate social services for food, housing, child care, and parenting issues.
The pregnant woman may need counseling and psychological support for herself and her partner, as well as referrals for substance abuse and detoxification programs.Peer counselors may be of particular assistance.Some patients may need legal or domestic violence services during and after pregnancy.Cooperation and communication between the obstetrician or nurse/midwife and the primary HIV provider are imperative throughout the pregnancy and early postpartum period.Referral to a maternal-fetal medicine specialist may be needed in complicated obstetric cases.
# Prenatal Care
All of the pregnancy-related complications seen in HIV-uninfected women, such as hypertensive disorders, ectopic pregnancy, psychiatric illness, multiple gestation, preterm delivery, and STIs, also can occur in HIVinfected women.These problems must be recognized quickly and treated appropriately to avoid life-threatening complications.Ideally, HIV-infected pregnant women are managed by both an experienced obstetrician-gynecologist and an HIV specialist.Communication between these specialists about medications, expectations, and complications is vital for the health and well-being of both mother and baby.If complications occur or abnormalities are detected, they should be evaluated and treated as indicated by the condition, and referral should be made to a maternal-fetal medicine specialist, if possible.Antenatal fetal surveillance and testing to identify fetal abnormalities should be carried out using guidelines established by the American College of Obstetricians and Gynecologists.
The suggested testing and monitoring practices for pregnant women with HIV infection, from the first trimester to labor and delivery, are presented in Tables 1 and 2.
# Immunizations and Opportunistic Infection Prophylaxis Immunizations During Pregnancy
Immunizations should be given before pregnancy, if possible.Immunizations should be considered during pregnancy when the risk of exposure to an infection is high, the risk of infection to the mother or fetus is high, and the vaccine is unlikely to cause harm.Some vaccinations (particularly live-virus vaccines such as measles/mumps/rubella) are contraindicated, and others should be given only if the anticipated benefit of the vaccination outweighs its risk.Special considerations for immunizations in HIV-infected individuals are discussed in chapter Immunizations for HIV-Infected Adults and Adolescents.
Some clinicians avoid giving immunizations during the third trimester of pregnancy because vaccinations may cause a transient increase in the HIV viral load and theoretically may increase the risk of perinatal HIV transmission. |
An increase in viral load may be prevented with effective ART, and some clinicians defer immunizations until ART is under way.
Recommendations related to immunizations during pregnancy are shown in Table 4.
# Hepatitis B virus (HBV)
Generally recommended for susceptible patients.
# Influenza (seasonal and H1N1 pandemic)
Generally recommended; give before flu season.As of 2010, H1N1 influenza vaccination also is recommended.
Measles/Mumps/Rubella (MMR) Contraindicated.
# Pneumococcus
Generally recommended; repeat in 5-7 years.
# Tetanus-diphtheria (Td); tetanus-diphtheria-pertussis (Tdap)
Recommended; give booster every 10 years.Give a single dose of Tdap for ages >19 to replace a booster dose of Td.
# Immune globulins (for postexposure prophylaxis in susceptible individuals) Comment
# Measles
Recommended after measles exposure, for symptomatic HIV-infected persons.
# Hepatitis A
Recommended after exposure (close contact or sex partner), or in case of travel to endemic areas.
# Varicella-zoster virus immune globulin (VariZIG)
Recommended for susceptible individuals after close contact with someone with varicella or herpes zoster (give within 96 hours).
# Hepatitis B immune globulin (HBIG)
Recommended for susceptible individuals after needlestick or sexual exposure to a person with hepatitis B infection.
# Genital herpes
Women with HIV infection are more likely than HIV-uninfected women to experience outbreaks of genital herpes.If HSV is transmitted to the infant, neonatal infection can be severe, even if it is detected and treated early.In addition, there is increased genital shedding of HIV in those with active genital HSV lesions.Some experts recommend obtaining HSV-2 serologies in a woman whose clinical history is unclear.Treatment for symptomatic HSV infections should be offered during pregnancy, and suppressive therapy should be given to women with frequent recurrences.If a woman has an active outbreak of genital HSV or experiences prodromal symptoms at the time of labor or membrane rupture, delivery by cesarean section is indicated.Prophylaxis with oral acyclovir late in pregnancy to prevent neonatal herpes transmission is controversial and is not recommended routinely.
# Tuberculosis
Prophylaxis is recommended for any woman with a positive PPD skin test result (≥5 mm induration), a positive IGRA result, or a history of exposure to someone with active tuberculosis, after active disease has been ruled out.Because of concern about possible teratogenicity from drug exposure, clinicians may choose to delay prophylaxis until after the first trimester.Patients receiving isoniazid also should receive pyridoxine to reduce the risk of neurotoxicity.
# Toxoplasmosis
All HIV-infected persons should be tested for IgG antibodies to Toxoplasma soon after HIV diagnosis, and this should be a part of antenatal testing for pregnant women with HIV infection.Women with a negative IgG titer should be counseled to avoid exposure to Toxoplasma (e.g., by avoiding raw or Section 4: Health Care Maintenance and Disease Prevention undercooked meats, unwashed or uncooked vegetables, and cat feces).Women with previous exposure to Toxoplasma (positive IgG titer) should be given prophylaxis during pregnancy, if the CD4 count is <100 cells/µL. For women who require prophylaxis, trimethoprim-sulfamethoxazole is the preferred agent; some specialists advise against giving pyrimethamine during pregnancy.
If secondary prophylaxis is used to prevent recurrence of toxoplasmosis, sulfadiazine should not be used, as it is contraindicated for use during pregnancy.
# Antiretroviral Therapy
Current U.S. Public Health Service guidelines recommend treating HIV infection in all pregnant women, using the same principles and modalities as used for nonpregnant individuals.HIV-infected pregnant women should receive potent combination ART regimens comprising at least three ARVs.The use of zidovudine (ZDV) prophylaxis alone (monotherapy) is not recommended but may be considered for the few women whose HIV RNA levels are <1,000 cells/µL on no ART and who decline combination ART.The choice of ARV regimen should be based on what is likely to be optimal for the woman's health, the potential effect on the fetus and infant, resistance test results, the woman's previous experience, if any, with ART, and her stage of pregnancy.ARV resistance testing should be performed before initiating or changing therapy.ZDV should be included in the regimens of all pregnant women unless there is severe toxicity or documented drug resistance.
ARV agents with known teratogenic effects, such as efavirenz, should be avoided, especially in the first trimester.Women who do not need ART for their own health and are taking ART only for the prevention of perinatal transmission may delay initiation of therapy until after the first trimester.This is a period of rapid organogenesis, and there is an increased risk of birth defects if teratogen exposure occurs.For women already taking ART at the time they become pregnant, the regimen should be reevaluated for its appropriateness during pregnancy to avoid potentially toxic medications and to ensure maximal virologic suppression.The ART regimen may be changed if necessary, but should continue without interruption.Discontinuation of ART could lead to an increase in viral load, which could result in a decline in immune status and an acceleration of disease progression, thereby increasing the risk of HIV transmission to the fetus.
For
# Pregnancy-Specific Complications and Management
Nutrition risk and inadequate weight gain Maternal nutrition and weight must be monitored throughout the pregnancy.A food diary may be a useful tool in assessing intake, and nutritional counseling is recommended.
# Nausea and vomiting
Women with signs of dehydration should be assessed and treated appropriately in collaboration with the obstetrician or nurse/ midwife.Any medication used for nausea and vomiting must be assessed for drug-drug interactions with all HIV-related medications the patient is taking.
# Hyperglycemia
Pregnancy is a risk factor for hyperglycemia, and women treated with PIs may have an even higher risk of glucose intolerance than other pregnant women and must be monitored carefully.New-onset hyperglycemia and diabetes mellitus, and exacerbation of existing diabetes, all have been reported in patients taking PIs.Clinicians should educate women taking PIs about the symptoms of hyperglycemia and closely monitor glucose levels.Some clinicians check glucose tolerance at 20-24 weeks and again at 30-34 weeks if the woman is taking PIs.The newborn should be checked for neonatal hypoglycemia at 1 and 4 hours after birth.
# Lactic acidosis
Lactic acidosis is a rare but life-threatening complication that has been reported in pregnant women taking nucleoside reverse transcriptase inhibitors, particularly didanosine and stavudine.The combination of didanosine and stavudine should be avoided during pregnancy.Clinical suspicion of lactic acidosis should be prompted by vague symptoms such as malaise, nausea, or abdominal discomfort or pain.Lactate levels, electrolytes, and liver function should be monitored carefully, including monthly in the third trimester.
# Hyperbilirubinemia
Women taking atazanavir or indinavir frequently develop elevated indirect bilirubin, but it is not known whether treatment during pregnancy exacerbates physiologic hyperbilirubinemia in newborns.Women who are taking indinavir may have an increased risk of nephrolithiasis, but evidence of harm to their newborns has not been demonstrated.
# Pain management
Pain management during labor and delivery may be complicated by drug interactions with ARV agents and by the higher medication tolerance in women who have addictions.
Additional pain medication may be needed for women with histories of drug use.
# Invasive perinatal procedures
The risk of HIV transmission to the fetus during invasive procedures (e.g., amniocentesis, chorionic villus sampling, and percutaneous or umbilical cord blood sampling) must be weighed carefully against the possible benefits of these procedures.
Current DHHS guidelines suggest that women undergoing such procedures should be on effective ART, preferably with undetectable HIV RNA.The use of fetal scalp electrodes and artificial rupture of membranes should be avoided if possible, and forceps or vacuum extractors and episiotomy should be used only if there are clear obstetric indications.
# Postpartum considerations
Because HIV can be transmitted to the infant through breast-feeding, breast-feeding is contraindicated in the United States and other resource-adequate countries where safe replacement feeding is available.Breast-feeding information should be removed from patient educational material pertaining to labor and delivery.Breast binding and ice packs can be used as needed to reduce lactation discomfort.Clinicians should recognize that women in some cultural groups are expected to breast-
# Patient Education
- Reinforce regularly and clearly the notion that, when the mother cares for herself, she is caring for her infant.Talk with the patient about stress, the importance of adequate mild-to-moderate exercise, and sufficient rest.
- Emphasize that regular prenatal care is extremely important to prevent complications of pregnancy.
- Use of a prenatal vitamin supplement is important, but cannot replace healthy food intake.Develop a plan with the patient for attaining the desired weight gain during pregnancy, while maintaining a healthy nutritional intake.
- Cigarette, alcohol, and drug use contribute to poor maternal nutrition and can harm the developing fetus.Illicit drug use increases the risk of transmitting HIV to the infant.Injection drug use can transmit HBV, HCV, and CMV to the mother and to the baby.Encourage cessation of cigarette, alcohol, and drug use, and offer referrals for treatment, as needed.
- Be sure the woman understands all planned procedures and treatments and understands their potential risks and benefits both to herself and to the fetus.
- Discuss the risks and benefits (to the woman and fetus) of each medication to be taken during pregnancy, including those for which there are limited data on teratogenicity.
- Discuss ART as part of the strategy to reduce the risk of perinatal HIV transmission to the fetus or newborn.For women at risk, diligent use of "safer sex" during pregnancy is important for preventing transmission of STIs and CMV, which can cause more complications when HIV is present.STIs can harm fetal development and may increase the risk of HIV transmission to the baby.New genital herpes infections during and Disease Prevention pregnancy can cause severe complications and even death in neonates.
- For women with negative Toxoplasma titers, explain the need to avoid undercooked meat, soil, and cat feces.
- Teach the pregnant woman how to obtain medical attention quickly at the first signs of OI or other complication.Discuss what to watch for and how to get help when emergencies arise in the evenings or on weekends or holidays.
- Help the patient clarify her child care options and encourage her to begin putting in place long-term child care and guardianship plans in case she becomes too sick to care for her child or children.
# References
# Epidemiology and Factors Affecting HIV Transmission
Heterosexual transmission of HIV is more efficient from man to woman than from woman to man.Transmission can occur through intact vaginal tissue; no damage to the vaginal lining is required.Women have specific risks of HIV acquisition at different phases of the lifespan:
- Young adolescents have immature genital tracts and increased cervical ectopy (increased vulnerability to HIV and other sexually transmitted infections )
- Women of reproductive age may desire pregnancy and childbearing (potentially increasing risky sexual behaviors)
- Married or partnered women may be monogamous with male partners who have risk factors for HIV infection (women may lack awareness of partner's risk behaviors)
- Postmenopausal or posthysterectomy women may have vaginal atrophy (decreasing the anatomic barrier to HIV), or may have no fear of pregnancy or have a perception that they are at low risk of infection (increasing risky sexual behaviors)
- Additionally, woman-to-woman transmission may occur if risk factors are present
# Psychosocial/Emotional Factors Unique to Women
Heterosexual women frequently are faced with unequal power and socioeconomic relationships with their male partners.These women may be more likely to exchange sex for money, less likely to successfully negotiate protected sex, and less likely to leave a relationship they perceive as risky.
Women may be more vulnerable to domestic violence and sexual coercion, especially those with histories of childhood sexual abuse.Also, women may inherit social roles and responsibilities as caretakers for extended family members and often for friends.
# ART Issues Particular to Women
In general, women on ART have virologic and immunologic responses comparable to those of men; however, several studies have shown that women discontinue ART more frequently than men.Women have higher rates of adverse effects from a number of antiretroviral (ARV) medications, in part because serum levels of at least some ARVs are higher in women.Pregnancy may require changes in ART, either because of pharmacokinetic changes or because of toxicity.See below.
# Baseline Reproductive History
Taking a careful reproductive history should be a part of routine primary care for any woman.Important information to gather includes the following:
- Age of menarche
- Menstrual history: last menstrual period (LMP), amenorrhea, menstrual irregularity, uterine fibroids, endometriosis
- Obstetrical history: G-P-A-L
- G (gravida, or number of pregnancies), P (parity, or number of births), A (abortion; number of miscarriages or terminations), L (number of living children)
- Pregnancy complications and outcomes: full-term, premature births, mode of deliveries
# Preconception Counseling
As discussed above, every visit with an HIVinfected woman in her reproductive years presents an opportunity to discuss pregnancy desires and options, including gathering information about her partner.It is important to assess the couple's sexual history, sexual decision making, and control of reproductive options.When a woman desires pregnancy, it is important to discuss the following, with the goals of educating her and decreasing risk of HIV transmission to an HIV-uninfected partner and to the fetus.Ideally, the partner will take part in the discussion.
- Options for conception that decrease risk of HIV transmission to an HIV-uninfected partner
- Recommendations for ART before and during pregnancy and delivery
# Menopause
There is evidence that HIV-infected women may be more likely to undergo premature physiologic menopause.Menopausal women are more at risk of premature bone loss, osteopenia, and osteoporosis; this risk may be increased by HIV infection.If indicated, bone density screening (DEXA) should be considered.
Hormone replacement therapy (HRT), especially of long duration, has been associated with an increased risk of breast cancer and cardiovascular and thromboembolic events, and its routine use is not currently recommended.HRT may be considered for women who experience severe vasomotor symptoms and vaginal dryness, but should be used only for a limited period of time and at the lowest effective dosage.Palliative care for patients with HIV infection comprises a continuum of treatment consisting of therapy directed at AIDS-related illnesses (e.g., infection or malignancy) and treatments focused on providing comfort and symptom control throughout the lifespan.This care may involve multidimensional and multidisciplinary services, including HIV medicine, nursing, pharmacy, social work, complementary or alternative medicine, and physical therapy.
# Palliative Care in the Era of Antiretroviral Therapy
With advances in HIV-specific therapy and care, HIV infection is no longer a rapidly fatal illness.Instead, patients who are able to tolerate antiretroviral therapy (ART) often experience a manageable, chronic illness.
The death rate from AIDS, however, continues to be significant: approximately 14,000 per year in the United States.In many parts of the world, patients still are not able to obtain specific treatments for HIV or for opportunistic illnesses, and supportive or palliative care may be the primary mode of care available to patients with advanced AIDS.Regardless of access to disease-specific treatment, people living with HIV continue to experience symptoms from HIV disease and its comorbid conditions, and those taking ART may experience adverse effects.Integrating palliative care and disease-specific care is important for treating patients with HIV in order to promote quality of life and relieve suffering.
# Advance Care Planning
Advance care planning involves planning for future medical care.Two main documents are produced:
- Advance directive (living will)
- Health care proxy (a person to speak for the patient or make decisions if the patient is too sick to do so)
The clinician should initiate these conversations and make referrals to helpful resources.
# Patient Education
- Discuss advance care planning with patients, and the option of hospice care, if appropriate.
- Provide patients and their family members with detailed information so that they understand the illness and associated treatments.
- Instruct patients to discuss their pain or other bothersome symptoms with their health care providers.
- Encourage patients to talk with their health care providers if they are feeling anxious, depressed, or fearful.
- Discuss with patients what their death might be like.Some patients may feel relieved to be able to talk openly about their last days.Assure them that their pain will be controlled and that their health care providers will be there to help them.
# Adherence Background
For HIV-infected patients with wild-type virus who are taking antiretroviral therapy (ART), adherence to ART is the major factor in ensuring the virologic success of an initial regimen and is a significant determinant of survival.Adherence is second only to the CD4 cell count as a predictor of progression to AIDS and death.
Adherence rates approaching 100% are needed for optimal viral suppression, yet the average ART adherence in the United States is approximately 70%.Individualized assessment of and support for adherence are essential for patients to be successful with ART.
Patients with suboptimal adherence are at risk not only of HIV progression, but also of the development of drug resistance (see chapter Resistance Testing) and consequent narrowing of options for future treatment.In one cohort study it was estimated that drug-resistant mutations will occur in 25% of patients who report very high but not perfect (92-100%) adherence to ART.It is important to note, though, that the relationship between suboptimal adherence and resistance to antiretroviral (ARV) medications is very complex and is not thoroughly understood.
Characteristics of the ARV regimen and individual patient pharmacokinetic variables also influence the likelihood of both virologic suppression and the development of resistance mutations.For example, in patients with wild-type virus on initial ART regimens, it appears that more drug resistance occurs in regimens that are based on an unboosted protease inhibitor or a nonnucleoside reverse transcriptase inhibitor, where the genetic barrier to resistance is relatively low, than in regimens that include a ritonavir-boosted protease inhibitor.In patients with suboptimal adherence, these factors can influence outcomes of therapy more strongly. |
# S: Subjective
Studies indicate that health care providers' assessments of their patients' adherence often are inaccurate, so a calm and open approach to this topic is very important.
Adherence assessment is most successful when conducted in a positive, nonjudgmental atmosphere.Patients need to know that their provider understands the difficulties associated with taking an ARV regimen.
# A: Assessment
Assess adherence at each visit using questions such as those in Tables 1 and 2, and assessment scales such as those found in Tables 4, 5, and 6 (Appendix).Ask these questions in a simple, nonjudgmental, structured format and listen carefully to the patient to invite honesty about issues that may affect adherence.Asking about adherence over the last 3 to 7 days gives an accurate reflection of longer-term adherence.
Ideally, a multidisciplinary team that includes primary providers as well as nurses, pharmacists, medication managers, and social workers works together to evaluate and support patient adherence. Before prescribing ARVs, some clinicians have their patients conduct adherence trials using placebo tablets or jelly beans to measure the patients' readiness to start therapy and their ability to adhere to a regimen.Such a trial allows patients to experience what a regimen will entail in real life, how therapy will affect their daily lifestyles, and what changes will be needed to accommodate the regimen.The shortcoming of placebo trials is that patients are not challenged with adverse effects as they might be with an actual regimen.Patients who can identify their medications (in their own words) and describe the proper dosing and administration have higher adherence rates.Providing patient education before writing a prescription helps ensure adherence to ARV regimens.Education can be provided in oral, written, or graphic form to assist the patient's understanding of the medications and their dosing.Basic information, including number of pills, dosages, frequency of administration, dietary restrictions, possible adverse effects, tips for managing adverse effects, and duration of therapy, will help patients to understand their ARV regimens.Patients should understand that the success of ART depends upon taking the medications every day and that adherence levels of >95% may be important in preventing virologic failure.
Close follow-up by telephone, clinic visits, or other contact with the patient during the first few days of therapy is useful in identifying adverse effects, assessing the patient's understanding of the regimen, and addressing any concerns before they become significant adherence barriers.Individualized interventions should be designed to optimize outcomes for each patient.Pharmacists, peer counselors, support groups, adherence counselors, behavioral intervention counselors, and community-based case managers are useful in supporting adherence for the HIVinfected patient.Multidisciplinary teams that include nurses, case managers, nutritionists, and pharmacists, in which each care provider focuses on adherence at each contact with the patient, are extremely effective, and peer support groups, in which patients share with one another their strategies for improving adherence, may be beneficial.
# and Disease Prevention
Many physical devices can be used to support adherence.The following are simple, inexpensive, and easy to incorporate into the routine of the HIV patient:
- Medication organizers include pillboxes and medi-sets.These are available in several shapes and sizes to fit the needs of the individual patient.They can be filled weekly so that the patient can easily determine whether a dose of medication was missed.
- Reminder devices include alarm watches, beepers, and cell phone alarms.They are effective in reminding the patient when to take medications.Medication diaries may be used for the patient to record doses that were taken.
- Visual medication schedules are calendars featuring photos or images of the patient's medications to remind the patient which drugs to take and at what dosages.
# Special Populations and Issues
# Mental Illness
Patients with mental health issues may have difficulty with adherence.In this population, it is particularly important to incorporate ARV medications into structured daily routines.Medication cassettes, reminder signs, and calendars have been very effective for these patients.Nursing care providers and family members may be instrumental in filling medication boxes or ordering prescription refills.
# Pediatrics
Adherence can be a challenge for young children who rely on parents and caregivers to provide their medications, but adolescents are more likely than younger children to have poor adherence.To improve adherence in this population, it is important to support the family.The U.S. Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection address some of the adherence issues and considerations for this patient population.
# Low Literacy
Health literacy is an important predictor of treatment adherence, particularly in low-income populations.Adherence interventions are necessary in this population to accommodate individuals who have difficulty reading and understanding medical instructions.Providers often fail to recognize this disability.In addition, adherence support is needed for patients who have difficulty navigating the health care system.
# Resource-Limited Settings
Research has shown that the level of adherence in resource-limited countries is at least as good as in resource-rich settings and that rates of virologic suppression are equivalent or better.Lack of access to a consistent supply of ARV medications, including financial barriers that
# Patient Education
- Educate patients about the importance of adherence and the need to take their ARV medications exactly as prescribed and to take every dose, every day.
- Advise patients that, if they miss an ARV dose on a rare occasion, that usually will not result in failure of the regimen.On the other hand, if they frequently miss or skip doses of their ARV medications, the regimen may become ineffective, and the HIV may develop resistance to ARVs.
- Tell patients to notify the clinic if they miss doses of the ARV medications.
- Work with patients to devise ways to improve their adherence, and reinforce good adherence behavior.
- Advise patients in advance that some people have adverse effects from the medications, and tell them to notify the clinic if they develop adverse effects.Discuss ways to reduce these effects. Interviewer Now I'm going to ask some questions about your HIV medications.
Most people with HIV have many pills or other medications to take at different times during the day.Many people find it hard to always remember to take their pills or medicines.For example:
- Some people get busy and forget to carry their pills with them.
- Some people find it hard to take their pills according to all the instructions, such as "with food" or "on an empty stomach," "every 8 hours," or "with plenty of fluids." -Some people decide to skip taking pills to avoid adverse effects or to just not take pills that day.Interviewer Now, I am going to ask you some questions about these drugs.Please put an "X" on the line below at the point showing your best guess about how much (DRUGS A-D) you have taken in the last 3-4 weeks.We would be surprised if this were 100% for most people. Section 5: Common
# HAND INSTRUMENT AND PEN TO RESPONDENT
# Interviewer
# Complaints
# Diarrhea Background
Diarrhea is a common complaint among HIV-infected individuals, and it has a variety of causes.
Episodes may be acute and brief, intermittent or recurrent, or, in some cases, chronic and severe.
If diarrhea persists, it may cause dehydration, poor nutrition, and weight loss.Diarrhea may diminish patients' quality of life significantly, and may interfere with adherence to and efficacy of antiretroviral (ARV) medications.
Diarrhea is defined in various ways, but commonly as more than four loose or watery stools per day for more than 3 days.Duration is classified as follows:
- Acute: <2 weeks - Persistent: 2-4 weeks
- Chronic: >4 weeks
The causes of diarrhea, both infectious and noninfectious, found in HIV-infected individuals with normal or mildly depressed CD4 cell counts are likely to be similar to those in HIV-uninfected persons.Among the noninfectious causes of diarrhea, adverse effects of ARVs and other medications are particularly common.Persons with advanced immunodeficiency are more likely to have infections, including opportunistic infections, as the cause of diarrhea.
Infectious diarrhea typically involves either the small or the large intestine, and the patient's history often suggests the site of the problem.Infections of the small intestine (enteritis) commonly produce generalized or periumbilical abdominal cramps, large-volume diarrhea without blood, and frequently dehydration.Large-intestine infections (colitis) often produce lower abdominal pain, an unproductive urge to defecate, and frequent small-volume stools with blood and pus.
# S: Subjective
The patient complains of diarrhea.Take a thorough history, including the following:
- Onset of diarrhea: sudden or gradual - Other associated symptoms (e.g., bloating, flatus)
- Allergies (to foods or medications)
- Aggravating factors (e.g., dairy products, fatty or spicy foods)
Section 5: Common Complaints
- Alleviating factors (e.g., fasting)
- Treatments tried (e.g., over-the-counter antidiarrheals)
- Contact with others with similar symptoms
- Previous episodes of diarrhea - Hydration status (skin turgor, mucous membrane moistness)
- Nutritional status (body habitus, muscle mass, skin and hair integrity)
- Oropharynx (lesions, candidiasis, ulcerations, Kaposi sarcoma)
- Optic fundi (signs of CMV infection)
- Abdomen (distention, bowel sounds, tenderness, organomegaly, masses, adenopathy)
- Rectum (masses, tenderness, bloody stool)
- Review recent CD4 cell counts.Low CD4 counts increase the risk of chronic or systemic illnesses and opportunistic infections.
# A: Assessment
The differential diagnosis of diarrhea is broad and includes the following infectious and noninfectious causes.The CD4 cell count is important in stratifying risk of infection with opportunistic pathogens; some organisms cause disease only with severe immunosuppression.
Section 5: Common
# Complaints
# Infectious Causes
Acute diarrhea, any CD4 count
# Noninfectious Causes
- Medication adverse effects, common with many medications including some ARVs:
- Protease inhibitors (especially ritonavir and nelfinavir)
- Didanosine buffered tablets (no longer available in the United States)
- Irritable bowel syndrome
# Treatment
Once a diagnosis is made, initiate appropriate treatment.For seriously ill patients, presumptive treatment may be started while diagnostic tests are pending.If the cause of the diarrhea cannot be identified, consult with an HIV expert or a gastroenterologist.
- For moderate to severe acute diarrhea, including dysentery (bloody diarrhea), empiric treatment can be given pending stool study results or in settings with limited resources for workup.If bacterial pathogens are suspected, use oral fluoroquinolones (e.g., ciprofloxacin 500 mg BID, norfloxacin 400 mg BID, or levofloxacin 500 mg once daily) for 5 days.Monitor effectiveness and adjust therapy according to the results of diagnostic studies and clinical response.Specific treatment with antimicrobials is guided by the pathogens identified in stool studies or on biopsy.
- For mild persistent diarrhea with no identified pathogen, treat with an antidiarrheal agent (see below).For patients whose diarrhea is suspected to be caused by ARV agents or other medications, symptomatic treatment also may be tried.Diarrhea owing to protease inhibitors often decreases after a few weeks without treatment.For persistent daily ARVassociated diarrhea, antidiarrheal agents may be given on a scheduled basis (rather than as needed).If the diarrhea cannot be controlled, a change in ARV regimen should be considered.
# Symptomatic treatments
- Antimotility agents such as loperamide (Imodium) in over-the-counter or prescription strengths and atropine/ diphenoxylate (Lomotil) are useful for many patients.The suggested dosage is 2 tablets after each loose bowel movement, not to exceed 8 tablets per day.These agents should not be used if patients have bloody diarrhea or if the presence of C. difficile is suspected.
- Pharmaconutritional approaches include the use of calcium supplementation (500 mg BID or TID).Patients with diarrhea related to protease inhibitors may find that taking calcium with each dose of protease inhibitors can decrease or prevent diarrhea.
Note that magnesium supplements may worsen diarrhea.
- Pancrelipase can be useful in managing chronic diarrhea caused by malabsorption.These come in different formulations with differing amounts of pancreatic enzymes; usual dosage is 2-3 capsules TID with meals, titrated downward according to response.
- Cholestyramine or psyllium (e.g., Metamucil) may reduce diarrhea by slowing peristalsis and adding bulk to stools.Avoid administering cholestyramine with other medications because it may impair their absorption.
- A combination of these treatments may be needed to control chronic diarrhea, and they can be continued for patients after an infectious process has been ruled out.
# Nutrition and hydration
Encourage frequent intake of soft, easily digested foods such as bananas, rice, wheat, potatoes, noodles, boiled vegetables, crackers, and soups.Encourage hydration with fruit drinks, tea, "flat" carbonated beverages, and water.Patients should avoid high-sugar drinks, caffeinated beverages, alcohol, high-fiber foods, greasy or spicy foods, and dairy products.Many patients may benefit from a trial of a lactose-free, - Combine 1/2 teaspoon of salt, 1 teaspoon of baking soda, 8 teaspoons of sugar, and 8 ounces of orange juice; add water to make 1 liter and drink.
- Drink 1 glass containing 8 ounces of apple, orange, or other juice; 1/2 teaspoon of corn syrup or honey; and a pinch of salt; then drink 1 glass containing 8 ounces of water and 1/4 teaspoon of baking soda.
- Mix 1/2 cup of dry, precooked baby rice cereal with 2 cups of water (boil first in areas with poor water quality); add 1/4 teaspoon of salt and drink.
# Patient Education
- Diarrhea can have many causes.Instruct patients to notify their health care provider if they develop new or worsening symptoms.
- Instruct patients to take their medications exactly as directed and to call their health care provider if they experience worsening diarrhea, or other symptoms such as fever, nausea, vomiting, or pain.
- Patients must stay nourished and well hydrated even if they are having diarrhea.Instruct patients to eat small, frequent meals and to avoid dairy products, greasy food, and high-fat meals.
- Instruct patients to maintain good handwashing practices during diarrheal illnesses to prevent infection in close contacts or household members.
- Some diarrheal illnesses are reportable; advise patients that they may be contacted by the local health department.
# References
# S: Subjective
The patient may complain of ear pain, decreased hearing or hearing loss, a feeling of fullness in the ear, vertigo, or a popping or snapping sensation in the ear.
Obtain information regarding the following during the history:
- Medications (prescription and over-thecounter) and herbal supplements, current and past
# Hearing Loss
A patient with hearing loss should be referred for evaluation or treated, depending on the cause.Avoid ototoxic medications (e.g., furosemide, aminoglycosides).
# Nose and Sinuses
Nasal and paranasal sinus conditions occur frequently in HIV-infected patients.Sinusitis, nasal obstruction, allergic rhinitis, and nasal lesions are common.Epistaxis can occur in patients with platelet disorders (e.g., idiopathic thrombocytopenic purpura ).
# S: Subjective
The patient may complain of "stuffy nose," rhinorrhea, epistaxis, frontal or maxillary headaches (worse at night or early morning), pain in the nostrils, persistent postnasal drip, mucopurulent nasal discharge, general malaise, aching or pressure behind the eyes, or toothache-like pain.
Obtain information regarding the following during the history:
- Medications (prescription and over-thecounter) and herbal supplements, current and past
- Current or recent sinus infection - Nasal obstruction may be caused by adenoidal hypertrophy, chronic sinusitis, allergic rhinitis, or neoplasm.
- Tumors may be caused by KS, squamous papilloma, or lymphoma; biopsy is necessary for determining the cause.
- Painful, ulcerated vesicles in the nasal mucosa may be caused by HSV or other infections.
# P: Plan
Acute Sinusitis
# Allergic Rhinitis
Patients should avoid exposure to known or suspected allergens.Nasal steroids may be very effective, but avoid fluticasone and budesonide nasal sprays with patients taking ritonavir (see "Potential ARV Interactions," below).Secondgeneration nonsedating antihistamines such as cetirizine, fexofenadine, and loratadine are not as effective as nasal steroids, but may give additional symptom relief.Note that ritonavir may increase the serum levels and half-life of cetirizine.Daily nasal lavage with normal saline often is beneficial.
# Nasal Obstruction
Perform magnetic resonance imaging (MRI) or computed tomography (CT) scan with biopsy for mass lesions or asymmetric nasal lymphoid tissue.Refer to an ENT specialist.
# Epistaxis
Epistaxis caused by coagulopathy or tumor is managed the same as for immunocompetent patients with these conditions.Cauterization of an identified bleeding point or packing may be necessary.ITP should be managed in collaboration with a hematologist; antiretroviral therapy (ART) typically is used for chronic management, and corticosteroids or other therapies may be used for acute management.Ritonavir may increase serum levels of cetirizine and may prolong its half-life; start with low dosage and monitor for adverse effects.
# Potential ARV Interactions
# Section 5: Common Complaints
# Mouth and Throat
The oral cavity is one of the most common areas of symptoms in patients with HIV infection.Conditions that arise in the oral cavity may be infectious, benign inflammatory, neoplastic, or degenerative processes.
# S: Subjective
The patient may complain of white patches and red areas on the dorsal surface of the tongue and the palate, decreased taste sensation, white lesions along the lateral margins of the tongue, ulcers, nonhealing lesions at the corners of the mouth, sore gums, loose teeth, dysphagia, or odynophagia.
Obtain information regarding the following during the history:
- Medications (prescription and over-thecounter) and herbal supplements (note that some medications may cause aphthous ulcers)
- Usual oral hygiene (toothbrushing, tongue brushing or scraping, flossing, use of mouthwash)
- Date of last dental examination
- Use of tobacco (cigarettes, chewing tobacco)
- Involuntary weight loss
# O: Objective
Recent CD4 count reflects degree of immunosuppression and is helpful in determining whether the patient is at risk of opportunistic infections as causes of oral complaints.
Thorough examination of the mouth and throat with a tongue depressor and a good light is mandatory.Observe for white patches or plaques on the mucous membranes that can be partially removed by scraping with a tongue blade (candidiasis).Examine the dorsal surface of the tongue and hard and soft palates for red, flat, subtle lesions (erythematous candidiasis). |
Look for ribbed, whitish lesions on the lateral aspects of the tongue that cannot be scraped off (oral hairy leukoplakia).Check for ulcerations, inflamed gums, and loose teeth (see section Oral Health).Look for discoloration or nodular lesions on the hard palate (Kaposi sarcoma).Check the pharynx for adenotonsillar hypertrophy.Rule out HIVunrelated causes of pharyngitis, including streptococci or respiratory viruses.
# A/P: Assessment and Plan
Perform biopsy, culture, and potassium hydroxide (KOH) preparation of lesions as indicated.
# Oral Candidiasis (Thrush)
Oral candidiasis is most likely to occur when the CD4 count is <200 cells/µL, but it can occur at any CD4 level and in HIV-uninfected individuals.It may appear as creamy white plaques on the tongue or buccal mucosa or as erythematous lesions on the dorsal surface of the tongue or the palate.The most common treatment strategy is empiric therapy with topical or systemic antifungal agents.For more details, see chapter Candidiasis, Oral and Esophageal.
# Angular Cheilitis
Angular cheilitis is also caused by Candida species, and it is characterized by fissuring at the corners of the mouth.For information on treatment, see chapter Candidiasis, Oral and Esophageal.
# Oral Hairy Leukoplakia
Oral hairy leukoplakia (OHL) is caused by Epstein-Barr virus and appears as raised, ribbed, "hairy" white lesions along the lateral margins of the tongue.Lesions are primarily asymptomatic, and treatment generally is not needed.Lesions often resolve with effective ART.For more details, see chapter Oral Hairy Leukoplakia.
# Aphthous Ulcers
Aphthous ulcers are eroded, well-defined lesions surrounded by erythema, ranging in size from <6 mm to several centimeters in diameter.The ulcers can appear anywhere in the oral cavity or pharynx and may be recurrent; they are extremely painful.
Treatment may involve topical steroids or other methods.For more details, see chapter Oral Ulceration.
# Oral Warts (Human Papillomavirus)
Oral warts may appear as solitary or multiple nodules.The lesions may be smooth, raised masses resembling focal epithelial hyperplasia, or small papuliferous or cauliflower-like projections.See chapter Oral Warts.
# Neisseria gonorrhoeae Pharyngitis
Neisseria gonorrhoeae may be transmitted by orogenital exposure; the patient may have mild symptoms (e.g., sore throat) or be asymptomatic.Physical examination may reveal an erythematous pharynx or exudates.Anterior cervical lymphadenopathy also may be present.Most cases of N. gonorrhoeae pharyngeal infection will resolve spontaneously without treatment and usually do not cause adverse sequelae.However, treatment should be initiated to reduce the spread of the infection (see chapter Gonorrhea and Chlamydia).Regular screening is recommended for patients at risk of N. gonorrhoeae infection.
# Medication-Related Mouth or Throat Lesions
- Candidiasis: antibiotics
- Xerostomia: antihistamines, anticholinergics, tricyclics, antipsychotic
- Gingival hyperplasia: phenytoin, calcium channel blockers
# Other Conditions
Most of these complications also can occur in the esophagus.See chapters Esophageal Problems, Candidiasis, Oral and Esophageal, and Cytomegalovirus Disease.
If patient is having mouth pain, anorexia, or problems with taste, treat the condition appropriately and refer to an HIV-experienced dentist for evaluation and further treatment as needed.Refer to a dietitian for assistance with dietary needs (e.g., nutritional supplements).
# Complaints
Esophageal Problems | 275
# Esophageal Problems Background
Esophageal problems in HIV-infected patients include difficulty swallowing (dysphagia) or midline retrosternal pain when swallowing (odynophagia).Pain may be diffuse throughout the esophagus or localized in specific areas.
Several conditions may cause esophageal problems.Of the infectious causes of dysphagia in HIV-infected patients, Candida is the most common (50-70%).Drug-induced dysphagia, gastroesophageal reflux disease (GERD), vomiting, and hiatal hernia also can cause esophagitis.
Less commonly, esophageal cancer or another cause of stricture may produce symptoms.
Neuromuscular or neurological causes may be seen in patients with advanced AIDS.
If untreated, esophageal problems may result in esophageal ulcers, scarring of the esophagus, dehydration, and weight loss.
# S: Subjective
The patient may complain of difficulty swallowing, a feeling of something being "stuck in the throat," retrosternal pain when eating, "hiccups," indigestion ("heartburn"), retrosternal burning, acid reflux, nausea, vomiting, or abdominal pain.
The history should include the following:
- Medications (prescription and over-the-counter) and herbal supplements, current and past
# O: Objective
Include the following in the physical examination:
- Measure vital signs (temperature may be elevated with certain infections, such as CMV, but not with herpes simplex virus , candidiasis, or idiopathic ulcers).
- Record weight (and compare with previous weights).
- Assess for oral candidiasis, lesions, and masses.
- Examine optic fundi to evaluate for CMV retinitis (in patients with CD4 counts of <50-100 cells/µL).
- Palpate for thyroid enlargement.
- Palpate the neck and supraclavicular and infraclavicular areas for lymphadenopathy.
- Assess the abdomen for masses, tenderness, and organomegaly.
- Perform a rectal examination to obtain stool for occult blood.
- Perform a neurologic examination.
- Check the CD4 cell count and HIV viral load to determine the level of immunosuppression and assess the risk Section 5: Common Complaints of opportunistic infections as causes of esophageal complaints.
# A: Assessment
Common causes of esophageal problems are as follows:
- Candidiasis (common with a CD4 count of <200 cells/µL or recent exposure to steroids or antibiotics)
# Diagnostic Evaluation
Diagnosis often can be made on clinical grounds; in this case, empiric treatment may be initiated (see below).If the diagnosis is unclear, consider endoscopy or radiographic imaging (e.g., computed tomography or barium swallow).
If the patient has dysphagia, odynophagia, unexplained weight loss, GI bleeding, anemia, or atypical symptoms, refer promptly for GI evaluation and endoscopy, or other evaluation as suggested by symptoms.
# Treatment
Determine whether the patient is able to swallow pills before giving oral medications.If pills are not tolerated, the patient may need liquids or troches.
For patients with severe oral or esophageal pain, viscous lidocaine 1% 5-10 mL 2-4 times daily (with swallowing precautions) or Magic Mouthwash (viscous lidocaine 1%, tetracycline, diphenhydramine, and nystatin compounded 1:1:1:1) may be tried.
Other treatments may depend on the underlying cause:
- Esophageal candidiasis: Fluconazole is the drug of choice.If symptoms resolve within 7-10 days, no further testing is required.See chapter Candidiasis, Oral and Esophageal for more treatment options and for dosing information.
- Medication related: Remove the offending drug(s), and institute a trial of H2 blockers or proton pump inhibitors (PPIs) as appropriate (caution: see "Potential ARV Interactions," below).
- Food related: Modify the diet and institute a trial of H2 blockers or PPIs as appropriate (caution: see "Potential ARV Interactions," below).
- "Heartburn" or GERD: Patients whose primary symptoms are more typical of "heartburn" or reflux, especially those with a history of GERD, should receive a trial of H2 blockers or a PPI as appropriate (these may decrease absorption of atazanavir; see "Potential ARV Interactions," below).
Reevaluate after 2-4 weeks; if symptoms are controlled, treat for 4-8 weeks, then reduce the dosage to the lowest effective amount.
Section 5: Common
# Complaints
Patients may require maintenance therapy for an indefinite period because of the high likelihood of recurrence.If symptoms do not respond to full-dose acid-blocking therapy, refer for GI evaluation.
- GERD: For nonpharmacologic treatment, in cases of obesity, counsel patients to lose weight, stop smoking, elevate the head of the bed, eat smaller meals, avoid eating food 2-3 hours before bedtime, and reduce fat in the diet to ≤30% of calorie consumption.
- CMV: Treat with anti-CMV medications (e.g., oral valganciclovir).See chapter Cytomegalovirus Disease for details.
- HSV: Treat with antiviral medications, including acyclovir, famciclovir, and valacyclovir.See chapter Herpes Simplex, Mucocutaneous.
- Aphthous ulcers: These may respond to oral corticosteroids (consult with a specialist before this is undertaken.Alternatively, a combination of H2 blockers and sucralfate may be effective.In some circumstances, thalidomide 200 mg Q24H may be used.
(Note: Thalidomide is teratogenic, and women of childbearing potential are not candidates for this therapy unless the potential benefits clearly outweigh the risks and appropriate prevention of pregnancy is undertaken.)Up to 40-50% of patients with aphthous ulcers experience relapse and require repeat treatment.
- Neoplastic disease: Treating this condition requires referral to an oncologist.
Esophageal conditions that do not resolve with treatment require referral to a GI specialist for diagnostic endoscopy, with biopsy and brushing for histopathology and cultures as appropriate.
# Diet
It is important that patients maintain adequate caloric intake, preferably with foods and liquids that can be swallowed easily.Nutritional supplements along with soft, bland, high-protein foods are recommended.Refer to a nutritionist as needed.
# References
# Potential ARV Interactions
Caution: H2 blockers and PPIs interfere with the absorption of atazanavir and several other PIs.For atazanavir, specific dosing strategies are required, and some combinations are contraindicated.See atazanavir package insert for dosage recommendations.
Section 5: Common
# Complaints
# Eye Problems Background
The immunosuppression caused by HIV infection increases the incidence of eye infections.However, the risk of serious eye problems associated with advanced immunosuppression, such as blindness caused by cytomegalovirus (CMV) retinitis, is much lower in patients treated with effective antiretroviral therapy (ART).Common problems not unique to HIV-infected patients include dry eye, blepharitis, keratitis, and presbyopia.Infections that may affect the eye include herpes simplex virus (HSV), herpes zoster virus (HZV), and syphilis.More severely immunocompromised patients (CD4 count <100 cells/µL) may experience CMV retinitis, Toxoplasma retinochoroiditis, cryptococcal chorioretinitis, and other conditions.Retinal detachment can result.Kaposi sarcoma (KS) also can affect the eye.
Immune reconstitution inflammatory syndrome (IRIS) may affect the eye in patients with advanced HIV disease soon after the initiation of effective ART.IRIS may lead to exacerbation of a previously treated opportunistic infection or a new presentation (often with unusual manifestations) of a previously subclinical infection.In the case of CMV, IRIS may present as retinitis, or less commonly as uveitis or vitreitis.IRIS retinitis typically occurs in patients whose CD4 counts have increased from <50 cells/µL to 50-100 cells/µL while receiving ART.
Drug-induced ocular toxicity can be caused by rifabutin, ethambutol, and cidofovir, and less often by high-dose didanosine (ddI, Videx), IV ganciclovir, IV acyclovir, and atovaquone.
# S: Subjective
The patient complains of dry eyes, blurred vision, floaters, sharp pains, flashing lights, central vision loss ("black holes"), vision field defects ("can only see half the page"), or peripheral vision loss ("looks like I'm in a tunnel").
Ascertain the following during the history:
- Pain: clarify type and characteristics
- Unilateral or bilateral problem
- Visual defects (central or peripheral vision loss or distortion), scotomata (an area of lost or depressed vision surrounded by an area of less depressed or normal vision); occurs with reading, distance, or both?
- Time course of symptoms
# O: Objective
Evaluate recent CD4 cell count and HIV viral load to determine whether the patient is at risk of opportunistic infections as causes of eye complaints.Also, do the following:
- Consider the patient's age.
- Check vital signs, including blood pressure and temperature.
- Administer a visual acuity examination using the Snellen chart.Test the patient's ability to read small print, such as classified ads.
Section 5: Common Complaints
- Consider using an Amsler grid to locate areas of retinal pathology.
- Examine the eyelids for lesions, inflammation, and swelling.
- Examine the external eye for edema, ptosis, conjunctival injection, and corneal clarity.
- Test cranial nerves II, III, IV, and VI.
- Perform funduscopic examination with pupillary dilatation, if available.Note retinal appearance, lesions, and condition of the disc, vessels, and macula.
- Examine the temples and scalp for tenderness
# A/P: Assessment and Plan
Refer to an HIV-experienced ophthalmologist for dilated retinal or slit-lamp examination and definitive diagnosis.If symptoms raise suspicion of serious or vision-threatening conditions such as herpes ophthalmicus, CMV retinitis, or retinal necrosis, ophthalmologic evaluation should occur within 24-72 hours.
Note that patients with HSV or VZV lesions in the V1 distribution (including the forehead, eyelids, or nose) should receive urgent ophthalmologic evaluation.
The differential diagnosis includes the following conditions:
# Dry Eye (Keratoconjunctivitis Sicca)
The patient may complain of intermittent eye pain, intermittent blurred vision that clears with blinking, and mild eye irritation.The condition worsens with extended reading or computer use.Keratoconjunctivitis sicca is related to HIV-mediated inflammation with damage to the lacrimal glands.It occurs in 10-20% of HIV-infected patients, most often in those with advanced HIV disease.In patients with a CD4 count of >400 cells/µL and no other signs or symptoms, confirm that results of a recent eye examination were normal or refer for same, prescribe artificial tears, and monitor.
# Blepharitis
Blepharitis is inflammation of the eyelids, a common condition with dry eyes.The patient may complain of discharge and erythema of the eyes or eyelids.Of the bacterial causes, Staphylococcus aureus is the most common.
Treatment includes cleaning of the eyelashes with warm water and mild shampoo, and applying antibiotic ointment if indicated.
# Infectious Keratitis
The patient may complain of photophobia, eye pain, decreased vision, and irritation.Section 5: Common
# Complaints
# Refraction Problems
The patient may complain of blurring vision with near or distance vision.Other findings include an abnormal Snellen test or inability to read fine print.The condition may be attributable to presbyopia or other causes.
Refer for ophthalmologic examination.
# Iridocyclitis/Anterior Uveitis
The patient may complain of redness or watering of the eyes, constriction of the pupil, and blurred vision.
# HIV Retinopathy
The patient typically has no symptoms, but may complain of blurred vision, visual field defects, floaters, or flashing lights.Cotton wool spots on the retina appear as small fluffy white lesions with indistinct borders and without exudates or hemorrhages.Usually, these findings are benign and do not progress.Refer for ophthalmologic examination to rule out other causes.
# CMV Retinitis
Patients with retinitis caused by CMV infection may be asymptomatic or may experience blurred vision, floaters, scotomata, or central or peripheral vision loss or distortion.Retinal examination shows creamy to yellowish lesions, white granular areas with perivascular exudates, and hemorrhages ("cottage cheese and ketchup").
The abnormalities initially appear in the periphery, but progress if untreated to involve the macula and optic disc.CMV is a common complication of advanced HIV infection in patients with CD4 counts of <50 cells/µL. Vision loss usually is permanent.Urgent ophthalmology consultation and initiation of anti-CMV therapy are required.See chapter Cytomegalovirus Disease.
# Acute Retinal Necrosis
The patient may complain of eye pain, decreased visual acuity, and floaters.Rapidly progressing peripheral necrosis frequently causes blindness.Retinal necrosis usually is caused by VZV, although HSV and CMV also have been implicated.Treatment should be initiated urgently.
# Toxoplasma Retinochoroiditis
Toxoplasma retinochoroiditis may occur in patients with CD4 counts of <100 cells/µL and cause blurred vision, visual field defects, floaters, or flashing lights.In HIV-infected patients, ocular manifestations often appear after the infection of the central nervous system with Toxoplasma (see chapter Toxoplasmosis).Retinal examination may reveal yellow-white infiltrates without hemorrhage and active vitreous inflammation.Evaluation requires consultation with an HIVexperienced ophthalmologist.If toxoplasmosis is confirmed or strongly suspected, treatment should be initiated as quickly as possible.
# Section 5: Common Complaints
# Neuro-Ophthalmologic Manifestations
Symptoms or signs of papilledema, optic neuritis, cranial nerve palsies, and visual field defects may indicate encephalopathy, increased intracranial pressure, neurosyphilis, toxoplasmosis, progressive multifocal leukoencephalopathy, meningitis, or central nervous system lymphomas.A thorough neurologic examination is required to determine whether additional diagnostic testing, such as imaging studies or cerebrospinal fluid testing, is needed in addition to ophthalmologic evaluation.
# Retinal Detachment
The patient may complain of flashes of light, sudden loss of vision, or both.This condition requires immediate referral to an emergency department.
# Patient Education
- Patients should report any changes in vision to their health care provider as soon as possible.
- Routine eye examinations should be part of the patient's primary care.
- Patients with CD4 counts of <50 cells/µL should be examined by an ophthalmologist at baseline and every 6 months thereafter.Section 5: Common
# Complaints
# Fatigue Background
Fatigue is one of the most common and debilitating complaints of HIV-infected people, with an estimated prevalence of 20-69%.It is defined by Aaronson et al.as "a decreased capacity for physical and/or mental activity due to an imbalance in the availability, utilization, and/ or restoration of resources needed to perform activity."The consequences of severe fatigue may include curtailment of work and other activities, need for frequent breaks, limitations in involvement with family and friends, and difficulty completing even the simplest household chores.
In HIV-infected individuals, fatigue may be caused by several comorbid conditions or by HIV itself.HIV-related fatigue is a broad term referring to fatigue that begins or significantly worsens after the patient is infected with HIV and that has no other identifiable causes.HIV-infected people with fatigue should be evaluated carefully for reversible causes, such as depression, anemia, hypogonadism, insomnia, and medication adverse effects, and should be treated aggressively if these are found.In some patients, fatigue may be related to advanced immunosuppression (with low CD4 cell counts) or to high levels of circulating HIV virus.Unfortunately, for many patients, a specific cause of fatigue is not identified.Research to date suggests that fatigue in many HIV-infected individuals may result from a complex interplay between physiologic and psychosocial variables, and studies are being conducted to define factors related to the onset or worsening of fatigue.
# S: Subjective
The patient complains of tiredness, easy fatigability, a lack of energy, a need for frequent rest or naps, or waking in the morning feeling unrefreshed.The patient may report difficulty working, difficulty concentrating, inability to exercise without experiencing profound fatigue, or impairment in social relations because of fatigue.
Consider the following during the history:
- No objective clinical indicators exist for fatigue; thus, making a diagnosis of fatigue rests on subjective data.
- Fatigue assessment tools may help in diagnosing fatigue and estimating its severity. |
One such tool, the HIV-Related Fatigue Scale, was developed specifically for use with HIV-infected individuals (see Barroso and Lynn in "References," below); this assesses the intensity of fatigue (on the day of the assessment and during the previous week), the circumstances surrounding fatigue (including patterns), and the consequences of fatigue.
- Take a thorough history of the fatigue symptoms, including onset, duration, exacerbating and alleviating factors, and associated symptoms.Evaluate for symptoms of other conditions that cause fatigue (e.g., hypothyroidism, hypogonadism, anemia, heart failure, poor nutrition).
- Depression can cause significant fatigue and is common among HIV-infected patients with fatigue.Screen the patient for depression.A single question -"Are you depressed?"-has been shown to be as valid and reliable as most depression instruments.See chapter Depression for further information.
- Inquire about social history, specifically any life stressors including those related to housing status, work stress, personal relationships, etc.
- Evaluate the patient's sleep patterns.
HIV infection can interfere with sleep architecture early in the illness.
# Section 5: Common Complaints
- Inquire about substance use or abuse.
- Obtain a list of all current medications, including herbal and over-the-counter preparations.
- Conduct a nutritional assessment.
# O: Objective
Check vital signs and orthostatic blood pressure and heart rate measurements, if indicated.Perform a physical examination including evaluation of nutritional status, affect, conjunctivae and skin (for pallor), thyroid, lungs and heart, and deep tendon reflexes.
# A: Assessment
The differential diagnosis includes the following:
- Anemia
# Diagnostic Evaluation
To rule out reversible causes of fatigue, perform laboratory tests, including:
- Hemoglobin and hematocrit
- Thyroid function tests
- Testosterone (in both men and women)
- Pregnancy test, if applicable Fatigue assessment tools, as mentioned above, may be used to assess the intensity of fatigue, the circumstances surrounding fatigue, and the consequences of fatigue.
# Treatment
If testing reveals a specific cause of fatigue, treat appropriately.For example:
- Treat anemia, hypothyroidism, or hypogonadism, as indicated.
- Treat depression with antidepressant medication, psychotherapy, or both; see chapter Depression.
- Treat insomnia and review good sleephygiene practices with the patient; see chapter Insomnia.
- Refer for treatment of substance use or abuse, if possible.
- Provide counseling regarding any current life stressors that may be contributing to fatigue.Involve social work and case management services regarding housing issues or other social needs that may be contributing to fatigue.
- Treat malnutrition, ideally in conjunction with a nutritionist.
- Treat opportunistic infections and other illnesses. (See section Comorbidities, Coinfections, and Complications.)
- Control other symptoms that could be causing fatigue (e.g., diarrhea).
Section 5: Common Complaints
- If fatigue seems to be related to antiretroviral medication(s), weigh the benefits of the medication(s) against the possible adverse effects, and discuss these with the patient.
After appropriate evaluation, if the fatigue is thought to be related to HIV infection or if no specific cause is identified, consider the following:
- If HIV infection is inadequately controlled, particularly if the CD4 count is low or the HIV viral load is high, initiate or optimize antiretroviral therapy (ART), if otherwise appropriate.
- Patients taking effective ART may still experience HIV-related fatigue.Prepare patients for the possibility that fatigue may persist despite ART initiation.
- Encourage patients to track their patterns of fatigue with a fatigue diary if necessary.Once patients recognize their individual patterns, they can better cope with fatigue by planning their daily activities accordingly (e.g., performing the most strenuous tasks during times of peak energy or staggering activities to avoid excessive fatigue).
- Ask patients what seems to aggravate their fatigue.This information, too, will help patients determine their patterns of fatigue and identify self-care actions they might take to avoid triggers that will worsen the fatigue.
- Recommend moderate exercise and frequent rest.
- Refer the patient to community-based agencies for assistance with housekeeping.
- Evaluate the need for occupational therapy (e.g., energy conservation techniques) or physical therapy (e.g., reconditioning and strengthening exercises).
- Medications such as stimulants (e.g., methylphenidate, modafinil) may be helpful for some patients with severe or debilitating fatigue.
# Patient Education
- Fatigue is often unrelated to the CD4 cell count or HIV viral load.Teach patients not to dismiss feelings of fatigue if they have higher CD4 counts and lower viral loads.Encourage them to discuss their symptoms with a provider.
- For patients with depression, advise them that appropriate treatment may reduce fatigue.
- Help patients identify how current life circumstances and stressors may contribute to fatigue and encourage them to seek the appropriate social services to help manage appropriately.
- Talk to patients about their sleep habits and recommend changes, as appropriate, to improve their sleep hygiene.
- Prepare patients to accept the fact that their fatigue (in some cases) may be a chronic condition, in which case it can be best managed by maintaining open communication with their provider and remaining engaged in care.
# References
# Fever | 287
Section 5: Common
# Complaints
# Fever Background
Although fever may accompany HIV infection at various stages of disease, fever in a patient with a low CD4 count (<200 cells/µL) should prompt the clinician to rule out opportunistic infections.
# S: Subjective
The patient complains of persistent fever, or new-onset fever of >101ºF (38.3ºC).
Assess the following during the history:
- Duration of fever
# Patient Education
- Patients should report any new fever to their health care provider.They should measure their temperature using a thermometer at home in order to report actual temperatures.
- Patients should know that fever usually is a sign that their bodies are battling an infection.Their health care providers may need to do special tests to find out what could be causing the fever.
- Many over-the-counter remedies are available to treat fevers.Patients should check with their care provider before taking these.Acetaminophen-containing products (e.g., Tylenol) generally are well tolerated.
Persons with liver disease should use acetaminophen only as prescribed.NSAIDs (ibuprofen, naproxen, etc.)may be used, but they can cause gastrointestinal adverse effects, especially if taken without food.Patients should let their care provider know if they need to take these medicines for more than 2 or 3 days.
Section 5: Common
# Complaints
# Headache Background
Headache in HIV-infected persons may result from many causes, particularly if the CD4 cell count is low.Possible causes include infections (opportunistic and other) and central nervous system malignancies, HIV-related systemic illnesses, and medication toxicity.In addition, of course, headache may be caused by any of the processes that cause headache in HIV-uninfected individuals.New or severe headache should be evaluated carefully.
# S: Subjective
The patient complains of a new type of headache.
Determine the following during the history:
- History of headaches or migraines
# O: Objective
Perform a physical examination as follows:
- Check vital signs.Look for fever, orthostasis, and hypertension.
- Examine the head and neck for trauma, sinus tenderness, scalp or temple tenderness, and neck mobility; check lymph nodes.
- Check the eyes, including funduscopic examination, for lesions or papilledema.
- Look for oral lesions, dental abscess, thrush, and pharyngeal drainage.
- Examine the lungs for abnormal sounds.
- Check the skin, including palms and soles, for rashes or lesions.
- Perform a complete neurologic examination, including mental status examination.
- Review recent CD4 measurements, if available, to determine the patient's risk of opportunistic illnesses as a cause of headache.
# Section 5: Common Complaints
# A: Assessment
A partial differential diagnosis includes the following:
- Cryptococcal meningitis
# P: Plan
# Diagnostic Evaluation
Evaluation should include the following:
- CD4 cell count (if not done recently), to help with risk stratification for opportunistic illnesses
- Complete blood count with differential (if fever or suspected anemia); see chapter Fever
# Treatment
- Once a diagnosis is made, appropriate treatment should be initiated.In seriously ill patients, presumptive treatment may be initiated while diagnostic test results are pending.In some cases, the source of headache cannot be identified.Consult with an HIV expert or a neurologist.
- Refer to disease-specific treatment guidelines or primary care management guidelines as appropriate.
- Treat symptomatically with nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, or narcotics, if indicated, to control pain.
# Patient Education
- Headache can be a sign of an opportunistic infection, especially in patients with low CD4 cell counts.Patients should notify their health care provider if they develop a new headache.
- Providers should inform patients that they may have to do additional tests to determine the cause of the headache.
- Many over-the-counter remedies are available for headache.Patients should check with their health care providers before taking these.Acetaminophen-containing products (e.g., Tylenol) generally are well tolerated.Persons with liver disease should use acetaminophen only as prescribed.
NSAIDs (e.g., ibuprofen, naproxen) may be used, but these agents can cause gastrointestinal adverse effects, especially if taken without food.Patients should inform their care provider if they need to take these medicines for more than 2 or 3 days.
Section 5: Common
# Complaints
# Lymphadenopathy Background
Lymphadenopathy is very common among HIV-infected individuals and may occur at any stage of HIV infection.It may be the first indication of a serious local or systemic condition, and it should be evaluated carefully.Rapid enlargement of a previously stable lymph node or a group of nodes requires evaluation to identify the cause and to determine whether treatment is needed.Similarly, nodes that are abnormal in consistency, tender to palpation, fluctuant, asymmetrical, adherent to surrounding tissues, or accompanied by other symptoms should be evaluated promptly.
Lymphadenopathy may be generalized or localized and usually is characterized by lymph nodes that are >1 cm in diameter.A multitude of conditions can cause lymphadenopathy, including HIV itself, opportunistic or other infections, and malignancies.The likely causes of lymphadenopathy, and thus the diagnostic workup, will depend in part on the patient's degree of immunosuppression.The risk of opportunistic and certain malignant conditions increases at lower CD4 cell counts (see chapter Risk of HIV Progression/Indications for ART).
Many individuals with primary HIV infection (see chapter Primary HIV Infection) have generalized lymphadenopathy that may resolve or may persist for months to years.If lymphadenopathy of >2 cm in size occurs in two or more noncontiguous sites and persists for more than 3 months, and if appropriate evaluation reveals no other cause, the patient is diagnosed with persistent generalized lymphadenopathy (PGL).PGL usually is caused by follicular hyperplasia from chronic HIV infection.As long as enlarged nodes are stable in number, location, and size, persons with PGL require no specific management other than monitoring of nodes at each physical examination (though consideration should be given to initiation of antiretroviral therapy ).Changes in the character of the lymph nodes should prompt further evaluation.Rapid involution of PGL may occur with advanced HIV disease and is a poor prognostic sign.
# S: Subjective
The patient complains of new, worsening, or persistent glandular swellings in the neck, axilla, groin, or elsewhere.
Ascertain the following during the history:
- Symptoms that accompany the lymphadenopathy, particularly constitutional symptoms such as fever, sweats, fatigue, and unintentional weight loss
- Localized symptoms or conditions that involve areas of the body with lymphatic drainage into the area of abnormal lymph nodes (e.g., in the case of axillary lymphadenopathy, ask about breast masses and skin conditions or trauma involving the arm)
- A full review of systems
# O: Objective
Review recent CD4 cell counts and HIV viral load measurements.
- Check vital signs.
- Perform a complete examination of lymph nodes, including the cervical, submandibular, supraclavicular, axillary, epitrochlear, and inguinal sites.Document the location, size, consistency, mobility, and presence or absence of tenderness of all abnormal nodes.In cases of localized lymphadenopathy, examine the area drained by the node.
- Check for hepatosplenomegaly.
- Perform a focused examination (e.g., lung, breast, skin, genitals) to identify signs of local or systemic illness.
# A: Assessment
The differential diagnosis of lymphadenopathy in HIV-infected patients depends in part on the degree of immunosuppression.For further information, see chapter Risk of HIV Progression/Indications for ART.
# Infectious Causes
Generalized lymphadenopathy
# Patient Education
- Lymphadenopathy may come and go throughout the course of HIV infection, but it may be a sign of a serious condition.
- Advise patients to notify their care provider if lymph nodes increase in size or change in character.
Section 5: Common
# Complaints
# Nausea and Vomiting Background
Nausea with or without vomiting, and occasionally vomiting without nausea, can occur at any stage of HIV infection.Nausea is a common adverse effect of many antiretroviral (ARV) and other medications, and it often occurs within weeks of starting new medications.In some cases, nausea causes significant discomfort and may interfere with medication adherence.Nausea and vomiting also may be symptoms of a serious complication of ARV therapy, or signs of an opportunistic infection or neoplasm in patients with late-stage AIDS.Clinicians must identify the cause of nausea and vomiting and initiate appropriate treatment.
# S: Subjective
The patient experiences nausea with or without vomiting, or vomiting without nausea.
Ascertain the following during the history:
- Duration of symptoms
# O: Objective
Check vital signs, including orthostatic blood pressure and heart rate measurements.
Conduct a thorough physical examination, including evaluation of the following:
- Skin turgor
- Eyes and fundi (retinal abnormalities such as papilledema)
- Oropharynx (dryness of oral mucosa, thrush, ulcerations)
- Neck (stiffness or other signs of meningeal irritation)
- Abdomen (tenderness, distention, masses, organomegaly)
- Pelvis (tenderness, masses)
- Neurologic system (mental status, focal neurologic abnormalities)
# Section 5: Common Complaints
Review recent CD4 measurements, if available, to determine the patient's risk of opportunistic illnesses.
# A: Assessment
A partial differential diagnosis includes the following conditions:
- Medication effect or reaction In the case of significant adverse effects from ARVs or other medications, substitute a less emetogenic ARV for the problematic medication, if possible (without compromising the efficacy of the treatment regimen).In the case of serious or life-threatening medication toxicities (e.g., lactic acidosis or abacavir hypersensitivity reaction), discontinue the Section 5: Common
# Complaints problematic medication (see chapter Adverse Reactions to HIV Medications).
After the workup and exclusion of lifethreatening illness, symptomatic treatment can be considered.If nausea and vomiting are attributable to medications that are vital to the patient, and these complications are not life-threatening, antiemetic therapy may be the best treatment.Chronic therapy is not always necessary.Some patients obtain adequate relief by breaking the "nausea cycle" with effective antiemetics for 1-2 days and then establishing meals or snacks with medications.Patients with dehydration may require administration of fluids (PO or IV) to relieve nausea.For patients with chronic nausea resulting in weight loss, refer to a nutritionist for assessment and nutritional support.
# Symptomatic treatment
Consider the following strategies for symptomatic treatment:
- For nausea that occurs in relation to an event or action (e.g., after taking ARVs) antiemetics may be given preemptively (e.g., 30 minutes beforehand).
- Ginger capsules have proven effective in clinical trials for the management of pregnancy-related and chemotherapy-related nausea.Foods and beverages containing ginger (e.g., tea, cookies, ginger ale, candies) may help provide relief.
- Promethazine (Phenergan) may be given as a 12.5-25 mg PO tablet Q4-6H as needed.
For patients unable to tolerate the PO formulation, promethazine suppositories (12.5 or 25 mg) may be used.
- Prochlorperazine (Compazine) may be given as a 5 mg or 10 mg PO tablet, or a 25 mg rectal suppository, Q6-8H as needed.Extended-release spansule, 10 mg Q12H or 15 mg QAM, also can be considered.
- Lorazepam (Ativan) may be given as a 0.5 mg PO tablet 30 minutes before taking medications for symptoms of anticipatory nausea.Patients with anticipatory nausea develop significant nausea or vomiting when even thinking about medications or reaching for the medications.
- Dronabinol (Marinol) may relieve nausea, especially when nausea is accompanied by a loss of appetite.This remedy is best tolerated by patients who have tolerated inhaled marijuana.The starting dosage is 2.5 to 5 mg BID or TID.
- 5-Hydroxytryptamine (5-HT3) receptor antagonists such as dolasetron 50 mg and 100 mg, granisetron 1 mg, and ondansetron 4 mg and 8 mg are highly effective are highly effective in relieving severe nausea and vomiting resulting from chemotherapy and other causes.However, access to these medications is limited by their cost.Their use should be considered a short-term strategy or reserved for cases of nausea/ vomiting refractory to other antiemetics.
- Metoclopramide (Reglan) may be used to enhance gastrointestinal motility in patients who experience nausea and vomiting caused by gastroparesis.The typical PO dose is 5-10 mg Q4-6H, or it can be taken TID with meals if the nausea or vomiting is associated with eating.
# Section 5: Common Complaints
# Patient Education
- Nausea and vomiting can have many different causes.Patients should let their health care provider know if they are having these symptoms so that the most likely cause can be determined.
- Patients should stay nourished and well hydrated even if they are experiencing nausea and vomiting.Eating small, frequent meals may be best tolerated, while avoiding dairy products, spicy or greasy foods, and high-fat meals.Taking medications with food may reduce symptoms of nausea (note that some medications must be taken on an empty stomach).
- Patients should not stop taking any of their medications without first discussing it with their health care provider.Many medications must be continued despite nausea.Nausea and vomiting owing to ARVs may resolve or become tolerable over time.
- Many patients wonder whether they should take their medicines again if they vomit after taking a dose.Generally, the medicines are still in the body unless the pills actually come back up.Patients should call their health care provider if they have any questions.
- Ginger may help to relieve nausea. |
Ginger can be taken in a variety of ways, including ginger ale, tea, cookies, candies, and ginger capsules.Patients can choose the form of ginger that works best for them.
Section 5: Common
# Complaints
# Neurologic Symptoms Background
The nervous system may be a site of complications throughout the course of HIV infection, and neurologic complaints are common among HIV-infected individuals.Neurologic symptoms may be caused by many factors, including infections (opportunistic and other), central nervous system (CNS) malignancies, medication toxicities, comorbid conditions (e.g., diabetes, cerebrovascular disease, chronic hepatitis, mental illness), and nervous system injuries related to HIV itself.
The risk of some conditions, such as CNS infection, malignancy, and dementia, increases with advancing immunosuppression, and the CD4 cell count will help to stratify the patient's risk of opportunistic illnesses (see Table 1 in chapter Risk of HIV Progression/Indications for ART.This chapter presents a general approach to neurologic symptoms in HIV-infected patients, with reference to other chapters in this manual for more detailed reading.For information on peripheral neuropathy, see chapter Pain Syndrome and Peripheral Neuropathy; for information on neurocognitive disease, see HIV-Associated Dementia and Other Neurocognitive Disorders.
# S: Subjective
The patient, or a friend or family member on his or her behalf, reports new neurologic symptoms such as pain, headache, seizures, altered mental status, or weakness.
Ascertain the following during the history:
- Onset and duration: rapid (hours to days), subacute, chronic
# O: Objective
- Check vital signs (temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation) and orthostatic measurements.
- Perform a careful physical examination as guided by the history, with special attention to the following:
- General appearance: mood, affect, mannerisms - Conduct a mental status examination.
- Review recent CD4 measurements, if available, to determine the patient's risk of opportunistic illnesses.
# A: Assessment
The differential diagnosis of neurologic abnormalities in patients with HIV infection may be broad, particularly if the CD4 count is low.Both HIV-related and HIV-unrelated causes should be considered; remember that more than one cause of symptoms may be present.
# Possible Causes of Neurologic Abnormalities
Causes related to the cerebrum or cranial nerves Note that organic causes of neurologic symptoms must be ruled out before concluding that symptoms are psychiatric in nature.
# P: Plan Diagnostic Evaluation
Unstable or seriously ill patients should be hospitalized for evaluation and treatment.Criteria for hospitalization include acutely altered mental status, fever with focal neurologic findings, and new or unstable seizures.
Perform laboratory work and other diagnostic studies as suggested by the history, physical examination, and differential diagnosis.This may include the following:
- Establish the CD4 count (if not done recently) to help with risk stratification for opportunistic illnesses.
- Determine which laboratory tests are appropriate, depending on the patient's presentation.The initial evaluation often includes a complete blood count with differential and monitoring of electrolyte and glucose levels.
- In patients with CNS symptoms or signs and low CD4 counts (<100 cells/µL), check serum levels of toxoplasma antibody (IgG) if not previously checked.Check serum cryptococcal antigen (CrAg) titer.
- In patients with symptoms of neuropathy or dementia, check serum levels of vitamin B12 and thyroid-stimulating hormone (TSH).
- In patients with cranial nerve abnormalities, meningoencephalitis, symptoms of dementia, or any symptoms of neurosyphilis, check syphilis serology by rapid plasma regain (RPR), Venereal Disease Research Laboratory (VDRL) test, or treponemal enzyme immunoassay (see chapter Syphilis).
- When CNS symptoms or signs are present, brain imaging by computed tomography (CT) scan with contrast is usually adequate as the initial test.Magnetic resonance imaging (MRI) is the modality of choice if the neurologic examination is nonfocal or if physical examination suggests a lesion in the posterior fossa.
- For patients with fever and CNS findings, perform lumbar puncture (LP) with cerebrospinal fluid (CSF) sampling.CT or MRI should be performed before the LP, if possible, to rule out a mass lesion that could cause herniation.
- Record the opening pressure, and send CSF for cell count and differential with protein and glucose measurements.Depending on the clinical suspicion, the fluid also should Section 5: Common Complaints be sent for bacterial culture, India ink stain for fungal organisms (75-85% sensitive), acid-fast bacilli smear and culture, VDRL test, and CrAg titer (95% sensitive).
- If CMV is suspected, perform polymerase chain reaction (PCR) for CMV DNA (62-100% sensitivity; 89-100% specificity).
- If PML is suspected, perform CSF PCR analysis for JC virus DNA (sensitivity approximately 70-90% with patients not taking ART; specificity 92-100%).
- For suspected drug or alcohol use, perform urine or serum toxicology screen. (Note that alcohol usually has been metabolized by the time withdrawal symptoms set in, typically 7-48 hours after the last alcohol intake.)
- For new-onset seizures, perform an electroencephalogram (EEG.)
- Consult with neurology specialists if the workup or the diagnosis is in question.
# Treatment
Specific treatment will depend on the cause of neurologic symptoms.Consult relevant chapters in this manual.For complex cases, consult with an HIV-experienced neurologist.
# Patient Education
- Inform patients that keeping the CD4 count >200 cells/µL (and preferably higher) with ART is the best way to prevent most HIVassociated neurologic diseases.
- Advise patients to take prophylaxis, as appropriate, to prevent opportunistic infections.
- When an antibiotic treatment is prescribed, advise patients to complete the entire regimen to prevent relapse of symptoms.Long-term treatment (secondary prophylaxis) will be needed to prevent recurrence of certain infections.
- Advise patients who have seizures that driving and other potentially dangerous activities will be prohibited until the condition is stable.
- Counsel patients to avoid substances that impair the nervous system, such as alcohol and recreational drugs.
- If a patient is forgetful, educate other members of the household about the medication regimen and help devise a plan for adherence to medications and appointments.
- Section 5: Common
# Complaints
# Pulmonary Symptoms Background
Shortness of breath and cough are common manifestations of acute or chronic respiratory diseases, but also may be symptoms of HIV-related opportunistic infections.Further, these symptoms may indicate nonpulmonary conditions such as anemia, cardiovascular disease, and sinusitis, or adverse effects of medications such as angiotensin-converting enzyme inhibitors (ACEIs).
The onset and duration of symptoms, and the presence or absence of other factors such as sputum production, fever, and weight loss, will guide the evaluation.In addition, the patient's CD4 cell count will establish a context for the evaluation, because it will help to stratify the risk of opportunistic infections.
# S: Subjective
The patient complains of dyspnea or cough.
Determine the following factors relating to the patient's history:
# Recent History
- Onset and duration of symptoms: rapid (hours to days), subacute, chronic
# A: Assessment
The differential diagnosis of pulmonary symptoms is broad (see Table 1).Both HIV-related and HIVunrelated causes should be considered; the patient's risk of HIV-related causes is strongly influenced by the CD4 count.More than one cause of symptoms may be present.
# Diagnostic Evaluation
Perform laboratory work and other diagnostic studies as suggested by the history, physical examination, and differential diagnosis.This may include the following:
- Chest X ray, especially if the patient has abnormal findings on chest examination, fever, or weight loss, or if the CD4 count is <200 cells/µL. Consider further imaging such as chest computed tomography (CT) scan or high-resolution chest CT (HRCT) if chest X-ray result is unremarkable in a setting of suspected PCP or persistent symptoms, or if there is question of pulmonary nodules or suspected empyema.
- Arterial blood gas (ABG) on room air, particularly if PCP is suspected, of if the oxygen saturation is low.
- Complete blood count and white blood cell (WBC) count with differential, metabolic panel, and lactate dehydrogenase (LDH).
- If fever is present (especially temperature >38.5ºC), obtain routine blood cultures (two specimens) for bacteria.If the CD4 count is <50 cells/µL, obtain blood culture for acidfast bacilli (AFB); if <100 cells/µL, check the serum level cryptococcal antigen (CrAg) and consider checking urine Histoplasma antigen.
- Induced sputum (outside, or in a negativepressure room or area that is safely vented to the outside, to prevent TB aerosolization) for AFB smear and cultures (three specimens), Gram stain and bacterial cultures, PCP stains, fungal stains and cultures, and cytology, as indicated.
- CD4 count and HIV viral load, if recent values are not known.
- Bronchoscopy with bronchoalveolar lavage (BAL) or biopsy if sputum studies are negative, if the diagnosis is unclear after initial evaluation or if the patient is not responsive to empiric therapy.
- Pulmonary function tests if no infectious or HIV-related pulmonary diagnosis is suspected and symptoms persist.
- Lactate level if lactic acidosis is suspected (e.g., nausea, tachypnea, abdominal pain, fatigue, in the setting of long-term nucleoside analogue therapy).
- Toxicology screen if symptoms are suspected to be related to recent drug use (e.g., crack cocaine pneumonitis).
# Treatment
Once the diagnosis is made, appropriate treatment should be initiated.In seriously ill patients, presumptive treatment may be started while diagnostic test results are pending.See the appropriate chapter in section Comorbidities, Coinfections, and Complications or relevant guidelines.In some cases, the source of dyspnea or cough cannot be identified.In these cases, consult with an HIV expert or a pulmonologist.
# Section 5: Common Complaints
# Patient Education
- Shortness of breath and cough can be signs of an opportunistic illness, especially in patients with low CD4 counts.Patients should notify their health care provider if they develop new or worsening symptoms.
- Patients taking antibiotics should be instructed to take their medications exactly as directed and to call their health care provider if they experience worsening fevers, shortness of breath, inability to take the prescribed medications, or other problems.
- Counsel smokers about the importance of smoking cessation; refer to tobacco cessation programs and prescribe cessation supports, as indicated; see chapter Smoking Cessation.
- Counsel drug users (particularly those who smoke or inject drugs) regarding the impact of illicit drugs on their overall health and especially their lungs; refer to appropriate cessation programs or rehabilitation programs.
Section 5: Common
# Complaints
# Vaginitis/Vaginosis Background
Vaginitis is defined as inflammation of the vagina, usually characterized by a vaginal discharge containing many white blood cells (WBCs); it may be accompanied by vulvar itching and irritation.Vaginosis presents with increased vaginal discharge without inflammation.Vaginitis usually is caused by an infection, but may be caused by other factors, such as chemicals or irritants.
Vaginal infections are common among HIV-infected women.The presence of vaginal infections or inflammation, in the case of bacterial vaginosis in particular, may facilitate acquisition of HIV and other sexually transmitted infections (STIs), and trichomoniasis may facilitate HIV transmission to HIV-uninfected partners.This chapter focuses on two of the most common types of vaginal infections: trichomoniasis and bacterial vaginosis (BV).For information on the topic of vulvovaginal candidiasis, see chapter Candidiasis, Vulvovaginal.
# S: Subjective
The patient complains of vaginal discharge with or without odor, itching, burning, pelvic pain, vulvar pain, or pain during intercourse.
Take a focused history, including the following:
- Duration of symptoms
# O: Objective
Perform a focused physical examination of the external genitalia, including perineum and anal area, for the following:
- Inflammation - Edema - Excoriation - Lesions
Perform speculum examination for:
- Discharge (note color, quality; note that the character of the discharge is not diagnostic)
- Erythema, edema, erosions, lesions
- Cervical friability
- Foreign body Perform a bimanual examination for masses or tenderness, if indicated.
# Section 5: Common Complaints
# A: Assessment
A partial differential diagnosis includes the following:
- BV
- Candidiasis
- Trichomoniasis
- PID
- Latex or condom allergy
- Urinary tract infection (UTI)
- Condyloma
- Herpes simplex virus (HSV)
- Contact dermatitis (e.g., from irritants, perfumes)
- Chlamydia
- Gonorrhea
- Normal vaginal discharge
# P: Plan Diagnostic Evaluation
- Obtain a cervical sample for STI testing, if indicated.
- Obtain samples (swabs) from the vaginal wall for wet mounts and pH testing.
- Wet mounts: Perform microscopic examination of saline and potassium hydroxide (KOH) preparations for the following:
- WBCs, clue cells, motile trichomonads (saline slide)
- Yeast forms (KOH)
- Perform a whiff test of KOH preparation; if positive, check pH (if >4.5, likely BV or trichomoniasis).
Treatment depends on the specific diagnosis, and in general is the same as for HIVuninfected women.
# Treatment during pregnancy
- Metronidazole, as in nonpregnant women (see above); the 7-day regimen may be better tolerated.
- Counsel patients about the potential risks and benefits of therapy.In pregnant women with asymptomatic trichomoniasis, may consider deferring therapy until after 37 weeks' gestation; consult with a specialist.
# Treatment notes:
Single-dose metronidazole is associated with more side effects than the other treatment regimens.
Sex partners should be treated.Patients should refrain from unprotected intercourse until both partners have resolution of symptoms and have completed treatment; this should be at least 7 days after single-dose therapy.
Sex partners should be treated.Patients must avoid alcohol while taking metronidazole or tinidazole, and for at least 1 day after discontinuing metronidazole and 3 days after
# Treatment failure
Certain strains of T. vaginalis have diminished susceptibility to metronidazole and must be treated with higher dosages.If treatment failure occurs on metronidazole, consider tinidazole as above, or if single-dose metronidazole was used initially, consider metronidazole 500 mg PO BID for 7 days.If this is not effective, consult with a specialist.
# Bacterial Vaginosis
BV is a clinical syndrome resulting from loss of the normal vaginal flora, particularly Lactobacillus, and replacement with anaerobic and other bacteria such as Gardnerella vaginalis and Mycoplasma hominis.The diagnosis is made on clinical and laboratory criteria.Usually, three of the following four characteristics should be present (note: only the clue cells are specific to BV):
- Homogeneous, gray-white, noninflammatory discharge on the vaginal walls
- Clue cells on the wet-mount slide
- Vaginal fluid pH level of >4.5
- Fishy odor to the vaginal discharge before or after the addition of KOH (whiff test)
Vaginal culture does not help establish the diagnosis.Rapid diagnostic test cards are available in some settings.
Many studies have documented an association between BV and infections such as endometritis, PID, and vaginal cuff cellulitis after gynecologic procedures.Therefore, the U.S. Centers for Disease Control and Prevention (CDC) recommends screening for and treating BV before invasive gynecologic procedures.
The sex partners of women with BV do not need to be treated.
# Treatment: Recommended regimen
- Metronidazole 500 mg PO BID for 7 days
- Metronidazole gel 0.75%, 1 full applicator (5 g) intravaginally QHS for 5 days
- Clindamycin cream 2%, 1 full applicator (5 g) intravaginally QHS for 7 days
# Treatment: Alternative regimens
- Tinidazole 2 g PO once daily for 2 days
- Tinidazole 1 g PO once daily for 5 days
- Clindamycin 300 mg PO BID for 7 days
- Clindamycin ovules 100 g intravaginally QHS for 3 days
# Treatment during pregnancy
- Symptomatic pregnant women should be treated with oral metronidazole (500 mg BID or 250 mg TID) or oral clindamycin for 7 days.
# Treatment notes:
- Patients must avoid alcohol while taking metronidazole or tinidazole, and for at least 1 day after discontinuing metronidazole and 3 days after discontinuing tinidazole.The combination of alcohol and these drugs may cause a disulfiram-like reaction.Patients taking ritonavir capsules or tipranavir also may experience symptoms because of the small amount of alcohol in the capsules.
# Treatment failure
Consider re-treatment for 7 days with metronidazole or clindamycin.Consider the possibility of an alternative or second cause of the patient's symptoms, as multiple conditions or pathogens may present concurrently.Perform testing for other conditions as suggested by symptoms, or if symptoms to do not resolve with initial treatment:
- Perform herpes culture if indicated by lesions; see chapter Herpes Simplex, Mucocutaneous.
# Section 5: Common Complaints
- Test for chlamydia and gonorrhea if indicated; see chapter Gonorrhea and Chlamydia.
- Perform urinalysis (with or without culture and sensitivities) if urinary symptoms are prominent.
- If an irritant or allergen is suspected, including N-9, discontinue use.
- If symptoms are related to the use of latex condoms, switch to polyurethane male or female condoms.
- For tenderness on cervical motion or other symptoms of PID, see chapter Pelvic Inflammatory Disease.
- Perform workup or obtain referral as needed for other abnormalities found on bimanual examination.
For information on other STIs or related conditions, see the CDC's treatment guidelines at www.cdc.gov/std/treatment.
# Patient Education
- Advise patients to avoid any form of alcohol while taking metronidazole or tinidazole and for 24 hours after taking the last dose (72 hours after the last tinidazole dose).Alcohol and metronidazole together can cause severe nausea, vomiting, and other immobilizing symptoms.
- Patients taking ritonavir may experience these symptoms because of the small amount of alcohol in the capsules and should be told to contact their health care provider if nausea and vomiting occur.
- Advise patients that clindamycin cream and ovules are oil based and will weaken latex condoms, diaphragms, and cervical caps.
Patients should use alternative methods to prevent pregnancy and HIV transmission.
- Recurrence of BV is common.Patients should contact their health care providers and return for repeat treatment if symptoms recur.
- Instruct patients to avoid douching.
- To avoid being reinfected by Trichomonas, patients should bring their sex partners to the clinic for evaluation and treatment.
Section 6: Comorbidities, Coinfections, and Complications
# Abnormalities of Body-Fat Distribution Background
Abnormalities of body-fat distribution are a recognized complication of HIV infection and of antiretroviral therapy (ART), and they are a common concern of patients.They include central fat accumulation (lipohypertrophy) and subcutaneous fat wasting (lipoatrophy).These morphologic changes are often referred to as lipodystrophy, though that term fails to distinguish between the two phenomena. |
Abnormalities in fat distribution and body shape have been noted in up to 40-50% of patients treated with ART, but the incidence may be much lower with the use of newer, less lipotoxic, antiretroviral (ARV) medications and with earlier initiation of ART.Lipohypertrophy and lipoatrophy are associated with other metabolic abnormalities, such as dyslipidemia and insulin resistance, and visceral fat accumulation (at least in HIV-uninfected persons) is a risk factor for cardiovascular disease.
Research on fat maldistribution has yielded varying results, in part because there are no standard clinical case definitions of lipodystrophy, lipoatrophy, or lipohypertrophy.The pathogenesis of fat abnormalities in HIV-infected individuals is not well understood, but research to date suggests that it is multifactorial and is associated with HIV-related immune depletion and immune recovery, ARV medications, disregulation of fatty acid metabolism, hormonal influences, individual genetic predispositions, and factors that are not related to HIV such as diet and obesity.Lipodystrophy has been associated with lower nadir CD4 count as well as with gender (central lipohypertrophy may be more common in women) and age (more common in older patients), and longer exposure to ART.Lipohypertrophy has not been definitively proven to be related to specific ARVs or to specific ARV classes, but has been variably associated with protease inhibitors (PIs) and with nucleoside reverse transcriptase inhibitors (NRTIs).However, morphologic changes occasionally develop in ARV-naive individuals.Lipoatrophy is most commonly associated with NRTIs, notably stavudine, as well as didanosine and zidovudine.
The most common morphologic changes seen in lipohypertrophy are a firm enlarged abdomen caused by central or visceral fat accumulation, breast enlargement (gynecomastia) in both men and women, development of a dorsocervical fat pad ("buffalo hump"), and neck enlargement.Lipoatrophy most commonly appears as the loss of subcutaneous fat in the face, arms, legs, and buttocks.Lipoatrophy differs from the generalized wasting seen in advanced AIDS, because lean cell mass generally is preserved.When lipohypertrophy and lipoatrophy occur together, the affected individuals show a mixed picture of abdominal obesity with thinning in the face, arms, and legs.
Severe lipoaccumulation can cause discomfort and, in some cases, impairment of breathing or other bodily functions.It may be associated with other metabolic abnormalities, including dyslipidemia, insulin resistance, and the metabolic syndrome.Both lipoaccumulation and lipoatrophy can be disfiguring, can damage self-image and quality of life, and can negatively influence ARV adherence.
# S: Subjective
The patient may report any of the following: abdominal fat accumulation with change in waist size, increased neck size, "buffalo hump," enlarged breasts, and reduced range of motion.Women may note an increase in bra size.Alternatively (or in addition), the patient may report sunken cheeks, decreased arm or leg circumference, prominence of veins in the arms or legs, or buttock flattening.
# P: Plan
# Diagnostic Evaluation
# Laboratory
Check for other metabolic abnormalities associated with the use of ARVs, such as dyslipidemia and impaired glucose metabolism (check fasting lipids and random or fasting
# Treatment
Treatments for lipohypertrophy and lipoatrophy have not reliably reversed body shape changes once these changes have occurred.In general, treatment interventions have shown poor results in patients with marked or severe fat maldistribution and inconsistent or limited responses in those with milder conditions.The best approaches to managing lipodystrophy are prevention and early intervention.
Clinicians can help to prevent body fat abnormalities by avoiding, whenever possible, ARV agents known to confer a greater risk of this disorder (particularly stavudine, didanosine, and zidovudine, which particularly are associated with lipoatrophy).All patients who take ARVs should be monitored carefully for the development of fat maldistribution.If abnormalities are noticed, intervention should be initiated, if possible.
The optimal management strategy for established lipoaccumulation or lipoatrophy is not known, although the following approaches can be considered (see below).Also consider referring the patient to clinical studies of lipodystrophy treatment, and for psychological or adherence support and counseling, if indicated.If the patient is distressed enough to consider discontinuing or interrupting ART, review with the patient any gains he or she has made on ART and discuss treatment options (see below).In some cases the patient may insist on discontinuing ARV medications; in this situation, carefully review the risks of treatment interruption as well as the alternatives to discontinuing treatment.
# ARV Substitutions
Avoiding thymidine analogue NRTIs, particularly stavudine, and avoiding the NRTI combination stavudine + didanosine have been shown to reduce the risk of lipoatrophy.
In patients with lipoatrophy, modest slow improvement in limb fat has been demonstrated after switching from thymidine analogues (stavudine, zidovudine) to nonthymidine NRTIs (such as abacavir or tenofovir) or to NRTI-sparing regimens.In patients with lipohypertrophy, similar NRTI switch strategies have had little effect on visceral or trunk fat.Studies in which PIs were eliminated from the ART regimen generally have not shown significant effects on body fat measures.
Before switching therapies, carefully assess the potential risk to the patient's long-term HIV management.
# Nonpharmacologic Measures Diet
The effects of diet on lipohypertrophy have not been evaluated thoroughly.If overall weight reduction is needed, recommend dietary changes and exercise.Avoid rapid weight loss plans, as lean body mass often is lost disproportionately.Refer to a dietitian to help the patient decrease intake of saturated fat, simple sugars, and alcohol.
# Exercise
Regular, vigorous cardiovascular exercise may help control central fat accumulation, whereas resistance exercises (strength training) will improve the ratio of muscle to fat.Some studies of exercise (done alone or in combination with diet) have shown a reduction in visceral fat accumulation with minimal or no changes in peripheral lipoatrophy.Moderate aerobic exercise should be encouraged for all patients.
# Pharmacologic Measures
# Insulin-sensitizing agents
In diabetic and non-HIV lipodystrophy,
# Recombinant human growth hormone
Treatment with recombinant human growth hormone (rHGH), 3-6 mg/day for 12 weeks followed by maintenance therapy with lower doses of 1-2 mg/day, has been shown to reduce visceral fat in many patients with minimal impact on peripheral fat wasting; other studies suggest efficacy (and improved tolerability) of lower dosages of rHGH.However, the high cost of rHGH, the high rate of adverse effects (including insulin resistance), and the frequent recurrence of visceral fat accumulation once rHGH is discontinued have resulted in a limited role for this treatment.
# Growth hormone-releasing factor
Tesamoralin, a synthetic growth hormonereleasing factor analogue, has been shown in Phase 3 clinical studies to reduce central fat accumulation by about 18% over the course of 12 months, without adverse effects on glucose or lipid parameters.As with rHGH, patients regain visceral fat when tesamoralin is discontinued.Tesamoralin currently is under review for approval by the U.S. Food and Drug Administration (FDA).
# Plastic and reconstructive surgery
Various techniques have been investigated, but generally have limited applicability and efficacy.Poly-L-lactic acid (Sculptra, New-Fill) is approved by the FDA as a treatment for facial lipoatrophy.This injectable material has shown good cosmetic results and often significantly improves patients' satisfaction with their appearance.Calcium hydroxylapatite (Radiesse) also has FDA approval for HIV-associated facial lipoatrophy.
Treatment effects of both agents typically wane with time and the procedures often must be repeated.Other facial fillers, as well as cheek implants and autologous fat transfer, have been used successfully in some cases.
For lipoaccumulation, treatments such as liposuction for focal areas of fat deposition (e.g., dorsocervical) and breast reduction may be effective in the short term, though fat often reaccumulates.
These interventions increasingly are covered by private-and public-payer sources, but still often are deemed to be the financial responsibility of the patient.In some cases, they may be only a temporary solution, because abnormalities may reappear after treatment.
# Patient Education
- Instruct patients who are receiving ARV medications to inform their health care provider if they notice changes in the shape or appearance of their bodies.
- Review the importance and benefits of ART and assess adherence to the regimen.
- For patients with lipohypertrophy, recommend aerobic and resistance exercise to reduce fat and build muscle.Assess local resources for safe muscle-strengthening possibilities.
- If weight reduction is needed, refer to a dietitian for consultation.Remind the patient that quick weight-loss diets may
# Background
HIV-infected individuals, both those on antiretroviral therapy (ART) and those who are untreated, appear to have higher rates of coronary heart disease (CHD) than HIV-uninfected individuals and higher rates of various risk factors for CHD, including dyslipidemia.As the average lifespan of patients on effective ART lengthens, and as people living with HIV become older, morbidity and mortality from CHD are likely to continue to increase.Thus, identification and reduction of modifiable risk factors for CHD are important aspects of primary care for HIV-infected patients.
Dyslipidemia is a well-described independent risk factor for CHD, and it occurs in a high proportion of persons with HIV infection.Current research suggests that this dyslipidemia is caused by a combination of factors related to HIV disease, ART regimens, and individual patient characteristics.HIV itself causes lipid perturbations, particularly in persons with more advanced immunosuppression; HIV-infected individuals who are not on antiretroviral (ARV) medications often have elevations in triglyceride (TG) levels and decreases in high-density lipoprotein (HDL) as well as in low-density lipoprotein (LDL) cholesterol and total cholesterol (TC).Lipid abnormalities also may be caused by or compounded by ARVs (see chapter Coronary Heart Disease Risk).They may appear or worsen within a few weeks to months after starting ART.With some patients, this may, at least in part, represent a return to pre-illness lipid levels, whereas the ARVs cause the abnormality in other cases.Not all ART-treated patients experience lipid abnormalities to the same degree.Patients with a personal or family history of dyslipidemia, glucose intolerance, diabetes, obesity, or a combination of these health problems may be genetically predisposed to lipid abnormalities that become evident once ART is initiated.
The use of potent combination ART, particularly the use of protease inhibitors (PIs), has increased the prevalence of abnormally high TG, TC, and LDL levels among HIV-infected patients.In fact, dyslipidemia has been associated not only with certain PIs but also with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs).In the PI class, ritonavir-boosted PIs (with the exception of atazanavir) are particularly likely to cause marked elevations of TG and LDL levels.NNRTIs also may contribute to increases in TC, LDL, and TG levels although the effects, particularly with efavirenz, are more variable (and efavirenz may increase HDL).Of the NRTIs, stavudine, zidovudine, and perhaps abacavir may increase TC and TG levels.To date, available agents from the integrase inhibitor and CCR5 antagonist classes do not appear to have significant adverse impacts on lipid levels.
The largest prospective study of CHD events related to ARVs (the D:A:D study) showed a small but significant increase in the risk of myocardial infarction among HIV-infected patients treated with ARVs; moreover, the effect increased with cumulative years of ARV exposure.This effect was largely but not entirely associated with increases in LDL cholesterol (see chapter Coronary Heart Disease Risk).
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection on ART who had a fasting lipid panel during the measurement year (Group 2 measure) Section 6: Comorbidities, Coinfections, and Complications
# S: Subjective
The history should focus on factors that suggest CHD, risk equivalents, or risk factors for CHD.Both CHD risks and CHD equivalents should be the focus of lifestyle modification strategies and lipid-normalizing treatment.
- CHD includes the following:
- A history of myocardial infarction - CHD risk factors are conditions associated with a greater risk of serious cardiac events.These are as follows:
- Male sex
- Age (≥45 in men; ≥55 in women)
- Hypertension
- Cigarette smoking
- Low HDL (60 mg/dL, subtract one risk factor
- Family history of premature CHD (firstdegree relative aged <55 or <65
- Assess for causes of secondary dyslipidemias, including insulin resistance, diabetes, hypothyroidism, obstructive liver diseases, chronic renal failure, and medications such as corticosteroids and progestins.
- Screen for other factors that contribute to hyperlipidemia, including obesity, chronic liver diseases, alcohol abuse, high-fat or high-carbohydrate diet, and prothrombotic or proinflammatory states.
- Screen for health behaviors that increase CHD risk, including smoking, highfat diet, sedentary lifestyle, and use of recreational drugs such as cocaine and methamphetamine.
- Review the patient's family history for premature CHD (as discussed above), obesity (body mass index ≥30), diabetes, and lipid abnormalities.
Identification and management of dyslipidemia in HIV-infected patients is an important part of HIV primary care.For patients with CHD or CHD risk equivalents (see below), ART regimens should, if possible, be selected to minimize the risk of hyperlipidemia.
# A: Assessment
Determine whether a specific intervention is appropriate based on the patient's lipid values and identified CHD risks, as indicated in Tables 1 and 2.
LDL is the main indicator for treatment, and the main target for lipid-lowering therapy.Hypertriglyceridemia is associated with CHD risk, but thresholds of risk have not been defined precisely, and targets for intervention are not entirely clear (for persons with triglyceride levels of ≥500 mg/dL the triglycerides usually are treated first; see "Treatment," below).Severe hypertriglyceridemia (e.g., TG >1,000 mg/dL) also increases the risk of pancreatitis.
For patients who do not have diabetes or preexisting CHD and who have two or more CHD risk factors, calculate the "10-year risk of cardiovascular events" by using the Risk Assessment Tool for estimating the 10-year risk of a major CHD event.Use the riskestimate tool at the end of this chapter or the online risk calculator at the National Institutes of Health website (hin.nhlbi.nih.gov/atpiii/ calculator.asp).
# P: Plan
# Diagnostic Evaluation
The 1 for LDL intervention levels).
The NCEP guidelines recommend that very high TG levels (≥500 ml/dL) be reduced before LDL is treated directly (see "Treatment of hypertriglyceridemia," below).
The LDL levels at which either therapeutic lifestyle change (TLC) or drug therapy should be initiated are shown in Table 1, along with the target goals for LDL cholesterol.The response to therapy should be monitored and therapeutic interventions should be intensified or augmented until lipid targets are met.
# Therapeutic lifestyle change
TLC, consisting of diet modification and exercise, is fundamental to the management of dyslipidemia for HIV-infected patients.
# Section 6: Comorbidities, Coinfections, and Complications
Target goals for lipid abnormalities are difficult to achieve without prioritizing these behavioral change efforts.Although TLC is hard to maintain, it can yield significant results in reducing CHD risk and improving quality of life.Effective TLC is best achieved with a multidisciplinary team approach.HIV primary care providers should be instrumental in identifying TLC as a treatment priority and providing referrals to nutritionists for dietary counseling, to mental health professionals for assessment of treatable mood disorders, and to social workers, peer counselors, or clinical nurse specialists for assistance with healthbehavior changes, self-care strategies, and identification of resources in the community for smoking cessation support and exercise programs.Specific recommendations for TLC goals and behavior change strategies are contained in the Adult Treatment Panel guidelines, which are available at www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
# Pharmacologic treatment for hypercholesterolemia
All patients with elevated lipid levels should initiate TLC.If pharmacologic intervention is indicated, statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are the first-line treatment for most patients.These agents can be effective in reducing TC, LDL, and non-HDL cholesterol levels in HIVinfected patients (see Table 3).
Recommended starting dosages of statins for patients taking PIs are as follows (Note: see "Potential ARV Interactions," below):
- Pravastatin: 20 mg PO once daily - Atorvastatin: 10 mg PO once daily Fibrates may be considered as an alternative or adjunct to statins (see "Treatment of hypertriglyceridemia," below, for further information).When given concomitantly, statins and fibrates increase the risk of rhabdomyolysis and must be used cautiously and with careful monitoring).Niacin may be effective as adjunctive therapy, but may worsen insulin resistance and may cause hepatotoxicity.It also causes uncomfortable flushing in some patients; the sustained-release formulations are better tolerated.Ezetimibe (Zetia) appears to be effective in combination with statins for patients whose cholesterol is not controlled adequately with a statin alone, but it has not been shown to decrease CHD events.Bile acid sequestrants generally should be avoided because they may interfere with the absorption of other drugs and may increase TG levels.
# Potential ARV Interactions
Clinicians should note that there are clinically significant drug interactions between most statins and both PIs and NNRTIs (see Table 4).PIs can increase serum levels of most statins significantly, thus increasing the risk of severe statin adverse events such as rhabdomyolysis.Of the statin drugs, pravastatin is the least affected by most PIs (darunavir is an exception) and is the recommended statin for most patients with hypercholesterolemia without hypertriglyceridemia.Atorvastatin, if used, should be initiated at low dosage (10 mg) and titrated slowly upward to achieve target lipid levels (note that atorvastatin may lower TG, TC, and LDL levels).Lovastatin and simvastatin are contraindicated for use by patients taking PIs, and pitavastatin is contraindicated for use by patients taking ritonavirboosted PIs.These can result in severe statin-related adverse events if prescribed.Other available statins include rosuvastatin and fluvastatin.These have not been as well studied but may be used with most PIs.When statins are given concurrently with interacting PIs, the statins should be started at low dosage and increased incrementally, if indicated; in general maximum dosages should not be used.
NNRTIs decrease levels of most statins (however, etravirine increases fluvastatin levels); higher dosages of statins may be needed to overcome this interaction.Be aware that various formulations and combination products contain these statins; check the generic name of components in new or unfamiliar cardiac prescriptions to determine whether they contain lipid-lowering agents.
Other classes of ARV drugs (NRTI, fusion inhibitor, CCR5 antagonist, and integrase inhibitor) do not have recognized interactions with statins. |
Other types of lipid-lowering medications generally are not metabolized by hepatic cytochrome P450 and are not affected by ARVs (an exception to this is gemfibrozil, whose levels are decreased by lopinavir/ritonavir, by an unknown mechanism). If a fibrate alone is inadequate in reducing TG levels, several options are possible.A statin (notably atorvastatin, which acts on TGs as well as cholesterol) could be added cautiously, although there is an increased risk of skeletal muscle toxicity with concomitant use of a fibrate and a statin.N-3 (omega-3) fatty acid supplements (e.g., fish oils), administered at 1-2 g BID or TID, have decreased TG levels in patients taking ART.Extended-release niacin at 1,500-2,000 mg/day also decreases both TG and TC levels, although its clinical utility is restricted because of associated insulin resistance and flushing.
☒ ☒ Pravastatin AUC ↑ up to 500% ☒ Fosamprenavir ☒ ☒ May need to ↑ pravastatin dosage ☒ Indinavir ☒ ☒ ☒ Lopinavir/ ritonavir ☒ ☒ Rosuvastatin C max ↑ 466% ☒ Nelfinavir Possible ↓ in nelfinavir levels ☒ No data ☒ Ritonavir ☒ ☒ ☒ Saquinavir ☒ ☒ Saquinavir + ritonavir: May need to ↑ pravastatin dosage ☒ Tipranavir Atorvastatin Cmax ↑ >760% ☒ ☒ Rosuvastatin C max ↑
# Switching antiretroviral therapy
For patients with CHD or CHD equivalents, ARV medications should, if possible, be selected to minimize the risk of hyperlipidemia.In patients with dyslipidemia caused by ARV agents, data suggest that it may be beneficial to discontinue ARVs known to increase lipids if reasonable alternatives exist.Substituting atazanavir or raltegravir in place of a lipogenic PI or replacing stavudine with tenofovir may improve the lipid profile.Before making ARV substitutions, however, consider carefully the possible effect of the substitution on HIV virologic control and the potential adverse effects of new ARVs.In some cases, antihyperlipidemic agents may be necessary even after ARV substitution.
# Patient Education
- Review the importance of reducing cardiovascular risk factors.This is of increasing importance for all patients with HIV infection, particularly as they age.
- Educate patients about the benefits of diet and exercise in improving lipid levels and reducing cardiovascular risk.
- If lipid-lowering medications are prescribed, advise patients on possible adverse effects, and advise them to contact their health care provider if these develop.
- Advise patients to talk with their health care provider before starting any new medications so they can be evaluated for possible drug-drug interactions.
Section 6: Comorbidities, Coinfections, and Complications
# Appendix: Calculations to Estimate the 10-Year Risk of Cardiac Events for Men and Women -Framingham Calculator
To calculate the 10-year risk of cardiac events, add up points from the following five tables pertaining to age, HDL, systolic blood pressure, TC, and smoking status (Tables 5.1-5.5).Note that in Tables 5.3-5.5, women's points are in parentheses.After adding points from all of the tables, consult Table 5.6. (Alternatively, an online calculator is available at hin.nhlbi.nih.gov/atpiii/calculator.asp.) (The Framingham Heart Study risk calculator has not been validated for HIV-positive individuals and may underestimate the risk in this population.)
Section 6: Comorbidities, Coinfections, and Complications Nonsmoker 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Smoker 8 ( 9) 5 ( 7) 3 ( 4) 1 ( 2) 1 ( 1)
# Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy Background
Diabetes is a substantial risk factor for coronary artery disease, stroke, and peripheral vascular disease, as well as for a number of other conditions including retinopathy and kidney disease.Patients taking antiretroviral (ARV) medications, especially certain protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), appear to have an increased risk of hyperglycemia and diabetes mellitus.In particular, the ARVs indinavir and stavudine (now seldom used in the United States) have been shown to induce insulin resistance in short-term studies of healthy HIV-uninfected volunteers, but other ARVs also perturb glucose homeostasis.
Disorders of glucose metabolism may present as the following:
- Insulin resistance: a state in which higher concentrations of insulin are required to exert normal effects; blood glucose levels may be normal but fasting insulin levels may be high because of compensatory insulin secretion by the pancreas
- Impaired glucose tolerance: glucose 140-199 mg/dL 2 hours after a 75 g oral glucose load
- Impaired fasting glucose: glucose 100-125 mg/dL after an 8-hour fast
- Diabetes mellitus: any of the following four criteria may be used (results must be confirmed by retesting on a subsequent occasion):
- Fasting glucose ≥126 mg/dL
- Glycosylated hemoglobin (HbA1c) level ≥6.5% (note that HbA1c testing has not been validated in HIV-infected persons; see "Diagnostic Evaluation," below)
- 2-hour glucose level ≥200 mg/dL during glucose tolerance testing
- Random glucose values ≥200 mg/dL in the presence of symptoms of hyperglycemia
The incidence of new-onset hyperglycemia among HIV-infected patients on ARV therapy (ART) has been reported as about 5%, on average.Even if fasting glucose levels remain normal in patients taking ARVs, up to 40% of those on a PI-containing regimen will show impaired glucose tolerance.The etiology of insulin resistance and hyperglycemia in HIV-infected patients probably is multifactorial, with varying contributions from traditional risk factors (e.g., obesity, family history), comorbid conditions (e.g., hepatitis C virus infection), and ARV-related factors (e.g., direct effects of PIs, cumulative exposure to NRTIs, hepatic steatosis, and fat redistribution).
Patients who have preexisting diabetes should be monitored closely when starting ART; some experts would consider avoiding PIs for these patients, if other options are feasible.Alternatively, PIs with favorable metabolic profiles (e.g., atazanavir) may be preferred for such patients.
Patients with no history of diabetes should be advised about the warning signs of hyperglycemia (polydipsia, polyuria, and polyphagia) and the need to use diet and exercise to maintain an ideal body weight.
# S: Subjective
Clinicians should consider the potential for abnormal glucose metabolism in the following types of patients:
- Those who are about to begin ART
- Those on an ARV regimen that includes a PI
- Those with extensive exposure to NRTIs
- Those who are obese or overweight
# Those with central fat accumulation or lipoatrophy
Although most patients with hyperglycemia are asymptomatic, some (rarely) may report polydipsia, polyuria, polyphagia, or blurred vision.
When recording the patient's history, ask about the following:
# Risk factors:
- Family history of diabetes
# O: Objective
Perform a physical examination that includes the following:
- Blood pressure, weight, body mass index (BMI) (see chapter Dyslipidemia)
- Heart and lung examination
- Peripheral pulses
- Examination of neck, dorsocervical area, breasts, and abdomen for fat accumulation; measurement of waist circumference
- For patients with hyperglycemia or diabetes:
- Retinal examination (refer to ophthalmologist for dilated examination)
- Visual inspection of feet (for ulcers)
- Sensory examination of feet (for neuropathy)
Section 6: Comorbidities, Coinfections, and Complications
# A/P: Assessment and Plan
# Diagnostic Evaluation
Determine whether the patient has normal blood glucose, impaired fasting glucose, or diabetes.
Most experts recommend routine checks of fasting blood glucose levels at baseline and within 3-6 months after starting or changing ART, if baseline results are normal.For patients with normal glucose levels, recheck every 6-12 months.Monitoring should be more frequent if abnormalities are detected or if any additional risk factors exist.Patients with risk factors for diabetes must be counseled about prevention of hyperglycemia before starting ART.
The role of 2-hour postprandial glucose measurements or the 75 g oral glucose tolerance test in screening for diabetes is uncertain but may be appropriate for patients with multiple risk factors.The use of HbA1c testing to screen for diabetes has yet to be validated for the HIV-infected population.Of note, HbA1c values may underestimate glycemia in HIV-infected patients, especially in the setting of elevated red blood cell mean corpuscular volume (MCV) (e.g., owing to zidovudine) or anemia.For patients with diabetes and those whose lifestyle changes are not adequate to control blood glucose, specific treatment should be started.
# Patients with diabetes
- Treatment should be instituted to control blood sugar and to modify other cardiovascular risk factors, with the aim of preventing heart disease and other endorgan disease.
- Control glucose: maintain the HbA1c level at <7%, while avoiding hypoglycemia.
- For hyperglycemia that is associated with the use of PIs, switching to an alternative agent (e.g., a nonnucleoside reverse transcriptase inhibitor or a different PI) may be effective if the HIV treatment history and resistance profile permit.
- Metformin usually is the initial drug of choice for overweight patients; other options include thiazolidinediones and sulfonylureas.
Section 6: Comorbidities, Coinfections, and Complications
- Metformin can worsen lipoatrophy and should be avoided in the presence of significant lipoatrophy.Metformin increases risk of lactic acidosis; it should not be used for patients with elevated serum creatinine (>1.5 mg/dL in men or >1.4 mg/dL in women), hepatic impairment, or metabolic acidosis.
- Thiazolidinediones should be avoided in patients with significant liver disease.Rosiglitazone may increase the risk of myocardial infarction and death (study results conflict); both rosiglitazone and pioglitazone have been associated with congestive heart failure and are contraindicated for use by patients with this condition.
- In some cases, insulin may be the safest drug therapy for patients with symptomatic hyperglycemia, although episodes of hypoglycemia are much more common with insulin than with most oral agents.
- Treat dyslipidemia: maintain low-density lipoprotein (LDL) at <100 mg/dL and maintain triglycerides at <150 mg/dL. (Note that diabetes is considered a coronary heart disease equivalent state when evaluating goals for lipid management; see chapter Dyslipidemia.)
- Treat hypertension: Maintain systolic blood pressure at <130 mm Hg and diastolic blood pressure at <80 mm Hg.
- Reduce cardiovascular risks through lifestyle modifications such as smoking cessation, exercise, weight loss, nutritional counseling, and moderation of alcohol intake.
- Decrease the risk of end-organ complications:
- Measure urine microalbumin and creatinine; if the urine albumin/ creatinine ratio is >30 mg/g, treat with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to slow the progression of nephropathy.
- Schedule annual retinal examination by an ophthalmologist.
- Perform an annual foot examination.
- Start aspirin therapy (75-162 mg daily) if the patient has evidence of macrovascular disease or a history of vascular events.
Consider daily aspirin for those with increased coronary heart disease risk e.g., men >50 years old and women >60 years old with ≥1 coronary heart disease risk factor (e.g., a family history of coronary artery disease, a history of smoking (see chapter Coronary Heart Disease Risk).
For further information, see the American Diabetes Association, Clinical Practice Recommendations, Diabetes Care, available online at: care.diabetesjournals.org.
# Patient Education
- ART can increase the risk of diabetes in some individuals.Patients should report any difficulty with excessive hunger and thirst and increased urination.Health care providers will monitor blood glucose when doing laboratory work, but it is important for the patient to report the presence of any symptoms.
- Review the patient's eating habits and explain the need to work with a dietitian to keep blood glucose (and triglycerides) within normal limits.Eating a proper diet can reduce the risk of permanent damage to the blood vessels of the eye, the kidney, and the brain, and it can reduce the risk of a heart attack.
- Emphasize other lifestyle modifications, such as weight loss (if appropriate).
- Encourage patients to get regular cardiovascular exercise; work with them to identify activities that might be realistic and acceptable for them.
- Provide medication-specific education, especially if the patient will be taking diabetes medications.
- Consider referral to a diabetes clinic for specialty needs.
# References
# Coronary Heart Disease Risk
# Marshall Glesby, MD
# Background
Epidemiologic studies suggest that the incidence of myocardial infarction or hospitalization for coronary heart disease (CHD) is increased up to two-to threefold in HIV-infected individuals compared with age-matched controls without HIV infection.This increased risk of ischemic events likely is attributable to a higher prevalence of certain CHD risk factors that are independent of HIV status, such as smoking, as well as to both HIV infection and antiretroviral (ARV) medications.These various factors may interact in ways that are complex and incompletely understood.
Among the traditional CHD risk factors, dyslipidemia is common among persons with HIV infection, and can be caused both by HIV itself (e.g., resulting in low high-density lipoprotein cholesterol) and by ARV therapy (ART); see chapter Dyslipidemia.Insulin resistance and diabetes also appear to be more prevalent in HIV-infected patients. (See chapter Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy.Visceral fat accumulation, a poorly understood complication of HIV or ART, also may contribute to CHD risk in certain patients (see chapter Abnormalities of Body Fat Distribution).
A number of studies suggest that inflammation and immune activation owing to uncontrolled HIV infection also likely contribute to atherosclerosis.For example, in the Strategic Management of Antiretroviral Therapy (SMART) study, CHD events were more common in patients on intermittent ART than in those on continuous ART, possibly because of adverse effects of intermittent HIV viremia on inflammation, coagulation, and lipid parameters.There is even preliminary evidence that so-called elite controllers -patients with undetectable HIV viremia and preserved CD4 counts in the absence of ART -have increased carotid intima-medial thickness (a marker of atherosclerotic burden) compared with HIV-uninfected subjects, after adjusting for other CHD risk factors.Limited data also suggest that initiation of ART leads to improvement of endothelial dysfunction (an early marker of atherosclerosis that is predictive of future CHD events) and to improvement in markers of inflammation and immune activation.Taken together, these observations suggest that earlier initiation of ART could reduce CHD risk.
On the other hand, even patients with virologic suppression on ART appear to have higher levels of various physiologic markers of cardiovascular risk than the HIV-uninfected persons, perhaps owing to persistent immune activation.Additionally, exposure to ARVs has been linked to risk of myocardial infarction in large cohort studies such as the D:A:D study.In particular, the risk has been associated with use of ARV regimens that are based on protease inhibitors (PIs) rather than nonnucleoside reverse transcriptase inhibitors (NNRTIs).The risk is attributable in part to adverse changes in lipid profiles, but there appears to be additional risk associated with PIs that is not accounted for by changes in lipids; this remains poorly understood.Among the nucleoside reverse transcriptase inhibitors (NRTIs), abacavir and didanosine have been associated with increased risk of myocardial infarction in some but not all studies.The mechanism of this potentially increased risk has not been determined.
# S: Subjective
Clinicians should ask all patients about CHD, CHD risk equivalents, and CHD risk factors.Assess the following during the history:
- Age (>45 for men, >55 for women) - Check fasting lipids and glucose annually; more frequently if abnormal.
- Patients with established or suspected CHD should undergo standard evaluations such as electrocardiography and exercise stress testing; refer to a cardiologist as appropriate.
# P: Plan
- Work closely with patients to reduce their risks of CHD events.
- For patients who smoke, smoking cessation is the single most important intervention to reduce risk of CHD events (see chapter Smoking Cessation).
- Manage dyslipidemia according to established guidelines (see chapter Dyslipidemia).
- Manage hypertension by lifestyle intervention (e.g., sodium restriction, exercise, weight loss) and pharmacologic therapy as indicated.
- Optimize glycemic control in patients with diabetes mellitus (see chapter Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy).
- Encourage weight loss in overweight and obese patients, with referral to a dietitian as appropriate.
- Encourage exercise, ideally 30 minutes at moderate intensity 5-6 times per week.
- Encourage a healthy diet that is low in saturated fats.
# Section 6: Comorbidities, Coinfections, and Complications
- Consider aspirin 81 mg once daily for primary prevention of CHD in patients at moderate to high risk who do not have contraindications to aspirin use.
- For patients who use cocaine or amphetamines, encourage cessation.
# Patient Education
- Both HIV infection and ARV medications may contribute to the risk of CHD, and the available data suggest that the risk of CHD is increased in HIV-infected patients relative to the general population.
- Review the benefits of smoking cessation.
- Review exercise possibilities to determine which activities might be realistic and acceptable for the patient.
- Review the patient's eating habits and explain the need to work with a dietitian to optimize lipid levels and keep blood glucose within normal ranges.
- Emphasize the importance of other lifestyle modifications, such as weight loss (if appropriate).
- Educate patients about any pharmacologic therapy that is indicated.
# Renal Disease
Alfredo Tiu, DO
# Background
The prevalence of renal complications among patients with HIV infection has increased as more patients with HIV are living longer as a result of effective antiretroviral therapy (ART) and opportunistic infection prophylaxis.More widespread access to and earlier initiation of ART has decreased the incidence of HIV-associated nephropathy (HIVAN), but other causes of renal disease persist, and in some cases are increasing in prevalence.These may be infections and other conditions related to HIV infection, other comorbidities (e.g., hypertension, diabetes), or medication adverse effects, including those caused by some antiretroviral (ARV) medications (see "Kidney disease associated with HIV infection" and Renal disease in HIV-infected individuals can occur as a primary disease, as a secondary disease in the setting of other systemic illness, or as an adverse effect of medications.In the United States, the most common causes of end-stage renal disease in the general population are diabetes mellitus and hypertension.HIV-infected patients are at a fourfold higher risk of developing diabetes mellitus and a threefold higher risk of developing hypertension compared with seronegative individuals.Chronic hepatitis C, seen in 30-40% of HIV-infected individuals in the United States, is associated with several types of chronic kidney disease, including progressive secondary glomerulonephropathy, membranoproliferative glomerulonephropathy, and mixed cryoglobulinemia. |
Note that ART should be given to HIV-infected individuals with renal disease, according to usual criteria for ART initiation; however, some ARVs must be avoided and some should be given at modified dosages according to the degree of renal dysfunction (see Table 3).Additionally, for patients with HIVAN, ART is the primary treatment.
# S: Subjective
As noted above, patients usually have no symptoms until late in the course of kidney disease and are diagnosed on the basis of laboratory abnormalities.
In symptomatic patients, presenting signs or symptoms are nonspecific.Patients with renal failure may present with fatigue, weakness, anorexia, nausea, pruritus, vomiting, edema, diminished urine output, discolored urine, altered mental status, and seizures.Those with renal disease associated with systemic illnesses may present with fever, arthralgias, respiratory symptoms, flank pain, abdominal pain, and diarrhea.
For patients with renal disease suspected on the basis of laboratory abnormalities (e.g., elevated serum Cr , electrolyte disturbances, acid-base disorders, proteinuria, hematuria, and anemia), and for symptomatic patients with known kidney disease, ask about the risk factors and symptoms described above, and about the following:
# O: Objective
Check blood pressure, temperature, and weight.Compare these with values from previous readings.Perform a physical examination, including evaluations of the following:
- Volume status (blood pressure, pulse, skin turgor, mucous membrane moistness, edema)
- Optic fundi (signs of retinopathy)
- Cardiovascular system (peripheral pulses, bruits), to assess for peripheral vascular disease
- Abdomen (auscultate for unilateral bruit , distention, mass, organomegaly, tenderness)
- Musculoskeletal system (bruises, muscle pain, muscle weakness, swollen joints)
- Skin (rash to help evaluate for drug reaction, vasculitis)
- Rectum (enlarged prostate, if obstruction is suspected)
Review previous laboratory values (e.g., serum Cr, blood urea nitrogen , electrolytes, urinalysis) to determine whether the kidney disease is acute or chronic.
- Acute kidney injury (AKI) is assumed if there are no previous serum Cr values.
The presence of an abnormal GFR (≤60 mL/ min for at least 3 months) suggests chronic kidney disease (CKD).
Review the CD4 cell count and HIV viral load.
# A: Assessment
Once the duration of the elevated serum Cr is assessed, a differential diagnosis can be made.
The causes of renal failure are classified traditionally based on the area of the renal anatomy where the injury occurred: prerenal, renal, and postrenal (obstructive uropathy).Acute tubular necrosis (ATN) is the most common cause of acute kidney injury. Determine whether the renal disease is acute or chronic, as above (see "O: Objective").
Perform a targeted laboratory evaluation, depending on results of initial tests, history, and physical examination.
- Urinalysis with microscopy and examination of urine sediment (e.g., hematuria, pyuria, casts) can help in identifying etiologies such as nephritic syndrome, ATN, or infection.
- Quantify the proteinuria by obtaining a random urine protein-to-urine creatinine ratio (U Pr/U Cr), if not done already; this correlates well with grams per day of proteinuria, as discussed above.
- Fractional excretion of sodium (FeNa) may be helpful in distinguishing causes of acute kidney injury.
- FeNa = Urine sodium ÷ Serum sodium
# Hematuria
For asymptomatic isolated microscopic hematuria, obtain a follow-up urinalysis.If hematuria is persistent, obtain a renal ultrasound.If the result is normal, the eGFR is normal, and there are no other urine abnormalities, conduct routine follow-up with urinalysis and serum Cr testing.Refer patients aged ≥40 with persistent hematuria to a urologist for formal evaluation.Consider checking urine cytology, though that test is not sensitive enough to rule out genitourinary malignancy.
# Red blood cell casts
Red blood cell casts strongly suggest glomerulonephritis, which can progress rapidly.
# ATN
ATN is the most common cause of AKI.A history of certain medication exposures, recent IV contrast, and concurrent illness may provide important clues to ATN.Laboratory findings that are consistent with ATN include increasing serum Cr and a characteristic urine sediment that shows "muddy brown" casts, which are casts that contain densely packed tubular cells.
# AIN
During AIN, the classic triad of AKI, fever, and rash are not always present.Laboratory findings suggestive of AIN in the setting of AKI include sterile pyuria and eosinophiluria.
# Sterile pyuria
Sterile pyuria also may occur in malignancy (e.g., renal, bladder), and in genitourinary tuberculosis.If tuberculosis is suspected, further testing usually requires three firstvoid urine specimens sent for acid-fast bacilli culture.
# Crystalluria and nephrolithiasis
Usual causes of nephrolithiasis should be considered in patients with hematuria, particularly if symptoms consistent with nephrolithiasis are present.Other causes in persons with HIV infection include some medications, including the ARVs indinavir and (rarely) atazanavir; see Table 2 above.Obtain radiographic imaging (see below) as part of the initial evaluation, and send the passed renal calculus, if available, for analysis in order to provide more specific recommendations for management.If there is suspicion that the condition is caused by a medication, order specific chemical analysis (e.g., for atazanavir).
In patients with multiple renal stones, active renal stone formation, and recurrent kidney stones, a metabolic evaluation should be done.This includes a serum intact parathyroid hormone measurement and 24-hour urine collection for Cr, sodium, calcium, oxalate, uric acid, and citrate.
# Imaging
Radiographic imaging of the kidneys is important in the evaluation of renal disease.The size and echogenicity of the kidneys may help differentiate acute and chronic kidney disease.Small and echogenic kidneys are consistent with CKD, though HIV, diabetes, and some other chronic conditions are associated with normal size or large kidneys.Imaging also helps identify obstruction (though the absence of hydronephrosis does not completely rule that out), malignancy, and other conditions.
Both spiral computed tomography (CT) scan and renal ultrasound are acceptable radiographic imaging studies for nephrolithiasis.The advantage of spiral CT scan is its ability to localize stones and assess their size without the use of contrast.Gallium renal scan may be helpful in AIN.
# Renal biopsy
Biopsy is not always indicated for patients
# Nevirapine
- An additional dose (200 mg) should be given after each dialysis session.
Available agents in the integrase inhibitor and fusion inhibitor classes do not appear to require dosage adjustment for patients with CKD.
# Patient Education
- Early diagnosis of kidney disease is important.Acute kidney injury usually is reversible but may take time and may require temporary hemodialysis support.
- Advise patients to report all the medications they take, including over-the-counter medications and herbs or supplements.
- Risk factors for kidney disease are uncontrolled HIV infection (viral load above 4,000 copies/mL and CD4 count <200 cells/ µL), coexisting conditions (diabetes mellitus, hypertension, hepatitis C), and ethnicity (African-Americans, Hispanic Americans, Asians, Pacific Islanders, and American Indians).Advise patients that it is important to reduce any modifiable risks, including optimizing HIV control and diabetes mellitus and/or hypertension management.
- Advise patients that control of blood pressure is important in slowing the progression of renal disease.Hypertension control can be maximized by both lifestyle modifications (e.g., weight lost, exercise, avoiding excessive alcohol intake) and antihypertensive medications.ACEIs or ARBs are the drugs of choice for patients with hypertension and kidney disease.Target blood pressure is <125/75 mm Hg for patients with proteinuric kidney disease.
- Educate patients that management of chronic kidney disease helps avoid or control complications such as high blood pressure, weak bones (osteodystrophy), anemia, and nerve damage (neuropathy).
- When the kidney disease progress to end-stage renal disease, several options can be explored.These are dialysis, kidney transplant, or palliative care.There are two modes of dialysis, hemodialysis and peritoneal dialysis.A nephrologist and the patient can decide which option is best.HIV control (suppressed viral load, optimal CD4) is required if kidney transplant is to be considered.
# Immune Reconstitution Inflammatory Syndrome Background
For most patients, initiating antiretroviral therapy (ART) improves immune responses to a wide range of opportunistic pathogens.The process of ART-induced immune reconstitution typically is uneventful.However, a small percentage of patients develop inflammatory disease in response to specific opportunistic pathogens within a few weeks or months after initiating therapy.This exuberant inflammatory response has been called the immune reconstitution inflammatory syndrome (IRIS), also known as immune reconstitution syndrome (IRS) or immune reconstitution disease (IRD).
The term IRIS is used to describe two distinct entities:
- An exacerbation of a partially or successfully treated opportunistic infection (OI), referred to as paradoxical IRIS
- A previously undiagnosed (subclinical) OI, referred to as unmasking IRIS IRIS may occur in response to many pathogens, including Mycobacterium tuberculosis, Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Cryptococcus, Pneumocystis, Toxoplasma, hepatitis B, and varicella-zoster virus.
Many of the IRIS cases described in the medical literature occurred within a few months after initiating ART and in the context of a rapid and marked rise in CD4 cell count from very low pretreatment levels (often <50-100 cells/µL).IRIS also can occur in the absence of ART, as has been reported during tuberculosis (TB) treatment.The specific mechanisms involved in the pathogenesis of IRIS are not well understood and may vary from one infection to another.However, experts believe that IRIS is caused by an enhanced immune response to disease-specific antigens, which leads to an overproduction of inflammatory mediators.
IRIS may be difficult to identify in clinical practice because the clinical presentation is nonspecific and, currently, there are no laboratory markers to identify the syndrome.To make the diagnosis of IRIS, the following must be excluded:
- Presence of a new OI or concomitant illness
- Failure of treatment for HIV infection (e.g., owing to poor adherence or drug resistance)
- Failure of treatment for a known OI (e.g., owing to drug resistance, inadequate treatment, or poor adherence)
The severity of IRIS varies widely, from mild to life-threatening.Treatment varies according to the specific pathogen and clinical situation, but typically includes continuing ART if possible, treating the OI as indicated, and adding antiinflammatory therapy as needed.
# Clinical Presentation
IRIS is largely a clinical diagnosis, and other conditions must be excluded, as indicated above.To consider IRIS in the differential diagnosis, clinicians must recognize the clinical findings (typical or atypical) of a specific OI and the temporal association with treatment (usually after ART initiation, but IRIS may occur with treatment of the OI alone).For example, for a patient with TB who has recently initiated ART after responding to treatment of TB, the "red flags" for a diagnosis of IRIS (rather than progression of the TB) would include new or worsening fever, new effusions, and new or worsening lymphadenopathy, in the absence of poor adherence to TB treatment and the absence of drug-resistant TB.
The clinical manifestations of IRIS associated with some common OIs are described below. (This is not an exhaustive list, but it includes most of the important IRIS manifestations seen in patients with HIV infection.)
# Tuberculosis
The
# CMV vitreitis and CMV uveitis
CMV vitreitis and CMV uveitis are seen exclusively in patients with previous CMV retinitis infection who responded to ART:
# CMV vitreitis
CMV vitreitis IRIS is an alarming syndrome, Section 6: Comorbidities, Coinfections, and Complications but a benign one.Patients who are receiving anti-CMV therapy typically present with acute onset of blurred vision and "floaters" caused by posterior segment inflammation.Ophthalmologic examination reveals numerous inflammatory cells in the vitreous humor.Symptoms usually resolve in 1 month without specific treatment and without any lasting visual effects.
# CMV uveitis
In patients with a history of CMV retinitis, CMV uveitis IRIS may occur within months of ART initiation, but typically is a late complication, occurring about 3 years after patients begin ART.Uveitis is painless and primarily involves inflammation in the iris, the ciliary body, and the choroid layers.However, CMV uveitis may have serious sequelae.It often results in macular edema, epiretinal membrane formation, or cataracts, which can lead to permanent vision loss.Because of the risk of vision loss, clinicians should have a high index of suspicion for CMV uveitis.
# Cryptococcal Meningitis
In patients with or without previously diagnosed cryptococcal meningitis, presentation of cryptococcal IRIS typically includes fever, headache, and meningeal signs and symptoms.Onset has been reported between 1 week and 11 months after initiation of ART.Lymphadenitis also has been reported (see chapter Cryptococcal Disease).
# Pneumocystis jiroveci Pneumonia
Pneumocystis jiroveci pneumonia (PCP) IRIS may occur in patients with current or recent PCP who are starting ART in the early weeks after initiation of PCP treatment.IRIS may present as worsening pulmonary symptoms and high fever in patients who had been improving on PCP therapy or in patients with recent successful treatment of PCP.Chest X rays may show worsening lung involvement, and oxygen saturation or arterial blood gas measurements may show worsening hypoxia or alveolar-arterial oxygen gradient.PCP IRIS sometimes causes severe acute respiratory failure (see chapter Pneumocystis Pneumonia).
# S: Subjective
Symptoms of IRIS will vary according to the specific illness.
Include the following in the history:
- Specific symptoms and time course of symptoms
# A: Assessment
In the appropriate clinical setting (especially in patients with advanced AIDS who recently initiated ART), IRIS should be considered in the differential diagnosis of patients who present with new or worsening symptoms.In these patients, the differential is broad, and
# P: Plan
# Diagnostic Evaluation
It is important to rule out new, incompletely treated, or untreated infections; malignancy; and other illnesses before concluding the patient has IRIS.
# Timing of ART initiation
The risk of IRIS is highest for patients who start ART with low CD4 counts (<50-100 cells/µL) and those for whom ART is initiated soon after OI treatment is begun.The optimal time for ART initiation in the setting of an OI is not known, but one randomized Section 6: Comorbidities, Coinfections, and Complications controlled trial suggests a mortality benefit to early ART initiation in patients with newly diagnosed OIs.Decisions about the timing of ART initiation may depend on a number of variables, including the specific pathogen, the severity of the OI, whether the CNS is involved (IRIS in the CNS may be life-threatening), the medication burden, and the potential for drug toxicity or drug interactions.In most cases, ART initiation should be considered within 1-2 weeks after initiation of OI therapy.For patients with cryptococcal or mycobacterial disease who are otherwise stable and for whom ART can be deferred temporarily, many specialists would recommend delaying ART until they have received appropriate OI treatment for 2-6 weeks.Ongoing trials will better define timing of ART in patients with TB and cryptococcal meningitis.
For decisions about initiating ART in patients with active OIs, consult with an HIV specialist.
# IRIS in resource-limited settings
As access to ART improves in resourcelimited countries, IRIS increasingly is being recognized in patients receiving ART.Clinicians should include IRIS in the differential diagnosis when evaluating patients who recently have begun ART and present with new or worsening symptoms of an OI.However, limited diagnostic testing resources may make it difficult to establish IRIS and other diagnoses.
Given that coinfection with HIV and TB is epidemic in many countries, and because IRIS is not uncommon in patients with TB, clinicians should be particularly vigilant about symptoms that may signal IRIS.As in resource-sufficient countries, consultation with a clinician trained in caring for patients with HIV is recommended if diagnosis or treatment is in question.
# Patient Education
- Patients starting ART who have CD4 counts of <100 cells/µL or known concomitant OIs should be counseled about the possibility of IRIS.
- All patients starting ART should be advised to contact the clinic promptly if they experience new or worsening symptoms.
- Advise patients to take their medications for HIV and for the treatment or prevention of OIs exactly as prescribed.
# Anal Dysplasia Background
Anal cancer is a squamous cell cancer associated with human papillomavirus (HPV), the same virus that is associated with cervical cancer (see chapter Cervical Dysplasia).The anal canal and cervical canal share a common embryologic origin: both have a squamocolumnar transition zone and are prone to infection with HPV, a sexually transmitted virus.HPV infection, in combination with cofactors, may stimulate dysplastic changes in the cervix or anus that may develop through precursor stages into squamous cell cancer.In the United States, the current incidence of anal cancer in the general population is approximately 1:100,000 per year.In HIV-infected men and women, the incidence of anal cancer and the prevalence of its precursors are significantly higher than in the general population.
Rates of anal cancer also are higher among men who have sex with men (MSM), whether HIV infected or uninfected, compared with the general population.Before the HIV epidemic, the anal cancer incidence among MSM was estimated to be as high as 37:100,000.This incidence is comparable to the incidence of cervical cancer in women before the introduction of screening using Papanicolaou (Pap) tests.Current rates in an HIV-infected MSM population are estimated to be as high as 70-144 per 100,000.
Although most studies have examined anal dysplasia and cancer among MSM, the prevalence of anal intraepithelial neoplasia (AIN), a precursor to anal cancer, also is high among HIV-infected women.A recent study found a significantly increased rate of AIN (16%) in a group of HIVinfected women when compared with a control group having similar risk factors.In some studies of HIV-infected women, anal dysplasia has been seen more frequently than cervical dysplasia, and it has not been exclusive to those with behavioral risk factors (e.g., history of anal intercourse).Some studies have shown that, among HIV-infected individuals, anal HPV infection is present in 93% of MSM and 76% of women, and anal dysplasia (any grade) is present in 56% of MSM and 26% of women.Receptive anal intercourse (RAI) may increase the likelihood of anal HPV infection, but is not a prerequisite for anal HPV or dysplasia.It is posited that HPV can spread throughout the anogenital region in the absence of sexual contact. |
In a study of HIV-infected heterosexual men with no history of RAI, anal HPV infection was found in 46% and anal dysplasia in 32%.Patients with lower CD4 cell counts appear to be at higher risk of developing anal dysplasia.
Screening strategies for anal dysplasia and cancer and the optimal management of abnormal test results are controversial areas in which questions remain unanswered.The rationale for screening for anal cancer and its precursors is based on the success of cervical Pap screening in reducing cervical cancer incidence and mortality.Because of the similarities between cervical and anal dysplasia, many experts postulate that many of the paradigms of managing cervical cytologic abnormalities may be translated to management of anal dysplasia.However, there are no randomized clinical trials that document the value of screening for anal precancers.
Currently, there are no national recommendations that call for routine screening for anal cancer, but many experts recommend screening all HIV-infected individuals for anal dysplasia, if adequate diagnostic and treatment resources and referral networks exist.The New York State Department of Health AIDS Institute recommends that an anal Pap test be done at baseline and annually thereafter for MSM, patients with a history of anogenital warts, and women with abnormal cervical or vulvar histology, and many HIV clinics elsewhere do routine screening.Further investigations are ongoing to define appropriate screening intervals, diagnostic approaches, indications for therapy, and modalities of treatment.
ART and subsequent immune reconstitution does not appear to alter the prevalence or distribution of anal cancers and anorectal disease nor does it appear to reduce the progression of AIN and other cancer precursors.
For information on prevention of HPV infection, see "Prevention," below.
Section 6: Comorbidities, Coinfections, and Complications
# P: Plan
# Screening
As mentioned above, there are no national guidelines for anal cancer screening in people with HIV infection.However, some experts recommend that anal Pap tests and digital anal examination be part of the initial evaluation of both male and female HIV-infected patients.The intervals for screening have not been established, but (based on recommendations for cervical cancer screening) if the first test result is normal, the anal Pap usually is repeated in approximately 6 months.If both results are normal, then anal Pap tests can be performed annually.Some clinicians would consider more frequent screening in patients with genital warts, cervical dysplasia, or a history of treatment for anal dysplasia.Any patients with positive results should be referred for further evaluation; see below.
An anal Pap test is done using a standard Pap kit.The swab or cytobrush should be inserted into the anal canal, past the anorectal junction, and withdrawn while rotating it against the anal walls to collect cells.The sample should then be handled according to the kit manufacturer's instructions. (See "References," below, for information about a video on how to conduct an anal Pap screen that is available from the Johns Hopkins University Local Performance Site of the Pennsylvania/ MidAtlantic AIDS Education and Training Center.)
As with cervical cytology, anal cytology is graded using the Bethesda 2001 system, which categorizes disease in increasing order of severity as follows:
- Negative for intraepithelial lesion or malignancy
- Atypical squamous cells of undetermined significance (ASCUS)
- Atypical squamous cells -cannot exclude HSIL (ASC-H)
- Low-grade squamous intraepithelial lesion (LSIL)
- High-grade squamous intraepithelial lesion (HSIL)
- Squamous cell carcinoma (SCC)
Other abnormalities, such as atypical glandular cells (AGC), may be noted.
All individuals with abnormal anal cytology, defined as ASCUS or higher, should be referred for HRA and biopsy to grade the lesion.HRA typically is performed at specialty anal cancer practices or clinics, colorectal surgery and gastrointestinal specialty facilities, and some academic medical centers.
# Evaluation of Cytologic Abnormalities
HRA of the anal canal should be performed using a colposcope for magnification (16×) and the application of 3% acetic acid with or without Lugol iodine solution to aid in visualization of dysplastic lesions.Abnormal areas should be examined by biopsy.Anoscopic features of high-grade disease are similar to those seen in the cervix; these include coarse punctation, mosaicism, and the presence of ring glands.
# Treatment
The goal of treatment is to prevent progression to anal cancer.Treatment of HSIL to prevent anal cancer is biologically plausible, following the model of cervical dysplasia treatment.However, the indications for treatment of anal dysplasia, the efficacy of treatment, and the most effective treatments have not been optimally defined.
The focus of treatment is on high-grade, premalignant dysplasia.For patients with HSIL, refer to an anal dysplasia specialty clinic, if possible.The optimal treatment for high-grade dysplasia is not known, and it should be individualized in consultation with a specialist.Specific treatment may vary
# Patient Education
- All HIV-infected men and women should be encouraged to use condoms during vaginal, anal, and oral sex to prevent the spread of HPV.However, condoms do not offer complete protection from HPV.
- All patients should be counseled on how to reduce or avoid unprotected anal receptive intercourse.
- Both women and men who are HIV infected have an increased risk of developing anal dysplasia and cancer.MSM are at higher risk than other men of developing anal dysplasia.
- Emphasize the importance of keeping follow-up appointments to allow for early detection of precancerous lesions, further grading of abnormalities by HRA, and appropriate monitoring and treatment of abnormalities.
- Patients who have anal dysplasia should be informed about anal cancer symptoms, such as new-onset anal pain, bleeding, or the development of a mass.Patients should call their health care provider if these symptoms develop.
- If an anal Pap test is being performed, advise patients to avoid having anal sex, douching, or using enemas before the test.
# Candidiasis, Oral and Esophageal Background
Oropharyngeal candidiasis ("thrush"), a fungal disease of the oral mucosa and tongue, is the most common intraoral lesion among persons infected with HIV.In the absence of other known causes of immunosuppression, oral thrush in an adult is highly suggestive of HIV infection.Although thrush in the absence of esophageal disease is not an AIDS-defining condition, it usually occurs with CD4 counts of <200 cells/µL. Three clinical presentations of thrush are common in people with HIV: pseudomembranous, erythematous, and angular cheilitis.Candida also may infect the esophagus in the form of esophageal candidiasis, which causes dysphagia (difficulty with swallowing) or odynophagia (pain with swallowing).Esophageal candidiasis is an AIDS-defining condition, generally occurring in individuals with CD4 counts of <200 cells/µL. It is the most common cause of esophageal infection in persons with AIDS.
Oropharyngeal and esophageal candidiasis are caused most commonly by Candida albicans, although non-albicans species increasingly may cause disease and may be resistant to first-line therapies.
# S: Subjective Oropharyngeal Candidiasis
The patient may complain of painless white patches on the tongue and oral mucosa, smooth red areas on the dorsal tongue, burning or painful areas in the mouth, a bad or unusual taste, sensitivity to spicy foods, or decreased appetite.
# Esophageal Candidiasis
The patient complains of difficulty or pain with swallowing, or the sensation that food is "sticking" in the retrosternal chest.Weight loss is common, and nausea and vomiting may occur.Fever is not common with candidal esophagitis and suggests another cause.The patient may note symptoms of oral candidiasis (as above).
# O: Objective
Perform a thorough oropharyngeal examination.Patients presenting with oral candidiasis may be totally asymptomatic, so it is important to inspect the oral cavity thoroughly.Patients with esophageal candidiasis usually have oral thrush and often experience weight loss.
Lesions can occur anywhere on the hard and soft palates, under the tongue, on the buccal mucosa or gums, or in the posterior pharynx.
Pseudomembranous oral candidiasis appears as creamy white, curdlike plaques on the buccal mucosa, tongue, and other mucosal surfaces.Typically, the plaques can be wiped away, leaving a red or bleeding underlying surface.Lesions may be as small as 1-2 mm, or they may form extensive plaques that cover the entire hard palate.
Erythematous oral candidiasis presents as one or more flat, red, subtle lesions on the dorsal surface of the tongue or the hard or soft palate.The dorsum of the tongue may show loss of filiform papillae.
Angular cheilitis causes fissuring and redness at one or both corners of the mouth and may appear alone or in conjunction with another form of oral Candida infection.
# Esophageal Candidiasis
- GERD
- Cytomegalovirus (CMV)
- Herpes simplex virus (HSV)
- Aphthous ulceration
# P: Plan
# Diagnostic Evaluation
# Oropharyngeal candidiasis
Clinical examination alone usually is diagnostic.If the diagnosis is unclear, organisms may be detected on smear or culture if necessary.
- On a potassium hydroxide (KOH) preparation of a smear collected by gentle scraping of the affected area with a wooden tongue depressor, visible hyphae or blastospheres on KOH mount indicate Candida infection.
- Culture is diagnostic and may detect nonalbicans species in cases resistant to first-line therapies.Sensitivities also may be needed in such cases to diagnose azole-resistant infections.
# Esophageal candidiasis
A presumptive diagnosis usually can be made with a recent onset of typical symptoms, especially in the presence of thrush, and empiric antifungal therapy may be started as a diagnostic trial.If the patient fails to improve clinically after 3-7 days of therapy, endoscopy should be performed for a definitive diagnosis.
# Treatment
# Treatment of oropharyngeal candidiasis
- Oral therapy is convenient and very effective as first-line treatment.Note that azole antifungal drugs are not recommended for use during pregnancy.
- Fluconazole 100 mg PO once daily for 7-14 days
- Alternative topical therapy is less expensive, safe for use during pregnancy, and effective for mild to moderate disease.Such therapies include 7-14 days of the following:
- Clotrimazole troches 10 mg dissolved in the mouth 5 times daily
- Nystatin oral suspension 5 mL "swish and swallow" QID
- Miconazole mucoadhesive tablet PO daily
- Other alternatives include 7-14 day therapy with the following (Note: These agents may present a greater risk of drug interactions and hepatotoxicity than do fluconazole or topical treatments, so these typically are reserved for use in cases of documented azole resistance or in cases clinically refractory to azole therapy):
- Itraconazole oral solution 200 mg PO once daily
- Posaconazole oral solution 400 mg PO BID for 1 day, then 400 mg PO once daily
# Treatment of esophageal candidiasis
- Fluconazole 200 mg PO as an initial dose, then 100 mg PO once daily for 14-21 days (fluconazole dose can range from 100-400 mg, as tolerated by the patient).IV therapy can be given if the patient is unable to swallow pills.
# Patient Education
- Patients should maintain good oral hygiene by brushing teeth after each meal.
- A soft toothbrush should be used to avoid mouth trauma.
- Advise patients to rinse the mouth of all food before using lozenges or liquid medications.
- Tell patients to avoid foods or liquids that are very hot in temperature or very spicy
- Patients who have candidiasis under a denture or partial denture should remove the prosthesis before using topical agents such as clotrimazole or nystatin.When not in use, the prosthesis should be stored in a chlorhexidine solution.
- Pregnant women and women who may become pregnant should avoid azole drugs (e.g., fluconazole, itraconazole, voriconazole) during pregnancy because they can cause skeletal and craniofacial abnormalities in infants.
- Patients should be informed of proper storage of oral solutions (i.e., refrigeration requirements, etc.)
# References
- Centers for Disease Control and Prevention.
# S: Subjective
The patient may complain of itching, burning, or swelling of the labia and vulva; a thick white or yellowish vaginal discharge; painful intercourse; and pain and burning on urination.
The most important elements in the history include the following:
- Type and duration of symptoms
# A: Assessment
Rule out other causes of vaginal discharge and pruritus:
- Bacterial vaginosis
# Candidiasis, Vulvovaginal Background
Vulvovaginal candidiasis is a yeast infection caused by several types of Candida, typically Candida albicans.This disease is common in all women, but may occur more frequently and more severely in immunocompromised women.
Although refractory vaginal Candida infections by themselves should not be considered indicators of HIV infection, they may be the first clinical manifestation of HIV infection and can occur early in the course of disease (at CD4 counts of >500 cells/µL).The frequency of vaginal candidiasis tends to increase as CD4 counts decrease; however, this may be attributable in part to increased use of antibiotics among women with advanced HIV infection.
Risk factors for candidiasis include diabetes mellitus and the use of oral contraceptives, corticosteroids, or antibiotics.
Section 6: Comorbidities, Coinfections, and Complications
# P: Plan
# Diagnostic Evaluation
A presumptive diagnosis is made on the basis of the clinical presentation and potassium hydroxide (KOH) preparation:
- Perform microscopic examination of a KOH preparation of vaginal secretions.This usually reveals pseudohyphae and Candida spores (presumptive diagnosis).
- Definitive diagnosis rarely is needed, but may be made by analysis of a culture of vaginal secretions; this may be useful if azole-resistant or non-albicans species are suspected.
- In the presence of urinary tract symptoms (beyond external vulvar burning), perform urinalysis, culture, or both on a clean-catch urine specimen.
- Consider testing for gonorrhea and chlamydia in patients with a history of possible sexual exposure.
# Treatment
# Uncomplicated infections
# Topical medications
- Prescribe topical vaginal antifungal agents in the form of cream or suppositories, including the following: butoconazole, clotrimazole, miconazole, nystatin, terconazole, and tioconazole.Treat for 3-7 days and offer refills depending on the time to the next scheduled clinic visit.The creams also may be used on the vulva for treatment of pruritus.
Note that the mineral-oil base in topical vaginal antifungal preparations may erode the latex in condoms, diaphragms, and dental dams.Advise the patient to use alternative methods to prevent HIV transmission or conception, or to discontinue intercourse while using these medications.Nonlatex condoms (plastic and polyethylene only) or "female" condoms (polyurethane) can be used.
# Oral medications
- Fluconazole 150 mg PO, single dose (see "Treatment notes," below)
- Itraconazole 200 mg PO BID for 1 day, or 200 mg PO once daily for 3-7 days (see "Treatment notes," below)
# Complicated infections
# Severe or recurrent candidiasis
Severe or recurrent candidiasis is defined as four or more episodes within 1 year.Consider the following treatments:
- Topical therapy as described above, for 7-14 days
- Fluconazole 150 mg PO every 3 days for 3 doses (see "Treatment notes," below)
For severe cases that recur repeatedly, secondary prophylaxis can be considered (e.g., fluconazole 150 mg PO weekly, or clotrimazole vaginal suppository 500 mg once weekly).
# Non-albicans candidiasis
- Non-fluconazole azole (posaconazole, voriconazole) for 10-14 days (see "Treatment notes," below)
- Boric acid 600 mg intravaginal gelatin capsules once daily for 2 weeks for refractory cases
- Consult with a specialist
# Treatment notes
- Systemic azole drugs are not recommended for use during pregnancy, and women taking azoles should use effective contraception.Topical azoles are recommended for the treatment of pregnant women.
- Resistance to azole medications may develop, especially with prolonged use of oral agents.
- Itraconazole should not be used by pregnant women or women considering pregnancy.
# Patient Education
- Advise patients to wash external genitals daily with a fresh washcloth or watersoaked cotton balls and to wipe the vulva and perirectal area from front to back after toileting.Women should not use baby wipes on inflamed vulval tissue because they may increase irritation.
- Women should avoid the use of perfumed soaps, bubble baths, feminine hygiene or vaginal deodorant products, and bath powders.
- Advise women not to douche.
- Women should wear cotton underwear and avoid tight, constrictive clothing, particularly pantyhose.
- If patients are prescribed medication for vaginal candidiasis, they should take the medication exactly as prescribed and finish the medicine even during a menstrual period.
- Women who continue to have symptoms can purchase Monistat or Gyne-Lotrimin medication over the counter.Advise patients to start using these as soon as symptoms return and to contact the clinic if symptoms worsen while they are taking these medicines.
- Women taking fluconazole or ketoconazole must avoid pregnancy.Some birth defects have been reported.
- The mineral-oil base in topical vaginal antifungal preparations may erode the latex in condoms, diaphragms, and dental dams.Advise patients to use alternative methods to prevent HIV transmission or conception or to discontinue intercourse while using these medications.Nonlatex condoms (plastic and polyethylene only) or "female" condoms (polyurethane) can be used.
# Potential ARV Interactions
There may be significant drug-drug interactions between certain systemic antifungals, particularly itraconazole, voriconazole, and posaconazole, and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or maraviroc.Some combinations are contraindicated and others require dosage adjustment of the ARV, the antifungal, or both.Check for adverse drug interactions before prescribing.
# Cervical Dysplasia Background
Cervical dysplasia and cancer are associated with human papillomavirus (HPV), a sexually transmitted virus.Carcinogenic strains of HPV, in conjunction with other factors, may cause dysplasia and cancer not only of the cervix, but also of the vulva, vagina, anus, and oropharynx.HIV-infected women have a higher prevalence of HPV infection than do HIV-uninfected women, and a higher prevalence of oncogenic HPV types.They are about 10 times more likely to develop cervical dysplasia, or squamous intraepithelial lesions (SIL), precursors to cervical cancer.Unfortunately, they also have a higher risk of invasive cervical cancer and tend to have more aggressive forms of cervical cancer and poorer responses to treatment.Invasive cervical cancer is an AIDS-defining illness.
The risk of high-grade cervical lesions appears to be higher for women with advanced immunodeficiency than for women with preserved CD4 cell counts.Other risk factors for dysplasia and cervical cancer include African-American ethnicity, a history of smoking, younger age at onset of sexual intercourse, and multiple sex partners. |
Effective antiretroviral therapy (ART) with immune reconstitution has not been shown to prevent the progression of dysplasia.
Screening for cervical dysplasia and appropriate intervention in women with high-grade dysplasia are effective in preventing cervical cancer.Frequent monitoring and careful follow-up in women with low-grade lesions are essential for preventing progression to invasive disease.Papanicolaou (Pap) testing should be performed routinely for all HIV-infected women, with testing initiated at the time of HIV diagnosis, repeated 6 months after the first test, then performed annually thereafter if the results are normal. (See chapter Initial and Interim Laboratory and Other Tests.)Because the risk of anal dysplasia also is increased among HIV-infected women (in some studies, rates of anal dysplasia were higher than rates of cervical dysplasia), many experts recommend concurrent screening for anal dysplasia.For further information, see chapter Anal Dysplasia.
For information on prevention of HPV infection, see "Prevention," below.
# HRSA HAB Core Clinical Performance Measures
Percentage of women with HIV infection who had a Papanicolaou screening in the measurement year (Group 2 measure)
# S: Subjective
Patients with cervical dysplasia or early cervical cancer usually are asymptomatic and disease will not be diagnosed unless screening is performed.Genital condylomata (warts) indicate infection with HPV and typically are associated with low-risk types of HPV; however, a mixture of HPV types may be present, and women with genital warts may have concurrent dysplasia.
The classic symptom of early invasive cervical neoplasia is intermittent, painless bleeding between menstrual periods, which may present initially as postcoital spotting.Late symptoms of invasive cervical carcinoma include flank and leg pain, dysuria, hematuria, rectal bleeding, and obstipation.Ask all female patients about risk factors for, previous history of, and preventive measures against cervical dysplasia and cancer, Cervical (and anal) cytology is graded using the Bethesda 2001 system (see "References," below), which categorizes disease in increasing order of severity as follows:
- Negative for intraepithelial lesion or malignancy
- Atypical squamous cells of undetermined significance (ASCUS)
- Atypical squamous cells, cannot exclude HSIL (ASC-H)
- Low-grade squamous intraepithelial lesion (LSIL)
- High-grade squamous intraepithelial lesion (HSIL)
- Squamous cell carcinoma (SCC)
Other abnormalities may be noted, including the following:
- Atypical glandular cells (AGCs), including the following subcategories:
- AGC NOS (includes endocervical, endometrial, or glandular cells not otherwise specified)
- AGC favor neoplasia (includes endometrial or glandular cells)
- AIS (endocervical adenocarcinoma in situ)
- Infectious organisms such as Trichomonas
# Evaluation of Cytologic Abnormalities
# Atypical squamous cells of undetermined significance
If ASCUS is present without inflammation or suspected neoplastic process, several options for management exist.
- Most experts recommend that all women with ASCUS be referred for colposcopy and directed biopsy, regardless of their degree of immunodeficiency.If the biopsy result shows no dysplasia (and the examination is adequate), the patient should be monitored by annual Pap tests.
# Atypical squamous cells, cannot exclude HSIL
Women with abnormalities suggestive of high-grade dysplasia should be referred for colposcopy.
# Low-grade squamous intraepithelial lesion
Women with LSIL should be referred for colposcopy and directed biopsy.
# High-grade squamous intraepithelial lesion or squamous cell carcinoma
Women with HSIL are at high risk of highgrade intraepithelial neoplasia or cervical cancer and should undergo colposcopy with endocervical assessment and directed biopsy as soon as possible.Refer to an oncology specialist for treatment.
# Atypical glandular cells
Because of the high rate of significant lesions in patients with AGS, colposcopy with endocervical sampling is recommended for all subcategories, including AIS.In women over age 35, endometrial sampling is recommended in addition to colposcopy and endocervical sampling.Refer to an appropriate specialist for evaluation.
# Treatment
The optimal management of precancerous cervical lesions has not been identified clearly for all classes of SIL.Consult with an HIVexperienced gynecologist, oncologist, or other dysplasia specialist.
# Prevention
Latex or plastic barriers may block transmission of HPV in areas covered by these barriers, but infection may occur through bodily contact outside the area covered by the barriers.Nonetheless, their use is recommended to prevent transmission or acquisition of HPV.
Two vaccines have been approved by the U.S. Food and Drug Administration for the prevention of certain HPV strains in women:
- Gardasil: includes HPV types 16 and 18 (which cause about 70% of cervical cancer, as well as vaginal and vulvar cancer), and Gardasil also has been approved for use with males of age 9-26 for prevention of genital warts; no data are available to evaluate efficacy in preventing cervical dysplasia or cancer in female partners.
These vaccines are not effective against HPV types other than those covered by the vaccine, and they may not be protective against a covered type to which a patient has been exposed previously.
The HPV vaccines have not been thoroughly studied in HIV-infected persons and thus are not specifically recommended for such patients; studies to evaluate efficacy, safety, immunogenicity, and tolerability are under way.The vaccines are not contraindicated for HIV-infected persons, and many clinicians do provide them.There are no data on the efficacy of the vaccines in preventing anal HPV; studies are under way.
# Patient Education
- Recommend the use of latex or polyurethane male or female condoms for vaginal or anal intercourse and plastic or latex barriers for oral sex to reduce the risk of transmitting HPV (the usual cause of cervical cancer) to partners.Barriers also reduce the risk of exposure to other sexually transmitted pathogens.
- Patients who smoke should be advised to quit.Cigarette smoking appears to heighten the risk of cervical cancer and makes HPV more difficult to treat.Discuss options for smoking cessation (see chapter Smoking Cessation), and refer patients to the American Lung Association if local programs are available.
- Emphasize the importance of keeping follow-up appointments for Pap screening or colposcopy to allow early detection of precancerous lesions and appropriate monitoring of abnormalities.
- For women with dysplasia who require treatment, emphasize that early treatment is essential for managing the disease and preventing the development of cancer.
Advise patients to keep all medical appointments.
# Cryptococcal Disease Background
Cryptococcosis is a systemic or central nervous system (CNS) fungal infection caused by the yeast Cryptococcus neoformans.The organism is ubiquitous, and is particularly plentiful in soils enriched with bird droppings.It also may be present in fruit skins or juices, and in unpasteurized milk.In immunocompetent patients, cryptococcal infection usually is asymptomatic, self-limited, and confined to the lungs.In persons with advanced HIV infection (e.g., those with CD4 counts of <100 cells/µL), Cryptococcus may cause life-threatening illness, either from a new exposure or through reactivation of a previously acquired latent infection.
In HIV-infected patients, Cryptococcus can infect almost all organs in the body, but most commonly causes meningitis or meningoencephalitis.Disseminated disease, pneumonia, and skin lesions also may be seen.
# S: Subjective
Symptoms depend upon the locus of infection.In the case of meningitis, the patient typically experiences subacute onset of fever, headaches, and malaise, which worsen over the course of several weeks.These symptoms may be accompanied by nausea with or without vomiting.Classic meningeal signs, nuchal rigidity, and photophobia are present in only about 25% of cases.Cryptococcal meningitis may cause confusion, personality or behavior changes, blindness, deafness, and, if left untreated, coma and death.If the disease involves the lungs, patients may experience cough or shortness of breath, pleuritic chest pain, and fever.Skin lesions may be present.
# O: Objective
Perform a thorough physical examination with particular attention to the following:
# Cryptococcal Meningitis
Physical examination may reveal papilledema with loss of visual acuity and cranial nerve deficits (particularly in cranial nerves III and VI).
# Cryptococcal Pulmonary Disease
Examination may reveal tachypnea or fine rales.
# Cutaneous Infection
Skin lesions are variable and may appear as papules, nodules, or ulcers; they often resemble molluscum lesions.
# A: Assessment
The differential diagnosis for cryptococcal meningitis or meningoencephalitis is broad and includes other infectious causes of meningitis (fungal, mycobacterial, bacterial, viral), syphilis, lymphoma, mass lesions, intoxication, HIV encephalopathy, and trauma. (See chapter Neurologic Symptoms.)
The differential diagnosis for cryptococcal pneumonia is broad and includes other
# Treatment
# Cryptococcal meningitis
Acute treatment of cryptococcal meningitis consists of two phases: induction and consolidation.Acute treatment is followed by chronic maintenance (suppressive) therapy.
# Induction
Patients with cryptococcal meningitis should be hospitalized to start 2 weeks of induction therapy with amphotericin B (0.7 mg/kg/day) IV plus flucytosine (25 mg/kg) PO Q6H.
Amphotericin B causes many adverse effects, including fever, rigors, hypotension, nausea, nephrotoxicity and electrolyte disturbances, anemia, and leukopenia.The patient's hemoglobin, white blood cell (WBC) count, platelets, electrolytes, magnesium, and creatinine must be monitored closely during treatment.Note that liposomal forms of amphotericin (AmBisome and Abelcet) cause fewer adverse effects and appear to be effective, although data on use for treatment of cryptococcal meningitis are limited.These liposomal forms should be considered for patients who have difficulty tolerating standard amphotericin B and for those who are at high risk of renal failure.Flucytosine is associated with bone marrow toxicity, and complete blood counts should be monitored during Section 6: Comorbidities, Coinfections, and Complications induction therapy.If available, flucytosine levels can be evaluated 3-5 days after the start of therapy, with a target 2 hour post-dose level of 30-80 mg/mL; a level of >100 mg/mL should be avoided.Note that the dosage of flucytosine must be adjusted for patients with renal insufficiency.
If amphotericin is not available, is contraindicated, or is not tolerated by the patient, alternative induction therapies may be considered.The primary alternative to amphotericin-based therapy is high-dose fluconazole (800-1,200 mg PO once daily), with or without flucytosine.Among the newer antifungal agents, echinocandins have no activity against Cryptococcus.Voriconazole and posaconazole have good in vitro activity and may be considered for treatment of relapsed disease but not as first-line agents.The efficacy of alternative regimens is not well defined.See "Potential ARV Interactions," below, regarding drug-drug interactions between these antifungals and ARVs.
Resistance testing may be considered for patients who have relapsed and for those for whom fluconazole failed to sterilize the CSF.
# Consolidation
After clinical improvement with 2 weeks of induction therapy, and a negative CSF culture on repeat LP, treatment can be switched to fluconazole (400 mg PO once daily to complete 8 weeks of acute treatment).Itraconazole (200 mg PO BID) sometimes is used as an alternative for patients who cannot take fluconazole.It should be noted that itraconazole is less effective than fluconazole and has significant drug interactions with commonly used medications.
# Maintenance
After completing acute treatment, the patient should receive chronic maintenance therapy with fluconazole (200 mg PO once daily) to prevent recurrence of cryptococcosis.An alternative treatment is itraconazole (200 mg PO once daily or BID) -with the caution indicated above.
Maintenance therapy should be continued for life, unless the patient has sustained CD4 cell recovery in response to effective antiretroviral therapy (ART) (CD4 count >200 cells/µL for at least 6 months during ART).Maintenance therapy should be restarted if the CD4 count declines to <200 cells/µL.
# Management of elevated ICP
Elevated ICP significantly increases the morbidity and mortality of cryptococcal meningitis and should be treated by the removal of CSF.The CSF opening pressure should be checked on the initial LP.If the initial opening pressure is >250 mm H 2 O, remove up to 30 mL of CSF to lower the ICP by 50%, if possible.LP and CSF removal should be repeated daily as needed for ICP reduction.A lumbar drain or ventriculoperitoneal shunt may be needed if the initial opening pressure is >400 mm H 2 O, or in refractory cases.There is no role for acetazolamide, mannitol, or steroids in the treatment of elevated ICP.
A repeat LP is not required for patients who did not have elevated ICP at baseline and are responding to treatment.If new symptoms develop, a repeat LP is indicated.Serum CrAg titers are not useful in monitoring response to treatment.
# Cryptococcal pulmonary disease, with negative CSF CrAg and culture results
After CSF cryptococcal disease has been excluded, treat with fluconazole if symptoms are mild or moderate, 400 mg PO once daily for 6-12 months, then 200 mg once daily for maintenance.Otherwise, consider amphotericin induction, as described above with CNS disease.Monitor fungal blood cultures and CrAg to verify the effectiveness of therapy.Itraconazole may be used as an alternative (200 mg PO BID for capsules; 100-200 mg once daily for oral suspension).Therapy should be continued for life, unless Section 6: Comorbidities, Coinfections, and Complications the patient has sustained CD4 cell recovery in response to effective ART (CD4 count of >200 cells/µL for at least 6 months during ART) and with a minimum of 12 months of antifungal therapy.Therapy should be restarted if the CD4 count declines to <200 cells/µL.
# Cutaneous infection, with negative CSF CrAg and culture results
Treat with fluconazole 400 mg PO once daily for 6-12 months, then continue with 200 mg once daily for chronic maintenance therapy, as discussed above.
# Asymptomatic antigenemia
Data are limited for management of asymptomatic antigenemia, which can be associated with development of subsequent disease.Fungal cultures of CSF and blood should be obtained; if either result is positive for cryptococcal growth, treatment should be initiated for symptomatic meningoencephalitis or disseminated disease.If no meningoencephalitis is found, fluconazole 400 mg PO once daily should be given until immune reconstitution occurs; treatment may be discontinued per maintenance guidelines described above.
# Cryptococcus IRIS
Immune reconstitution through ART is effective for preventing recurrence of cryptococcal infections.However, initiating ART within the first 1-2 months after cryptococcal infection may result in worsening or recurrence of symptoms because of immune reconstitution inflammatory syndrome (IRIS).IRIS can be life-threatening in cryptococcal meningeal disease.IRIS and relapse of cryptococcal disease (e.g., treatment failure) must be differentiated; in IRIS, the serum and CSF cultures are negative. (See chapter Immune Reconstitution Inflammatory Syndrome.)
Optimal timing of ART initiation in cryptococcal CNS disease is unknown.Some experts recommend treating cryptococcosis with effective antifungal therapy for 1-2 months before starting ART, to decrease the risk of IRIS.
# Other treatment notes
Pregnancy: Fluconazole and other azole drugs are not recommended for use during pregnancy, especially in the first trimester.
During the first trimester, pregnant women should be treated with amphotericin for both induction and consolidation therapy.
Flucytosine is teratogenic at high doses in rats and class C in humans; it should be used during pregnancy only if the benefits clearly outweigh the risks.
Preventive therapy: Studies have suggested that routine primary prophylaxis for cryptococcal disease in patients with CD4 counts of <100 cells/µL is effective at preventing cryptococcal infection but is not cost efficient.Therefore, it is not routinely recommended.
# Potential ARV Interactions
There may be significant drug-drug interactions between certain systemic antifungals, particularly itraconazole, voriconazole, and posaconazole, and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or maraviroc.Some combinations are contraindicated and others require dosage adjustment of the ARV, the antifungal, or both.Check for adverse drug interactions before prescribing.
# Cryptosporidiosis Background
Cryptosporidiosis is caused by a species of protozoan parasite that typically infects the mucosa of the small intestine, causing watery diarrhea.Diarrhea may be accompanied by nausea, vomiting, abdominal cramping, and occasionally fever.The infection is spread by the fecal-oral route, usually via contaminated water, and is highly contagious.The course of infection depends on the immune status of the host.In immunocompetent individuals, cryptosporidiosis usually is selflimited and can cause a mild diarrheal illness.However, in HIV-infected patients with advanced immunosuppression, cryptosporidiosis can cause severe chronic diarrhea, electrolyte disturbances, malabsorption, and profound weight loss.Infection also can occur outside the intestinal tract and can cause cholangitis, pancreatitis, and hepatitis.In severe cases, cryptosporidiosis can be lifethreatening without aggressive fluid, electrolyte, and nutritional support.Patients at greatest risk of acquiring cryptosporidiosis are those with CD4 counts of <100 cells/µL. Immune reconstitution inflammatory syndrome (IRIS) has not been described in association with cryptosporidiosis.
# S: Subjective
The patient may complain of some or all of the following: watery diarrhea (can be profuse), abdominal pain or cramping, flatulence, nausea, vomiting, anorexia, fever, and weight loss.
The history should include questions about the presence and characteristics of the symptoms listed above, as well as the following:
Stool frequency (typically 6-26 bowel movements daily)
- Stool volume (up to 10 liters per day and can be described as "cholera-like" in some patients with AIDS)
- Duration of symptoms (subacute or acute onset)
- Associated symptoms
# O: Objective
Perform a thorough physical examination with particular attention to the following:
- Vital signs
- Hydration status (e.g., orthostatic vital signs, mucous membrane moistness, skin turgor)
- Weight (compare with previous values; document weight loss)
- Signs of malnourishment (e.g., cachexia, wasting, thinning hair, pallor)
- Abdominal examination for bowel sounds (usually hyperactive), tenderness (can be diffuse), rebound
- Recent CD4 count
# A: Assessment
In HIV-infected patients with advanced immunosuppression, the differential diagnosis includes other infectious causes of subacute or chronic diarrhea or cholangitis, such as microsporidia, Isospora, Giardia, cytomegalovirus (CMV), and Mycobacterium avium complex (MAC), as well as lymphoma.
Section 6: Comorbidities, Coinfections, and Complications
# P: Plan
# Diagnostic Evaluation
- Test the stool for ova and parasites, including Cryptosporidium.Diagnosis is made by microscopic identification of the Cryptosporidium oocysts in stool.
- Be sure to ask the laboratory to look for Cryptosporidium; certain labs do not look for these parasites or their precursor, the oocyst, unless requested.
- Test for fecal leukocytes.The result usually is negative in cryptosporidiosis; if positive, consider the possibility of a second enteric infection, especially if the CD4 count is low, or a different infection.
- Among persons with profuse diarrhea, a single stool specimen usually is adequate for diagnosis.
- For patients with milder disease, repeat stool sampling is recommended. |
- If stool is negative for ova and parasites, consider a referral for biopsy of the gastrointestinal mucosa or flexible sigmoidoscopy.
- If cholangitis is suspected, consider abdominal ultrasound to look for biliary ductal dilatation, and endoscopic retrograde cholangiopancreatography (ERCP).
- Check electrolytes; conduct liver function studies including alkaline phosphatase and bilirubin to check for possible biliary or hepatic infection.
- If fever is present, obtain blood cultures.
- Conduct other diagnostic testing as indicated by the history and physical examination (e.g., evaluation for CMV, MAC, and other infectious causes of diarrhea or cholangitis) (see chapter Diarrhea).
# Treatment
- Effective antiretroviral therapy (ART) with immune reconstitution (and CD4 count >100 cells/µL) can resolve cryptosporidiosis, and it is the primary treatment.All patients with cryptosporidiosis should be offered ART (see chapter Antiretroviral Therapy).
Patients who are on incompletely suppressive ART should have their regimens optimized.
- Provide supportive care and symptomatic relief (this may require hospitalization in cases of severe dehydration), including the following:
- Aggressive fluid and electrolyte replacement as needed
- Oral rehydration (solutions containing glucose, sodium bicarbonate, potassium, magnesium, and phosphorus); in severe cases, IV hydration may be required
- Antidiarrheal agents: atropine/ diphenoxylate (Lomotil), loperamide (Imodium), tincture of opium (Paregoric)
- Antispasmodics
- Antiemetics
- Topical treatment for the anorectal area, as needed (witch hazel pads ), sitz baths)
- No antiparasitic therapy has been proven to consistently and effectively cure cryptosporidiosis if used without ART.
- Nitazoxanide is approved for use in children and adults with diarrhea caused by Cryptosporidium parvum, the most common strain of Cryptosporidium.It may increase the likelihood of clinical response.It should be given in conjunction with ART, but never instead of ART.
- Usual adult dosage: 500-1,000 mg PO BID for 14 days Section 6: Comorbidities, Coinfections, and Complications
- Adverse events associated with nitazoxanide are limited and typically mild; there are no important drugdrug interactions
- Paromomycin with or without azithromycin does not appear to be effective, especially for patients with CD4 counts of <100 cells/µL. Current data do not support a recommendation for use.
- For patients with weight loss, nutritional supplementation is a critical aspect of treatment.In some cases, partial or total parenteral nutrition may be necessary while patients are awaiting clinical improvement in response to ART or other therapies.
Consult or refer to a dietitian or nutritionist, if available.If not, assess food intake and counsel the patient about increasing caloric and nutritional intake.
# Cryptosporidiosis in Resource-Limited Settings
Cryptosporidium infection in HIV-uninfected populations is more common in countries with overcrowding and poor sanitary conditions.The disease is also associated with rainy seasons and is frequent among children <2 years of age.
The prognosis for HIV-infected patients with cryptosporidiosis who lack access to ART is poor.In one study, the mean survival time of coinfected patients was 25 weeks.
# Prevention of Disease and Exposure
- Rifabutin or clarithromycin, when taken for MAC prophylaxis, have been found to protect against cryptosporidiosis.However, current data are insufficient to warrant a recommendation of their use as prophylaxis.
- Scrupulous handwashing can prevent the spread of cryptosporidiosis, and HIVinfected patients should be advised to wash their hands after potential contact with human feces (diapering small children, handling pets, gardening, and before and after sex).
- HIV-infected patients should avoid sexual practices that could lead to direct (e.g., oralanal) or indirect (e.g., penile-anal) contact with feces and should be advised to use barrier methods during sex (e.g., condoms and dental dams).
- HIV-infected persons should avoid drinking water from lakes or rivers.Waterborne infection also can result from recreational activities such as boating, fishing, and swimming.
- HIV-infected patients should avoid raw oysters as the cryptosporidial oocysts can survive in oysters for >2 months.
# Patient Education
- Recommend scrupulous handwashing for the patient and all contacts, especially household members and sex partners.
- Explain that effective ART is the best treatment for alleviating symptoms and helping the immune system eradicate the parasite.
- Advise the patient to increase fluid intake (not alcohol), and avoid foods that aggravate diarrhea.A lactose-free diet may improve symptoms.
- Educate the patient about healthful food choices that increase calorie intake and nutrition.
- Provide supportive counseling; discuss how to manage symptoms and the isolation that may accompany chronic diarrhea.
Section 6: Comorbidities, Coinfections, and Complications
# Cytomegalovirus Disease Background
Although chronic infection with cytomegalovirus (CMV) rarely causes disease among immunocompetent persons, it is a major cause of morbidity and mortality in HIV-infected patients with CD4 counts of <50 cells/µL. CMV infection causes disease in several organ systems, including the central nervous system (CNS) (chorioretinitis, encephalitis, polyradiculopathy, myelopathy) and the gastrointestinal (GI) tract (oral ulcers, esophagitis, hepatitis, colitis, intestinal perforation), as well as life-threatening adrenalitis and pneumonitis.The prevalence of chronic infection with CMV, a member of the human herpesvirus family, is high among sexually active adults (40-60% in resource-rich countries and 80-90% in resource-poor countries).CMV is spread by sexual or other types of close personal contact, blood-to-blood contact (via transfusion or needle sharing), organ transplantation, and perinatal transmission.As with other herpesviruses, CMV is not cleared from the body, but is kept in a state of latency by an intact immune system.Symptomatic disease represents either primary infection or reactivation of latent infection that has escaped immunologic control.Effective antiretroviral therapy (ART) greatly reduces the risk of CMV reactivation and disease.
# Immune reconstitution inflammatory syndrome:
Although effective ART greatly reduces the risk of CMV reactivation and disease, patients on effective ART may experience CMV-related visual changes.
- Patients without a previous history of CMV disease will occasionally present with full-blown CMV retinitis after starting ART.This is thought to reflect delayed restoration of CMV-specific immunity.It is diagnosed and treated in an identical manner as for patients diagnosed with CMV disease who are not taking effective ART.
- Approximately 20% of patients with previously treated CMV retinitis may experience CMVrelated immune reconstitution uveitis (IRU) after starting successful ART.Symptoms include floaters and moderate, occasionally severe, vision loss.The most common causes of vision loss are posterior disease, specifically cystoid macular edema (CME) and epiretinal membrane formation (ERM), although inflammation of the anterior region and cataract formation also can occur.It is not clear whether treatment with steroids or anti-CMV antivirals is effective. (See chapter Immune Reconstitution Inflammatory Syndrome.)
# S: Subjective
The patient may present with symptoms involving various organ systems, including the following:
CNS, including the eye:
- Floaters, scotomata (blind spots), "flashing lights," loss of peripheral or field vision (chorioretinitis)
- Headache, difficulty concentrating, sleepiness, personality changes (encephalitis, dementia)
- Bilateral lower extremity weakness, urinary retention, incontinence, spasticity (polyradiculopathy)
- Low back pain, especially radiating to the perianal area (polyradiculopathy, myelitis)
Section 6: Comorbidities, Coinfections, and Complications
- Family members or caregivers may report confusion, apathy, lethargy, somnolence, withdrawal, or personality changes in the patient (CMV encephalitis, dementia)
# GI tract disease:
- Mouth ulcerations
- Dysphagia or odynophagia (esophagitis)
- Abdominal pain and bloody diarrhea, weight loss, rectal ulcers, fever (colitis)
Disease outside the CNS or GI tract:
- Persistent fever, fatigue, weight loss (adrenalitis)
- Shortness of breath, dyspnea on exertion, dry cough (pneumonia; rare in patients with advanced HIV infection)
- Pancytopenia (bone marrow infection)
The history should include questions about the presence and characteristics of the symptoms listed above, as well as the following:
- Duration of symptoms
# O: Objective
Perform a thorough physical examination, with particular attention to the following:
- Vital signs: Document fever.
- Weight: Compare with previous values; document weight loss.
- Eyes: Funduscopic examination in patients with CMV retinitis may show pathognomonic "cottage cheese in ketchup" yellow-white lesions, representing vascular hemorrhages and exudates.
- Nervous system: Evaluate mental status and perform a complete neurologic examination, including cranial nerves, sensation (sensory deficits may occur with preserved vibratory sense and proprioception), motor, deep tendon reflexes, coordination, and gait.
# A: Assessment
For HIV-infected patients with advanced immunosuppression, the differential diagnosis includes the following:
- For suspected CMV retinitis: consider cotton-wool spots, HIV retinopathy, and progressive outer or acute retinal necrosis.
- For suspected CMV encephalitis: consider other causes of neurologic deterioration such as progressive multifocal leukoencephalopathy, toxoplasmosis, CNS lymphoma, and other mass lesions.
- For suspected CMV enteritis: consider gastrointestinal pathogens such as Mycobacterium avium complex, Cryptosporidium, other parasites, and lymphoma.
- For suspected CMV pneumonitis: consider Pneumocystis jiroveci and other respiratory pathogens.
# P: Plan
# Diagnostic Evaluation
CMV can be detected by serology, culture, antigen testing, nucleic acid amplification, or examination of tissue samples.However, serologic tests are not reliable for diagnosing CMV disease because most adults are seropositive and because patients with advanced AIDS may serorevert while remaining infected.Furthermore, for HIV-infected patients, demonstration of CMV in the blood, urine, semen, cervical secretions, or bronchoalveolar lavage (BAL) fluid does not necessarily indicate active disease, although patients with end-organ disease usually are viremic.
# Section 6: Comorbidities, Coinfections, and Complications
Diagnosis of end-organ disease generally requires demonstration of tissue invasion.The recommended evaluation is as follows:
# CMV retinitis
Dilated retinal examination should be performed emergently by an ophthalmologist experienced in the diagnosis of CMV retinitis.The diagnosis usually is based on the identification of typical lesions.Diagnosis and monitoring should include serial examinations with photography to assess and follow response to treatment and to detect failure to respond early enough to change therapy.
# Other sites
Detection of CMV at other sites requires visualization of typical lesions (e.g., on endoscopy or BAL) and tissue biopsy.Viral inclusions ("owl's eye cells") in tissue biopsy samples demonstrate invasive disease (as opposed to colonization).Because retinitis is the most common manifestation of CMV disease, patients with CNS, gastrointestinal, or pulmonary disease should undergo ophthalmologic evaluation to detect subclinical retinal disease.
# Neurologic CMV disease
- Encephalitis: Magnetic resonance imaging (MRI) of the brain should be done to rule out mass lesions.CMV effects may appear as periventricular or meningeal enhancement.Lumbar puncture should be performed; cerebrospinal fluid (CSF) should be analyzed for CMV (by PCR, which is sensitive and specific), cell count (may show lymphocytic or mixed lymphocytic or polymorphonuclear pleocytosis), glucose (may be low), and protein (may be high).
A brain biopsy may be performed if the diagnosis is uncertain after imaging and CSF evaluation.
- Polyradiculopathy: Spinal MRI should be done to rule out mass lesions.In CMV disease, nerve root thickening may be present.Lumbar puncture with CSF analysis should be performed, as described above.
- Myelitis: Spinal MRI should be done to rule out mass lesions.Cord enhancement may be present.Lumbar puncture with CSF analysis should be performed, as described above.
Gastrointestinal CMV disease (esophagitis or colitis)
- Perform endoscopy with visualization of ulcers and obtain tissue biopsy to look for inclusion bodies.
# Pulmonary CMV disease
- Perform chest radiography showing interstitial pneumonia and obtain lung biopsy to look for inclusion bodies.
# Treatment
Ganciclovir, valganciclovir, foscarnet, and cidofovir may be effective for treating CMV end-organ disease.The choice of therapy depends on the site and severity of the infection, the level of underlying immunosuppression, the patient's ability to tolerate the medications and adhere to the treatment regimen, and the potential medication interactions.
Immune reconstitution through ART is a key component of CMV treatment and relapse prevention.The optimal timing of ART initiation in relation to the treatment of CMV is not clear.CMV flares may occur if patients develop immune reconstitution inflammatory syndrome (see chapter Immune Reconstitution Inflammatory Syndrome), but in most cases of nonneurologic disease, ART probably should not be delayed.
# CMV retinitis
Treatment consists of two phases: initial therapy and chronic maintenance therapy.
# Initial therapy
Before the advent of valganciclovir, the preferred strategy for treating CMV retinitis involved ganciclovir intraocular implants Section 6: Comorbidities, Coinfections, and Complications and systemic therapy.Because implants deliver a higher dose of drug to the retina than any other modality (1.4 mcg/hour for up to 8 months), many experts still prefer them for patients with sight-threatening (zone 1) disease.About half of patients treated with implants develop disease in the contralateral eye, and one third experience systemic disease, within 3 months of implantation.Therefore, patients with implants also should be treated systemically with valganciclovir (900 mg once daily; some experts increase this to 900 mg BID for patients with vision-threatening disease).
For patients with peripheral retinitis (beyond zone 1), oral valganciclovir alone (see below) is the preferred treatment because it is easy to administer and is not associated with the surgery-or catheter-related complications seen with intraocular treatments and IV therapies.This formulation quickly converts to ganciclovir in the body and has good bioavailability.Valganciclovir should be used only if the patient is thought to be capable of strict adherence.Other possible IV treatments include ganciclovir, ganciclovir followed by oral valganciclovir, foscarnet, and cidofovir.See below for dosing recommendations.
- For sight-threatening disease: treat with ganciclovir intraocular implants plus valganciclovir 900 mg PO once daily or BID.
- For peripheral disease: treat with valganciclovir 900 mg PO BID for 14-21 days.
Alternatives for initial therapy:
- IV ganciclovir 5 mg/kg Q12H for 14-21 days
- IV foscarnet 60 mg/kg Q8H or 90 mg/kg Q12H for 14-21 days
- IV cidofovir 5 mg/kg weekly for 2 weeks, then every other week (must be given with probenecid and IV saline to decrease the risk of renal toxicity)
- Intraocular injections with antiviral agents Note: Valganciclovir, ganciclovir, and foscarnet require dosage adjustment in patients with renal insufficiency.Cidofovir is contraindicated for use by patients with renal insufficiency or proteinuria.
Monitor patients closely to gauge the response to therapy.Repeat the dilated retinal examination after completion of induction therapy, 1 month after initiation of therapy, and monthly during anti-CMV therapy, with photography to document progression or resolution of disease.Consult with a specialist if the response to therapy is suboptimal.
Note: Retinal detachment may occur in up to 50-60% of patients in the first year after diagnosis.Regular follow-up with an ophthalmologist is required for all patients.
Patients should be instructed to report any vision loss immediately.
# Chronic maintenance therapy
After initial CMV treatment, lifelong maintenance therapy with valganciclovir or IV foscarnet should be given to prevent recurrence, and patients need regular reevaluation by an ophthalmologist.Recommended dosages for maintenance therapy are as follows:
- Valganciclovir 900 mg PO once daily
- IV foscarnet 90-120 mg/kg once daily Discontinuation of maintenance therapy can be considered for patients with inactive CMV and sustained immune reconstitution on ART (CD4 count of >100-150 cells/µL for at least 6 months).However, the decision should be guided by factors such as the extent and location of the CMV lesions and the status of the patient's vision.An ophthalmologist who is experienced in caring for HIV-infected patients with CMV should be involved in making any decision to discontinue therapy, and patients should receive regular Section 6: Comorbidities, Coinfections, and Complications ophthalmologic follow-up.Maintenance therapy should be resumed if the CD4 count drops below 100-150 cells/µL or the patient develops other signs of HIV progression.
# Neurologic CMV disease
The optimal treatment for neurologic disease has not been determined.Prompt initiation of dual therapy with IV ganciclovir and foscarnet may be effective for some patients.
# Gastrointestinal and pulmonary CMV disease
These infections are usually treated with IV ganciclovir or foscarnet for 21-28 days unless the patient is able to absorb oral medications, in which case valganciclovir PO is an option (refer to the dosing suggestions above).Some specialists recommend a follow-up endoscopy to verify regression of lesions before discontinuing therapy.Many experts do not recommend maintenance therapy for gastrointestinal CMV infections unless the disease recurs.
# Immune reconstitution inflammatory syndrome retinitis or uveitis
Urgent consultation with experts is recommended.
# Monitoring CMV therapies
The medications used to treat CMV have several important potential adverse effects, and monitoring for these is required.Valganciclovir and ganciclovir have been associated with bone marrow suppression, neutropenia, anemia, thrombocytopenia, and renal dysfunction.Foscarnet has been associated with cytopenia, renal insufficiency, electrolyte abnormalities, and seizures.For patients taking these medications, perform complete blood count with differential and check electrolytes and creatinine twice weekly during initial therapy and once weekly during maintenance therapy.Cidofovir has been associated with renal insufficiency and ocular hypotony.For patients taking cidofovir, check creatinine and blood urea nitrogen and perform urinalysis (for proteinuria) before each dose.Intraocular pressure must be checked at least every 6 months.
# Patient Education
- Educate patients about the importance of ART in treating CMV.Urge patients to start ART if they have not done so already.
- Patients with CMV retinitis may have to remain on suppressive therapy for life to prevent blindness.Patients with CMV esophagitis or enteritis usually see improvements within 2-4 weeks after starting therapy.
- Treatment of CMV retinitis halts progression of the infection but does not reverse the damage already done to the retina.Warn patients that vision will not return to pre-CMV status.
- Advise patients to report any visual deterioration immediately.Retinal detachment or progression of CMV must be treated immediately to avoid further vision loss.
- For patients who experience significant vision loss, offer referral to education, training, and support services to help them adjust.
- With gastrointestinal disease, recurrence of symptoms warrants repeat endoscopy.Advise patients to report any recurrence of symptoms.
- Adverse reactions to current therapies are common.Educate patients about these and advise them to promptly report any adverse reactions.
- Help patients cope with the possibility of therapeutic failure, and, in the case of CMV retinitis, permanent loss of vision.
- Teach patients how to maintain indwelling venous access lines, if used.Have patients demonstrate these techniques before discharge.
# Gonorrhea and Chlamydia Background
Gonorrhea, caused by Neisseria gonorrhoeae (GC), and chlamydia, caused by Chlamydia trachomatis (CT), are sexually transmitted infections (STIs). |
These infections may be transmitted during oral, vaginal, or anal sex; they also can be transmitted from a mother to her baby during delivery and cause significant illness in the infant.
Both organisms can infect the urethra, oropharynx, and rectum in women and men; the epididymis in men; and the cervix, uterus, and fallopian tubes in women.Untreated GC or CT infection in women may lead to pelvic inflammatory disease (PID), which can cause scarring of the fallopian tubes and result in infertility or ectopic pregnancy (tubal pregnancy).The organisms also can affect other sites; N. gonorrhoeae can cause disseminated infection involving the skin, joints, and other systems.Infection with GC or CT may facilitate transmission of HIV to HIV-uninfected sex partners.
# Certain strains of CT can cause lymphogranuloma venereum (LGV).
This infection is common in parts of Africa, India, Southeast Asia, and the Caribbean.Outbreaks among men who have sex with men (MSM) have been reported in recent years in Europe and the United States.
LGV may cause genital ulcers, followed by inguinal adenopathy; it also can (as seen in the recent cases among MSM) cause gastrointestinal symptoms, notably anorectal discharge and pain.
Patients with symptoms of gonorrhea or chlamydia should be evaluated and treated as indicated below.Although GC or CT urethritis in men typically causes symptoms, urethral infection in women and oral or rectal infections in both men and women often cause no symptoms.In fact, a substantial number of individuals with GC or CT infection have no symptoms.Thus, sexually active individuals at risk of GC and CT exposure should receive regular screening for these infections as well as for syphilis and other STIs.Patients frequently are infected with both GC and CT, so they should be tested and treated for both.
# S: Subjective
Symptoms will depend on the site of infection (e.g., oropharynx, urethra, cervix, rectum).Symptoms are not present in all patients.
If symptoms are present, women may notice the following: During the history, ask the patient about the following:
- Any of the symptoms listed above, and their duration
- Previous diagnosis of gonorrhea or chlamydia
- New sex partner(s)
- Unprotected sex (oral, vaginal, anal)
- For women: last menstrual period, and whether the patient could be pregnant; use of an intrauterine device
# O: Objective
# Physical Examination
During the physical examination, check for fever and document other vital signs.
For women, focus the physical examination on the mouth, abdomen, and pelvis.Inspect the oropharynx for discharge and lesions; check the abdomen for bowel sounds, distention, rebound, guarding, masses, and suprapubic or costovertebral angle tenderness; perform a complete pelvic examination for abnormal discharge or bleeding; check for uterine, adnexal, or cervical motion tenderness; and search for pelvic masses or adnexal enlargement.Check the anus for discharge and lesions; perform anoscopy if symptoms of proctitis are present.Check for inguinal lymphadenopathy.
For men, focus the physical examination on the mouth, genitals, and anus/rectum.Check the oropharynx for discharge and lesions, the urethra for discharge, the external genitalia for other lesions, and the anus for discharge and lesions; perform anoscopy if symptoms of proctitis are present.Check for inguinal lymphadenopathy.
# A: Assessment
A partial differential diagnosis includes the following:
- Urinary tract infection
# Diagnostic Evaluation
Test for oral, urethral, or anorectal infection, according to symptoms and possible exposures.Perform concurrent testing for both gonorrhea and chlamydia.The availability of the various testing methods varies according to the specific clinic site.Consider the following:
- Culture (oropharynx, endocervix, urethra, rectum)
- Nucleic acid amplification test (NAAT): urine specimens (first stream) and urethral (men), vaginal, and endocervical swab specimens; also used with pharyngeal and rectal swab specimens (although not yet FDA approved for this use)
- Nucleic acid hybridization assay (DNA probe): endocervical and male urethral swab specimens; not approved for rectal or pharyngeal swabs
- Gram stain (pharyngeal, cervical, or urethral discharge), for evidence of GC
# Treatment
Treatments for gonorrhea and chlamydia are indicated below.Fluoroquinolone-resistant GC is widespread in the United States, Pacific Islands, Asia, and Britain.Thus, the U.S. Centers for Disease Control and Prevention (CDC) recommends that fluoroquinolones not be used for treatment of GC in MSM or in any infected patient in the areas listed above, unless antimicrobial susceptibility test results are used to guide therapy.Similarly, resistance of GC to azithromycin is emerging, and azithromycin should be used to treat GC only in select patients in whom other treatments should be avoided.
Because dual infection is common, patients diagnosed with either GC or CT should receive empiric treatment for both infections, unless the other infection has been ruled out.Reinfection is likely if reexposure occurs.Any sex partners within the last 60 days, or the most recent sex partner from >60 days before diagnosis, also should receive treatment.Patients should abstain from sexual activity for 7 days after a single-dose treatment or until a 7-day treatment course is completed.
Adherence is essential for treatment success.Single-dose treatments maximize the likelihood of adherence and are preferred.Other considerations in choosing the treatment include antibiotic resistance, cost, allergies, and pregnancy.For further information, see the CDC STI treatment guidelines (see "References," below).
# Treatment of Gonorrhea
Treatment options include the following (see the full CDC STI treatment guidelines, referenced below); the current guidelines emphasize that ceftriaxone should be used, if possible, for GC infection at any anatomic site and that azithromycin or doxycycline also should be given, to improve likelihood of cure and decrease risk of emergent cephalosporin resistance.Note that GC infection of the pharynx is more difficult to cure than GC infection at other sites.Patients who report possible oral sexual exposures should be treated with ceftriaxone 250 mg, if possible (see below).
# Recommended regimens
- Ceftriaxone 250 mg IM injection in a single dose, plus azithromycin 1 g PO in a single dose or doxycycline 100 mg PO BID for 7 days (for pharyngeal GC, this is the only recommended regimen) If ceftriaxone is not an option; for GC of the urethra, cervix, and rectum ONLY:
- Cefixime 400 mg PO in a single dose (tablet or oral suspension), plus azithromycin or doxycycline as above; cefixime is NOT sufficiently effective to treat pharyngeal GC
- Single-dose injectable cephalosporin plus azithromycin or doxycycline as above; efficacy for pharyngeal GC is uncertain Alternative regimens (for GC infection of the urethra, cervix, and rectum ONLY; inadequate for pharyngeal GC)
- Cefpodoxime 400 mg PO in a single dose
- Cefuroxime axetil 1 g PO - Spectinomycin 2 g IM injection in a single dose (currently not available in the United States)
- Azithromycin 2 g PO in a single dose (concern for possible emergence of resistance; use other agents if possible)
If penicillin allergy:
- Cephalosporins are contraindicated only in patients with a history of severe reaction to penicillin.
- Consultation with an infectious disease specialist is recommended.
- Spectinomycin can be used for urogenital or rectal infection (inadequate for pharyngeal GC).
Section 6: Comorbidities, Coinfections, and Complications
- Azithromycin 2 g PO; use caution owing to concerns over emerging resistance to macrolides.
- Consider cephalosporin treatment following desensitization.
Note: Fluoroquinolones are not recommended for treatment of gonococcal infection because of widespread resistance in the United States.
Please see full CDC STI treatment guidelines regarding treatment of PID, epididymitis, and disseminated gonococcal infection.
# Treatment of Chlamydia
(See the full CDC STI treatment guidelines, referenced below.)
# Recommended regimens
- Azithromycin 1 g PO in a single dose
- Doxycycline 100 mg PO BID for 7 days
# Alternative regimens
- Erythromycin base 500 mg PO QID for 7 days
- Erythromycin ethylsuccinate 800 mg PO QID for 7 days
- Ofloxacin 300 mg PO BID for 7 days (see Note above)
- Levofloxacin 500 mg PO once daily for 7 days (see Note above)
# Treatment of LGV
# Recommended regimens
- Doxycycline 100 mg PO BID for 21 days
# Alternative regimens
- Erythromycin base 500 mg PO QID for 21 days
- Azithromycin 1 g PO once weekly for 3 weeks (limited data)
For recent sex partners (within 6 days of the onset of patient's symptoms), test for urethral or cervical CT, treat with azithromycin 1 g PO in a single dose or doxycycline 100 mg PO BID for 7 days.
# Treatment During Pregnancy
Use of fluoroquinolones and tetracyclines should be avoided during pregnancy.
# Recommended GC regimens
- A recommended cephalosporin or azithromycin 2 g PO (see above)
# Recommended CT regimens
- Azithromycin 1 g PO in a single dose
- Amoxicillin 500 mg PO TID for 7 days
# Alternative CT regimens
- Erythromycin base 500 mg PO QID for 7 days
- Erythromycin base 250 mg PO QID for 14 days
- Erythromycin ethylsuccinate 800 mg PO QID for 7 days
- Erythromycin ethylsuccinate 400 mg PO QID for 14 days
# Follow-up
- Evaluate the patient's sex partners; treat them empirically if they had sexual contact with the patient during the 60 days preceding the patient's onset of symptoms.
(Some clinics provide empiric treatment for partners via "partner packs," or a treatment regimen that the patient takes to the partner(s); this approach does not require the partner to present for evaluation and may be effective if the partner(s) is/are unlikely to come to the clinic.)
- Most recurrent infections come from sex partners who were not treated.
- If symptoms persist, evaluate for the possibility of reinfection, treatment failure, or a different cause of symptoms.If treatment failure is suspected, perform culture and antimicrobial sensitivity testing.
- The CDC recommends rescreening male patients 3 months after treatment.
Section 6: Comorbidities, Coinfections, and Complications
- For pregnant women with chlamydia, retest (by culture) 3 weeks after completion of treatment.
- Screen for gonorrhea, chlamydia, syphilis, and other STIs at regular intervals according to the patient's risk factors.The sites of sampling (e.g., pharynx, urethra, endocervix, anus/rectum) will be determined according to the patient's sexual exposures.
- Evaluate each patient's sexual practices with regard to the risk of acquiring STIs and of transmitting HIV; work with the patient to reduce sexual risks.
# Patient Education
- Instruct patients to take all of their medications.Advise patients to take medications with food if they are nauseated and to call or return to clinic right away if they experience vomiting or are unable to take their medications.
- Sex partners from the previous 60 days need to be tested for sexually transmitted pathogens, and treated as soon as possible with a regimen effective against GC and CT, even if they have no symptoms.Advise patients to inform their partner(s) that they need to be tested and treated.Otherwise, patients may be reinfected.
- Advise patients to avoid sexual contact until the infection has been cured (at least 7 days).
- Provide education about sexual risk reduction.Instruct patients to use condoms with every sexual contact to prevent reinfection with GC or CT, to prevent other STIs, and to prevent transmission of HIV to sex partners.
# Hepatitis B Infection
Rena Fox, MD
# Background
Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide.Chronic HBV can cause necroinflammation and over time can cause hepatic fibrosis and eventually cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC).It is estimated that 350 million people have chronic HBV infection, with approximately 1.25 million of them in the United States.HBV is a DNA virus that is spread through exposure to infected blood and body fluids.It typically is transmitted by parenteral, sexual, and vertical exposures, but may be transmitted through person-to-person contacts among household members, especially because HBV can survive outside the body for long periods of time.Because HIV and HBV share transmission routes, up to 90% of HIVinfected patients have evidence of HBV exposure.In the United States, chronic HBV infection has been identified in 6-15% of HIV-infected persons.
The epidemiology of HBV infection varies by geographic region.In Southeast Asia and sub-Saharan Africa, HBV is highly prevalent and almost all infections occur perinatally or during early childhood.In the United States and Western Europe, most infections occur through sexual exposure or high-risk injection drug use behavior.
To identify patients with HBV coinfection, and to identify and vaccinate susceptible individuals, all HIV-infected persons should be tested for HBV (see chapters Initial and Interim Laboratory and Other Tests and Immunizations for HIV-Infected Adults and Adolescents).In addition, all patients with chronic HBV infection should be tested for HIV and all patients with evidence of prior resolved HBV infection should be strongly considered for HIV testing.
It is universally recommended that HBV vaccination should be given to all HIV-infected persons who test negative for all HBV seromarkers (see "Interpreting HBV test results," below, and chapter Immunizations for HIV-Infected Adults and Adolescents).If possible, it is recommended that the vaccine series be given when CD4 counts are >200 cells/µL, as doing so is associated with higher rates of vaccine response.For patients with CD4 counts of 200 cells/µL. HBV vaccination also is recommended for persons who test negative for HBV seromarkers but are at high risk (e.g., men who have sex with men , persons who are infected with hepatitis C virus , and persons who are in close contact with someone who has HBV infection).
The natural history of HBV infection is complex.The likelihood of developing chronic HBV after exposure varies with age, mode of infection, and immunocompromised status.Among newborns born to HBV-infected mothers, 90% develop chronic hepatitis B, whereas 30% of exposed infants and young children and <5% of exposed adults develop chronic infection.Most adults who become
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection who completed the vaccination series for hepatitis B (Group 2 measure)
Percentage of clients with HIV infection and hepatitis B or C who received alcohol counseling in the measurement year Section 6: Comorbidities, Coinfections, and Complications infected with HBV are able to clear the virus without treatment, and they subsequently become immune to HBV.Progressive HBV can lead to cirrhosis and then to decompensated liver disease including ascites, portal hypertension, esophageal varices, coagulopathy, thrombocytopenia, and hepatic encephalopathy.HCC can develop in patients with or without cirrhosis; in fact, 30-50% of HCC cases attributable to HBV occur in the absence of cirrhosis.
Factors associated with increased rates of cirrhosis include the following:
- Longer duration of infection - Core promoter mutation
- Coinfection with HCV Among individuals who are not taking ART, HIV infection significantly modifies the natural history of HBV infection.HIV infection appears to increase the risk of developing chronic HBV infection after acute HBV, and it is associated with a higher level of HBV DNA replication and lower rates of spontaneous HBeAg seroconversion.In patients with chronic HBV, HIV coinfection is associated with faster progression of liver disease and cirrhosis and increased rates of liver-related deaths.Although HIV coinfection itself is not known to increase the risk of HCC development, it does increase the risk of cirrhosis, which in turn increases the risk of HCC.
Treatment of HIV infection with effective ART has increased the life expectancy of HIVinfected patients in recent years, and paradoxically has given HIV/HBV-coinfected patients a longer lifespan during which cirrhosis may develop.Partly for this reason, the relative proportion of deaths attributable to liver disease among HIV-infected patients is rising.On the other hand, ART can positively impact the natural history of HBV infection.Effective ART can improve patients' immune responses against HBV.ART also may be used to treat HBV in coinfected patients.Several of the nucleoside analogues (NRTIs) used against HIV also are active against HBV, and these should be included in an ART regimen to treat both HIV and HBV for coinfected persons (see "Antiviral Treatment of Chronic HBV Infection," below).Withdrawal of NRTIs with anti-HBV activity can precipitate a reactivation of HBV.ART that contains anti-HBV NRTIs also may prevent acute infections in patients who are receiving them.
Section 6: Comorbidities, Coinfections, and Complications
# S: Subjective
Persons with acute HBV infection may have symptoms including fatigue, nausea, vomiting, arthralgias, fever, right upper quadrant pain, jaundice, dark urine, and clay-colored stools.Some patients may have no symptoms at all.Persons with chronic HBV, even with early cirrhosis, may be asymptomatic or may experience only fatigue or mild right upper quadrant tenderness.Patients with decompensated cirrhosis may experience increased abdominal girth, easy bruising, telangiectasis, pruritus, gastrointestinal bleeding, or altered mentation.Patients with early or small HCC may have no additional symptoms or may develop significant abdominal pain, weight loss, nausea, or bone pain.
Ask patients with known HBV infection about symptoms that suggest complications of HBV such as cirrhosis, decompensation, risk factors for worsening liver disease, and hepatotoxins.Questions should address the symptoms listed above, and the following:
- Fatigue - Weight loss - Impaired concentration - Chronic HCV - Alcohol intake - Substance use - Antiretroviral (ARV)
# Interpreting HBV test results
Routine baseline HBV serologic screening tests for HIV-infected individuals are outlined in Table 1.
Markers of chronic hepatitis B can manifest in a number of patterns (see Table 1). 1).Successful vaccination to HBV (in someone who has never been infected) will result in positive HBsAb but negative HBcAb results.Prior exposure to HBV may result in positive HBcAb and HBsAb findings, indicating the development of immunity.However, prior exposure may present as positive HBcAb only, with negative results for HBsAb, HBsAg, and HBV DNA.This pattern shows that the patient was previously infected with hepatitis B but did not develop chronic infection, and lost the HBsAb.This sometimes is termed "isolated core Ab," and it is seen more commonly in patients coinfected with HIV or HCV.It is not known whether patients who display this pattern would have sufficient immunity to ward off another HBV infection if they were reexposed. |
Some experts recommend vaccinating such patients so that they do mount an HBsAb response whereas others do not believe that vaccination for these patients is necessary.
# Section 6: Comorbidities, Coinfections, and Complications
In acute HBV infection, HBV DNA will be detectable before HBsAg, if highly sensitive nucleic acid testing is used.Otherwise, HBsAg (which takes an average of 30 days to develop) is the only marker detected during the first 3-5 weeks after infection.HBcAb develops at approximately 6 weeks after infection and both immunoglobulin M (IgM) and immunoglobulin G (IgG) will be evident.The IgM will decline within 6 months but the IgG will persist for life.Among individuals who recover from acute HBV infection, HBeAg typically seroconverts to HBeAb at approximately 3 months whereas, for those who develop chronic HBV infection, HBeAg typically persists for years.
# Diagnostic Evaluation of Acute HBV infection
When approaching the diagnosis of a patient with acute hepatitis B infection, the following steps should be taken:
1.Obtain history and perform physical examination.
Determine the time and route of infection if possible.Take a complete history, including HIV disease course and treatment, and other medical history.Perform physical examination, focusing on evidence of acute liver dysfunction.
2.Assess HBV replication serially.
As soon as acute infection is suspected, check HBsAg, HBV DNA, HBeAg, HBeAb, ALT, HBcAb-IgM, and HBsAb.
Recheck each every 4 weeks to track the serologic course of infection.
3.Assess liver function serially.
When ALT is abnormal and rising, additional tests of liver function should be serially evaluated until it is clear that ALT is trending back down.Tests should include albumin, total bilirubin, prothrombin time, and platelet count.
4.Determine whether HBV infection resolves or persists as chronic HBV infection.
If the HBsAg is still present at 6 months after acute infection, the HBV infection has persisted and patient has chronic hepatitis B infection.
# Initial Diagnostic Evaluation of Chronic HBV Infection
When approaching the diagnosis of a patient with chronic HBV infection, the following steps should be taken:
- Take a complete history, including family history of HBV or HCC, and HIV disease course and treatment.Perform physical examination.
- Assess HBV replication to determine HBV DNA level, HBeAg and HBeAb serostatus, and ALT level.Note that HBV DNA levels may be difficult to interpret in patients who are on ARVs that have anti-HBV activity (HBV may be low or undetectable because of these medications).
- Assess liver disease -check complete blood cell count with platelet count, albumin, total bilirubin, transaminases (especially ALT), and prothrombin time.
- Assess for possible overlying liver diseases (e.g., HCV, alcoholic liver disease, fatty liver disease).
- Consider liver biopsy to assess histological degree of inflammation and fibrosis, especially if the result would affect the decision to use treatment.
- Screen for HCC at baseline via ultrasound.
- Test for hepatitis A antibodies (IgG) and vaccinate against hepatitis A if not immune.
Section 6: Comorbidities, Coinfections, and Complications
# Long-Term Monitoring of Chronic HBV Infection
For patients who are not on treatment for HBV, regular monitoring of HBV replication and liver function should be performed.
For patients with the following seromarkers, recommendations are as indicated:
Negative HBeAg, low ALT, and low-level DNA (<2,000 IU/mL) (inactive HBV):
HBV DNA, HBeAg, and ALT testing should be performed every 3 months for the first year to determine whether the virus is truly inactive.If it remains inactive (with, negative HBeAg, normal ALT, and low-level DNA), monitoring can continue every 6-12 months; some specialists recommend more frequent monitoring.
Negative HBeAg, elevated ALT, and high HBV DNA (>20,000 IU/mL):
Biopsy should be considered, and treatment should be considered.If treatment is not started, monitoring should occur every 3 months.
Negative HBeAg, moderately elevated ALT, and moderately elevated DNA (2,000-20,000 IU/mL):
Follow-up should be performed every 3-6 months if treatment is not started.
# Positive HBeAg, moderately elevated ALT:
Monitoring should be performed every 3 months and, if ALT is persistently elevated, a biopsy should be considered to guide the decision regarding initiation of HBV treatment.
Positive HBeAg, high HBV DNA (>20,000 IU/ mL) but low-level ALT:
Monitoring should be performed every 3-6 months to check for changes in ALT.If ALT rises significantly, treatment should be considered.
# Cirrhosis:
Treatment should be considered.If not treated, monitoring should be performed every 3-6 months.
# Antiviral Treatment of Chronic HBV Infection
The goals and markers of HBV treatment for HIV/HBV-coinfected patients are the same as for HBV-monoinfected patients.
The goals of treatment are as follows:
- To decrease progression of liver disease
- To prevent development of cirrhosis
- To prevent development of HCC Treatment endpoints for the HBV/HIVcoinfected population are not well defined but efficacy is determined by the following measures:
- HBeAg seroconversion to HBeAb (this is harder to achieve for coinfected patients than for HBV-monoinfected persons)
- HBV DNA suppression
- ALT normalization, which usually follows the changes in HBV DNA
The optimal duration of treatment is not clearly known; it generally is considered to be long-term, with the primary risks being the development of drug resistance and a subsequent reactivation of HBV.
The timing of treatment and choice of treatment for HBV/HIV-coinfected patients are important.Determine the patient's need for anti-HIV treatment (see chapters Risk of HIV Progression/Indications for ART and Antiretroviral Therapy).
- If treatment for HIV is indicated, HBV should be treated concurrently with the HIV by using an ART regimen that includes two NRTIs that are active against both viruses (tenofovir + emtricitabine or tenofovir + lamivudine), if possible.In this situation, liver biopsy to stage disease is not necessary Section 6: Comorbidities, Coinfections, and Complications because HBV treatment will be undertaken (incorporated into the HIV regimen).Note that treatment of HBV with a single NRTI is not recommended, because of the risk of HBV resistance; if tenofovir cannot be used, entecavir (plus combination ART) is the preferred alternative (see Table 2).
- If treatment for HIV is deferred, the hepatitis B should be treated if the patient otherwise meets criteria for HBV treatment (see below).ALT, HBeAg, and HBV DNA results, and possibly a liver biopsy, should be used to determine whether HBV should be treated.
- Inactive chronic hepatitis B (HBV DNA is <2,000 IU/mL, HBeAg is negative and ALT is not elevated: the HBV can be monitored and does not require treatment.
- HBeAg positive, ALT is more than two times the upper limit of normal (ULN), and HBV DNA >20,000 IU/mL: consider HBV treatment.
- HBeAg negative, ALT is more than two times the ULN and HBV DNA >2,000 IU/ mL: consider HBV treatment.
- HBeAg positive, HBV DNA >20,000 IU/ mL, but ALT is less than two times the ULN: can use a biopsy to determine the need for HBV treatment.
- HBeAg negative, DNA >2,000 IU/mL, but ALT is less than two times the ULN: can use a biopsy to determine the need for HBV treatment.
- Any patient with cirrhosis (if not decompensated) and a detectable DNA level: should be considered for HBV treatment, regardless of HBeAg status and regardless of ALT level.
- Patients with decompensated cirrhosis should not be treated for HBV but should be referred for transplant.
- Some specialists recommend HBV treatment for all patients with detectable HBV DNA, particularly if ALT is elevated or inflammation or fibrosis is seen on liver biopsy.
- If HBV treatment is indicated, HIV infection should be treated concurrently, if possible.As stated above, the recommended treatment is a potent ARV regimen that includes two dual-acting (anti-HIV and anti-HBV) drugs (i.e., tenofovir + emtricitabine or lamivudine).If tenofovir is contraindicated, entecavir or another anti-HBV drug should be used (with emtricitabine or lamivudine) to construct a two-drug therapy for HBV, and the HIV ART regimen should be designed for complete HIV suppression (see Table 2).
- If a decision is made to treat HBV but not HIV, HBV treatment should not include agents that are dually active, as that could lead to early HIV resistance.This limits choices to pegylated interferon alfa-2a (although it has not been studied in HBV/HIV-infected patients) or adefovir dipivoxil.Data on possible anti-HIV activity of telbivudine are conflicting but it is recommended that telbivudine not be used in this setting.Tenofovir, lamivudine, emtricitabine, and entecavir should not be used as monotherapy for HIV/HBVcoinfected patients, because HIV (and HBV) resistance may develop (see Table 2). Additional points about treatment for HIV/ HBV-infected patients:
- When lamivudine is used as a single agent, HBV resistance develops in many patients by 1-2 years.Although combination therapy has not been well studied, specialists recommend using dual-NRTI combinations that have activity against HBV (lamivudine + tenofovir, or emtricitabine + tenofovir ) as part of the ARV regimen, to treat HBV and to prevent HBV resistance.
- For patients infected with HCV as well as HBV and HIV, evaluate the need for HIV therapy first.If ART is not required, consider treating HCV first, because interferon therapy is active against both HCV and HBV (see chapter Hepatitis C Infection).Also consider consultation with an expert if optimal timing for treatment of the three infections is not clear.If interferonbased therapy for HCV has failed, consider treating chronic HBV with an oral agent.
- Some patients treated with ART may experience worsening of HBV symptoms and laboratory markers in the weeks after ART initiation, because of immune Section 6: Comorbidities, Coinfections, and Complications reconstitution inflammatory reactions.Hepatic decompensation owing to immune reconstitution must be distinguished from other causes, such as medication toxicity, or other infection.Liver function tests should be monitored closely for patients starting ART.
- Some ARV medications are hepatotoxic and should be avoided or used cautiously.These include nevirapine, tipranavir, and highdose ritonavir.Numerous other medications (e.g., fluconazole, isoniazid) are hepatotoxic and can pose problems for patients with impaired liver function.
- Discontinuation of HBV medications in patients with HIV/HBV coinfection may cause a flare of liver disease.Be very cautious when discontinuing HBV-active medications from an anti-HIV ART regimen.If the HBV DNA is suppressed, options include continuing the HBV-active ARVs, even if there is HIV resistance (modify the ART regimen for maximal HIV suppression) or substituting other HBV-active medications to avoid rebound liver inflammation and decompensation.For example, if it is decided to discontinue lamivudine/tenofovircontaining ART in an HIV/HBV-coinfected patient on ART, consider starting adefovir or interferon to maintain activity against HBV.If HBV therapy is discontinued and a flare occurs, consider reinstating HBV therapy as soon as possible.
# Screening for HCC in patients with chronic HBV infection
Persons with chronic HBV are at increased risk of developing HCC.Note that HCC may occur even in the absence of cirrhosis.HCC screening should be performed every 6-12 months using ultrasound (computed tomography is an alternative); alphafetoprotein should be monitored if ultrasound reliability is low.
HBV-infected patients who should be screened for HCC include the following:
- Anyone with cirrhosis
- Anyone over age 40 with elevated ALT or HBV DNA >2,000 copies/mL
- Asian men aged >40
- Asian women aged >50
- Persons of African descent aged >20
- Anyone with a family history of HCC
# Interventions to slow progression and prevent complications
Persons with HCV infection should be counseled to avoid exposure to hepatotoxins, including alcohol and hepatotoxic medications (e.g., acetaminophen in large doses, fluconazole, isoniazid).Heavy alcohol use is a risk factor for increasing rate of fibrosis.It is not clear what degree of alcohol consumption is safe, so many experts recommend complete abstinence from alcohol.
- No specific dietary measures are recommended.
- Patients who are not already immune to hepatitis A should be vaccinated against hepatitis A.
- Patients should be counseled on ways to avoid infection with hepatitis C.
# Preventing transmission
All patients with HBV infection should receive individualized counseling on ways to reduce the risk of HBV transmission (including by sexual or needle-sharing behavior, perinatal routes, or household exposure), as appropriate.
Household members and sexual contacts should be vaccinated against HBV.
Women who are pregnant or considering pregnancy should consult with a specialist in both HBV and HIV to discuss ways of decreasing the infection risk for the fetus; this may include treatment for HBV and HIV.
Infants born to coinfected women should receive HBV immune globulin and start the Section 6: Comorbidities, Coinfections, and Complications
HBV vaccine series within 12 hours after birth (with subsequent vaccine doses per usual protocol).
# Patient Education
- Advise patients that most people with HBV will remain asymptomatic for several years.However, ongoing injury to the liver occurs during this time and can culminate in liver failure.Patients can slow the damage by avoiding alcohol and any medications (including over-the-counter drugs and recreational drugs) that may damage the liver.Patients should contact their pharmacist or health care provider if they have questions about a specific medication or supplement.
- As with HIV, patients must avoid passing HBV to others.Instruct patients not to share toothbrushes, dental appliances, razors, sex toys, tattoo equipment, injection equipment, or personal care items that may have blood on them.Emphasize to patients the importance of safer sex to protect themselves and their partners.
- Tell patients to discuss HBV with their sex partners, and suggest that partners be tested for HBV.
- Nonimmune sex partners and individuals in close contact with persons with chronic hepatitis B (e.g., family and household members) should be vaccinated.
- Pregnant women have a high risk of transmitting HIV or HBV to the fetus because each virus makes it easier to transmit the other.Women who are pregnant or considering pregnancy should talk with a specialist in HIV and HBV to discuss ways of decreasing the infection risk for the fetus.
- Advise patients who are on treatment for HBV that abrupt discontinuation of HBV treatment can cause a flare of HBV; they should not stop treatment without medical supervision.
- Certain ARV drugs are more likely than others to cause hepatotoxicity.Advise patients that their liver function should be monitored carefully if they start an ARV regimen, in order to determine whether the body is able to process the medicines.
Section 6: Comorbidities, Coinfections, and Complications
# Hepatitis C Infection
# Rena Fox, MD
# Background
Liver disease owing to hepatitis C virus (HCV) infection has become a leading cause of death among HIV-infected patients, as the widespread availability of antiretroviral therapy (ART) has led to a decrease in AIDS-related causes of death.HCV is common among patients with HIV infection in the United States.It is estimated that 30-40% of the HIV-infected population in the United States is coinfected with HCV, but the prevalence varies with risk factor for transmission.Among HIV-infected injection drug users and hemophiliacs in the United States, 70-95% may be coinfected with HCV; among HIV-infected men who have sex with men, 1-12% are coinfected with HCV.
HCV is a single-stranded RNA virus that is transmitted primarily through blood exposure and, less commonly, through sexual or vertical transmission.HCV/HIV coinfection is common because of these shared risk factors.However, HCV is more likely than HIV to be transmitted via a bloodborne route; there is an approximately 10-fold greater risk of HCV transmission after needlestick exposure compared with the risk of HIV transmission, and the concentrations of HCV in a given volume of blood are greater than those of HIV.Women who are coinfected with HIV and HCV have a higher risk of transmitting HIV to their infants than do women with HIV infection alone.Coinfected women also are more likely than HCVmonoinfected women to pass HCV to their infants.Approximately 20% of babies born to HIV/ HCV-coinfected mothers acquire HCV, compared with 5-6% of infants born to HCV-infected women without HIV.Breast-feeding is not known to transmit HCV, although HIV-infected women are advised against breast-feeding because of the risk of transmitting HIV.
Coinfection with HIV adversely impacts the natural history of HCV infection.HIV/HCVcoinfected patients have lower rates of spontaneous HCV clearance, increased HCV viral loads, decreased rates of successful virologic response to HCV treatments, faster progression to cirrhosis, and increased risk of developing liver decompensation, end-stage liver disease, and hepatocellular carcinoma (HCC).HCV coinfection does not appear to increase HIV-and AIDS-related complications or decrease rates of successful HIV antiretroviral (ARV) treatment.
# HRSA HAB Core Clinical Performance Measures
Percentage of clients for whom hepatitis C screening was performed at least once since the diagnosis of HIV infection
(Group 2 measure)
Percentage of clients with HIV infection and hepatitis B or C who received alcohol counseling in the measurement year (Group 3 measure)
# Acute HCV Infection
Acute infection can be symptomatic and severe but rarely is fulminant.Patients who do present with onset of jaundice, weakness, anorexia, abdominal pain, or malaise without a known cause should be tested for acute HCV infection.Symptoms usually subside after several weeks.Patients who present after a potential exposure, such as a needlestick injury, should be tested for acute infection whether or not they are symptomatic.Overall, approximately 25% of patients acutely infected with HCV will clear the virus spontaneously, but there are few prospective studies on the natural history of acute HCV infection with preexisting HIV infection.Because it is Section 6: Comorbidities, Coinfections, and Complications difficult to establish the precise timing of HCV infection, prospective natural history studies are difficult to perform.
# Chronic HCV Infection
For the majority of HCV patients, other than laboratory abnormalities, there are no clinical manifestations of infection until the development of cirrhosis.Cirrhosis develops in approximately 20% of HCVmonoinfected patients, usually 20 years or more from the time of infection.More than 20% of HIV/HCV-coinfected patients are thought to develop cirrhosis, and at a faster rate.Once patients have developed cirrhosis, approximately 50% will decompensate within the first 5 years.Typically, the first sign of decompensation is the development of ascites. |
Of patients with cirrhosis, approximately 1-4% per year will develop HCC, or approximately 20% of cirrhotic patients in total.The median survival time from the onset of HCC is approximately 5 months and, the 1-year survival rate is 29%.
# S: Subjective
Patients with HCV infection, whether acute or chronic, often have no symptoms, and the infection is discovered via screening tests or on workup of an abnormal liver test result.
Patients with acute HCV infection typically are asymptomatic but may present with symptoms such as jaundice, abdominal pain, and malaise.If symptoms from acute infection develop, they usually do so within 4 weeks after infection has occurred.Most patients with chronic HCV cannot recall a time when they were acutely symptomatic, and HCV is detected because of an incidental finding of abnormal transaminases or through a screening test.
Ask patients with known HCV infection about symptoms that suggest complications of HCV, such as cirrhosis, decompensation, risk factors for worsening liver disease, and hepatotoxins, and about drugs whose metabolism may be affected by liver disease.
- Fatigue
# Diagnostic Evaluation
Acute HCV infection After initial exposure, HCV RNA can be detected in blood within 1-3 weeks and is present at the onset of symptoms.Antibodies to HCV can be detected in only 50-70% of patients at the onset of symptoms, but in >90% after 3 months.Within an average of 4-12 weeks, liver cell injury is manifested by elevation of serum alanine aminotransferase (ALT).It is important to understand the timeline of these diagnostic tests in order to appropriately diagnose acute infection and follow for potential resolution versus persistent infection.
In patients with suspected acute HCV infection, check HCV antibody (IgG), HCV RNA, and ALT immediately and then weekly until the ALT has begun to decline and HCV antibody has seroconverted to positive status.The seroconversion of HCV antibody establishes the diagnosis of acute infection.At that point, check the HCV RNA every 2-4 weeks for the following 3 months.If HCV RNA is still present at 3 months, strongly consider starting treatment for acute HCV promptly.If treatment is not initiated and RNA is still present at 6 months after infection, the likelihood of spontaneous clearance is extremely low, and the patient is diagnosed with chronic infection.
# Chronic HCV infection HCV antibodies
All HIV-infected patients should be tested for HCV infection with the HCV antibody test.Patients with risk factors for HCV infection should be retested at regular intervals.In HIVinfected patients, the HCV antibody test result sometimes is falsely negative; therefore, if HCV infection is suspected (e.g., because of a history of high-risk behavior, unexplained elevated ALT, or evidence of cirrhosis), the HCV RNA should be tested even if the HCV antibody test result is negative.A false-negative HCV RNA result is very unlikely in chronic infection.
# HCV RNA
All patients who test positive for HCV antibody should have HCV RNA testing performed.As noted above, if patients have negative results on HCV antibody tests but persistently abnormal transaminases or suspected acute or chronic infection, HCV RNA testing should be performed.
The definition of chronic HCV infection is the presence of HCV RNA 6 months after the estimated time of infection.If a patient is HCV antibody positive but HCV RNA negative, the patient has cleared the HCV and does not have chronic HCV infection.
There are quantitative RNA tests and qualitative RNA tests.Although both types of RNA tests are highly sensitive and specific, the qualitative tests can detect lower levels of viremia than the quantitative tests.The choice of RNA test can be important.
The quantitative RNA tests will be reported as a value, with a measured number of international units per milliliter (IU/mL).Quantitative tests are useful for determining the prognosis of HCV treatment and then monitoring while on HCV treatment.Qualitative RNA tests will be reported as a present or absent value, but without a numerical value.They are useful for serial testing during suspected acute infection and for determining whether spontaneous viral clearance has occurred, a sustained virological response has occurred during treatment, or a relapse has occurred after treatment.
# Genotyping
The HCV genotype is the strongest predictor of response to HCV treatment and also is Section 6: Comorbidities, Coinfections, and Complications a critical determinant of the dosage and duration of treatment.HCV genotyping should be performed once for all patients with detectable HCV RNA; it does not need to be repeated.
# Alanine aminotransferase
Monitoring of ALT can be useful to assess acute infection, chronic liver inflammation, and response to HCV treatment.However, ALT does not always correlate with the degree of fibrosis and in addition, ALT can be persistently normal in 25% of HCV patients, including patients with cirrhosis or advanced liver disease.Small fluctuations in ALT usually are not clinically significant in HCV, though trends can be significant during or following HCV treatment.
# Additional tests
Check complete blood cell count with platelet count, albumin, total bilirubin, and prothrombin time.
Test all patients for hepatitis B (HBsAg, anti-HBsAb, and anti-HBcAb).For those with a positive HBsAg or a positive anti-HBcAb result (absent anti-HBsAb), test for active HBV infection (HBV DNA and HBeAg) (see chapter Hepatitis B Infection).Patients with a negative HBsAg and negative anti-HBsAb result should be vaccinated against HBV.
Test for hepatitis A virus (HAV) antibodies (total).All patients with a negative HAV antibody result should be vaccinated against HAV.
# Imaging
Ultrasonography can be performed to screen for cirrhosis or focal hepatic masses.Computed tomography (CT), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) are more expensive and generally are reserved for further evaluation of liver masses detected by ultrasound.
# Liver biopsy
Liver biopsy is used to define the degree of inflammation (the grade) and degree of fibrosis (the stage) to determine the need for HCV treatment.Unless there is clear evidence of cirrhosis, laboratory tests and radiology studies are unable to quantitate the degree of fibrosis in the liver.Liver biopsy carries some risk, primarily from bleeding (the risk of significant bleeding or fatality is approximately 1/10,000).
Patients with severe thrombocytopenia or coagulopathy should not undergo liver biopsy.
Fibrosis is scored from 0 to 4, with 0 indicating no fibrosis and 4 indicating cirrhosis.
Biopsy can be useful in making management decisions for some HCV patients, for example when determining whether to treat a patient, particularly those with genotype 1 virus (see below).If the biopsy reveals only mild-tomoderate fibrosis, it may be preferable to defer treatment and monitor the patient.Conversely, if the biopsy reveals more advanced fibrosis, treatment should be considered more urgently.With genotype 2 or 3 patients, some providers consider biopsy to be unnecessary because treatment outcomes are sufficiently high that findings from a biopsy would not necessarily change the management strategy.For HIV/ HCV-coinfected patients, a biopsy may be particularly useful in determining the stage of disease and in planning whether or when to initiate HCV treatment, as the course of liver disease may accelerate.Overall, deciding whether to conduct a biopsy largely is a matter of individual choice.It is not a requirement for treatment of any patient, but may be useful for helping the provider and patient make a decision about whether or when to undergo treatment.
# Treatment Treatment of acute HCV
The presence of HIV infection is not a contraindication to treatment of acute HCV Section 6: Comorbidities, Coinfections, and Complications infection.With HIV/HCV-coinfected patients, as with HCV-monoinfected patients, early treatment of acute HCV infection yields a much higher rate of sustained virological response (SVR) than does treatment of chronic HCV infection.In three prospective trials of treatment for acute HCV in HIVcoinfected patients, using pegylated interferon (PEG-IFN) alpha-2a and ribavirin for 24 or 48 weeks, the SVR for genotype 1 HCV was 55-75%, compared with 100% for genotype 3.By contrast, in the largest study of in chronic HCV treatment in HIV-coinfected patients (n = 868), the SVR was about 29% for genotype 1 and 62% for genotype 2 or 3.
As mentioned above, RNA should be tested repeatedly for 12 weeks from the time of infection to ascertain whether spontaneous clearance will occur.If RNA is still present at 12 weeks, treatment should be strongly considered.
# Treatment of chronic HCV
HIV coinfection is a strong indication for treatment of chronic HCV infection, because the risk of accelerated fibrosis and cirrhosis is higher for coinfected patients.Treatment of chronic HCV infection in HIV/HCVcoinfected patients has lower rates of SVR than treatment in monoinfected patients (see below), but HIV-coinfected patients should be strongly considered for HCV treatment.HIVinfected patients with low CD4 cell counts should not be excluded from HCV treatment on the basis of CD4 count alone; this is particularly true for patients already on ART.For timing of HCV treatment, see "Timing of HCV treatment and HIV treatment," below.
Patients with a high risk of progression to cirrhosis, including coinfected patients, should receive higher priority for treatment.For patients with minimal fibrosis, especially those with genotype 1 virus, treatment can be deferred.Patients who have developed cirrhosis but remain compensated should be treated as soon as possible if they are otherwise candidates.Patients with decompensated liver disease should not receive HCV treatment (risks outweigh benefits); appropriate candidates can be considered for liver transplantation.
The most effective treatment for HCV in patients with or without HIV is combination therapy with pegylated interferon-alfa (PEG-IFN) plus ribavirin.Among HIV-uninfected patients, approximately 45% with genotype 1 achieve HCV viral clearance using this combination.HCV/HIV-coinfected patients have much lower rates of response, from 14-44%, varying by genotype, duration of treatment, and dosage.Several novel drugs, including HCV-specific protease inhibitors, are being investigated as adjuncts to standard therapy.
Data suggest that early virologic response (EVR), defined as a ≥2 log 10 decrease in HCV viral load 12 weeks into treatment, predicts SVR; treatment may be stopped if patients do not demonstrate EVR.The recommended duration of treatment in patients with HCV genotype 1 and EVR is 48 weeks.For genotype 2 or 3, the optimal duration of treatment is not clear; some guidelines state that treatment can be limited to 24 weeks, whereas others recommend 48 weeks of treatment for any HIV/HCV-coinfected patient.
# Adverse effects of treatment
HCV therapy may cause significant adverse effects.IFN reduces total white blood cell counts, and can cause neutropenia.It also decreases CD4 cell counts, although the CD4 percentage usually does not change.IFN can reduce HIV RNA somewhat (by approximately 0.5 log 10 copies/mL).IFN also may produce flulike symptoms, depression, peripheral neuropathy, and other symptoms.Ribavirin can cause anemia and other adverse effects.Zidovudine and didanosine should be avoided, if possible, with patients taking ribavirin, because of the risk of compounded toxicities Section 6: Comorbidities, Coinfections, and Complications (anemia with zidovudine, neuropathy, lactic acidosis, liver toxicity, and pancreatitis with didanosine).
HCV treatment should not be given during pregnancy, and women receiving HCV treatment should avoid pregnancy.IFN may cause fetal growth abnormalities, and it is abortifacient in animals.Ribavirin is teratogenic, and both women and men must use contraception consistently during treatment with ribavirin and for 6 months after discontinuation of treatment.
# Timing of HCV treatment and HIV treatment
The decision of whether and when to treat HCV among people infected with HIV must be determined individually.When coinfected patients require treatment for both infections, some experts begin with HIV treatment in hope that improved CD4 cell counts will enhance the response to HCV therapy, even though CD4 counts by themselves are not firmly associated with increased likelihood of an SVR.With patients who are not considered to require ART (e.g., because their CD4 counts are very high), many experts recommend treating HCV first, with ART delayed until after completion of HCV treatment.This strategy is intended to simplify treatment and improve the tolerability of both therapies.
Patients already on ART generally should remain on ART throughout HCV treatment.
Consult with an HCV treatment expert to determine the appropriateness and timing of HCV treatment.
Some patients with HCV will experience worsening of hepatic function during ART, and liver function tests should be monitored closely.Some ARV medications are hepatotoxic and should be avoided or used cautiously; these include nevirapine, tipranavir, and highdose ritonavir.Numerous other medications (e.g., fluconazole and isoniazid) are hepatotoxic and can pose problems for patients with impaired liver function.
# Other Care Issues
Acute HAV or HBV infection in persons with chronic HCV can cause fulminant liver disease.
All patients with HCV infection should be tested for immunity to HAV and HBV; patients who are not immune should be vaccinated.
Persons with HCV infection should be counseled to avoid exposure to hepatotoxins, including alcohol and hepatotoxic medications (e.g., acetaminophen in large doses, fluconazole, and isoniazid).
As appropriate, all persons with hepatitis C should receive individualized counseling on ways to reduce the risk of HCV transmission to others (including by unprotected sex, sharing of injection drug equipment, other blood exposures (e.g., from sharing razors or tattoo equipment), and via perinatal exposure).
# Patient Education
- Advise patients that most people with HCV will remain asymptomatic for several years.However, ongoing injury to the liver occurs during this time and can culminate in liver failure.Patients can slow the damage by avoiding alcohol and any medications (including over-the-counter drugs and recreational drugs) that may damage the liver.Patients should contact their pharmacist or health care provider if they have questions about a specific medication or supplement.
- As with HIV, patients must avoid passing HCV to others.Instruct patients not to share toothbrushes, dental appliances, razors, sex toys, tattoo equipment, injection equipment, or personal care items that may have blood on them.Emphasize the importance of safer sex to protect themselves and their partners.
- Tell patients to discuss HCV with their sex partners, and suggest that partners be tested for HCV.
- Pregnant women have a high risk of transmitting HIV or HCV infection to the Section 6: Comorbidities, Coinfections, and Complications fetus because each virus makes it easier to transmit the other.Women who are pregnant or considering pregnancy should talk with a specialist in HIV and HCV to discuss ways to decrease the infection risk for the fetus.
- HCV medications (ribavirin and interferon)
should not be given during pregnancy.Both men and women who are taking ribavirin should use contraception consistently during ribavirin therapy and for 6 months after completion of treatment.
- For children who are born after their mothers were infected with HCV, consider having them tested as well.Even though their risk is low, they should be screened for HCV.
- Certain ARV drugs are more likely to cause problems with the liver because of HCV.Advise patients that their liver function should be watched carefully if they start an ARV regimen in order to determine whether the body is able to process the medicines.
- HAV can cause severe illness, liver damage, or even death in people with HCV.Patients who are not immune to HAV need to receive two vaccinations 6 months apart.
- HBV also can worsen liver function greatly if it is acquired in addition to HCV.Patients who are not immune to HBV should complete the vaccine series, which consists of three shots.If patients have been vaccinated in the past, they should have the anti-HBV titer checked to make sure that they are protected.
- Patients who are not immune to HBV should use safer sex (latex barriers) to avoid exposure.Patients who use injection drugs should not share needles or injection equipment.
- HCV-infected patients who use injection drugs should consider entering a treatment program.Quitting drug use will reduce strain on the liver, protect against other bloodborne illnesses that can affect the liver, and help prevent transmission of HCV to others.Patients who are not ready to stop injection drug use should let their providers know so that they can try to find a source for clean, single-use needles.
- HCV is not spread by coughing, sneezing, hugging, sharing food and water, or other casual contact.
- The HCV treatments interferon-alfa and ribavirin can cause flulike symptoms, body aches, fevers, anemia, neuropathy, and depression.Most of these adverse effects are treatable with medications.Patients should contact their medical provider right away if they experience depression.Antidepressant medications can help to relieve depression, but they take a couple of weeks to become effective.
# S: Subjective
The patient may complain of eruption of red, painful vesicles or ulcers ("fever blisters") with or without an exudate in the mouth, on the lips (and occasionally in nares), on the genitals, or in the perianal area.The patient may complain of burning, tingling, or itching before eruption of the lesions.
The vesicles will rupture and ulcerate, generally crusting over and healing in approximately 7-14 days.The lesions may be pruritic and are often painful.As immunosuppression progresses, the lesions may recur more frequently, grow larger or coalesce, and become chronic and nonhealing.
Perform a history, asking the patient about the symptoms described above, duration, associated symptoms, and history of HSV or similar infection.
# O: Objective
Look for grouped vesicular or ulcerative lesions on an erythematous base on the mouth, anus, or external genitals, or ones that are visible on speculum or anoscopic examination.When immunosuppression is severe, lesions may coalesce into large, painful, and nonhealing ulcerations that spread to the skin of the thighs, lips, face, or perirectal region.These chronic erosive lesions may be confused with a chronic bacterial infection or decubitus ulcer, and should prompt consideration of acyclovirresistant HSV infection.Recurrent lesions may start atypically, first appearing as a fissure, pustule, or abrasion. |
# A: Assessment
A partial differential diagnosis includes the following:
- Oral aphthous ulcers - Chancroid - Syphilis - Cytomegalovirus - Candidiasis - Drug-related eruption
# P: Plan
# Diagnostic Evaluation
A clinical diagnosis of HSV often can be made on the basis of the patient's symptoms and clinical appearance, but symptoms and signs may be variable.Also, HSV-1 (rather than HSV-2) is increasingly the cause of initial episodes of anogenital herpes.For these reasons, current guidelines recommend laboratory testing to establish the diagnosis of HSV and to determine its type.
# Herpes Simplex, Mucocutaneous Background
Herpes simplex virus (HSV) types 1 and 2 cause both primary and recurrent oral and genital disease.HSV usually appears as a vesicular eruption of the mucous membranes of the oral or perioral area, vulva, perianal skin, rectum, and occasionally the inguinal or buttock areas.The eruption develops into tender or painful ulcerated lesions that frequently are covered with a clear yellow crust.In some patients, however, the typical painful vesicular or ulcerative lesions may be absent.Persons with HIV disease and low CD4 cell counts have more frequent recurrences of HSV and more extensive ulcerations than do HIV-uninfected people.Persistent HSV eruption (lasting >1 month) is an AIDS-indicator diagnosis.
# Section 6: Comorbidities, Coinfections, and Complications
For cell culture or polymerase chain reaction (PCR), obtain a specimen from a freshly opened vesicle or the base of an ulcer for culture confirmation.Note that lesions that are >72 hours old or are beginning to resolve may not show HSV in culture.
PCR is more sensitive for detection of herpes DNA in ulcerative lesions, but is more expensive to perform and is less widely available than viral culture.If virologic test results are positive, typing should be performed to determine the type of HSV.Negative results do not rule out the possibility of HSV infection.
If cultures are negative and there is a high suspicion of HSV infection, skin may be taken from the edge of an ulcer for biopsy.Biopsy material also may be cultured.Tzanck smears are not sensitive or specific.
Type-specific serologic tests may be useful in the evaluation of patients in whom a diagnosis of genital HSV is not clear.Current guidelines also recommend that serologic testing be considered for HIV-infected individuals, for MSM, and for those who present for STI evaluation.Glycoprotein G (gG)-based serologic assays are recommended, as older assays do not reliably differentiate HSV-1 antibody from HSV-2 antibody.
Strongly consider checking for syphilis with a rapid plasma regain (RPR) or Venereal Disease Research Laboratory (VDRL) test in any patient who presents with genital, anal, or oral ulceration.
# Treatment
Empiric treatment for suspicious lesions often is initiated in the absence of laboratory confirmation.In some instances, treatment can be started empirically and, if no response is seen within 7-10 days, laboratory studies can be undertaken.
# Episodic outbreak
- Acyclovir 400 mg PO TID
- Valacyclovir 1,000 mg PO BID
- Famciclovir 500 mg PO BID Note: Dosage must be adjusted for patients with renal impairment.
Duration of treatment: 5-10 days.Short-course therapy (1-3 days) usually is not recommended for persons with HIV infection.
Symptomatic treatment helps the healing of lesions but does not prevent recurrences.Large, extensive ulcers may need to be treated for a longer period of time.
# Severe disease
Treat initially with acyclovir 5 mg/kg IV Q8H (10 mg/kg for encephalitis).
# Acyclovir-resistant HSV
The diagnosis of acyclovir-resistant HSV should be suspected if lesions fail to respond to 7-10 days of standard therapy and should be confirmed with culture and sensitivities.Cross-resistance to valacyclovir and ganciclovir will be present, and crossresistance to famciclovir is likely.The usual alternative treatment is foscarnet (40 mg/kg IV Q8H); other possibilities include IV cidofovir, topical imiquimod, and topical cidofovir.An HIV specialist should be consulted.
# Chronic suppressive therapy
Consider suppressive therapy with acyclovir (400 mg PO BID), famciclovir (500 mg PO BID), or valacyclovir (500 mg PO BID) for patients with frequent or severe recurrences and those with HSV-2.Acyclovir dosage may need to be increased to 800 mg BID or TID for individuals whose HSV episodes are not adequately suppressed by 400 mg BID.Treatment may be continued indefinitely.Note that suppressive therapy also reduces the risk of transmission of HSV.Effective antiretroviral therapy (ART) also may reduce the frequency of HSV outbreaks.
# HSV During Pregnancy
Acyclovir appears to be safe and effective for use by pregnant women and remains the drug of choice.Few data are available on the use of valacyclovir and famciclovir during pregnancy.
It is important to avoid peripartum transmission of HSV.For women with recurrent or new genital HSV late in pregnancy, obstetric or infectious disease specialists should be consulted.All women should be evaluated carefully for symptoms and signs of genital HSV.
# Patient Education
- Patients should be told that HSV has no cure, and outbreaks may occur at intervals for the rest of their lives.
- HSV is spread easily through kissing (if mouth or lips are infected) and sexual contact (oral, anal, or vaginal).HSV can be transmitted when no lesions are present, so it is important that patients inform their sex partners of their herpes infection before sexual activity.Patients must avoid all sexual contact when lesions are visible, because a high volume of virus is present at those times.Condom use at each sexual encounter offers the best chance of preventing HSV transmission.If HSV is transmitted, sex partners also will have it for life.
- Instruct patients to avoid use of occlusive dressings or ointments, which can prevent healing of sores.
- Treatment is most effective when taken early in the outbreak, so patients not taking suppressive therapy should keep medication on hand and start treatment at the first signs of eruption.
# Herpes Zoster/Shingles Background
Shingles is a skin or mucosal infection caused by the varicella-zoster virus (VZV) that occurs along a dermatome and represents a reactivation of varicella (chickenpox).Zoster is common in patients with HIV infection, including apparently healthy individuals before the onset of other HIV-related symptoms.The incidence may be higher among patients with low CD4 cell counts and during the four months after initiating potent antiretroviral therapy.
Zoster may be particularly painful or necrotic in HIV-infected individuals.Disseminated infection, defined as outbreaks with >20 vesicles outside the primary and immediately adjacent dermatomes, usually involves the skin and the visceral organs.Neurologic complications of zoster include encephalitis, aseptic meningitis, cranial nerve palsies, optic neuritis, transverse myelitis, and vasculitic stroke.
# S: Subjective
The patient complains of painful skin blisters or ulcerations along one side of the face or body.Loss of vision may accompany the appearance of facial lesions.Pain in a dermatomal distribution may precede the appearance of lesions by many days (prodrome).
Assess the following during the history:
- Duration of pain or blisters (average of 2-3 weeks if untreated)
- Location of pain or blisters; severity of pain - History of chickenpox (usually in childhood)
# O: Objective
Perform a skin and neurologic examination to include the following:
- Vesicular lesions with erythematous bases in a dermatomal distribution; may be bullous or hemorrhagic
- Necrotic lesions; may persist for as long as 6 weeks
- Dermatomal scarring (particularly in darkskinned individuals)
- Lesions in the eye area or tip of nose, along the trigeminal nerve; these represent ophthalmic nerve involvement, which requires immediate evaluation and IV treatment (see below)
A: Assessment
- Rule out other causes of vesicular skin eruptions (e.g., herpes simplex virus, severe drug reactions).
- Assess contact exposures (see below).
# P: Plan
# Diagnostic Evaluation
The diagnosis usually is clinical and is based on the characteristic appearance and distribution of lesions.If the diagnosis is uncertain, perform viral cultures or antigen detection by direct fluorescent antibody from a freshly opened vesicle or biopsy from the border of a lesion.
# Treatment
- Treatment ideally should begin within 72 hours of an outbreak or while new lesions are appearing and should be continued for 7-10 days.Early treatment may attenuate a herpes zoster attack. -Dosage reductions of these drugs are required for patients with renal impairment.
- If new blisters are still appearing at the end of treatment, repeat course of PO therapy or consider IV treatment.
Adjunctive corticosteroids aimed at preventing postherpetic neuralgia are not recommended.
- Consult an ophthalmologist immediately if lesions appear in the eye area or on the tip of the nose, or if the patient complains of visual disturbances, because VZV-related retinal necrosis can cause blindness.Because of the rapid progression associated with this diagnosis, hospitalization for administration of IV acyclovir and possibly foscarnet is recommended.
- VZV from zoster lesions is contagious, and contact or airborne spread from vesicle fluid may cause chickenpox in nonimmune people.If a zoster patient's household includes a pregnant woman (HIV infected or uninfected) or an HIV-infected child, consult with a specialist immediately for advice on management of exposed household members. (See "Postcontact Chickenpox Prevention," below.)
- Give analgesics for pain; narcotics may be required.
- Postherpetic neuralgia (PHN) is a common sequela of zoster.Antiviral therapy may reduce the risk of PHN, but PHN often requires special treatment for pain control.Treatment options include:
- Nortriptyline 10-25 mg.To be taken QHS and increased by 25 mg every 3-5 days to a maximum dosage of 150 mg daily until pain is controlled, assuming adverse effects remain tolerable.Other tricyclics may be used.
- Gabapentin 100-300 mg PO BID; this may be increased by 300 mg every 3 days until reaching 3,600 mg total daily dosage.Adjust gabapentin dosage in patients with kidney disease.
- Pregabalin 75 mg BID (or 50 mg TID) in patients with estimated creatinine clearance of >60 mL/minute; this may be increased to 300 mg total daily dosage over the course of a week as needed.
- Lidocaine 5% patches provide good local relief with minimal systemic absorption.Up to 3 patches may be applied simultaneously to the affected area for up to 12 hours in a 24-hour period.
- Capsaicin cream may be applied to the affected area TID or QID.Patients should wear gloves to apply the cream and wash their hands with soap and water afterward.
- Sustained-release opiates may be required.
(See chapter Pain Syndrome and Peripheral Neuropathy for more options and specific recommendations.)
# Severe or unresponsive cases
- IV acyclovir may be indicated if:
- The patient is severely immunocompromised
- The ophthalmic branch of the trigeminal nerve is affected (as noted above)
- Dissemination has occurred
- Lesions are not responsive to oral therapy
- Pain is intractable in the setting of active skin lesions
- The usual adult dosage is 10-15 mg/kg Q8H for 7-14 days; dosage reduction is required for patients with renal impairment.Refer to an infectious disease specialist.
- Acyclovir resistance may occur in patients previously treated with acyclovir or related drugs, and foscarnet may be required for
# Prevention
The vaccine for prevention of herpes zoster (Zostavax) currently is not recommended for HIV-infected patients but is under study.
# Postcontact Chickenpox Prevention
All susceptible persons, including pregnant women, who have close contact with a patient who has chickenpox or zoster must be treated to prevent chickenpox.Exposed individuals who have no history of chickenpox or shingles or no detectable antibody against VZV should be administered varicella zoster immune globulin (VariZIG) as soon as possible, but at least within 96 hours after contact.Some experts also would recommend varicella vaccination for exposed patients with CD4 counts of ≥200 cells/µL, or preemptive treatment with acyclovir; these approaches have not been studied in HIV-infected persons.Even immunocompetent adults with primary VZV (chickenpox) can develop viral dissemination to the visceral organs.HIVinfected patients may develop encephalitis, pneumonia, or polyradiculopathy during primary varicella (chickenpox) or reactivated zoster (shingles).
# Patient Education
- Patients should bathe the skin lesions in mild soap and water.For necrotic lesions, use warm, moist compresses 2-3 times a day to remove debris.
- Antibiotic ointments may help prevent secondary infection and keep dressings from sticking.
- Advise patients to take their medications as directed, and to contact the clinic if symptoms worsen.
Section 6: Comorbidities, Coinfections, and Complications
# S: Subjective
Histoplasmosis may be difficult to diagnose because the symptoms are nonspecific.In addition, clinicians may not suspect this diagnosis in low-prevalence areas.
Patients may experience fever, weight loss, fatigue, cough, and shortness of breath.They also may develop skin lesions, adenopathy, central nervous system (CNS) changes, oropharyngeal ulcers, nausea, diarrhea, and abdominal pain.Symptoms usually begin several weeks before patients present for care.On occasion, histoplasmosis presents abruptly as a sepsis-like syndrome.
# Histoplasmosis Background
Histoplasmosis is caused by Histoplasma capsulatum, a fungus that thrives in soil contaminated by droppings from birds and bats.In the United States, H. capsulatum is found most often along the Ohio and Mississippi River Valleys, in the central, mid-Atlantic, and south-central states, and from Alabama to southwest Texas.In highly prevalent areas, such as Indianapolis and Kansas City, more than 80% of the population has been exposed to Histoplasma through inhalation of airborne infectious elements.Histoplasmosis also is found in the Canadian provinces of Quebec and Ontario, Puerto Rico, Mexico, Central and South America, Africa, East Asia, and Australia.
The initial infection in most cases either produces no symptoms or manifests only as a mild flulike illness.However, immunosuppressed individuals may develop disseminated disease.Progressive disseminated histoplasmosis often represents a reactivation of latent infection, occurs late in the course of HIV disease (the CD4 count usually is <150 cells/µL), and is an AIDS-defining illness.Pulmonary histoplasmosis (without dissemination) may occur in people with higher CD4 counts.Within endemic areas, histoplasmosis accounts for 5% of opportunistic infections among patients with AIDS.In hyperendemic areas, the prevalence of histoplasmosis may reach 25% among AIDS patients.The incidence of histoplasmosis in the United States has declined with the use of effective antiretroviral therapy (ART).
Common clinical features that may be associated with histoplasmosis are shown in Table 1.
# O: Objective
Measure vital signs and document fever.
Perform a complete physical examination, with special attention to the lymph nodes, lungs, abdomen, skin, and neurologic system.
Common findings include enlargement of the liver, spleen, and lymph nodes.Skin lesions and oropharyngeal ulcers may be seen.
# A: Assessment
A partial differential diagnosis includes the following:
- Other deep-seated fungal infections, such as cryptococcosis and coccidioidomycosis
- Mycobacterial disease (Mycobacterium tuberculosis or Mycobacterium avium complex)
- Pneumocystis pneumonia
# Lymphoma
Section 6: Comorbidities, Coinfections, and Complications
# P: Plan
# Diagnostic Evaluation
- The H. capsulatum antigen test is sensitive and specific.The test is most sensitive for urine samples (95% in disseminated disease), but can be used on serum (85% sensitive in disseminated disease), bronchial fluids, or cerebrospinal fluid (CSF) specimens.Results may be obtained in a few days' time.Urine antigen levels can be used to monitor the response to therapy.
- Cultures of blood, bone marrow, and specimens from other sources have reasonable sensitivity (about 85%), but obtaining results may take several weeks.
- Wright stain of the buffy coat of a blood specimen may reveal intracellular organisms.
- Biopsies of lymph nodes, liver, cutaneous lesions, and lungs may be diagnostic in up to 50% of cases; bone marrow can be stained with methenamine silver to show the organism within macrophages.
- Meningitis can be challenging to diagnose.Diagnostically, Histoplasma antigen or anti-Histoplasma antibodies can be detected in CSF in up to 70% of cases, whereas results for cultures are often negative.Nonspecific findings in the CSF include elevated protein and low glucose as well as a lymphocytic pleocytosis.A diagnosis of Histoplasma meningitis should be considered if the patient has known disseminated disease and other more common etiologies of meningitis have been ruled out.
- Lactate dehydrogenase (LDH) and ferritin, although not specific, may be markedly elevated in disseminated disease.
- Complete blood count and chemistry panels may show pancytopenia, elevated creatinine, or abnormal liver function.
# Treatment
Treatment consists of two phases: induction and chronic maintenance.Treatment should be continued for at least 12 months.
Mild to moderate disseminated histoplasmosis without CNS involvement - Induction and maintenance therapy: itraconazole 200 mg PO TID or 300 mg PO BID for 3 days followed by itraconazole 200 mg BID to complete 12 months of therapy.Liquid formulation of itraconazole is preferred.
# Severe disseminated histoplasmosis
Severe infection requires IV induction therapy with a lipid formulation of amphotericin; standard amphotericin is less effective and is associated with more adverse effects, but may be used as an alternative.
- Induction therapy:
- Preferred: liposomal amphotericin B lipid formulation 3 mg/kg IV daily
- Alternatives: amphotericin B 0.7 mg/kg IV daily or amphotericin B lipid complex 5 mg/kg IV daily
- Maintenance therapy: After ≥2 weeks of therapy or improvement of the patient's clinical status, therapy may be switched to itraconazole 200 mg PO TID for 3 days, then BID to complete 12 months of therapy.Liquid formulation of itraconazole is preferred.
# Histoplasma meningitis
Amphotericin B must be used because itraconazole has poor penetration into the CNS:
- Induction therapy: liposomal amphotericin B 5 mg/kg daily for 4-6 weeks
# Monitoring and relapse
Monitor either serum or urine Histoplasma antigen, as well as clinical status, to evaluate response to therapy; a rise in the antigen level suggests relapse of histoplasmosis.A drug level of itraconazole should be measured at least once during therapy as absorption of this drug can be erratic.
In cases of treatment failure, both voriconazole and posaconazole have been successful in a few case reports; if treatment failure is suspected, an infectious disease specialist should be consulted. |
# Primary Prophylaxis
Currently, there are no studies that prove any survival benefit in using primary prophylaxis; however, for patients with CD4 counts of <150 cells/µL, prophylaxis with itraconazole 200 mg PO once daily can be considered for high-risk patients (e.g., those with occupational exposure and those who reside in hyperendemic regions).HIV-infected patients with CD4 counts of ≤150 cells/µL should be educated about precautions for avoiding exposure.
Primary prophylaxis can be discontinued if the CD4 count remains >150 cells/µL for 6 months on effective ART; prophylaxis should be restarted if the CD4 count drops to ≤150 cells/µL.
# Potential ARV Interactions
Note that azoles (particularly itraconazole, posaconazole, and voriconazole) may interact with certain protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and other medications); some combinations are contraindicated.
# Patient Education
- Histoplasmosis is not transmitted from person to person, so isolation is not necessary.
- Patients should take all their medications exactly as prescribed by their health care provider.
- Even with maintenance therapy, relapses can occur.Patients should contact their provider immediately if symptoms worsen.
- The azoles may cause birth defects.Women who are taking azole medications should avoid pregnancy.In addition, itraconazole and other azoles interact with some antiretrovirals and other medications; patients should tell their provider if they begin taking any new medications while receiving itraconazole.
# Kaposi Sarcoma Background
Kaposi sarcoma (KS) is an endothelial neoplasm that usually occurs as skin or oral lesions but may involve the internal organs.It is the most common AIDS-associated neoplasm and is an AIDSdefining disease.AIDS-associated KS is one of four types of KS, along with classic, endemic, and organ transplant-associated KS.Although the types vary in epidemiology and clinical presentation, all are associated with human herpesvirus type 8 (HHV-8), also known as KS-associated herpesvirus.The clinical manifestations of AIDS-associated KS (sometimes called epidemic KS) range in severity from mild to life-threatening.The progression of disease may be rapid or slow, but the overall prognosis is poor in the absence of treatment.The skin lesions of KS, even when they do not cause medical morbidity, may cause significant disfigurement and emotional distress.
AIDS-associated KS usually occurs in HIV-infected persons with advanced immunosuppression (CD4 count of <200 cells/µL), but may occur at any CD4 count.In the United States and Europe, KS occurs in all HIV risk groups, but most frequently among men who have sex with men (MSM).Risk factors for MSM include multiple sexual partners and a history of sexually transmitted infections (STIs); risk factors for other groups have not been clearly identified.The transmission of HHV-8 is not well understood.Although experts believe HHV-8 is transmitted sexually, it apparently also passes from person to person by other routes.
The incidence of KS in resource-abundant countries has declined markedly since the early 1990s, in part because of the widespread availability of effective combination antiretroviral therapy (ART).In parts of sub-Saharan Africa, where endemic KS has long existed in people with normal immune function, the incidence of KS has risen sharply in people with HIV.ART appears to be effective in reducing the risk of AIDS-associated KS, particularly when initiated before the development of advanced immunosuppression.
# S: Subjective
# Skin Lesions
The cutaneous presentation of KS is the most common, occurring in 95% of cases.Lesions may occur anywhere on the skin.Common sites include the face (particularly under the eyes and on the tip of the nose), behind the ears, and on the extremities and torso.Lesions may be macules, papules, plaques, or nodules.At first, the lesions are small and may be flat.Their color may vary from pink or red to purple or brown-black (the latter particularly in dark-skinned individuals), and they are nonblanching, nonpruritic, and painless (lesions may become painful in the setting of immune reconstitution inflammatory syndrome associated with KS).Over time, the lesions often increase in size and number, darken, and rise from the surface; they may progress to tumor plaques (e.g., on the thighs or soles of the feet), or to exophytic tumor masses, which can cause bleeding, necrosis, and extreme pain.
# Oral Lesions
Oral lesions may be flat or nodular and are red or purplish.They usually appear on the hard palate, but may develop on the soft palate, gums, tongue, and elsewhere.Oral lesions, if extensive, may cause tooth loss, pain, and ulceration.
# Physical Examination
Perform a careful physical examination, with particular attention to the following:
- Vital signs
- Skin (examine the entire skin surface including the scalp and conjunctiva)
- Oropharynx
- Extremities and external genitals (look for lesions, edema)
- Lymph nodes Examine the lungs, abdomen, rectum, and other systems as indicated.
# A: Assessment
The partial differential diagnosis depends on the type of symptoms present.
For cutaneous, oral, and lymph node presentations, consider the following:
- Bacillary angiomatosis
- Lymphoma
- Dermatofibromas
- Bacterial or fungal skin infections
- Venous stasis For pulmonary symptoms, consider the following:
- Pneumocystis jiroveci pneumonia (PCP)
- Cytomegalovirus (CMV) pneumonia - Pulmonary lymphoma (rare)
# P: Plan
# Diagnostic Evaluation
For cutaneous or oral KS, a presumptive diagnosis often can be made by the appearance of skin or mucous membrane lesions.Biopsy of a lesion (or a suspect lymph node) is strongly recommended to verify the diagnosis and rule out infectious or other neoplastic causes.Biopsy is particularly important if the lesions are unusual in appearance or if the patient has systemic or atypical symptoms.
If respiratory symptoms are present, obtain chest X rays or computed tomography (CT)
Section 6: Comorbidities, Coinfections, and Complications studies.The chest X ray typically shows diffuse interstitial infiltrates, often accompanied by nodules or pleural effusion.Radiographic findings may be suggestive of KS, but cannot provide a definitive diagnosis.Bronchoscopy with visualization of characteristic endobronchial lesions usually is adequate for diagnosis.
For patients with gastrointestinal symptoms and suspected KS, perform endoscopy.
If the patient has fever or respiratory, gastrointestinal, or constitutional symptoms, evaluate for other infectious and malignant causes (e.g., by culture or biopsy) as suggested by the history and physical examination.
# Treatment
Treatment of KS is not considered curative, and no single therapy is completely efficacious.ART is a key component of the treatment of KS and should be initiated (or optimized to achieve complete HIV RNA suppression) for all persons with KS, unless contraindicated (for further information, see chapter Antiretroviral Therapy).KS often regresses and sometimes resolves in patients treated with effective ART.Some data suggest that protease inhibitors may have an anti-KS effect; however, non-PI-containing regimens also lead to KS regression.The role of specific antiretroviral agents beyond HIV control in KS remains unclear, although some experts prefer to use PIs for patients with active KS.KS-associated IRIS has been described, and patients may experience painful enlarged lesions or progression of KS lesions during the first months of ART; they should be advised of this possibility.
Specific treatment of KS depends on various factors such as the number, extent, severity, and location of lesions; cosmetic considerations; and presence of visceral involvement.The goals of therapy may vary according to the clinical presentation and may include controlling symptoms, improving cosmetic appearance, reducing edema, eliminating pain, and clearing lesions.
Local treatment (preferably in conjunction with ART) usually is given to patients who have a few small lesions causing only minor symptoms.Systemic therapy (in conjunction with ART) is needed for more extensive or more severe disease, including symptomatic visceral disease, widespread skin involvement, significant edema, and rapidly progressive KS.Consultation with a KS-experienced oncologist or dermatologist is recommended.
# Local treatment of limited disease
Options for local treatment of limited disease include the following:
- ART with observation for response (limited, stable cutaneous disease may require no specific treatment)
- Topical treatment with alitretinoin gel (Panretin) 0.1%
- Intralesional chemotherapy (e.g., vinblastine)
- Radiation therapy, for localized or facial lesions (may cause mucositis when used for oropharyngeal lesions)
- Cryotherapy
- Laser therapy
# Treatment of extensive or rapidly progressing disease
Extensive or rapidly progressing disease may include lymphedema, intraoral or pharyngeal disease that interferes with eating, painful or bulky lesions, and symptomatic pulmonary or visceral disease.Options for treatment include the following:
- Intralesional chemotherapy (e.g., vinblastine)
- Systemic chemotherapy (e.g., liposomal formulations of doxorubicin or daunorubicin, paclitaxel, or vinorelbine)
# Patient Education
- KS often responds to treatment.Educate patients that ART is a cornerstone of treatment; encourage them to start and adhere to ART.
- Swollen or edematous lesions increase the risk of cellulitis, whereupon lesions can become infected and progress rapidly.Advise patients to avoid injuring swollen or edematous lesions, to keep them clean, and to call their health care provider if lesions appear to be spreading or if swelling worsens.
- Advise patients to return to the clinic if respiratory or gastrointestinal symptoms develop.
- Patients may use cosmetic preparations to cover facial lesions.Refer patients to support groups or counseling services if they are having difficulty coping with their physical appearance.
# References
# Molluscum Contagiosum Background
Molluscum contagiosum is a viral infection of human epidermal keratinocytes, caused by a double-stranded DNA virus of the Poxviridae family.Molluscum appears as papules or nodules and sometimes is called "molluscum warts."It is seen most frequently in HIV-uninfected children (up to 5% of children in the United States), in sexually active young adults, and in immunocompromised persons.It occurs in 5-18% of HIV-infected persons.Molluscum is benign but may cause extensive and cosmetically bothersome lesions, particularly in persons with advanced HIV infection.
Transmission occurs by person-to-person skin-to-skin contact (e.g., sexual activity, contact sports , or simply touching) or via fomites (towels, bedclothes, clothing , soft toys, shaving utensils, electrolysis equipment, tattooing tools, and sponges).The virus may be spread to other areas via self-inoculation (e.g., scratching, shaving, or touching a lesion).
In immunocompetent persons, the infection usually resolves spontaneously after 6-12 months, though genital lesions may remain longer.In HIV-infected persons, the lesions may be more extensive and persistent.There is a strong correlation between the degree of immunosuppression and the risk of molluscum infection, the number of lesions, and the ability of lesions to resist treatment.
# S: Subjective
Patients complain of new papules on the trunk, axillae, antecubital and popliteal fossae, face, or genital/crural area.Papules of molluscum contagiosum may cause no symptoms but also can be intensely pruritic or tender to the touch.Ask patients whether others in the home (especially children and adolescents) or their sex partners have similar papules.Genital lesions are transmitted sexually; patients may recall seeing such lesions on the genitals of a previous partner.
Ask about fever or other systemic symptoms to evaluate for other causes of the papules.
# O: Objective
Perform a thorough evaluation of the skin, genitals, and mouth.Molluscum commonly presents as multiple grouped lesions.The lesions are white, pink, or flesh colored; shiny, smooth surfaced, firm, pearly, and spherical (dome-shaped) papules (2-5 mm) or nodules (6-10 mm), with umbilicated, or dimpled, centers.Patients with HIV infection may develop giant lesions (>1 cm) or clusters of hundreds of small lesions.Occasionally, molluscum will have a polyp-like appearance.Lesions are usually found on the head, face, or neck or in the genital area, but may affect every part of the body except the palms and soles.Molluscum may occur inside the mouth, vagina, and rectum, and around the eyes.Lesions on the eyelids can cause conjunctivitis.
# A: Assessment
A partial differential diagnosis includes the following:
- Disseminated cryptococcosis
# Diagnostic Evaluation
The diagnosis of molluscum usually is based on the characteristic appearance of the lesions.Perform histologic or other laboratory testing to confirm the diagnosis or to exclude other infections or malignancies.Special staining will show keratinocytes containing eosinophilic cytoplasmic inclusion bodies.Electron microscopy will show poxvirus particles.
# Treatment
Because molluscum does not cause illness and rarely causes symptoms, the treatment usually is undertaken primarily for cosmetic purposes.
For individuals with large or extensive lesions, molluscum may be disfiguring or stigmatizing, and treatment may be important for their well being.Treatment (particularly of genital lesions) can be considered to prevent transmission to others.
In HIV-infected patients, molluscum is difficult to eradicate and lesions often recur, particularly if immune suppression persists.Effective antiretroviral therapy may achieve resolution of lesions or significant improvement in the extent or appearance of molluscum.
Lesions that remain after weeks of antiretroviral therapy should be treated to prevent further spread.Refer complex cases to a dermatologist.
Choice of treatment modality is based on age, likelihood of compliance, number and size of lesions, and potential adverse effects of treatment.Therapeutic options include the following:
- Local excision: may be done by curettage, electrocautery, evisceration, or cryotherapy.Adverse effects include pain, irritation, soreness, and mild scarring.Repeated treatments are necessary.Curettage appears to be most efficacious (even for children) but is painful and requires anesthesia and a large time commitment over the course of several visits; it also has a risk of scarring.Relapse is common.
- Imiquimod 5% (Aldara): an immune response modifier; stimulates production of interferon-alfa and other proinflammatory cytokines, inducing a tissue reaction associated with viral clearance from the skin.Apply TIW for up to 16 weeks or QPM for 4 weeks.Clearing can take up to 3 months.Limited studies; painless.
- Tretinoin (Retin-A) 0.1% cream: can be applied to lesions BID.Adverse effects include drying, peeling, irritation, and soreness.
- Podophyllum resin (podophyllin): can be administered by a health care provider and washed off after 1-4 hours.This treatment is caustic, may cause significant irritation, and has limited effectiveness.It is contraindicated for use during pregnancy.Patient-administered podophyllotoxin (Podofilox) may be a safer alternative to podophyllum.Adverse effects include burning, pain, inflammation, erosion, and itching.
- Trichloroacetic acid: can be administered by a health care provider.Controlling the depth of acid penetration is difficult.Adverse effects include pain and irritation; mild scarring is common.
- A combination of salicyclic and lactic acid: response is highly variable and recurrence is common.
- Laser therapy: safe, efficient, tolerable, and efficacious.
- Cidofovir 1-3% topical cream: applied BID for 2 weeks, followed by a 30-day rest period and then two additional cycles.This treatment has been shown to be effective in several small studies and case reports, but it is expensive and difficult to compound.No systemic adverse effects are noted.
- Silver nitrate paste may be used to burn each lesion individually.
- Cantharidin 0.7%: can be applied by a health care provider.One study of 300 children found that lesions cleared after two visits.This treatment may cause allergic reactions, stinging, and blistering.Do not use cantharidin around the eyes.
# Patient Education
- Molluscum infection is benign but may be distressing.
- Molluscum infection may be transmitted both sexually and nonsexually, through direct contact with lesions.Molluscum also can be transmitted indirectly by contact with infected objects.
- Latex condoms or barriers may not prevent transmission of genital molluscum.
- To prevent the spread of molluscum, instruct patients to take the following precautions:
- Avoid close contact between their molluscum lesions and the skin, mouth, and genitals of other people.
- Avoid picking at, squeezing, or puncturing the lesions, as a lesion's central plug is full of viral particles that can be spread easily by coming into contact with other parts of the body.In addition, lesions may become secondarily infected.
- Wash hands frequently.
- Keep fingernails short.
- Avoid shaving in areas with lesions because shaving could result in lesions spreading to other areas.
- Avoid sharing towels, bedclothes, clothing, shaving utensils, bathing equipment, or other objects that have been in contact with molluscum lesions.
- Wash all contaminated items in very hot, but not scalding, water.
- Cover lesions with clothing, if possible.
# Mycobacterium avium Complex Background
Mycobacterium avium complex (MAC) is an opportunistic infection caused by species of Mycobacterium that can produce severe illness in people with advanced AIDS but rarely affects others.The risk of disseminated MAC (DMAC) is directly related to the severity of immunosuppression.DMAC typically occurs in persons with CD4 counts of <50 cells/µL, and its frequency increases as the CD4 count declines.In the absence of antibiotic prophylaxis, DMAC occurs in up to 40% of AIDS patients with CD4 counts of <50 cells/µL. Antimicrobial therapy, especially if given in conjunction with antiretroviral therapy (ART) that achieves immune reconstitution, can be successful in treating MAC disease.Specific antimicrobial prophylaxis and effective ART also may be used to prevent MAC in patients with advanced AIDS (see chapter Opportunistic Infection Prophylaxis).
Mycobacterium organisms are common in the environment.They are found worldwide and have been isolated from soil, water, animals, birds, and foods.They usually enter the body through the respiratory or gastrointestinal tract and disseminate to cause multisystem infection, typically manifested by nonspecific symptoms and signs such as fever, sweats, weight loss, abdominal pain, fatigue, chronic diarrhea, and anemia and other cytopenias.MAC also can cause local disease such as central nervous system infection, lymphadenitis, soft-tissue or bone infections, and rarely, isolated pulmonary disease.Focal MAC disease is more common among patients on ART, whereas DMAC is the more common manifestation among those with low CD4 cell counts who are not on ART.Unlike Mycobacterium tuberculosis, M. avium is not thought to be transmitted via person-to-person contact.In patients with subclinical or incompletely treated MAC who have recently started ART, an immune reconstitution inflammatory syndrome (IRIS) may occur with localized lymphadenitis or paradoxically worsening symptoms (see chapter Immune Reconstitution Inflammatory Syndrome). |
# S: Subjective
The patient complains of one or more of the following symptoms:
# O: Objective
Perform a full physical examination with particular attention to the following:
- Vital signs (temperature, heart rate, blood pressure, respiratory rate)
- Weight (compare with previous measurements)
Section 6: Comorbidities, Coinfections, and Complications
- General appearance (cachexia, wasting, signs of chronic illness, jaundice, pallor)
- Lymph nodes (lymphadenopathy)
- Abdomen (hepatosplenomegaly, tenderness)
Review previous laboratory values, particularly the CD4 count (usually <50 cells/µL).
# A: Assessment
Rule out other infectious or neoplastic causes of constitutional symptoms, anemia, or organomegaly.A partial differential diagnosis would include the following:
- M. tuberculosis infection
# Treatment
Because antimicrobial resistance develops quickly with single-drug therapy, multidrug regimens must be administered for DMAC.
# Recommended regimen:
- Clarithromycin 500 mg BID + ethambutol 15 mg/kg once daily Clarithromycin is the preferred cornerstone of MAC therapy, as it has been studied more extensively and is associated with more rapid clearance of MAC bacteremia.If clarithromycin cannot be tolerated or if there is concern regarding drug interactions, azithromycin 500-600 mg once daily may be substituted for clarithromycin.Clarithromycin dosages should not exceed 1 g per day, as highdose clarithromycin has been associated with excess mortality.
Ethambutol is the recommended second agent, to be given with a macrolide.
Some experts recommend including a third agent for more advanced disease and for Section 6: Comorbidities, Coinfections, and Complications patients who are not receiving effective ART.The addition of rifabutin (300 mg daily) has been associated with a mortality benefit in one study and with reduced emergence of mycobacterial resistance in two other trials.A fluoroquinolone (e.g., ciprofloxacin, levofloxacin) or amikacin may be used instead of rifabutin as a third agent, or in addition to rifabutin as a fourth agent; however, studies have not confirmed the clinical benefit of these medications.
Because immune reconstitution is essential for controlling MAC, all patients who are not already receiving ART should begin ART, if possible.Patients who are receiving suboptimal ART should be evaluated for enhancement of their regimens.The optimal timing of ART initiation in relation to MAC treatment is unclear.Because immune reconstitution from effective ART may cause a paradoxical inflammatory response if started during active DMAC infection, some experts recommend treating DMAC for at least 2 weeks before adding antiretroviral (ARV) medications (see chapter Immune Reconstitution Inflammatory Syndrome).This strategy also helps to avoid or forestall interactions between DMAC and ARV drugs and the additive toxicities of those medications.
# Potential ARV Interactions
Clarithromycin and rifabutin have a number of significant drug interactions, including interactions with some commonly prescribed ARVs.These interactions should be reviewed prior to initiation of MAC therapy.Dosage adjustments or alternative medications may be required.Interactions of concern include the following:
- Atazanavir may raise clarithromycin levels by 50% while decreasing levels of clarithromycin's active metabolite; some experts recommend using azithromycin in place of clarithromycin, dosage reduction of clarithromycin by 50%, or an alternative ARV regimen.
- Darunavir may increase clarithromycin levels; dosage reduction of clarithromycin is recommended for patients with renal impairment.
- Tipranavir decreases levels of clarithromycin's active metabolite; also, tipranavir levels may be increased.
- Efavirenz may lower clarithromycin levels; some experts recommend use of azithromycin in place of clarithromycin.
- Etravirine may lower clarithromycin levels, while clarithromycin may in turn increase etravirine levels.Avoid this combination, if possible.
- Nevirapine may decrease clarithromycin levels and increase levels of its active metabolite.
Protease inhibitor-based ART (e.g., lopinavir or darunavir) or integrase inhibitor-based ART may be the preferred HIV treatment for patients on MAC therapy, because of limited drug interactions associated with those ARV classes.
Rifabutin has significant interactions with many drugs, including nonnucleoside reverse transcriptase inhibitors and protease inhibitors, and therefore dosage adjustments or alternative agents may be needed (for further information, see chapter Mycobacterium Tuberculosis.
# Patient Education
- Advise patients that antimycobacterial therapy alone will not eradicate MAC infection, but should decrease symptoms and improve quality of life.A response to treatment may take up to 4 weeks.If medications are discontinued, the disease almost always recurs, unless the CD4 count has increased to >50-100 cells/µL in response to ART.
- Patients must take all medicines exactly as prescribed.If doses are missed, or if the medication is stopped and restarted, MAC can develop resistance to the medications.If patients are having trouble taking the medications on schedule, they should contact their health care provider promptly.
- Advise patients that MAC IRIS is a common complication of effective ART and MAC therapy, and its occurrence in the course of treatment should be anticipated.
- Urge patients to contact the clinic immediately if they notice worsening of existing symptoms or the development of new symptoms.
- DMAC is an opportunistic infection of latestage HIV and it is indicative of profound immunosuppression.Some patients may not respond to MAC treatment or to ART.Because this is a life-threatening disease, clinicians should discuss advance directives and durable power of attorney with patients.
Referral to a social worker, mental health clinician, or chaplain experienced in such issues may facilitate the discussion.
# Mycobacterium tuberculosis
# Background
In HIV-infected individuals, tuberculosis (TB) causes more deaths worldwide than any other condition.A biologic synergy exists between HIV and TB such that HIV-induced immunosuppression increases susceptibility to TB infection, whereas active TB infection enhances HIV replication through immunologic stimulation.The populations infected by these two pathogens overlap in many respects, creating epidemiologic synergy.Poverty, crowded living conditions, and inadequate efforts to reduce transmission combine to enhance the transmission of both organisms.
In the United States, most cases of TB occur among immigrants, and TB is a relatively infrequent AIDS-defining illness.Nevertheless, TB remains important to HIV clinicians in the United States because it is highly infectious, though curable with proper treatment, and because improper treatment leads to drug resistance both in the infected patient and in those to whom that patient transmits.Although other conditions increase the risk of TB disease (e.g., malnutrition, diabetes, end-stage renal disease, pulmonary silicosis, and iatrogenic immunosuppressive drugs ), HIV infection is by far the most important risk factor.
TB is an infection caused by organisms in the Mycobacteria genus.These organisms grow slowly and can be identified only with special staining techniques, a trait that led to the name "acidfast bacteria."This chapter focuses on disease caused by Mycobacterium tuberculosis (MTB); other chapters describe diagnosis and management of latent MTB infection (see chapter Latent Tuberculosis) and diagnosis and management of disease caused by Mycobacteria avium (see chapter Mycobacterium avium Complex).
MTB most often causes a chronic pneumonia, but it can affect organs other than the lungs as well.The lung destruction caused by MTB may create cavities, similar to abscesses; these contain huge numbers of organisms.TB is transmitted almost always by persons with active pulmonary TB who release large numbers of organisms in their sputum.The organisms remain suspended in the air for hours or days, making TB among the most easily transmitted respiratory pathogens.Organisms are inhaled and infect the lung.In most people, the initial lung infection is contained by an effective immune response.It usually is asymptomatic but leads to foci in the lung (and sometimes in other organs) of latent TB, which may reactivate and cause disease years later.Shortly after the onset of infection with MTB, before its containment in the lung by the immune system, organisms can spread to other organs and establish latent infection in those areas as well.Reactivation in these other organs can lead to local disease (e.g., in the lymph nodes, meninges, bone, pericardium, peritoneum or intestine, and urogenital tract).
Persons with limited immunity, such as persons with HIV-associated immunosuppression and very young children, are at high risk of developing progressive primary TB at the time of initial MTB infection.Primary progressive MTB usually causes pulmonary disease, but also can cause meningitis or disseminated disease (blood, liver, spleen, lung, and other organs).Persons who have latent TB infection and then develop immunodeficiency are at high risk of developing reactivation disease.For example, compared with the 10% lifetime risk of developing active TB in immunologically normal persons, an HIV-infected person with latent TB has about a 10% chance each year of developing active disease.
# Section 6: Comorbidities, Coinfections, and Complications
Classical pulmonary tuberculosis, with upper lobe infiltrates and cavitary lesions, may occur in HIV-infected persons with relatively intact immunity.As the CD4 count decreases (particularly to <200 cells/µL), TB is more likely to manifest atypically in the chest (without cavitary disease, or with lower lobe disease, adenopathy, pleural effusions, or interstitial or military infiltrates), and as extrapulmonary or multiorgan disease (particularly in lymph nodes, peritoneum, pericardium, and meninges), and disseminated infection.Granulomas may be seen in the tissues; in persons with advanced immunodeficiency, these may be poorly formed and non-caseating.Bone, joint, and urogenital TB are less commonly associated with HIV-induced immunosuppression.Symptoms and signs in HIV-infected persons therefore can vary widely.
Before an effective treatment for TB was developed, one half of persons with TB died within a period of about 5 years; others recovered, but relapses sometimes occurred.Appropriate use of modern chemotherapy applied to drug-susceptible MTB disease cured at least 95% of persons in the pre-HIV era.Nowadays, drug-susceptible TB remains highly curable, even for persons with HIV infection.However, drug resistance seriously reduces the cure rate.Drug resistance usually is caused by improper or erratic treatment, and is spreading rapidly and becoming more severe.Effective diagnosis and cure of drug-susceptible TB not only reduces the disease burden in the individual and reduces further transmission, it also is crucial to avoiding drug resistance.
MTB resistance to a single drug may extend or complicate treatment but usually does not prevent successful treatment of TB.Resistance to several drugs (polydrug resistance or PDR) requires a longer course of therapy using medications that are less potent and have more side effects, and it markedly reduces the chance of cure.Resistance to both isoniazid and rifampin, with or without resistance to other first-line drugs, is called multidrug resistance (MDR), and it makes treatment especially difficult.Extreme drug resistance (XDR) occurs when, in addition to isoniazid and rifampin resistance, there is resistance to specific second-line drugs: a fluoroquinolone plus an injectable agent (either kanamycin, amikacin, or capreomycin).Treatment of drug-resistant TB should be managed by experts or in consultation with experts.
Effective antiretroviral treatment (ART) is a critical component of the care of persons with TB, and ART should be initiated or optimized in all persons with active TB.This chapter will discuss the evaluation and management of TB in the United States and other high-income settings.For management of TB in resource-limited settings, see the relevant World Health Organization guidelines and other resources.
Section 6: Comorbidities, Coinfections, and Complications
# S: Subjective
Persons with TB generally describe an illness lasting several weeks to months, associated with systemic features such as high fevers, night sweats, loss of appetite, and weight loss.These symptoms are nonspecific, but should raise the possibility of TB.
- Pulmonary TB presents with a chronic productive cough and sometimes with hemoptysis; shortness of breath occurs late in the disease course.
- TB adenitis presents with enlarged lymph nodes (usually asymmetric involvement in one region) that may suppurate and drain but usually are not painful, hot, or erythematous.
- TB meningitis presents with headache, gradual change in mental status, and at times with cranial nerve abnormalities such as double vision or decreased hearing.
- Disseminated TB may occur with only systemic manifestations such as fever, sweats, and weight loss, with no localizing features.
# O: Objective
- Measure vital signs, including oxygen saturation.
- Measure weight; compare with previous values.
- Perform thorough physical examination with particular attention to the lungs, heart, abdomen, lymph nodes, and neurologic system.
Systemic signs of chronic disease and inflammation are common, including fever, night sweats (which may occur without awareness of the high fever that precedes them), and weight loss.
In patients with pulmonary TB, the breath sounds may be normal or focally abnormal; tachypnea and hypoxia occur only with extensive lung damage.
Extrapulmonary TB may present with focal adenopathy without local signs of inflammation, but perhaps with a draining sinus.
TB meningitis presents as subacute or chronic meningitis, with neck stiffness and changes in mental status.Symptoms may include cranial nerve palsies owing to inflammation at the base of the brain or increased intracranial pressure.
Pericardial disease can cause the pain and friction rub of pericarditis or signs of pericardial tamponade.
Infiltration of the bone marrow can produce pancytopenia.
Disseminated TB may cause diffuse adenopathy, hepatic or splenic enlargement, and abnormal liver function, although hepatic failure is rarely attributable to TB alone.Infection of the adrenal glands can cause adrenal insufficiency.
Section 6: Comorbidities, Coinfections, and Complications occur; these require different treatment.Drug susceptibility testing is necessary because improper treatment of drug-resistant TB will lead to treatment failure, more severe drug resistance within the patient, and increased risk of transmission of drug-resistant TB.
Three specimens of expectorated sputum should be sent for acid-fast staining and mycobacterial culture on each of three days or at least 8 hours apart, including at least one first-morning specimen.A presumptive diagnosis of pulmonary TB can be made if acid-fast bacilli are seen, but confirmation is required.Sputum induction with nebulized saline (e.g., by respiratory therapists) can be used for patients who do not have spontaneous sputum production. (Young children cannot produce sputum, so gastric lavage on three successive mornings can be performed to obtain swallowed sputum for smear and culture.)Many laboratories will perform nucleic acid hybridization on acid-fast-positive sputum to identify the species of infecting Mycobacteria, and probes are available to confirm MTB and certain non-TB Mycobacteria.Two NAA tests are licensed in the United States, and some U.S. clinical laboratories use "in-house" NAA tests.Other NAA tests are licensed and available in other countries.These tests confirm M. tuberculosis in sputum smear-positive patients with a specificity of >95%, and results can be available within 24 hours of obtaining a positive smear.The rapid identification of MTB facilitates appropriate respiratory infection control precautions, contact tracing, and immediate treatment of MTB.NAA tests also are useful in making a presumptive diagnosis in smear-negative patients who are suspected to have active pulmonary TB, pending culture results.However, these tests can yield falsepositive results, particularly with persons in whom pulmonary TB is unlikely.Also, false negatives can occur in both smear-positive and smear-negative patients.Other NAA tests can be used to diagnose non-TB Mycobacteria.If a non-TB Mycobacterium is diagnosed, respiratory precautions can be discontinued, and treatment for the specific or suspected organism can be started.
Patients with suspected pulmonary TB and negative sputum microscopy or NAA should undergo bronchoscopy and transbronchial biopsy (which is more sensitive than bronchoalveolar lavage for TB).The Gen-Probe AMPLIFIED MTD Test also is approved by the U.S. Food and Drug Administration (FDA) for smear-negative cases but sensitivity in this scenario is as low as 66%, whereas specificity remains close to 100%.If the NAA test result is negative, diagnosis of TB may not be excluded, and decisions about treatment must be based on clinical assessment.
A diagnosis of extrapulmonary TB generally requires an examination of infected tissue or body fluid by microscopy and culture.NAA for MTB and some other atypical Mycobacteria also can be performed on tissue and body fluids (such as CSF); specimens that are fresh or frozen generally are preferable to specimens preserved in formalin or a similar chemical.Specimens of organs with suspected TB can be obtained by peripheral lymph node aspiration, CT-guided or other guided aspiration and biopsy, liver biopsy, bone marrow biopsy, or thoracoscopy-or laparoscopy-guided biopsies of pleura or peritoneum.In some cases, surgery is required to obtain appropriate specimens.Blood cultures for Mycobacteria (using appropriate mycobacterial media rather than standard blood culture media) may be positive in disseminated TB; the technique is the same as in culturing blood for M. avium complex organisms.Urine culture is used to diagnose renal TB, although this condition is rare among HIV-infected persons.
# Respiratory Precautions
Respiratory infection control precautions should be implemented for HIV-infected patients with an undiagnosed chronic cough or undiagnosed inflammatory infiltrate on chest X ray.Individual institutions have specific guidelines that should be followed; patients usually are housed in single negativepressure rooms and persons entering the rooms are required to wear protective respirators.If three sputum smears yield negative results on AFB staining, or if a single deep specimen (bronchial lavage or tracheal aspirate) is smear negative, infectious TB is unlikely and respiratory precautions can be discontinued.Patients who are highly suspect for MTB and lack an alternate diagnosis may be kept on precautions and empiric treatment may be started.Persons who have responded to treatment for an alternative diagnosis (e.g., bacterial pneumonia), and those who cannot produce the requisite three sputum samples, may be released from the TB precautions.
The impact of TB transmission is greater in a health care setting, where immunosuppressed persons may be exposed, than at home, where exposure has already occurred prior to the TB evaluation.Of course, children younger than age 5 and immunosuppressed persons in the home are at increased risk.
# Treatment
Treatment for TB should be instituted promptly when TB is considered likely and the proper specimens to prove the diagnosis have been obtained.It is ideal to have a positive smear result (and confirmation by NAA) prior to initiating treatment, but empiric treatment can be started while the initial specimens are collected from patients in whom the suspicion of TB is high, in severely ill persons, or in circumstances in which positive smear results are unlikely (e.g., the cerebrospinal fluid smears).
Randomized trials have demonstrated that ART decreases mortality in HIV-infected persons with active TB; thus, effective ART should be initiated or optimized in everyone with TB/HIV coinfection; see "Coordinating with Antiretroviral Therapy," below. |
Adherence is the most important treatment issue once the decision to treat is made and an appropriate regimen is selected.It is the responsibility of the treating clinician to ensure that the patient completes a full course of therapy.Therefore, it is strongly recommended that patients be referred to public health departments for TB treatment.Health departments usually can provide free TB treatment and have specific resources Section 6: Comorbidities, Coinfections, and Complications and systems to promote adherence.It is recommended that all patients receive directly observed therapy (DOT), an approach by which the taking of every dose of anti-TB medication is observed and documented.The intermittent therapies shown in Table 1 (regimens 1b, 2, and 3) were designed to simplify DOT; however, twice-weekly regimens should not be used for persons with CD4 counts of <100 cells/µL and once-weekly regimens with rifapentine should not be used for anyone with HIV infection.
Clinical trials have documented that DOT with enhancements to maximize adherence not only improves the rate of completion of therapy but also reduces mortality among HIV-infected TB patients.If a health department manages the TB treatment, the HIV clinician must coordinate with the health department for the following reasons: 1) to coordinate TB and HIV treatment regimens; 2) to avoid or adjust for drug interactions; 3) to assist the health department in avoiding diagnostic or treatment confusion in the event of immune reconstitution inflammatory syndrome (IRIS) or incident opportunistic diseases; and 4) to maximize adherence with the TB medications, ART, opportunistic infection treatment or prophylaxis, and any other medications.U.S. guidelines for TB treatment in HIVinfected persons are shown in Table 1; dosages are given in Table 2.
# Recommended (drug-susceptible TB):
- Initial Phase: Isoniazid + rifampin (or rifabutin) + pyrazinamide + ethambutol once daily for 8 weeks
- Continuation Phase: isoniazid + rifampin or rifabutin Four anti-TB drugs are administered for the first 2 months, then two drugs are administered for an additional 4 months (if the organism is susceptible to standard medications).The initial phase of TB treatment usually consists of isoniazid, rifampin or rifabutin (see below), pyrazinamide, and ethambutol; the continuation phase typically is simplified to isoniazid and rifampin.Pyridoxine (vitamin B6) at a dosage of 10-50 mg per day usually is included to minimize the risk of isoniazid-induced peripheral neuropathy.If drug resistance or MDR is suspected, more drugs can be used initially, and treatment should be directed by experts.
Resistance may be suspected among persons exposed to TB in countries with high rates of endemic resistance, those for whom previous treatment has failed, those who have been on and off treatment erratically, those who may have had a specific exposure to drug-resistant TB, and those who have been diagnosed during an outbreak.
In certain circumstances treatment duration is extended.In cavitary TB or TB in an HIVinfected person that remains sputum culture positive after 2 months of treatment, the twodrug continuation phase should be extended to 7 months for a total treatment course of 9 months.For extrapulmonary TB in HIVinfected persons, a 6-to 9-month course of treatment is recommended.Exceptions include meningeal TB and bone or joint TB, which are treated for 9-12 months.If cultures obtained prior to treatment demonstrate drug resistance, the regimen and the duration of therapy may need to be changed.
For TB meningitis or pericarditis, a course of corticosteroids may be given in addition to specific anti-TB therapy: dexamethasone 0.3-0.4 mg/kg/day tapered over the course of 6-8 weeks or prednisone 1 mg/kg/day for 3 weeks followed by a taper over the course of 3-5 weeks.For adrenal insufficiency, replacement corticosteroids should be given.
# Considerations during pregnancy
Pyrazinamide has not been formally proven safe for use during pregnancy; however, it is used during pregnancy in many countries and there have been no reports of problems.Some health departments in the United States avoid the use of pyrazinamide for pregnant women and extend the continuation phase to 7 months, whereas others prescribe the standard regimens shown in Table 1 during pregnancy.
Streptomycin and certain second-line drugs should be avoided during pregnancy.HIVinfected women in the United States are instructed not to breast-feed, so there usually are no issues regarding TB treatment of HIVinfected women during breast-feeding.ART should be started as early as possible; consult with an expert.
# Coordinating with Antiretroviral Therapy
ART and TB treatment must be coordinated for both to be successful.ART is indicated for all adults and adolescents with active TB, and both metaanalyses and randomized trials have demonstrated reduction in mortality when ART is combined with anti-TB chemotherapy.
# Drug-Drug Interactions
Drug interactions between TB medications and ARVs may require dosage adjustments or modifications in treatment (see Table 3).Rifampin is a potent inducer of cytochrome P450 enzymes and has many clinically important drug interactions.It reduces the blood levels of nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), the integrase inhibitor raltegravir, and the CCR5 antagonist maraviroc, but does not affect nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) or the fusion inhibitor enfuvirtide.Triple nucleoside regimens can be administered safely during rifampin treatment but are less potent than first-line ARV combinations and generally are not recommended.The safest ARV combination to use with rifampin is a two-drug NRTI backbone with efavirenz (see Table 3).Some clinicians increase the efavirenz dosage to 800 mg/day because efavirenz blood levels may be reduced 25% by concomitant rifampin.Limited clinical data support the use of Section 6: Comorbidities, Coinfections, and Complications nevirapine at standard dosages in combination with rifampin.This is not a favored approach because nevirapine levels are reduced up to 50% when combined with rifampin.In one study, 20% of patients on ARV and TB treatment with rifampin had trough nevirapine levels that were below target, although they achieved the same rates of HIV RNA suppression as patients on efavirenz.
To avoid rifampin-ARV interactions, rifabutin typically is used in place of rifampin.Rifabutin has fewer marked effects on the pharmacokinetics of other drugs, although its own blood concentrations can be affected by certain ARVs.Dosing recommendations for rifabutin with ARVs are found in Table 3.Rifabutin is expensive; some public health systems do not provide rifabutin as part of TB treatment and it generally is not available in resource-limited countries.The FDA characterizes rifabutin in pregnancy category B: it has been safe in animal studies of pregnancy but has not been proven safe for humans.For pregnant women who require both TB and ARV therapy, the use of rifabutin rather than rifampin allows the use of nonefavirenz-based ARV regimens.
Persons who are already on ART when TB treatment is begun must have their ARV regimens reassessed; the appropriate dosages of rifampin or rifabutin must be chosen or the ARV regimen must be modified, at least until completion of TB treatment.
# Patient Education
- All patients with TB-positive sputum or bronchoscopy specimens can infect others with TB.All close contacts, especially children, should be screened for TB as soon as possible and given medication to prevent (or treat) active disease.
- The health department will be notified of each TB case and will provide the required follow-up care.
- Patients must take all medicines exactly as prescribed.If doses are missed, or if the medication is stopped and restarted, the TB bacteria can develop resistance to even the best medications and become even more dangerous.If patients are having trouble taking the medication on schedule, they should contact their health care provider immediately.
- If patients become ill, if their skin or eyes turn yellow, or if their urine darkens to a cola color, they should contact their health care provider immediately.
- Patients must keep all follow-up appointments.Blood tests will be done regularly to ensure that the liver is working well, and patients will be checked for medication adverse effects.They should show their health care provider all medications, vitamins, and supplements they are taking so that the provider can check for drug interactions.
- Rifampin and rifabutin will make urine, sweat, and tears turn orange; this is not harmful.They will cause staining of plastic contact lens; patients should avoid wearing contact lenses if they are taking rifamycins.
- Rifampin and rifabutin will cause birth control pills to become ineffective.An alternative method of contraception should be used when the patient is undergoing treatment.
- The use of alcohol should be avoided during treatment with TB drugs to avoid the risk of liver damage.
# Pelvic Inflammatory Disease Background
Pelvic inflammatory disease (PID) is the syndrome resulting from the ascent of microorganisms from the vagina and cervix to the uterine endometrium, fallopian tubes, ovaries, or contiguous abdominal structures.Many episodes of PID go unrecognized, because of lack of symptoms or mild, nonspecific symptoms (e.g., dyspareunia, abnormal bleeding, and vaginal discharge).Infecting organisms may include Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT), which are sexually transmitted, as well as anaerobic bacteria (Gardnerella vaginalis or Haemophilus influenzae), gram-negative rods (Escherichia coli), Streptococcus agalactiae, gastrointestinal flora, and mycoplasmas (Mycoplasma hominis).It is thought that PID generally is caused by sexually transmitted infections (STIs) and that additional organisms become involved after infection spreads and protective immunological barriers are disrupted.
Between 20% and 40% of women with cervical chlamydial infection and 10-20% of women with gonococcal infection eventually develop PID, but accurate estimates of the incidence of PID and infertility resulting from GC and CT are difficult to obtain.Hospitalizations for PID declined steadily throughout the 1980s and 1990s but remained relatively constant between 2000 and 2006, at approximately 80,000 annually.
PID is co-epidemic with HIV among some urban populations of reproductive age.Data on PID outcomes among HIV-infected women are limited.Many studies have documented no difference in length or severity of lower abdominal pain, vaginal discharge, fever, abnormal vaginal bleeding, or low back pain between HIV-infected and HIV-uninfected women with PID.However, there is a higher rate of tubo-ovarian abscesses and severe salpingitis and pyosalpinx among HIV-infected women.
Clinical presentation may include salpingitis, endometritis, tubal and ovarian abscess, and pelvic peritonitis, although PID may present with subtle or mild symptoms even in HIV-infected women.Long-term complications of PID may include infertility, ectopic pregnancy, pelvic adhesions, and chronic pain.After a single episode of PID, a woman's risk of ectopic pregnancy increases sevenfold.Approximately 13% of women are infertile after a single episode of PID, 25-35% after two episodes, and 50-75% after three or more episodes.
Diagnosis of PID usually is based on clinical findings, and providers should maintain a low threshold for diagnosing and promptly treating this disease, as it can wreak havoc on a woman's reproductive health.All women who are diagnosed with PID should be tested for GC and CT.
# S: Subjective
The patient may complain of mild-to-moderate lower abdominal pain and tenderness, pain with intercourse, vaginal discharge, fever, chills, heavy menstrual bleeding, or other abnormal vaginal bleeding.
Inquire about the following during the history:
# A: Assessment
A partial differential diagnosis includes the following:
- Pregnancy, uterine or ectopic The following signs support a diagnosis of PID:
- Oral temperature >101°F (>38.3°C)
- Abnormal cervical or vaginal mucopurulent discharge - Presence of abundant numbers of white blood cells on saline microscopy of vaginal secretions (this also can detect concomitant infections such as bacterial vaginosis and trichomoniasis)
- Elevated erythrocyte sedimentation rate (ESR)
- Elevated C-reactive protein (CRP)
- Laboratory documentation of cervical infection with GC or CT (the absence of infection from the lower genital tract, where samples are usually obtained, does not exclude PID and should not influence the decision to treat)
Definitive diagnosis may be made on the basis of:
- Endometrial biopsy with histopathologic evidence of endometritis
- Transvaginal sonogram or other imaging showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex
- Laparoscopic abnormalities consistent with PID
# Treatment
Because clinical diagnostic criteria for PID are not always conclusive, presumptive diagnosis and early empiric treatment is common.The positive predictive value of a clinical diagnosis is 65-90%.
Empiric therapy for PID should be started in women who have one or more of the minimal criteria, plus pelvic or lower abdominal pain and risk factors for PID (sexually active young women, women at risk of STIs), unless another cause for the symptoms is identified.
# Treatment considerations
Antimicrobial regimens must be broadly effective against likely pathogens (see below).HIV-infected women appear to respond as well to standard antibiotic regimens as do HIV-uninfected women.It is not known whether HIV-infected women with advanced immunosuppression should be treated more aggressively; decisions about whether to use oral or parenteral therapy must be individualized.
Resistance to fluoroquinolone by GC is widespread in the United States and elsewhere; thus, this class of antibiotics is no longer recommended for treatment of PID.
No evidence suggests that IUDs should be removed in women diagnosed with PID.However, caution should be used if the IUD remains in place, and close clinical follow-up is recommended.
The goals of treatment include the following:
- Alleviate the pain and systemic malaise associated with infection
# Pregnancy
If the patient is pregnant, aggressive treatment is essential to prevent preterm delivery, fetal loss, and maternal morbidity.Some medications should be avoided to reduce the risk of fetal toxicity; these include doxycycline and gentamicin.Hospitalization for parenteral antibiotic therapy is recommended.
# Antibiotic Regimens
Recommended Oral/Outpatient Regimens - Ceftriaxone 250 mg IM in a single dose + doxycycline 100 mg PO BID for 14 days, with or without metronidazole 500 mg PO BID for 14 days
- Cefoxitin 2 g IM in a single dose and probenecid 1 g PO concurrently in a single dose + doxycycline 100 mg PO BID for 14 days, with or without metronidazole 500 mg PO BID for 14 days
- Other parenteral third-generation cephalosporin (e.g., ceftizoxime or cefotaxime) + doxycycline 100 mg PO BID for 14 days, with or without metronidazole 500 mg PO BID for 14 days
# Alternative Oral Regimens
If parenteral cephalosporin therapy is not feasible, consult with an expert.Some evidence supports the use of amoxicillin/clavulanic acid with doxycycline, and azithromycin with or without metronidazole or ceftriaxone.Because of the prevalence of fluoroquinolone-resistant GC, use of fluoroquinolones is no longer recommended but may be considered, with or without metronidazole, if the community prevalence and patient's risk of gonorrhea is low.For more information, see the CDC STD Treatment Guidelines (see "References," below).
# Recommended Parenteral Regimens
- Cefotetan 2 g IV Q12H + doxycycline 100 mg PO BID
- Cefoxitin 2 g IV Q6H + doxycycline 100 mg PO BID
- Clindamycin 900 mg IV Q8H + gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) Q8H; single daily dosing (3-5 mg/ kg) may be substituted
# Alternative Parental Regimen
- Ampicillin/sulbactam 3 g IV Q6H + doxycycline 100 mg PO BID Women who are started on oral antibiotics but do not respond within 72 hours should be reevaluated to confirm the diagnosis of PID and should be administered parenteral therapy on either an outpatient or inpatient basis.Patients who are treated with parenteral antibiotics usually can be transitioned to oral antibiotics within 24 hours of clinical improvement.
Section 6: Comorbidities, Coinfections, and Complications
# Follow-Up
- Patients should show significant clinical improvement within 3 days of initiation of therapy (e.g., improvement in fever, abdominal tenderness, and uterine, adnexal, and cervical motion tenderness).
If the patient has not improved, consider hospitalization, additional diagnostic testing, or surgical intervention.Patients who are hospitalized for treatment initially may be switched to an oral regimen and be discharged on oral therapy after they have improved clinically.
- Evaluate sex partners and offer them treatment if they had sexual contact with the patient during the 60 days preceding the patient's onset of symptoms.Treat empirically for both chlamydia and gonorrhea.
- Some specialists recommend rescreening for GC and CT after therapy is completed in women with documented infection with these pathogens.
- Provide education about sexual risk reduction.Instruct patients to use condoms with every sexual contact to prevent reinfection with GC and CT, to prevent other STIs, and to prevent passing HIV to sex partners.
- Studies of patients treated for CT infection show reinfection rates as high as 13% within 4 months of treatment, highlighting the need for follow-up and partner treatment.
# Patient Education
- Instruct patients to take all of their medications.Advise patients to take medications with food if they feel nauseated, and to contact the clinic promptly if they experience vomiting or are unable to take their medications.
- Sex partners from the previous 60 days need to be tested for sexually transmitted pathogens and treated as soon as possible with a regimen effective against GC and CT, even if they have no symptoms.Advise patients to inform their partners that they need to be tested and treated.Otherwise, they may be reinfected.
- Advise patients to avoid sexual contact until the infection has been cured.
- Provide education about sexual risk reduction.Instruct patients to use condoms with every sexual contact to prevent becoming reinfected, to prevent other STIs, and to prevent passing HIV to sex partners.
- Advise patients that PID can recur, and that they should contact the clinic if symptoms such as pain or fever develop.
- Patients must not drink beer, wine, or any other alcoholic beverage while taking metronidazole, and for at least 24-48 hours after the last dose.Metronidazole may cause a disulfiram-like reaction, resulting in severe nausea and vomiting.Note that patients taking ritonavir capsules may experience symptoms caused by the small amount of alcohol in the capsules; advise patients to contact the clinic if nausea and vomiting occur.
# Pneumocystis Pneumonia Background
Pneumocystis jiroveci pneumonia (previously called Pneumocystis carinii pneumonia, and still abbreviated PCP), is caused by an unusual fungus, P. jiroveci. |
Many humans appear to be infected in childhood, but clinical illness occurs only in people with advanced immunosuppression, either through new infection or reactivation of latent infection.More than 90% of PCP cases occur in patients with CD4 counts of <200 cells/µL. Cases of PCP in otherwise healthy young homosexual men were among the first recognized manifestations of AIDS, in 1981.The organism can affect many organ sites, but pneumonia is by far the most common form of disease.In the United States, the incidence of PCP has declined sharply since the use of prophylaxis and effective antiretroviral therapy (ART) became widespread, but PCP is still many patients' initial presenting opportunistic infection, and it is a significant cause of morbidity and mortality among HIV-infected patients.
# S: Subjective
The patient reports fever, shortness of breath, particularly with exertion, nonproductive cough, night sweats, weight loss, or fatigue.Typically, the symptoms worsen over the course of days to weeks.Pleuritic pain and retrosternal pain or burning also may be present.There may be minimal symptoms early in the disease course of PCP.
Ask the patient about fever, fatigue, and weight loss, which may be present for weeks, with gradual worsening of shortness of breath.PCP may present less commonly with acute onset symptoms of fevers, chills, sweats, dyspnea, and cough.
Note: Given the possibility of HIV-associated tuberculosis (TB), patients with cough should be kept in respiratory isolation until TB is ruled out.
# O: Objective
Perform a full physical examination, with particular attention to the following:
- Vital signs, including temperature, heart rate, blood pressure, respiratory rate, oxygen saturation at rest and after exertion (there is often a sharp drop in oxygen saturation with exertion)
- Appearance
# Lung examination
Patients may appear relatively well, or acutely ill.Tachypnea may be pronounced, and patients may exhibit such a high respiratory rate (e.g., >30 breaths per minute) that they are unable to speak without stopping frequently to breathe.Chest examination may be normal, or reveal only minimal rales, although coughing is common on deep inspiration.Cyanosis may be present around the mouth, in the nail beds, and on mucous membranes.Cough is either unproductive, or productive of a thin layer of clear or whitish mucus.
# A: Assessment
A partial differential diagnosis includes the following:
- Pneumococcal pneumonia
# Diagnostic Evaluation
- CD4 cell count: Check records for a recent CD4 count (CD4 is 90% of PCP cases).Note that a CD4 count obtained in the setting of acute illness (e.g., when the patient presents with pneumonia) may be substantially lower than the usual baseline, and may be difficult to interpret.
- Pulse oximetry at rest and after exercise: Oxygen desaturation with exercise suggests an abnormal alveolar-arterial O2 gradient (A-a gradient).
- Arterial blood gas (ABG): Hypoxemia is common, as is elevation in A-a gradient.Generally, PO2 levels and A-a gradient are associated with disease severity.Poorer outcomes are seen with PO2 35 mm Hg.
- Lactate dehydrogenase (LDH): Elevated serum LDH (>300-500 IU/L) is common.
- Chest X ray: Typically shows bilateral interstitial infiltrates, but atypical patterns with cavitation, lobar infiltrates, nodules, or pneumothorax may occur, and chest X-ray findings may be normal in some cases.
Upper-lobe predominance is common if the patient is receiving aerosolized pentamidine for PCP prophylaxis.
- Thin-section chest computed tomography (CT) scan: May show ground glass opacities; in a patient with clinical signs or symptoms of PCP, these are suggestive but not diagnostic of PCP.
- Sputum induction: The patient inhales saline mist to mobilize sputum from the lungs.The respiratory therapist collects expectorated sputum, which is stained with Giemsa and examined for P. jiroveci organisms.This technique is useful because of its noninvasive approach, but it requires an experienced technician, and therefore may not be available at all centers.Sensitivity varies widely (10-95%), depending on the expertise level of the staff at a particular center. (If there is any chance that the patient has TB, sputum induction should be performed in a confined space in a negative pressure area or near an exhaust fan vented safely outside, and samples should be sent for acid-fast bacilli smear and culture.)
- Bronchoscopy with bronchoalveolar lavage (BAL): If induced sputum tests negative for PCP organisms, definitive diagnosis is made through detection of organisms in BAL fluid obtained during bronchoscopy.Sensitivity is >95% at centers with an experienced staff.BAL fluid can be evaluated for bacteria, mycobacteria, and fungi, as well as for P. jiroveci.
- Transbronchial biopsy may be performed if lung disease is progressive despite treatment, to look for diagnoses other than PCP.Open lung biopsy rarely is performed.
# Treatment
Presumptive treatment often is initiated on the basis of clinical presentation, chest X-ray findings, and ABG results, while definitive diagnostic tests are pending.The standard and alternative treatment regimens are shown in Table 1.
# Standard Therapy
# Trimethoprim-sulfamethoxazole
Trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra, cotrimoxazole) is the drug of choice: 15-20 mg/kg of the TMP component plus 75-100 mg/kg of the SMX component, divided into three or four doses daily and administered IV or PO for 21 days (a typical PO dose is two double-strength tablets TID).Adverse effects of TMP-SMX (e.g., rash, fever, leukopenia, anemia, gastrointestinal intolerance, hepatotoxicity, hyperkalemia) are common, mostly mild, and usually "treated through" successfully.Patients who have had previous reactions to sulfa drugs also may be desensitized successfully (see chapter Sulfa Desensitization).TMP-SMX requires dosage adjustment for patients with renal insufficiency.
# Adjunctive corticosteroids
Adjunctive corticosteroids should be given if the patient's PO2 is 35 mm Hg.Corticosteroids should be given as early as possible (preferably before or with the first dose of antibiotic therapy) and within 36-72 hours of the start of anti-PCP therapy:
- Prednisone 40 mg BID days 1-5; 40 mg once daily on days 6-10; 20 mg once daily on days 11-21.IV methylprednisolone can be given, at 75% of the prednisone dosage.
# Other therapy notes
- Patients started on IV therapy can be switched to an oral treatment regimen to complete the 3-week course when they are afebrile, have improved oxygenation, and are able to take oral medications.
- Paradoxical worsening of PCP resulting from presumed immune reconstitution inflammatory syndrome (see chapter Immune Reconstitution Inflammatory Syndrome) has been reported in some patients who initiated ART close to the time of diagnosis and treatment for PCP.However, recent data suggest that unless other compelling contraindications are present, early initiation of ART (near the time of initiating OI treatment) should be considered for most patients with most acute OIs, including PCP.
- Consultation with HIV experts is advisable when considering initiation of ART in the setting of PCP.
# Treatment failures
The average time to clinical improvement for hospitalized patients is 4-8 days, so premature change in therapy should be avoided.For patients who fail to improve on appropriate therapy, it is important to exclude other diagnoses, rule out fluid overload, and consult an infectious disease specialist.Some patients do not respond to any therapy, and the mortality rate of hospitalized patients is about 15%.
# Secondary Prophylaxis
Anti-PCP prophylaxis (chronic maintenance therapy) should be given to all patients who have had an episode of PCP.Prophylaxis should be continued for life, unless immune reconstitution occurs as a result of ART and the CD4 count has been >200 cells/µL for more than 3 months.
In patients with stable CD4 count of >200 cells/µL on effective ART, it is recommended that PCP prophylaxis be discontinued because it offers little clinical benefit but may cause drug toxicity, drug interactions, and selection of drug-resistant pathogens, plus it adds to the cost of care and to the patient's pill burden.
If PCP occurred at a CD4 count of >200 cells/ µL, it is recommended to continue prophylaxis for life despite immune reconstitution; however, data to support this approach are limited.
# Prophylactic therapy
Preferred:
- TMP-SMX, one double-strength tablet PO once daily, or one single-strength tablet PO once daily
Alternative:
- TMP-SMX: one double-strength tablet PO TIW (e.g., Monday, Wednesday, Friday)
- Dapsone- 100 mg PO once daily, or 50 mg PO BID
# Primary Prophylaxis
Primary prophylaxis against PCP should be given to all HIV-infected patients with CD4 counts of <200 cells/µL or CD4 percentages of <14%, or a history of oral candidiasis; see chapter Opportunistic Infection Prophylaxis.
# Patient Education
- Patients should be instructed to take all medications exactly as prescribed.
- Patients should call their health care providers if symptoms worsen.
- Patients being treated with TMP-SMX or dapsone who develop rash, fever, or other new symptoms should call their providers to be evaluated for a drug reaction.
- Patients should understand that taking anti-PCP prophylaxis is extremely important for preventing repeat episodes of illness.
Patients should not stop taking these medicines without talking with their health care providers, and should not let their supply of medications run out.
# Progressive Multifocal Leukoencephalopathy Background
# Classic PML
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of latent infection with JC virus, a polyomavirus that infects and lyses oligodendrocytes.Demyelination can occur along any part of the white matter, and often does so at multiple sites (hence the term multifocal).The severity of symptoms increases as demyelination progresses.
Among HIV-infected patients, PML occurs classically and most frequently in those with CD4 counts of <100 cells/µL. They typically present with multiple focal deficits of the cerebrum and brainstem, such as cognitive decline, focal weakness, and cranial nerve palsies, with one focal deficit often predominating.Symptoms typically progress over the course of several weeks.Imaging studies show noninflammatory, nonenhancing white matter lesions, without mass effect, with an anatomical location that maps to deficits on the neurological examination.A presumptive diagnosis of PML often can be made on the basis of the patient's clinical presentation and results of neuroimaging studies.Cerebrospinal fluid (CSF) often tests positive for JC virus DNA by polymerase chain reaction (PCR), although brain biopsy is sometimes needed for definitive diagnosis.
Although PML classically occurs in patients not receiving antiretroviral therapy (ART), it can occur in patients on ART, with suppressed HIV RNA but low CD4 counts.Among untreated patients, the interval between the first manifestation of neurologic symptoms and death may be as short as 3-4 months.Although the prognosis for patients with PML has improved with the use of potent ART, there is no specific treatment for PML, and mortality rates remain high.Patients who survive PML are likely to have permanent neurologic deficits.
# Inflammatory PML
Whereas PML in the absence of ART usually is not an inflammatory condition, initiation of ART may cause an immune reconstitution-like syndrome, involving new or worsening neurologic deficits and inflammatory changes seen on brain imaging and biopsy specimens. (See chapter Immune Reconstitution Inflammatory Syndrome.)The initiation of ART in a patient with late-stage HIV-related disease may even reveal previously undetected PML.Although many patients with inflammatory PML improve or at least stabilize, some suffer exacerbation of symptoms, rapid progression of disease, cerebral edema, herniation, and death.
# S: Subjective
The patient or a caregiver may note symptoms such as weakness, gait abnormalities, difficulties with speech, visual changes, altered mental status, personality changes, and seizures.Hemianopia, ataxia, dysmetria, and hemiparesis or hemisensory deficits are often seen.The onset is likely to be subacute, with progression over the course of weeks, though neurologic disturbances may become profound.PML is not associated with headache or fever; this may help to distinguish it from other opportunistic illnesses of the CNS.
# O: Objective
- Measure vital signs.
- Perform a full physical examination, including a thorough neurologic and mental status and evaluation.Look for focal or nonfocal neurologic deficits, particularly cranial nerve abnormalities, visual field defects, weakness, gait abnormalities, and abnormalities in cognitive function, speech, or affect; deficits are likely to be multiple.The patient typically is alert.
- Review previous laboratory values, particularly CD4 count (usually <100 cells/µL in patients with PML).
# A: Assessment
Rule out other causes of the patient's neurologic changes.A partial differential diagnosis includes the following:
- CNS lymphoma
# Other Studies
- Other diagnostic tests should be performed as indicated to rule out other potential causes of the patient's symptoms.
- A brain biopsy should be considered if the diagnosis is unclear.
# Treatment
- There is no specific treatment for JC virus.Potent ART with maximal virologic suppression and effective immune reconstitution is the only treatment that may be effective for patients with PML.Even with ART, however, mortality rates approach 50%, and neurologic deficits are unlikely to be reversible.
- Initiate ART for patients who are not already receiving treatment.It is not clear whether antiretroviral agents with good CNS penetration are more effective than those that are less likely to cross the blood-brain barrier.
- For patients who are on ART with incomplete virologic suppression, change the ART regimen appropriately to achieve virologic suppression, if possible.For patients on ART with poor immunologic response, consider changing or intensifying therapy with the goal of improved immunologic recovery. (See chapter Antiretroviral Therapy.)
- If symptoms are caused by immune reconstitution, consider adding corticosteroids (e.g., dexamethasone) to help decrease inflammation.
- The following agents have been proposed as specific therapy for PML, but have not been shown to be effective by prospective studies and are not recommended for treatment: cidofovir, cytarabine, topotecan, interferonalpha, and inhibitors of the serotonergic 5-HT2a receptor.
- Depending on the patient's cognitive and physical status, he or she may need a care provider in the home to assure that medications are taken on schedule.
- The patient is likely to need supportive care for personal hygiene, nutrition, safety, and prevention of accidents or injury; refer as indicated.
Section 6: Comorbidities, Coinfections, and Complications
# Patient Education
- Most patients diagnosed with PML will need supportive treatment for an undetermined period of time, and hospice referral should be considered if the patient does not show clinical improvement in response to ART.
- If the patient is receiving ART, be sure that caregivers, family members, and friends are taught about the medications and are able to help the patient with adherence.
- When a diagnosis of PML has been established or suspected, initiate a discussion of plans for terminal care (including wills, advanced directives, and supportive care and services) with the patient and family members or caregivers.
# Seborrheic Dermatitis Background
Seborrheic dermatitis is one of the most common skin manifestations of HIV infection.It occurs in 3-5% of the general HIV-uninfected population but in up to 85-95% of patients with advanced HIV infection.Among HIV-infected individuals, seborrheic dermatitis often begins when their CD4 counts drop to the 450-550 cells/µL range.The disease is more likely to occur among young adults (because they have oilier skin) and males, and is more common in areas with cold, dry winter air.It is rarely found in African blacks, unless the person is immunocompromised.It is more common during times of mental stress and severe illness.
Seborrheic dermatitis is a scaling, inflammatory skin disease that may flare and subside over time.It is characterized by itchy reddish or pink patches of skin, accompanied by greasy flakes or scales.It most commonly occurs in the scalp and on the face, especially at the nasolabial folds, eyebrows, and forehead, but also may develop on the ears, chest, upper back, axillae, and groin.Dandruff is considered to be a mild form of seborrheic dermatitis.Occasionally, seborrheic dermatitis may be severe, may involve large areas of the body, and may be resistant to treatment.Severe manifestations are more likely with advanced HIV infection.
The etiology of seborrheic dermatitis is not entirely clear.Malassezia yeast (formerly called Pityrosporum ovale), a fungus that inhabits the oily skin areas of 92% of humans, is the most likely culprit.This same yeast also is thought to cause tinea versicolor and Pityrosporum folliculitis.Overgrowth of the Malassezia yeast in the oily skin environment, failure of the immune system to regulate the fungus, and the skin's inflammatory reaction to the yeast overgrowth appear to be the chief factors that cause the dermatitis.
# S: Subjective
The patient complains of a new rash, sometimes itchy, or of "dry skin" that will not go away despite the application of topical moisturizers.
# O: Objective
Perform a thorough evaluation of the skin with special attention to the scalp, medial eyebrows, eyelashes and eyelids, beard and other facial hair areas, nasolabial folds, postauricular areas, the concha of the auricle, glabella, umbilicus, central chest, back, axillae, and groin.Seborrheic dermatitis appears as white to yellow greasy or waxy flakes over red or pink patches of skin; however, discrete fine scales may indicate a mild form of the disease.Around the eyes, seborrheic dermatitis can cause eyelid erythema and scaling.The distribution usually is symmetrical.
# A: Assessment
The diagnosis of seborrheic dermatitis is based on the characteristic appearance.A partial differential diagnosis includes psoriasis, atopic dermatitis, contact dermatitis, erythrasma, tinea capitus (can be present on the scalp without hair loss), rosacea, and rarely, dermatomyositis. - Selenium sulfide/sulfur preparations (the most common is selenium sulfide shampoo).
# P: Plan
- Whole coal tar, crude coal tar extract: shampoos, creams, and gels.
- Lithium succinate or lithium gluconate ointment, available in some countries as a combination of lithium succinate 8% and zinc sulfate 0.05% (may have antifungal or antiinflammatory effects).Not for use on the scalp.
- Honey, 90% diluted with warm water, may be used to treat seborrheic dermatitis and dandruff.
- Azelaic acid, 15% gel or 20% cream, has sebosuppressive, antimicrobial, antifungal, and antiinflammatory activity (also used for acne and rosacea).
- Noncorticosteroid topical immunomodulators (calcineurin inhibitors):
- Tacrolimus
- Pimecrolimus
- Oral therapy may be used for patients who are refractory to topical treatment (may interact with protease inhibitors and nonnucleoside reverse transcriptase inhibitors; check for possible drug-drug interactions with antiretroviral and other medications before prescribing). |
There are limited data regarding the efficacy of systemic medication.
- Fluconazole 300 mg once weekly for 2 weeks
# Sinusitis Background
Sinusitis is defined as an inflammation involving the membrane lining of any sinus, and is a frequent finding in people with HIV infection.It occurs very commonly as part of a viral upper respiratory infection (URI), and usually is self-limited.Bacterial sinusitis usually occurs as a secondary complication of a viral URI, which causes decreased patency of the nasal ostia, decreased nasal ciliary action, and increased mucus production.Acute sinusitis is defined as lasting up to 4 weeks, whereas chronic sinusitis persists for at least 12 weeks.
HIV-infected patients are susceptible to sinusitis for a number of reasons related to their immunosuppression.Pathophysiologic mechanisms for this susceptibility may include proliferation of lymphatic tissue contributing to nasal obstruction, defects in B-cell and T-cell immunity owing to HIV, and defects in production of immunoglobulins, specifically IgE, resulting in an exaggerated allergic response in the nasal mucosa.As in the general population, the most common pathogens causing acute bacterial sinusitis are Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae.However, HIV-infected patients have a greater incidence of sinusitis caused by Staphylococcus aureus and Pseudomonas aeruginosa.The bacterial causes of chronic sinusitis are not well defined, but may involve more polymicrobial and anaerobic infections.In patients with severe immunosuppression, particularly those with CD4 counts of ≤50 cells/µL, sinusitis may be caused by Aspergillus and other fungal pathogens.
# S: Subjective
The patient may complain of facial pain, frontal or maxillary headache, postnasal drip, or fever.
Ask the patient about specific symptoms, the duration and progression of symptoms, and treatments attempted.
# O: Objective
- Document vital signs.
- Perform a careful physical examination focusing on the head and face, neck, and lungs.Examine the nose, mouth, ears, and sinuses.
- Look for nares inflammation and drainage from sinus ostia.
- Examine the tympanic membranes and external auditory canals.
Section 6: Comorbidities, Coinfections, and Complications
- Evaluate the oropharynx for mucus drainage, lesions, and exudates.
- Check the teeth and gums for tenderness and erythema.
- Palpate for tenderness over frontal and maxillary sinus cavities.
- Examine the face and orbits for swelling or erythema.
- Perform cranial nerve examination.
- Auscultate the chest for abnormal lung sounds.
# A: Assessment
A partial differential diagnosis includes the following:
- Allergic rhinitis
# Patient Education
- Instruct patients in the correct use of medications used to treat sinusitis, including proper technique for nasal irrigation or steam inhalation, as required.
- Instruct patients to take antibiotics on schedule until the entire prescription is gone in order to prevent recurrence of the infection.
- Advise patients that drinking eight glasses (8-12 oz each) of fluid daily helps to keep the mucus thin enough to drain the sinus passages.
- Advise patients to call or return to clinic for swelling of the face or swelling around the eyes, increased facial tenderness, new or worsening fever, or other concerning symptoms.
Section 6: Comorbidities, Coinfections, and Complications
# Syphilis Background
Syphilis is a sexually transmitted infection (STI) caused by the spirochete Treponema pallidum.It is a complex disease with protean variations that can mimic many common infections or illnesses.HIV infection may alter the natural history and management of syphilis, causing a more rapid course of illness, higher risk of neurologic complications, and potentially greater risk of treatment failure with standard regimens.Because many individuals with syphilis have no symptoms, or have symptoms that subside without treatment, sexually active individuals at risk of syphilis should receive regular screening for syphilis, as well as for other STIs.Many clinicians strongly recommend routine syphilis testing every 3-6 months for patients at risk of syphilis.
There has been a resurgence of syphilis in metropolitan areas of the United States and western Europe.This trend is concerning, because syphilis can have major health consequences if it is undetected and untreated, and because it is associated with increased risk of new HIV infections.Risk assessment should be conducted at each patient visit for unprotected sex (including oral sex), multiple sex partners, and use of recreational drugs (methamphetamine and cocaine, in particular, are associated with high-risk sexual practices among men who have sex with men ).Asymptomatic persons at risk of acquiring syphilis should be screened at regular intervals (with rapid plasma reagin or Venereal Disease Research Laboratory testing, as discussed below), depending on their risk factors.MSM with multiple partners should be tested every 3-6 months.
The natural history of untreated syphilis infection is divided into stages based on length of infection.
# Primary Syphilis
Primary syphilis usually manifests after an incubation period of 1-3 weeks from exposure and is characterized by a painless self-limiting ulcer (chancre) at the site of sexual contact.HIVinfected individuals may have multiple or atypical chancres that could be misidentified.Some patients have no primary lesion, or have a primary lesion that is not visible.Associated regional lymphadenopathy can occur.HIV-infected individuals sometimes have a chancre concurrently with rash typical of secondary syphilis.
# Secondary Syphilis
Secondary syphilis usually develops 2-8 weeks after initial infection and is caused by ongoing replication of the spirochete, with disseminated infection that may involve multiple systems.Rash is the most common presenting symptom; skin lesions may be macular, maculopapular, papular, or pustular, or they may appear as condyloma lata (which may look like the condyloma of papillomavirus).The rash often appears on the trunk and extremities and may involve the palms and soles of feet.Constitutional symptoms, lymphadenopathy, arthralgias, and myalgias
# HRSA HAB Core Clinical Performance Measures
Percentage of adult clients with HIV infection who had a test for syphilis performed within the measurement year (Group 2 measure) Section 6: Comorbidities, Coinfections, and Complications are common, and neurologic or other symptoms may occur.In the absence of treatment, the manifestations of secondary syphilis last days to weeks, then usually resolve to the latent stages.
# Latent Syphilis
Latent syphilis follows resolution of secondary syphilis.As in HIV-uninfected individuals, latent syphilis is asymptomatic and the diagnosis is determined by positive serologic tests.Latent syphilis is further classified as "early latent" if the infection is known to be 1 year in duration, or "latent syphilis of unknown duration" if the duration of infection is not known.
# Late or Tertiary Syphilis
Late or tertiary syphilis is caused by chronic infection with progressive disease in any system causing serious illness and death in untreated patients.The most common manifestations include neurosyphilis, cardiovascular syphilis, and gummatous syphilis.
# Neurosyphilis
Neurosyphilis can occur at any time after initial infection, owing to spread of the spirochete to the central nervous system (CNS).In HIV-infected individuals, neurosyphilis may occur more commonly early in the course of infection, during secondary or latent syphilis.It is associated with neurologic symptoms, including cranial nerve abnormalities (particularly extraocular or facial muscle palsies, tinnitus, and hearing loss) or symptoms of meningitis.Uveitis and other eye disease may occur in conjunction with neurosyphilis.
# S: Subjective
Symptoms depend on the site of initial infection, the stage of disease, and whether neurosyphilis is present.Symptoms are not present in all patients.
If symptoms are present, the patient may experience the following:
- Painless sore(s) or ulcer(s) in the genital area, vagina, anus, or oral cavity
- New rash, usually on the trunk, often on extremities, soles of the feet, or palms; patchy hair loss - Fever, malaise, swollen glands, arthralgias, myalgias
- Altered mental status, weakness, paralysis - CSF-VDRL: This test is specific but not very sensitive; a positive result is diagnostic but a negative result does not rule out neurosyphilis.
- Leukocytes: Elevated white blood cell count (>10 cells/µL) is suggestive but not specific.Note that mononuclear pleocytosis (up to 5-20 cells/µL) is not uncommon in patients with HIV infection, particularly those with higher CD4 cell counts.
- Some recommend checking CSF FTA-ABS.This is very sensitive but not very specific; a negative result indicates that neurosyphilis is highly unlikely.
# Other testing
All patients who test positive for syphilis should be tested for gonorrhea and chlamydia, with sampling sites based on sexual practices and exposures (oropharyngeal, urethral, vaginal, or anorectal testing).Patients not known to be HIV infected also should be tested for HIV.
# Treatment
Treatment of syphilis in HIV-infected individuals essentially is the same as in HIVuninfected individuals, and depends on stage and the presence or absence of neurosyphilis.
It is important to follow patients closely to assure the success of treatment.For further information, see the Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases Treatment Guidelines (see "References," below).
An RPR or VDRL test should be sent on the day of treatment; the titer will be the reference point for assessing treatment efficacy (see "Follow-Up," below).
Early syphilis (<1 year in duration ); nonneurologic - Recommended: benzathine penicillin G, 2.4 million units IM (single dose)
- Alternatives: note that penicillin is strongly preferred; consider allergy testing and desensitization to penicillin; in penicillinallergic, nonpregnant patients, consider the following; note that these therapies are not as well proven in HIV-infected individuals; close monitoring for treatment response is recommended.
- Doxycycline, 100 mg PO BID for 14 days
- Tetracycline, 500 mg PO QID for 14 days - CSF examination to rule out neurosyphilis should be done on all patients with a history of syphilis >1 year in duration or of unknown duration.
- If CSF examination result is negative, treat with benzathine penicillin G, 2.4 million units IM weekly for 3 consecutive weeks (7.2 million units in total).
- In penicillin-allergic clients, refer for desensitization to penicillin.As an alternative, some specialists consider doxycycline 100 mg PO BID for 28 days.
Referral to infectious disease specialist and close clinical monitoring are required, as treatment efficacy is not proven in HIVinfected individuals.
# Tertiary syphilis
Consult with specialists.
Neurosyphilis (syphilis at any stage with neurologic or ocular symptoms or CSF findings of neurosyphilis)
Ideally, patients should be hospitalized and given 2 weeks of penicillin IV under close observation.Penicillin-allergic patients should be referred for desensitization, if possible.
- Recommended: aqueous crystalline penicillin G, 18-24 million units IV per day (3-4 million units Q4H for 10-14 days).
- Alternatives (require strict adherence with therapy):
- Procaine penicillin 2.4 million units IM per day, plus probenecid 500 mg PO QID, both for 10-14 days
- Some experts consider use of ceftriaxone 2 g IM or IV once daily for 10-14 days with close clinical monitoring
- Some experts recommend administration of benzathine penicillin, 2.4 million units IM weekly for 3 weeks, after completion of the standard 10-to 14-day course of therapy for neurosyphilis.
- Recheck CSF leukocyte count every 6 months until the cell count normalizes (if CSF pleocytosis was present at initial evaluation).If the leukocyte count is not lower at 6 months, consider retreatment (consult with a specialist).
Note that a Jarisch-Herxheimer reaction may occur after initial syphilis treatment, especially in primary, secondary, or even latent syphilis.This self-limited treatment effect should not be confused with an allergic reaction to penicillin.It usually begins 2-8 hours after the first dose of penicillin and consists of fever, chills, arthralgias, malaise, tender lymphadenopathy, and intensification of rash.It resolves within 24 hours and is best treated with rest and acetaminophen.Patients should be warned about the possibility of a Jarisch-Herxheimer reaction.
# Pregnancy
Pregnant women should be treated with penicillin, if possible, using a regimen appropriate for the stage of infection (see above).Additional treatment may be indicated; consult with a specialist.Penicillin-allergic pregnant women should be referred for desensitization to penicillin.Doxycycline and tetracycline may cause fetal toxicity and should not be used during pregnancy; erythromycin is not sufficiently effective in treating syphilis in the fetus.Azithromycin and erythromycin do not have adequate efficacy in treating pregnant women or their fetuses and should not be used.The efficacy of ceftriaxone during pregnancyhas not been studied adequately.
Women treated during the second half of pregnancy are at risk of contractions, early labor, and fetal distress if they develop a Jarisch-Herxheimer reaction; thus, they should be monitored carefully.
# Sex partners
Syphilis is transmitted sexually only when mucocutaneous lesions of syphilis are present; this is uncommon after the first year of infection.Nevertheless, sex partners of a patient who has syphilis in any stage should be evaluated.
- Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, as they may be infected with syphilis even if they are seronegative.
- Persons exposed more than 90 days before the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively if serologic test results are not available immediately and their follow-up is in doubt.Otherwise, they should receive serologic testing and be treated appropriately if the test result is positive.Note that some specialists recommend presumptive treatment of all persons potentially exposed to syphilis.For patients with primary syphilis, that means partners within the previous 3 months; for secondary, within 6 months; for early latent, within 1 year.
# Follow-Up
All HIV-infected patients treated for syphilis should be evaluated clinically and serologically at 3, 6, 9, 12, and 24 months (at 6, 12, 18, and 24
# Toxoplasmosis Background
Toxoplasma gondii is a common intracellular protozoan that preferentially infects the central nervous system (CNS) of immunodeficient patients, causing severe neurologic disease.T. gondii also can cause local disease such as chorioretinitis and pneumonia.Toxoplasma has an infectious reservoir in almost all animals; humans acquire infection either through ingestion of tissue cysts contained in undercooked meat (usually pork, lamb, or beef) or oocysts on contaminated vegetables or through exposure to cat feces containing oocysts.There is no transmission by person-to-person contact.
Clinical disease usually occurs through reactivation of latent infection in patients who have CD4 counts of <100 cells/µL. Seroprevalence varies widely, from 15% in the United States to 75% in some European countries, and even higher in certain resource-limited countries.In the absence of prophylaxis, toxoplasmic encephalitis occurs in more than 30% of patients with advanced HIV infection who are seropositive for T. gondii.There have been case reports of CNS toxoplasmosis in the setting of immune reconstitution on antiretroviral therapy (ART); see chapter Immune Reconstitution Inflammatory Syndrome.
CNS toxoplasmosis is an AIDS-defining condition that can be progressive and fatal.However, antimicrobial therapy, especially if given in conjunction with ART that results in immune reconstitution, can be successful in treating toxoplasmosis.Specific prophylaxis and effective ART also may be used to prevent toxoplasmosis in patients with advanced AIDS who have latent T. gondii infection (as demonstrated by the presence of anti-Toxoplasma immunoglobulin G antibodies; see chapter Preventing Exposure to Opportunistic and Other Infections).
# HRSA HAB Core Clinical Performance Measures
Percentage of clients with HIV infection for whom Toxoplasma screening was performed at least once since the diagnosis of HIV infection (Group 3 measure)
# S: Subjective
The patient may complain of subacute onset of dull, constant headache, fever, visual changes or other focal neurologic symptoms, confusion, or disorientation.Seizures may occur.Caregivers may report subtle alterations in mental status or mood.Take a careful history from the patient and caregivers about the symptoms listed above and their duration, progression, and severity.Inquire about other related symptoms.Ask whether the patient is taking Toxoplasma prophylaxis or ART.
# O: Objective
- Measure vital signs (temperature, heart rate, blood pressure, respiratory rate).
- Perform a full physical examination including a thorough neurologic examination, looking for focal or nonfocal neurologic deficits, particularly weakness, cranial nerve abnormalities, visual field defects, gait disturbances, and abnormalities in speech, cognitive, or affective functions.
- Review previous laboratory values, particularly the following:
- CD4 count (usually <50-100 cells/µL in patients with toxoplasmosis) Note: Patients at risk of G6PD deficiency should be checked for G6PD deficiency before starting pyrimethamine.
# Alternatives
- Pyrimethamine + folinic acid (administered as described above) + one of the following:
- Clindamycin 600 mg PO or IV Q6H; recommended for patients with significant allergic reactions to sulfa medications
# Chronic Maintenance Therapy
After at least 6 weeks of initial therapy and significant clinical and radiologic improvement, chronic maintenance therapy can be considered.
# Preferred
# Considerations During Pregnancy
All pregnant women should be tested for T. gondii.If the result is positive, evaluate the pregnant woman for signs or symptoms of toxoplasmosis and the neonate for evidence of congenital infection.Perinatal transmission usually occurs only with acute maternal infection, but in advanced HIV, it may occur with reactivation of chronic infection.If T. gondii infection occurs during pregnancy, consult with maternal-fetal and infectious disease specialists.Treatment for pregnant women is the same as for nonpregnant adults (see above).Note that sulfadiazine taken at the time of delivery may increase the risk of neonatal hyperbilirubinemia and kernicterus.
# Patient Education
- Advise patients that antimicrobial therapy alone will not eradicate toxoplasmosis, but should decrease symptoms and improve quality of life.If medications are discontinued, the disease is likely to recur, unless the CD4 count increases to >100-200 cells/µL in response to ART.
- Inform patients that suppressive therapy must be continued to prevent recurrence.The duration of this therapy may be lifelong.
- It is essential for patients to take all medicines exactly as prescribed.If doses are missed, or if the medications are stopped and restarted, Toxoplasma can develop resistance to the medications.If patients are having trouble taking the medication on schedule, they should contact their health care provider immediately.
- Educate patients about the benefits of ART in strengthening the immune system and preventing opportunistic infections such as toxoplasmosis.
- Advise patients to contact the clinic promptly if symptoms worsen or if new symptoms develop.
- Toxoplasmosis is a late-stage HIV opportunistic infection that indicates profound immune suppression.Some patients may not respond to treatment or to ART. |
As with any patient who is at risk of a life-threatening HIV-related disease, clinicians should discuss advance directives and durable power of attorney with patients.
Referral to a social worker, mental health clinician, or chaplain experienced in such issues may facilitate this discussion.
# Background
Clinicians and patients face many challenges associated with antiretroviral therapy (ART).These include making decisions about when to start therapy, what regimen to start with, when to change medications, and how to switch if a regimen is failing.Although clinical research guides the selection of antiretroviral (ARV) regimens, it is important to remember that the best regimen for any patient is the regimen that individual is willing and able to take.No regimen, no matter how potent, will be effective if the patient does not take it properly.Adherence to ART is one of the most important predictors of treatment efficacy.Although many factors may interfere with proper adherence to ART, adverse reactions to the medications are among the most important.In one trial, patients experiencing adverse events were 13 times less likely than those not experiencing adverse events to have the highest levels (95-100%) of adherence.Monitoring and managing adverse reactions to ARVs are crucial to establishing a successful HIV regimen.
Although adverse reactions are common and often predictable, their management must be individualized.Several factors will affect the management of adverse reactions, including comorbid conditions, the patient's other current medications, the availability of alternative medications, and the patient's history of medication intolerance.In some cases, the patient's report of the severity of adverse effects can be inconsistent with the clinical interpretation (i.e., some patients may overemphasize symptoms, whereas others underemphasize them), and this must be considered when determining the management of adverse reactions.
Using a case-based approach, this chapter suggests strategies for the evaluation and management of adverse effects, and it reviews several of the most commonly noted adverse effects in patients starting an ARV regimen.It is not intended as a comprehensive guide to adverse effects.For detailed information regarding assessment of symptoms, see the complaint-specific chapters found in section Common Complaints of this manual.For information on common adverse reactions to ARV agents and to medications used to prevent and treat opportunistic infections, see chapter Antiretroviral Therapy of this manual.In each case of suspected medication adverse effects, the patient should be evaluated for other possible causes of the symptoms.Consultation with an HIV expert can help in determining the best management strategy when symptoms may have multiple and overlapping causes.
# S: Subjective
A patient presents 3 weeks after starting a new ARV regimen.She complains of fatigue, nausea, and rash.Her current ARV medications are nevirapine (NVP) plus a fixed-dose combination of zidovudine (ZDV), lamivudine (3TC), and abacavir (i.e., Trizivir).This was selected on the basis of her preferences and her past treatment history.She also is taking trimethoprim-sulfamethoxazole (TMP-SMX) as prophylaxis against PCP.Although she reports that she had not missed any doses of her medications and she likes the low pill burden of this regimen, she does not want to continue because she has been feeling so sick that she cannot adequately care for her children.She is asking to stop her ARV therapy because of "too many side effects."
The patient should be evaluated in the clinic for her complaints about adverse effects.
# O: Objective
The following are suggestions for this evaluation; they are not intended to be a complete review of the workup and management of each symptom or objective finding.For more-detailed information, refer to the complaint-specific chapters of this manual, as noted above.
Vital signs: Fever may indicate a hypersensitivity reaction (HSR) or acute hepatitis attributable to medications, or an immune reconstitution inflammatory syndrome in relation to an opportunistic infection in the setting of early ART therapy.See chapter Fever for a more complete discussion about fever workup and considerations.Tachycardia or hypotension may suggest anemia, HSR, dehydration, infection, or another illness.
Physical examination: Pay special attention to the skin (rash, pallor), mucous membranes, and liver (enlargement or tenderness).
Positive physical examination findings should be evaluated for severity and extent of involvement.
Laboratory tests: Check the complete blood count when monitoring drugs that may cause bone marrow toxicity (e.g., anemia, neutropenia).Perform a complete metabolic panel including electrolytes and liver function tests (LFTs).If the history suggests pancreatitis, evaluate amylase or lipase.
Other studies: Perform as indicated by symptoms and examination (e.g., chest X ray if respiratory symptoms are present).
# A: Assessment
Step 1: Clarify the patient's reports of adverse reactions by requesting the following information for each symptom the patient describes:
- Characterize the symptoms by asking about severity, onset, timing, and frequency.It is helpful to have the patient describe whether the symptoms have been improving or worsening over time.
- Ask whether the patient has tried any remedies to alleviate the symptoms and whether they were helpful.
- Explore how the patient is currently taking the regimen.Open-end questions (e.g., "What are your current medications?" "How often do you take them?" "How many pills of each medicine do you take?"and "Do you take your medicines with or without food?")can be helpful in determining whether the patient has been taking medications correctly.Incorrect administration of medications (e.g., taking higher dosages than recommended) can lead to adverse effects and often is overlooked by providers.
Step 2: Assess the severity of the reaction against the need to continue the current regimen.For this assessment, it is important to have an understanding of the relative availability of alternative ARV regimens.Also try to determine the patient's risks for adverse reactions to specific medications.A review of the patient's clinical status, treatment history, resistance tests, and other testing is important.Section 7: ARV Interactions and Adverse Events
- More severe reactions often require discontinuation of the offending medication.These include fever, liver function abnormalities, rash with mucous membrane involvement, or severe systemic symptoms.
- Determining which medication in a multidrug regimen is causing the reaction is often challenging because it is common for patients to concurrently take several medications with overlapping toxicities.
- Some patient factors affect the risk of particular adverse drug effects.For example, patients with higher CD4 cell counts at the time that nevirapine is initiated have a greater risk of hepatotoxicity (specifically, women with CD4 counts of >250 cells/µL or men with CD4 counts of >400 cells/µL), and patients with the HLA-B*5701 allele have higher rates of abacavir HSR (see "Abacavir Hypersensitivity Reaction," below).
- It is important to consider the possibility that non-ARV medications in the patient's regimen could be causing the adverse effects.Even with patients who have been on other non-ARV medications for months or years, initiation of a new ARV regimen (e.g., one with potent hepatic CYP 450 inhibition or induction effects) may alter serum levels of these other medications (see chapter Drug-Drug Interactions with HIV-Related Medications).For example, an increase in anxiety symptoms after starting a new ARV regimen could be attributable to altered drug concentrations of a chronic antidepressant or antianxiety medicine caused by an ARV, not to the new ARV medications themselves.
- The threshold for stopping a medication depends in part on the availability of alternative agents for the individual patient.Some patients have limited alternatives because their virus is resistant to other ARVs (e.g., patients on salvage ARV regimens) or because they have not tolerated certain ARVs in the past.For patients who develop significant adverse effects when starting their first ARV regimen, consider substituting alternative ARV medications (chosen with efficacy considerations in mind) that are better tolerated as early as possible to prevent nonadherence arising from a desire to avoid the adverse effects.For these situations, single-drug substitutions often improve tolerance and make it more likely that long-term viral suppression can be achieved.
- Some patients may refuse to attempt symptomatic treatment or to make substitutions in the ARV regimen.Although treatment interruptions generally should be avoided, in certain situations it may be best to discontinue all ARVs and return to an adherence-readiness assessment (see chapter Adherence) to determine when to restart ART and what medications to restart (see chapter Antiretroviral Therapy).
# Gathering Additional Subjective and Objective Information
For the patient who reported nausea, fatigue, and rash 3 weeks after starting nevirapine and ZDV/3TC/abacavir (Trizivir) (see above), additional history, physical examination, and laboratory work yielded the following information:
- Nausea: This has been present since she started ART 3 weeks ago.She has had difficulty taking the ARVs with food, because of nausea.No actual vomiting or other abdominal pain has occurred.She has not tried any remedies.The nausea is not worsening and perhaps has improved slightly over the past few days.
- Fatigue: This has been present since she started ARVs 3 weeks ago.She is able to exercise and perform normal daily activities.
- Vital signs: Normal, with no fever or signs of hemodynamic changes.
- Skin: Skin and conjunctival pallor is noted, along with mild-to-moderate maculopapular rash on the trunk, back, and extremities.
# Section 7: ARV Interactions and Adverse Events
These are associated with slight itching, but no pain.No mucous membrane involvement is noted.The rash has been present for 6 days, with slight improvement over the past day.
- Abdomen: Nontender, with normal liver size.
- Complete blood count: Normal, except for a slight increase in mean corpuscular volume (MCV), probably from ZDV therapy and not indicating macrocytic anemia.
- LFTs: Normal.
- Pretreatment laboratory results: CD4 count of 190 cells/µL, HLA-B*5701 negative.
# Assessing Availability of Alternative Regimens
A clarified ARV history yielded the following information.The patient took ZDV for 5 months during one of her pregnancies a few years ago, and she recalls similar feelings of nausea and fatigue that caused her distress at the time.She was able to continue ZDV through the end of her pregnancy.She has taken several ritonavir-boosted protease inhibitors briefly in the past; she did not tolerate these and subsequently has refused treatment with protease inhibitors.Her virus is resistant to lamivudine and emtricitabine.She has no significant comorbidities.The patient has a number of treatment options, but these may be limited by tolerance issues (e.g., to protease inhibitors).
# Summary Assessment
# Rash
Rash is a common adverse effect of certain ARVs and many other medications.It may present with a wide range of severity, as follows:
- Mild rash with no other related symptoms, resolving over the course of days or weeks
- Moderate rash, may be accompanied by systemic symptoms (e.g., fever, liver function abnormalities, myalgias)
- Life-threatening rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) associated with pain, mucous membrane involvement, fever, liver function changes, and myalgias If a patient is taking two or more medications that have rash as a possible adverse effect, it may be difficult to determine which medicine is the most likely cause of the rash.In the case of the patient described above, rash may be related to one of three medications.Her rash currently is mild, but drug rash can range from mild to severe and life-threatening (including Stevens-Johnson syndrome).
- Abacavir
- Mild abacavir rash: usually a selflimited reaction that can be treated symptomatically If the clinician discontinues all of the suspect medications and the rash resolves, the patient will be relieved, but the clinician will not be able to determine which medication caused the rash.In cases of mild rash, it is reasonable to try to identify the offending agent by discontinuing one medication at a time (a
# Other Adverse Reactions
Patients may describe any number of adverse effects after starting new medications.
Although some adverse effects are caused directly by the medications themselves, some symptoms may occur simply in the process of starting ART.The start of ART may precipitate a significant psychological shift in a patient's perception of self, in living with HIV infection, and in daily routine.In particular, patients who have kept their HIV infection distant from their "everyday" lives may notice significant psychological changes as they take medications every day, go to the pharmacy to pick up medications, and make frequent visits to the clinic for evaluation and laboratory work.Some patients become depressed upon realizing that the severity of their illness now requires them to be on treatment.These psychological adjustments can cause significant symptoms that should be assessed and managed in a manner similar to the way in which pharmacologic adverse reactions are managed.
These psychological effects can be considered "process" effects from starting ART rather than adverse effects of the ARV medications themselves.As with the self-limited adverse effects of early-stage ARV therapy, process effects should become more tolerable over time as the medication regimen becomes routine for the patient.One of the most common process effects is fatigue.Many patients hope that their ARV regimen will give them increased energy and health, and they become frustrated when they notice increasing fatigue after starting the regimen.These patients must be evaluated to rule out common adverse effects that contribute to fatigue (e.g., anemia, hepatitis, lactic acidosis
# Patient Education
- All medications have potential to cause adverse reactions, which are defined as negative, unintended effects of medication use.
- Advise patients to report any adverse reaction to their medical care provider as soon as possible.
- Before starting a new medication, medical care providers or pharmacists should counsel patients about the most common adverse effects and about any remedies that are available to minimize the severity of those effects.
- Advise patients to talk to their provider or pharmacist before starting any new medications (including over-the-counter medications and herbs) because some drugs may interact with ARVs or other medications and can increase side effects or cause unwanted reactions.
- Nausea is one of the most common adverse effects.Counsel patients that nausea can be minimized by taking medications with food (if indicated, as some medications should be taken on an empty stomach) or by using ginger-based food or beverages (e.g., ginger ale, tea, cookies).If these measures do not work, patients should talk with their medical care provider; they may need medications to treat the symptoms.
- Counsel patients that they should not stop taking any medications unless instructed to do so by their medical care provider.
# Background
Drug-drug interactions are common concerns of patients with HIV and their health care providers.The issues involved in evaluating drug interactions are complex.Although many questions can be articulated simply (e.g., "What antidepressant is least likely to have drug interactions with antiretroviral medications?"),the responses to these questions involve more complex concerns (e.g., "In choosing an antidepressant for my patient with HIV, I must consider efficacy, adverse effects, and tolerability as well as drug interactions.").
This complexity is increased because antiretroviral (ARV) agents, particularly protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and the CCR5 antagonist maraviroc, can cause or be affected by alterations in the activity of the cytochrome (CYP) P450 enzyme system in the liver, as well as by other mechanisms of drug metabolism.Interactions between an ARV and another drug (whether another ARV or a different type of medication) may result in an increase or a decrease in the serum levels of either the ARV or the interacting drug, potentially changing the effectiveness or the toxicity risk of substrate drugs.Understanding drugdrug interactions is challenging because of several factors, including the following:
- Different drugs affect different P450 enzymes.
- Some medications have dose-related responses that influence their effects on P450 enzymes.
- Formal pharmacokinetic studies on drug combinations are limited.
- Even when pharmacokinetic data exist for specific drug combinations, the clinical significance of any changes in pharmacokinetic parameters may not be clear.
- Patients taking ARVs often have complex drug regimens.Patients typically are taking three or more medications that could influence interactions.Pharmacokinetic studies that evaluate the clinical significance of drug interactions involving more than two medications are less likely to be available.
- Other metabolic pathways of medications such as P-glycoprotein (P-gp) and UDPglucuronosyltransferase (UGT)-1A1, can be altered by drug interactions.The integrase inhibitor raltegravir, for example, is metabolized by UGT-1A1 and also is a substrate of P-gp.
- The P450 system is not the only influence on medication activity.Other influences include absorption, food-drug interactions, protein binding, altered activation of medications intracellularly, and altered efflux-pump activity.
Information on various drug-drug interactions is available in guidelines and via the Internet (see "Resources," below).Such resources can provide data regarding two-drug combinations, but rarely consider all the complexities outlined above.What follows, therefore, is a suggested approach to considering drug-drug interactions in managing HIV-infected patients and making patientspecific decisions.
# O: Objective
Review the patient's pharmacy records for current medications, and ask about use of overthe-counter (OTC), herbal or natural products, and dietary supplements.As requested, the patient has brought in all medications from home for review.The current medication list includes the following:
- Clarithromycin 500 mg BID - Milk thistle (silymarin) (patient takes as needed for energy and liver health)
# A: Assessment
Step 1: Identify interactions and classify them as follows:
- Definite interactions
- Probable interactions
# Possible interactions
# Definite Drug Interactions
A drug interaction is definite if a high level of evidence is available regarding the drug combination, the clinical significance of the interaction is well understood, and consensus exists regarding the management strategy (e.g., whether dosage adjustments are required, or concurrent use is contraindicated).
# P: Plan
Step 2:
# Patient Education
- Instruct patients that HIV medications, in particular PIs, NNRTIs, and maraviroc, have a high potential for significant drug interactions.
- Tell patients to bring all their medicines, including any herbal, nutritional, and dietary supplements and OTC remedies, with them to all medical appointments.If they cannot bring the actual containers with them, they should bring a list of current prescribed medications, supplements, and OTC medications. |
- Patients should have their primary care provider or pharmacist review any newly prescribed medications along with their current list of medicines.This is especially important if another physician prescribes a new medication.
- Patients should not "borrow" medications from friends or family.Assure patients that if they have a problem that needs medical treatment, their primary care provider will discuss it and choose the safest treatments for them.
- Tell patients that, if they are considering buying a new nutritional or herbal supplement or an OTC product, they should consult their pharmacist or primary care provider about interactions with drugs on their current medication list.
- Not all drug interactions are cause for alarm.Some drug combinations are safe for certain people, but less safe for others.Warn patients not to stop taking any medicines without the advice of their primary care provider.
# Resources
# Antiretroviral Medications and Hormonal Contraceptive Agents Background
Few pharmacokinetic or clinical studies have examined interactions between antiretroviral (ARV) medications and hormonal contraceptives, but it is known that certain protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) do interact with hormonal contraceptives.These interactions may increase the risk of medication failure or medication adverse effects -of either the ARV or the contraceptive.There are no known interactions between hormonal contraceptives and nucleoside analogues, integrase inhibitors, or CCR5 antagonists.
# Oral Contraceptives
All oral contraceptives currently marketed in the United States, with the exception of progestinonly pills (which contain norethindrone), contain both ethinyl estradiol and a progestin (desogestrel, drospirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, or norgestrel).The oral contraceptives ethinyl estradiol and norethindrone may interact in complex ways with PIs and NNRTIs.The mechanism of these interactions may be multifactorial and includes the activity of these agents on cytochrome P450 enzymes.Pharmacokinetic studies have shown changes (either increases or decreases) in levels of ethinyl estradiol and norethindrone in women who are taking certain PIs or NNRTIs.Other studies have shown decreases in levels of amprenavir in women taking oral contraceptives.
The clinical significance of these drug interactions has not been evaluated thoroughly, but may cause oral contraceptive failure, ARV failure, or medication toxicity, depending on whether drug levels are lowered or raised by the interacting drug.The consequences of decreased hormone levels may include an increased risk of pregnancy, so an alternative or additional method of contraception commonly is recommended.The consequences of decreased ARV levels may include virologic failure and development of resistance mutations.The consequences of a higher level of hormones may include risk of thromboembolism, breast tenderness, headache, nausea, and acne.
# Peripheral Neuropathy
Pain from HIV-associated peripheral neuropathy is particularly common, and may be debilitating.Peripheral neuropathy is clinically present in approximately 30% of HIV-infected individuals and typically presents as distal sensory polyneuropathy (DSP).It may be related to HIV itself (especially at CD4 counts of <200 cells/µL), to medication toxicity (e.g., from certain nucleoside analogues such as stavudine or didanosine), or to the effects of chronic illnesses (e.g., diabetes mellitus).
Patients with peripheral neuropathy may complain of numbness or burning, a pins-and-needles sensation, shooting or lancinating pain, and a sensation that their shoes are too tight or their feet are swollen.These symptoms typically begin in the feet and progress upward; the hands may be affected.Patients may develop difficulty walking because of discomfort, or because they have difficulty feeling their feet on the ground.Factors associated with increased risk of peripheral neuropathy include the following:
- Previous peripheral neuropathy To evaluate peripheral neuropathy: Check ankle Achilles tendon reflexes and look for delayed or absent reflexes as signs of peripheral neuropathy.Distal sensory loss often starts with loss of vibratory sensation, followed by loss of temperature sensation, followed by onset of pain.Findings are usually bilateral and symmetric.
# A: Assessment
Pain assessment includes determining the type of pain, for example, nociceptive, neuropathic, or muscle spasm pain.
# Nonpharmacologic interventions
The following Interventions can be used at any step in the treatment plan:
- A therapeutic provider-patient relationship
# Pharmacologic interventions
# Principles of pharmacologic pain treatment
- The dosage of the analgesic is adjusted to give the patient adequate pain control.
- The interval between doses is adjusted so that the pain control is uninterrupted.It can take 4-5 half-lives before the maximum effect of an analgesic is realized.
- Chronic pain is more likely to be controlled when analgesics are dosed on a continuous schedule rather than "as needed."Sustainedrelease formulations of opioids should be used whenever possible.
- For breakthrough pain, use "as needed" medications in addition to scheduled-dosage analgesics.When using opiates both for scheduled analgesia for breakthrough pain, a good rule of thumb is to use 10% of the total daily dosage of opiates as the "as needed" opiate dose for breakthrough pain.
- Oral administration has an onset of analgesia of about 20-60 minutes, tends to produce more stable blood levels, and is cheaper.
- Beware of the risk of prolonged analgesic half-lives in patients with renal or hepatic dysfunction.
- Caution when using combination analgesics that are coformulated with ingredients such as acetaminophen, aspirin, or ibuprofen.Determine the maximum daily dosage of all agents.
The following three steps are adapted from the WHO analgesic ladder.Agents on higher steps are progressively stronger pain relievers but tend to have more adverse effects.Step 3: Opioid agonist drugs for severe pain (pain scale 7-10)
- Morphine is the drug of choice in this step.Start with short-acting morphine and titrate the dosage to adequate pain control, then divide the 24-hour total in half to determine the dosing for the sustained-release morphine, given Q12H. When converting from IV to PO morphine, PO dosage is about two to three times the parenteral dose.
- Other agents used are oxycodone, hydromorphone, fentanyl, levorphanol, methadone, codeine, hydrocodone, oxymorphone, and buprenorphine.
- Avoid meperidine because of the increased risk of delirium and seizures.
- Around-the-clock, sustained-release PO dosing will achieve optimum pain relief.
- Patients unable to take PO therapy may use transdermal fentanyl patches or do rectal administration of sustained-release tablets such as long-acting morphine.Note that the onset of analgesia with fentanyl patches can take more than 12 hours, and the analgesic effect can last more than 18 hours after the patch is removed.
- Anticipate and treat complications and adverse effects of opioid therapy, such as nausea, vomiting, and constipation.Constipation often leads to nausea and can be prevented with prophylactic stool softeners (such as docusate) and stimulant laxatives (such as senna).
# Adjunctive treatments
The addition of antidepressant medications can improve pain management, especially for chronic pain syndromes.These agents, and anticonvulsants, usually are used to treat neuropathic pain (discussed in more detail below), but should be considered for treatment of other chronic pain syndromes as well.
# Treatment of neuropathic pain
Assess the underlying etiology, as discussed above, and treat the cause as appropriate.
Review the patient's medication list for medications that can cause neuropathic pain.Discontinue the offending agents, if possible.For patients on stavudine or didanosine, in particular, switch to another nucleoside analogue if suitable alternatives exist, or at least consider dosage reduction of stavudine to 30 mg BID (consult with an HIV expert).
For patient on isoniazid, ensure that they are taking vitamin B6 (pyridoxine) regularly to avoid isoniazid-related neuropathy.
# Nonpharmacologic interventions for neuropathic pain
The nonpharmacologic interventions described above can be useful in treating neuropathic pain.Adverse effects include sedation, anticholinergic effects (e.g., dry mouth, urinary retention), QT prolongation, arrhythmias, and orthostatic hypotension.
Monitor TCA levels and EKG at higher dosage levels.There is a risk of overdose if taken in excess.
- SSRIs: See chapter Depression for dosing, side effects, and drug interactions associated with this class of agents.SSRIs are less effective than TCAs in treating chronic pain.
- Venlafaxine (Effexor): Starting dosage is 37.5 mg daily.Usual maintenance dosage is 75-300 mg daily in divided doses or by extended-release formulation (Effexor XR).
Note that there are limited data on using venlafaxine for patients with HIV infection.
- Duloxetine (Cymbalta): Starting dosage is 30-60 mg daily.Dosages of >60 mg per day are rarely more effective for either depression or pain treatment.Note that there are limited data on using duloxetine for patients with HIV infection.
# Anticonvulsants
The following agents may be effective for neuropathic pain:
- Gabapentin (Neurontin): Considered first-line for HIV sensory neuropathy for its tolerability.Starting dosage is 100-300 mg QHS; may be increased every 3-5 days to BID or TID to achieve symptom relief.
Monitor response and increase the dosage every 1-2 weeks by 300-600 mg/day.Usual maintenance dosage is 1,200-3,600 mg/day in divided doses.Adverse effects include somnolence, dizziness, fatigue, weight gain, and nausea.To discontinue, taper over the course of 7 or more days.
- Pregabalin (Lyrica): Starting dosage is 25-50 mg TID; may be increased by 25-50 mg per dose every 3-5 days as tolerated to achieve symptom relief.Maximum dosage is 200 mg TID.Adverse effects are similar to those of gabapentin.To discontinue, taper over the course of 7 or more days.
- Lamotrigine (Lamictal): Starting dosage is 25 mg QOD; titrate slowly to 200 mg BID over the course of 6-8 weeks to reduce the risk of rash (including Stevens-Johnson syndrome).Adverse effects include sedation, Section 8: Neuropsychiatric Disorders dizziness, ataxia, confusion, nausea, blurred vision, and rash.Note that lopinavir/ ritonavir (Kaletra) may decrease lamotrigine levels; higher dosages may be needed.To discontinue, taper over the course of 7 or more days.
- Although phenytoin and carbamazepine have some effectiveness in treating neuropathy, they have significant drug interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, and their use with HIV-infected patients is limited.Topiramate and valproic acid have been used for migraine prophylaxis and anecdotally may be useful for treating peripheral neuropathy, but have not been well-studied in HIV-related neuropathies.
# Treatment of Muscle Spasm Pain
Stretching, heat, and massage may help the pain of muscle spasm.This pain also can respond to muscle relaxants such as baclofen, cyclobenzaprine, tizanidine, benzodiazepines, as well as intraspinal infusion of local anesthetics for spinal injuries.
# Substance Abuse, HIV, and Pain
- Some health care providers hesitate to treat pain in patients with current or past substance abuse because of concern about worsening these patients' dependence on opioids or suspicion that such patients are seeking pain medications for illicit purposes.
However, the following points should be considered:
- Many patients with current or past substance abuse do experience pain, and this pain should be evaluated by care providers and treated appropriately.
- Failure to distinguish among addiction, tolerance, and dependence can lead to undertreatment of chronic pain by health care providers.
- Addiction (substance abuse) is a complex behavioral syndrome characterized by compulsive drug use for the secondary gain of euphoria.
- Pharmacologic tolerance refers to the reduction of effectiveness, over time, of a given dosage of medication.
- Physical dependence is the consequence of neurophysiologic changes that take place in the presence of exogenous opioids.
- Aberrant use of pain medications, if it develops, is best managed by an interdisciplinary team of providers from HIV clinical care, psychiatry, psychology, pharmacy, social services, and drug addiction management.
- Drug-drug interactions between certain antiretroviral medications and methadone can decrease methadone serum concentrations (see chapter Drug-Drug Interactions with HIV-Related Medications).
If this occurs, methadone dosages may need to be increased to prevent opiate withdrawal.
- As part of chronic pain management in patients with substance abuse, consider establishing a written pain-management contract to be signed by the clinician and the patient.The contract should:
- Clearly state limits and expectations for both the patient and provider.
- Identify a single clinician responsible for managing the pain regimen.
- Tell the patient what to do if the pain regimen is not working.
- Describe the procedure for providing prescriptions (e.g., one prescription given to the patient, in person, for a limited period of time, such as 1 month).
- List the rules for dealing with lost medications or prescriptions.
# Patient Education
- Pain management is part of HIV treatment, and patients should give feedback to allow the best treatment decisions.If pain persists for more than 24 hours at a level that interferes with daily life, patients should inform their health care provider so that the plan can be changed and additional measures, if needed, can be tried.
- Patients should not expect full pain relief in most cases, but enough relief that they can perform their daily activities.
- "Mild" pain medications (e.g., NSAIDs, aspirin, acetaminophen) usually are continued even after "stronger" medications are started because their mechanism of action is different than that of opiates.This combination of pain medication has additive effects, so that pain may be controllable with a lower narcotic dosage.
- Patients taking "around-the-clock" medications, should take them on schedule.Those taking "as needed" medications should take them between doses only if they have breakthrough pain.
- Opiates may cause severe constipation.
Patients must remain hydrated and will likely need stool softeners, laxatives, or other measures.They should contact their health care provider promptly if constipation occurs.
- Patients should avoid use of recreational drugs and alcohol when taking opiates because opiates can interact with them or cause additive adverse effects, possibly resulting in central nervous system depression, coma, or death.
- Patients taking opiates should avoid driving and operating machinery.
# Disorders
# HIV-Associated Dementia and Other Neurocognitive Disorders
# Background
HIV is a neurotropic virus that directly invades the brain shortly after infection.HIV replicates in brain macrophages and microglia, causing inflammatory and neurotoxic host responses.HIV may cause cognitive, behavioral, and motor difficulties.These difficulties may range in severity from very mild to severe and disabling; if moderate or severe, they constitute minor cognitive motor disorder (MCMD) or HIV-associated dementia (HAD), respectively.These conditions are distinguished from the milder cognitive changes seen in some people with HIV infection by the greater impact and duration of the functional deficits.MCMD is thought to involve neuronal cell dysfunction, whereas HAD often involves actual cell death.
A note on nomenclature: There have been multiple shifts in the nomenclature used to describe HIV-associated neurocognitive disorders.The most recent proposed system, published in the journal Neurology in 2007, suggests three categories: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HAD.However, the diagnoses of ANI and MND require neuropsychological testing that is more likely to be available in research settings as opposed to clinical settings.This chapter will therefore address the clinical diagnoses of MCMD and HAD.
Both MCMD and HAD are AIDS-defining conditions (listed as "Encephalopathy, HIV related" in the classification system used by the U.S. Centers for Disease Control and Prevention), and are risk factors for death.Neurocognitive disorders associated with HIV are among the most common and clinically important complications of HIV infection.However, they are diagnoses of exclusion, and other medical causes must be ruled out.
Risk factors for developing an HIV-associated neurocognitive disorder include the following:
- Older age
- Female gender
- More advanced HIV disease (including CD4 count <100 cells/µL, wasting)
- High plasma HIV RNA (viral load)
- Comorbid conditions (especially anemia and infection with cytomegalovirus, human herpesvirus 6, and JC virus)
- History of injection drug use (especially with cocaine)
- History of delirium Section 8: Neuropsychiatric
# Disorders
The use of effective antiretroviral therapy (ART) that maintains the plasma HIV RNA at undetectable or low values is the best way to prevent and treat HIV-related neurocognitive disorders.Thus, it is essential to choose an ART regimen that takes into consideration resistance testing and adherence issues.
# Minor Cognitive Motor Disorder
MCMD is characterized by mild impairment in functioning and may escape diagnosis by the clinician.The course and onset of MCMD can vary dramatically.The more demanding the activities of a particular individual, the more likely that person would be to notice the difficulties.MCMD does not necessarily progress to dementia.
# HIV-Associated Dementia
HAD is characterized by symptoms of cognitive, motor, and behavioral disturbances.There is often a progressive slowing of cognitive functions, including concentration and attention, memory, new learning, sequencing and problem solving, and executive control.HAD also can present with behavioral changes, which mainly take the form of apathy, loss of motivation, poor energy, fatigue, and social withdrawal.Motor changes, including slowing, clumsiness, unsteadiness, increased tendon reflexes, and deterioration of handwriting may occur.
# S: Subjective
If a neurocognitive disorder is suspected, obtain a history of the patient's symptoms (see below).Whenever possible, obtain a parallel history of the patient's past history and recent mental status changes from significant others or caretakers.
Patient self-reports of cognitive problems and bedside cognitive status tests may be insensitive, particularly to subtler forms of impairment.
To help clarify factors that may be causing the changes in mental status, inquire about the following:
- Acuity of onset
# A: Assessment
A differential diagnosis includes the following medical conditions, which may present with cognitive changes or delirium:
- Substance use: intoxication or withdrawal from alcohol, opioids, stimulants, etc.
- Psychiatric disorders, especially major depression
# P: Plan Laboratory and Diagnostic Evaluation
A change in the mental status of an HIVinfected person should prompt a thorough search for underlying biological causes.As noted above, HIV-related neurocognitive disorders are diagnoses of exclusion, and other causes of the patient's symptoms should be ruled out.
Section 8: Neuropsychiatric
# Disorders
# Treatment
There are no specific treatments for HIVassociated neurocognitive disorders, but ART may reverse the disease process, and a number of therapies may be helpful.The treatment of MCMD and HAD ideally utilizes a multidisciplinary approach that may involve HIV specialists, neurologists, psychiatrists, psychologists, nurse practitioners, social workers, and substance-use counselors.
Neurocognitive impairment in patients with HIV infection often is multifactorial. |
In addition to treating HIV-associated neurocognitive disorders themselves, it is important to correct, as much as possible, all medical conditions that may adversely affect the brain (e.g., psychiatric comorbidities, endocrinologic abnormalities, adverse medication effects).For patients using alcohol or illicit or nonprescribed drugs, implement strategies to reduce their use; these agents can further impair cognition.
# Pharmacologic Management of HIV-Associated Neurocognitive Disorders
- ART: Maximal suppression of HIV replication via ART may partially or fully reverse HIV-associated neurocognitive disorders, and ART is the treatment of choice for both treatment and prevention of HIV-associated neurocognitive disorders, including dementia.In general, ART regimens that effectively suppress HIV RNA in the serum also suppress HIV in the CNS.However, ARV medications vary in their ability to penetrate the blood-brain barrier and, therefore, in their ability to act directly on the HIV virus in the CNS.Limited data suggest that using ARVs with good CNS penetration may be important in treating or preventing neurocognitive disorders, and some experts recommend the use of these ARVs, if otherwise appropriate, for patients with HIV dementia.ARVs with the best CNS penetration include the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, emtricitabine, and zidovudine (AZT, ZDV); the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine; the protease inhibitors (PIs) indinavir/ ritonavir and lopinavir/ritonavir; and the CCR5 antagonist maraviroc.There currently is no role for testing levels of HIV RNA in the CSF outside research settings.
- Stimulants: Stimulant medications (e.g., methylphenidate, dextroamphetamine) have been used as palliative agents to help manage symptoms of fatigue, decreased concentration, and memory deficits among patients with MCMD and HAD.Starting dosages of both is 5 mg/day; maximum dosage is 60 mg/day.The response to stimulants is idiosyncratic and varies from patient to patient; begin with the lowest dose of 5 mg QAM and titrate upward as needed.
If BID dosing is required as a result of afternoon fatigue, the afternoon dose should be taken before 2 pm to prevent interference with sleep.Consider referral to a psychiatrist or neurologist for evaluation and initiation of treatment; after a stable dosage is achieved, treatment may be continued.These medications should be used with caution for patients who have a history of stimulant abuse.
- For comorbid depression, consider prescribing antidepressant medications as for other medically ill HIV-infected patients (see chapter Depression).
- Antipsychotic medications may be useful in treating agitation and hallucinations but should be used for patients with dementia only when nonpharmacologic measures are insufficient for patient management; consult with a psychiatrist.All antipsychotic medications increase the risk of death in elderly patients with dementia.Start antipsychotic medications at the lowest possible dosage and increase slowly as needed.
Section 8: Neuropsychiatric
# Disorders
- Many agents are being studied for either their neuroprotective effects or their therapeutic effects on HIV-associated neurocognitive disorders.The data are not sufficient at present to make specific recommendations.Patients with dementia often are sensitive to medication side effects; follow closely.
- Benzodiazepines have been shown to increase confusion and decrease concentration, and generally should be avoided.
# Nonpharmacologic Management of MCMD and Mild HAD
- Encourage patients to remain appropriately active
- Explain the benefits of structured routines
- Encourage good nutrition
- Use strategies to minimize use of alcohol and illicit drugs
- Use memory aids such as lists
- Simplify complex tasks, especially drug regimens
- When giving instructions, do the following:
- Repeat information
- Write instructions to provide structure for patients and caregivers
- Ask patients to express the information and instructions in their own words
- Adherence to medical regimens, including ART, often is particularly difficult for patients with neurocognitive disorders.Encourage use of medication adherence tools such as pill boxes, alarms, and, if available, packaged medications (e.g., blister packs) or prefilled medi-sets.Encourage patients to enlist adherence support from family members and friends.
- Cognitive skills building can be helpful (e.g., reading, solving puzzles, intellectual conversation).
# Nonpharmacologic Management of Moderate to Severe HAD
The strategies noted above should be utilized, but additional measures are needed.
Management of patients with severe or latestage HAD requires an evaluation of their safety and a determination of the environment and level of supervision that are needed.The clinician should attend to the following:
- Help determine whether patients can be left alone at home or whether doing so would present the risk of them wandering away or sustaining an injury in the home (e.g., from the use of an appliance such as the oven).
- For patients who cannot be left alone at home, assess options for support (e.g., help from family members or paid home attendants).
- Utilize fall prevention strategies.
- For patients who smoke, decide whether smoking can be done safely; if smoking is deemed unsafe, consider smoking cessation programs or supervision.
- If lesser measures fail, explore options for placement in a skilled nursing facility.
Additional helpful strategies for managing patients who are confused, agitated, or challenged by their experience include the following:
- Keep their environments familiar to the extent possible (e.g., in terms of objects, people, locations).
- Redirect or distract patients from inappropriate behavior.
- Remain calm when patients become confused or agitated; refrain from confronting an agitated patient; reorient confused or agitated patients.
- Provide a clock and calendar in the room to help keep patients oriented to time and to day of the week.
Section 8: Neuropsychiatric
# Disorders
- Provide lighting that corresponds with day and night.
- Emphasize routines.
- Ensure that patients who require eyeglasses or hearing aids wear them to help lessen confusion and disorientation.
- Prepare patients for any planned changes.
- Ensure that patients are receiving their prescribed medications.
- Protect wandering patients.
- Supervise any cigarette smoking.
- Offer activities that keep their minds alert.
- Educate family members about the nature of dementia and methods for helping patients maintain activities of daily living.
- Suggest that patients or their family members make arrangements for financial, health, and other matters in the event they become unable to make decisions about their affairs (e.g., advance health care directives, durable powers of attorney, wills).
# Patient Education
- Advise patients that ART can be effective in preventing and treating HIV-related neurocognitive impairment.
- Inform patients and family members of the many other strategies may aid in managing neurocognitive impairment.Such strategies may help patients maintain the highest possible level of skills and independence.
- Family members and significant others can be important sources of support (e.g., by providing assistance with medication adherence).
- Advise patients with advanced HAD that placement in a residential facility may be the best option for ensuring their safety.Patients with untreated depression experience substantial morbidity and may become selfdestructive or suicidal.They are at continuing risk of engaging in unsafe behaviors that may lead to HIV transmission and poor adherence to care and treatment.
Major depression in persons with comorbid medical illness, including HIV infection, has been associated with the following:
- Decreased survival
- Impaired quality of life
- Decreased adherence to antiretroviral therapy (ART)
- Increased risk behaviors Stress and depressive symptoms, especially when they occur jointly, are associated with diminished immune defenses in HIV-infected individuals, and severe depression is associated with higher mortality rates.Anxiety symptoms are common among people with major depression (see chapter Anxiety).Psychotic symptoms may occur as a component of major depression and are associated with an increased risk of suicide.Even one or two symptoms of depression increase the risk of an episode of major depression.
All clinicians should do the following:
- Maintain a high index of suspicion for depression and screen frequently for mood disorders.
- Elicit any history of psychiatric diagnoses or treatment.
Rule out medical conditions that may cause mood or functional alterations.
# Major Depression
The patient may complain of either or both of two cardinal symptoms:
- Diminished interest or pleasure in activities
- Depressed mood, sadness
If either or both of these are present, other complaints may be used to diagnose major depression, including the following:
- Decreased ability to concentrate
- Appetite changes with weight changes (increase or decrease)
- Fatigue or loss of energy The diagnosis of major depression is made if five of the above symptoms occur on most days for at least 2 weeks.Depressed mood or diminished interest or pleasure must be one of the five symptoms present.
Other subjective symptoms of depression may include:
- Hopelessness
- Helplessness
- Irritability or anger
- Somatic complaints in addition to those noted above
# Other Depressive Disorders
- Dysthymia is another very common depressive disorder found among HIVinfected patients.It is not uncommon for dysthymia to coexist with major depression, and the treatments for the two conditions are similar.
Dysthymia is characterized by more chronic but less severe symptoms than those found in major depression.The diagnosis is made
# PHQ-2
Over the past 2 weeks, how often have you been having little interest or pleasure in doing things?0 = Not at all 1 = Several days 2 = More than half the days 3 = Nearly every day Over the past 2 weeks, how often have you been feeling down, depressed, or hopeless?0 = Not at all 1 = Several days 2 = More than half the days 3 = Nearly every day Calculate the total point score:
Score interpretation: Section 8: Neuropsychiatric Disorders when a person has had a depressed mood for most of the day, for more days than not, for at least two years.While depressed, the patient exhibits two or more of the following symptoms:
- Poor appetite or overeating In addition, the symptoms must cause clinically significant distress or impairment in functioning, and there can have been no major depressive episode during the first two years of the disturbance.
- Bipolar disorder: Major depression may be a manifestation of bipolar disorder.Bipolar disorder should be ruled out before giving an antidepressant to a patient with major depression, as bipolar disorder usually requires the use of mood stabilizers before, or instead of, beginning antidepressant medications (antidepressant therapy may precipitate a manic episode).Bipolar disorder should be suspected if a patient has a history of episodes of high energy and activity with little need for sleep, has engaged in risky activities such as buying sprees and increased levels of risky sexual behavior, or has a history of taking mood stabilizers (lithium and others) in the past.If bipolar disorder is suspected, refer the patient to a psychiatrist for further evaluation and treatment.
- Other forms of depression include adjustment disorder with depressed mood (acute reaction to a life crisis, such as the loss of a job) and depressive disorder not otherwise specified.
- Bereavement is not a disorder but may be accompanied by symptoms that look similar to those of major depression.The diagnosis of major depression generally is not given unless depressive symptoms persist for 2 months after the loss.
# S: Subjective
- Inquire about the symptoms listed above, and about associated symptoms.
- Take a careful history of the timing and duration of symptoms, their relationship to life events (e.g., HIV testing, loss of a friend, onset of physical symptoms), and any other physical changes noted along with the mood changes.
- Elicit personal and family histories of depression, bipolar disorder, or suicidal behavior.
- Probe for suicidal thoughts, plans, and materials to execute the plans (see chapter Suicide Risk).
- Inquire about hallucinations, paranoia, and other symptoms.
- Ask about current and past medication use and substance abuse.
# O: Objective
Perform mental status examination, including evaluation of affect, mood, orientation, appearance, agitation, or psychomotor slowing; perform thyroid examination, inspection for signs of self-injury, and neurologic examination if appropriate.
# A: Assessment Partial Differential Diagnosis
Rule out nonpsychiatric causes of symptoms, which may include the following:
- Hypothyroidism or hyperthyroidism
- Hypotestosteronism (hypogonadism) -
# Psychotherapy
Individual psychotherapy with a skilled, HIV-experienced mental health professional can be very effective in treating depression.Several specific types of individual and group psychotherapies for depression (e.g., interpersonal therapy, cognitive-behavioral therapy, behavioral activation, supportive psychotherapy, coping effectiveness) have been shown to be effective for HIV-infected individuals.
# Pharmacotherapy
For most patients, a selective serotonin reuptake inhibitor (SSRI) or a selective norepinephrine reuptake inhibitor (SNRI) is the most appropriate initial treatment for depression.For patients who experience treatment failure with these agents (or have an incomplete response) at a customary therapeutic dosage, consultation with a psychiatrist is recommended.
When selecting antidepressant medications, consider their side effect profiles as a means to manage other symptoms the patient may Disorders be experiencing.For example, activating antidepressants (taken in the morning) may help patients who complain of low energy; antidepressants that increase appetite may be useful for patients with wasting syndrome; sedating antidepressants (taken at bedtime) may help patients with insomnia.Medications that may be lethal if overdosed (e.g., tricyclic antidepressants) should not be prescribed to patients for whom suicidality may be a concern.
The information below describes specific antidepressant medications, with information on dosage and possible adverse effects.Most antidepressants should be started at low dosages and gradually titrated upward to avoid unpleasant side effects that might lead to nonadherence.Antidepressant effect usually is not noticed until 2-4 weeks after starting a medication.If there is no improvement in symptoms in 2-4 weeks, and there are no significant adverse effects, the dosage may be increased.
A therapeutic trial consists of treatment for 4-6 weeks at a therapeutic dosage.If the patient's symptoms have not improved, an increase in dosage or a switch to another medication should be considered.Patients who remain depressed should be referred to a psychiatrist.
Monitor all patients closely after starting them on antidepressant medications.Some patients may be at risk of worsening depression, including suicidality, after initiation of therapy; improved energy is the initial effect of antidepressants, whereas hopelessness and sadness improve later.In addition, some young persons are at risk of worsening depression caused by antidepressants.Blackbox warnings advise that antidepressants may cause increased risk of suicidality in children, adolescents, and young adults (<24 years of age) with major depressive or other psychiatric disorders, especially during the first month of treatment.
Medications should be continued for 6-9 months beyond the resolution of symptoms to reduce the risk of recurrence.After this time, treatment may be tapered down gradually if the patient wishes, with careful monitoring for recurrence of symptoms.The risk of recurrence is higher if the first depressive episode is inadequately treated or if the patient has had multiple depressive episodes.For patients with recurrent depression, consider long-term maintenance antidepressant treatment.See "Discontinuing antidepressant medication," below.
# Potential ARV Interactions
Interactions may occur between certain ARVs and agents used to treat depression.Some combinations may be contraindicated and others may require dosage adjustment.Refer to medication interaction resources or consult with an HIV expert, psychiatrist, or pharmacist before prescribing.
Some ARV medications (particularly protease inhibitors ) may affect the metabolism of some antidepressants via cytochrome P450 interactions.For example, ritonavir can significantly increase serum levels of tricyclic antidepressants, increasing the risk of tricyclic toxicity.In the case of most other antidepressants, interactions with ARVs generally are not clinically significant, but most antidepressants used concomitantly with PIs should be started at low dosages and titrated cautiously to prevent antidepressant adverse effects and toxicity.On the other hand, some PIs may decrease levels of paroxetine, sertraline, and bupropion, and efavirenz also lowers sertraline and bupropion levels; these antidepressants may require upward titration if used concurrently with interacting ARVs.Further information is presented under individual agents and classes, below.
For patients who are starting ARV medications (particularly PIs) and are on a stable antidepressant regimen, monitor carefully for adverse effects and for efficacy of the antidepressant; dosage adjustments may be required.The adverse effects of tricyclics can be used to treat insomnia or diarrhea, for example, and tricyclics can be effective for neuropathic pain.
- Imipramine (Tofranil): FDA indications for depression and chronic pain.The full recommended dosage for either problem is 150-300 mg QHS.Starting dosage: 25-75 mg PO QHS.
- Doxepin (Sinequan): FDA indications for depression and anxiety at adult dosages of 150-300 mg QHS.Starting dosage: 25-75 mg PO QHS.
- Three other available tricyclics have an FDA indication for depression only: nortriptyline (Pamelor) at dosages of 50-150 mg QHS; desipramine (Norpramin) at dosages of 50-200 mg a day; and protriptyline (Vivactil) at dosages of 5-10 mg, either TID or QID.
- Tricyclics need to be started at low dosages and titrated gradually.Lower dosages often are more appropriate for patients who are elderly, medically ill, or taking ritonavir or a ritonavir-boosted PI.
Section 8: Neuropsychiatric
# Disorders
- Trazodone (Desyrel): a highly sedating antidepressant that is rarely used at an antidepressant dosage.Rather, it is often given at lower dosage for insomnia associated with depression, at a dosage of 25-50 mg 1-2 hours before bedtime.
Ritonavir and other PIs can increase trazodone levels significantly; start at low dosage and use the lowest effective dosage; monitor for adverse effects; do not use with saquinavir/ritonavir.
- Nefazodone (Serzone): an antidepressant that usually should be avoided in people with HIV infection.Little information on interactions with ARVs is available, but it appears that nefazodone may increase levels of maraviroc and saquinavir, and that ritonavir may increase nefazodone levels.It has a black-box warning for severe liver toxicity.If the patient has ever had liver toxicity from the drug, restarting it is contraindicated.
- St. John's wort: an herbal antidepressant that can significantly decrease serum concentrations of PIs, NNRTIs, and maraviroc; it is contraindicated for use by patients taking those ARVs.
- Treatment may involve antidepressant combinations, including psychostimulants; consult with a psychiatrist.
# Discontinuing antidepressant medication
Antidepressant medication generally should be continued for at least 6 months following improvement from a first episode of major depression.Longer term, and even indefinite, maintenance treatment may be necessary for people with recurrent major depression. |
When discontinuing antidepressants, except for the few mentioned above (e.g., fluoxetine), they need to be tapered gradually to avoid withdrawal symptoms (as below) or rebound depression.
Abrupt discontinuation of SSRI and SNRI antidepressants often precipitates the emergence of unpleasant withdrawal symptoms.This is particularly true for paroxetine and venlafaxine.Withdrawal symptoms may include confusion, agitation, irritability, sensory disturbances, and insomnia.The abrupt discontinuation of SSRIs is associated with a return or worsening of depressive symptoms.
# Brain stimulation treatments
There are a variety of brain stimulation treatments that usually are reserved for patients who have inadequate responses to medication.Electroconvulsive therapy (ECT) is the best known of these treatments and, despite the stigma associated with it, is more effective than antidepressant medication.Newer brain stimulation treatments also are available.These treatments require referral to the specialty care locations that offer them.Antidepressant medication often is used for maintenance after stabilization with ECT, but for some people, maintenance ECT is needed to prevent the relapse of depression.
Section 8: Neuropsychiatric
# Disorders
# Patient Education
- Providers should explain to patients that illness (physical or emotional) is not a character flaw or a moral or spiritual weakness.It is a common aspect of HIV infection.Sadness is a normal part of life, but major depression always is abnormal and often can be alleviated with medication, psychotherapy, or both.
- Providers should help patients identify the symptoms of depression and the factors that led them to seek treatment.Patients will need to monitor themselves for recurrences or exacerbations and get help if the symptoms recur.Patients should be told to contact providers if they notice changes in their sleep, appetite, mood, activity level, or concentration, or if they notice fatigue, isolation, sadness, or feelings of helplessness.
- When starting an antidepressant medication, patients should expect that it will take 2-4 weeks for them to notice any improvement.Their symptoms should continue to decrease over the following weeks.If they do not have much improvement in symptoms, providers may choose to adjust the dosage of the medication or to change medications.
Patients must continue taking their medications so that the symptoms of depression do not return.
- Providers should let patients know that St. John's wort can lower levels of ARVs and cannot be taken if they are on ART.
- Antidepressants typically are given for a long time, usually for a year or longer, to help patients with the chemical imbalances associated with major depression.Patients should be told that they should not suddenly stop antidepressants they have been taking for a long time, and that these medications need to be discontinued gradually.
- Some patients develop problems with sexual function while they are taking antidepressants.They should report any problems to their prescribers. (Note: Providers should let patients know that sexual well-being is fundamental to quality of life and can be talked about and addressed in the clinical setting.)
Section 8: Neuropsychiatric
# Disorders
# Suicide Risk Background
Transient suicidal thoughts are common for some people throughout the course of HIV disease and often do not indicate significant risk of suicide.However, persistent suicidal thoughts with associated feelings of hopelessness and intent to die are very serious and must be assessed promptly and carefully.Compared with people at high risk of suicide who are not HIV infected, people living with HIV have significantly increased frequency and severity of both suicidal ideation and thoughts of death.The risk of suicide is especially high for patients who are depressed and for those at pivotal points in the course of HIV infection.Stigma, quality of life concerns, and issues regarding disclosure may be contributing factors.
Suicidality may be the direct physiological result of HIV (e.g., owing to the impact of HIV in the brain), a reaction to chronic pain, an emotional reaction to having a chronic and life-threatening illness (e.g., major depression as a result of physical illness or psychiatric side effects caused by medications used to treat HIV infection and associated comorbidities).Many events may trigger suicidal thoughts among people with HIV.Such events include learning of their positive HIV status, disclosing to family and friends, starting antiretroviral therapy (ART), noticing the first symptoms of infection, having a decrease in CD4 cell count, undergoing a major illness or hospitalization, receiving an AIDS diagnosis, losing a job, experiencing major changes in lifestyle, requiring evaluation for dementia, and losing a significant relationship.
Evaluation of suicide risk must be included as part of a comprehensive mental health evaluation for HIV-infected patients.Note that asking patients about suicidal thoughts does not increase their risk of suicide.
# S: Subjective
The patient expresses or exhibits, or a personal care giver discloses, the following:
- Active suicidal ideation with intent and plan, such as giving away significant personal belongings, saying goodbye, acquiring the means (e.g., gun, pills), writing a suicide note - Depressed mood, hopelessness, agitation, intoxication with alcohol or other drugs
- Passive withdrawal from therapy or medical care or decreased adherence (e.g., stopping medications, missing appointments)
- A desire for HIV disease to progress more rapidly
Inquire about the following during the history (again, note that asking patients about suicidal thoughts does not increase their risk of suicide):
- Previous suicide attempt(s) -one of the best predictors of eventual death by suicide
- Friend or family member who has committed suicide
- Personal or family history of depression
- Previous episode of psychosis
- Presence of risk factors described above Probe for other depressive symptoms and the immediacy of potential suicidal intent.Sample questions may include the following:
- "It sounds as if you're in great pain.Have you ever thought that life is not worth living?"
- "Do you often think of death?"
- "Do you think about hurting yourself?"
- "How might you do that?"
- "Do you have a plan?"Ask whether the patient has access to the components of the plan (e.g., gun, pills)
- "Is this something you feel you might do?"
- "What would prevent you from doing this?"
- "Have you ever attempted suicide?What did you do?"
# O: Objective
- Perform a mental status examination and suicide assessment.
- Look for signs of self-inflicted injuries such as wrist lacerations or neck burns.
- Look for signs of depression, agitation, or intoxication.
# Suicide Risk | 555
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# Disorders
# A: Assessment
See chapter Depression for differential diagnosis of possible causes of depression and suicidality.
# P: Plan Evaluation
Evaluate the patient for depression, risk factors for suicide, and contributing psychiatric illnesses or situational stressors.Determine the immediacy of potential suicidal intent.If a mental health professional is available on site or can be summoned, an urgent consultation often is helpful in making these determinations.
# Treatment
- If the patient exhibits active suicidal ideation with a plan, hospitalize the patient immediately, preferably in a psychiatric facility.
- If suicidal thoughts are passive, refer for evaluation for specific psychiatric disorders and refer for psychotherapy with an HIVexperienced mental health provider.
- Encourage the patient to contact you or another specified clinician for help, or to go to a hospital if suicidal ideation worsens or patient worries about acting upon suicidal thoughts.
- Note that making a contract with a patient against suicide is not recommended; research shows is not effective, and it can provide a false sense of security.
- Inform patients about local suicide prevention resources, including suicide hotlines, emergency response (e.g., 911), and local emergency departments.
- Contact the patient between appointments.Enlist the help of significant others (if the patient agrees); invite them to accompany the patient on the next visit and see all of them together.Consider a support group or peer referral, if available.
- Consider dispensing medications on a weekly basis for the following purposes:
- Monitoring emotional status and treatment adherence
- Preventing the availability of lethal doses of medications
- Perform appropriate follow-up.In consultation with a skilled mental health provider, be sure that the patient is receiving appropriate ongoing treatment for underlying or persisting psychiatric illness.Assess at each visit for adherence to mental health care and for recurrence of symptoms.
# Patient Education
- Suicidal ideation and severe depression are not normal aspects of HIV infection, and usually can be treated effectively.
- Patients should report suicidal thoughts to their health care providers.
- Inform patients about local suicide prevention resources, including suicide hotlines, emergency response (e.g., 911), and local emergency departments.
# O: Objective
Measure vital signs, with particular attention to heart rate (tachycardia) and respiratory rate (shortness of breath, hyperventilation).
Perform a physical examination, including mental status and neurologic, cardiopulmonary, and thyroid examinations.
# A: Assessment
A differential diagnosis may include the following medical conditions:
- Substance use (e.g., amphetamines, cocaine)
- Substance or medication withdrawal (e.g., alcohol, benzodiazepines)
- Excessive caffeine intake
# Diagnostic Evaluation
Perform the following tests:
- Blood glucose, electrolytes
- Thyroid function tests (TSH, T4)
- Electrocardiogram (EKG) if patient has shortness of breath or palpitations
- Arterial blood gases (if frank difficulty breathing is not self-limited)
- Other tests as indicated by symptoms and physical examination
# Treatment
Once medical disorders have been ruled out, and the diagnosis of an anxiety disorder is established, several options are available:
# Psychotherapy
Options include cognitive-behavioral therapy, interpersonal therapy, exposure therapy, a stress-management group, relaxation therapy, visualization, guided imagery, supportive psychotherapy, and psychodynamic psychotherapy.Long-term psychotherapy may be indicated if experienced professionals are available and the patient is capable of forming an ongoing relationship.If possible, refer to an HIV-experienced therapist.The type of psychotherapy available to the patient often depends on the skills and training of the practitioners in a given health care system or region.In addition, the patient may be referred to available community-based support. -Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRI) are effective in treating patients with anxiety.They are favored for long-term use when a specific anxiety disorder is present and persistent.These medications do not cause tolerance or pose a risk of addiction.Below is a list of antidepressants that includes their U.S. Food and Drug Administration (FDA) approvals for specific anxiety disorders and the usual recommended dosages.FDA recommendations are based on availability of specific study data, but all SSRIs (regardless of whether they have an FDA indication for anxiety) may be helpful for a broad range of anxiety disorders.See chapter Depression for further information about antidepressant medications, including adverse effects.
- SSRI antidepressants:
- Fluoxetine (Prozac): FDA indication for panic disorder with a recommended dosage of 20 mg once daily.Also recommended for obsessive-compulsive disorder, but higher dosages are needed, sometimes up to 80 mg daily.
- Escitalopram (Lexapro): FDA indication for generalized anxiety disorder at a dosage of 10 mg once daily.
- Citalopram (Celexa): Does not have specific FDA indications for anxiety disorders.Suggested dosage: start at 10 mg once daily and titrate as needed; maximum dosage: 60 mg daily.
- Paroxetine (Paxil): FDA indications for obsessive-compulsive disorder and panic disorder both at a recommended dosage of 40 mg once daily.Also indicated for social anxiety disorder at a dosage of 20-40 mg daily.Usual starting dosage: 10 mg daily.
- Sertraline (Zoloft): FDA indications for panic disorder and PTSD at dosages of 50-200 mg once daily.Usual starting dosage: 25 mg daily.
- SNRI antidepressants:
- Venlafaxine timed-release formulation (Effexor XR): FDA indication for generalized anxiety disorder, at recommended dosages of 75-225 mg per day.Note: There is a risk of hypertension at the higher dosages of venlafaxine; monitor blood pressure.
- Duloxetine (Cymbalta): FDA indication for generalized anxiety disorder at a recommended dosage of 60 mg once daily.
- Other antidepressants:
- Some sedating antidepressants are effective, nonaddictive agents that are helpful when taken at bedtime for both insomnia and anxiety symptoms.These include trazodone (Desyrel) 25-100 mg QHS or imipramine (Tofranil) 25 mg QHS.Note that imipramine and other tricyclics must be used with caution but are not contraindicated for use by patients taking ritonavir (including ritonavirboosted protease inhibitors ).
- Gabapentin (Neurontin), a mood stabilizer, may be given at dosages of 200-400 mg BID to QID and may sometimes help to diminish anxiety.
# Panic Disorder Background
Panic disorder is an anxiety disorder whose essential feature is the presence of recurrent, unexpected panic attacks.Panic attacks are discrete, sudden-onset episodes of intense fear or apprehension accompanied by specific somatic or psychiatric symptoms (e.g., palpitations, shortness of breath, fear of losing control).A patient is diagnosed as having panic disorder when he or she has experienced such attacks, and at least one of the attacks has been followed by ≥1 month of persistent concern about additional attacks, worry about the implications or consequences of the attack, or a significant change in behavior related to the attack.
Panic disorder is classified as being either with or without agoraphobia.Agoraphobia refers to anxiety about being in places or situations from which escape might be difficult or embarrassing, or in which help might not be available in the event of a panic attack or panic-like symptoms.These situations might include being alone outside one's home, being in a crowd, being on a bridge, driving, traveling in a bus or train, or even visiting health care providers for medical appointments.
The patient avoids these situations or endures them with marked distress.
The symptoms of panic disorder usually begin in late adolescence to the mid-30s and may coincide with the presentation of major depressive disorder, social phobia, or generalized anxiety disorder.Panic disorder can interfere with the ability to conduct activities of daily living.Patients with panic disorder have an increased incidence of suicide.
Symptoms may mimic those of various physical illnesses or be caused by other medical conditions (e.g., hyperthyroidism, brain tumors, adrenal tumors, heart arrhythmias, hypoglycemia, anemia).Substance or alcohol intoxication or withdrawal also may cause panic symptoms.Patients with panic symptoms should be evaluated for other causative conditions
Major depressive disorder occurs in 50% to 65% of people with panic disorder.Major depression may precede or follow the onset of panic disorder.Patients with panic disorder therefore should be screened for depression initially and periodically thereafter (see chapter Depression).Anxiety also commonly is experienced by persons with panic disorder; see chapter Anxiety for further information about this condition.
# S: Subjective
The patient complains of discrete periods of intense fear or discomfort in which four or more of the following symptoms developed abruptly and reached a peak within 10 minutes:
- Shortness of breath or smothering sensation
# A: Assessment
A differential diagnosis may include the following conditions:
- Congestive heart failure, myocardial ischemia, arrhythmias
# Treatment
Once other diagnoses have been ruled out, consider the following treatments:
# Psychotherapy
Options include cognitive-behavioral therapy, interpersonal therapy, exposure therapy, a stress-management group, relaxation therapy, visualization, guided imagery, supportive psychotherapy, and psychodynamic psychotherapy.Long-term psychotherapy may be indicated if experienced professionals are available and the patient is capable of forming an ongoing relationship.If possible, refer to an HIV-experienced therapist.The type of psychotherapy selected often will depend on the skills and training of the practitioners available in a given health care system or region.In addition, refer the patient to available community-based support.Emergency referrals may be needed for the most anxious patients and those with comorbid depression.
# Pharmacotherapy
Patients with advanced HIV disease, like geriatric patients, may be more vulnerable to the central nervous system (CNS) effects of certain medications.Medications that affect the CNS should be started at low dosage and titrated slowly.Similar precautions should apply to patients with liver dysfunction.
# Options
Five medications have an approved indication by the U.S. Food and Drug Administration (FDA) for panic disorder.These are the serotonin reuptake inhibitors (SSRIs) and benzodiazepines listed below.
For most patients, SSRIs are preferable to benzodiazepines for the treatment of panic disorder because they do not have the potential for addiction and they do not pose the same level of risk if drug interactions cause an elevation of their levels.Other medications used to treat anxiety disorders, such as serotonin/norepinephrine reuptake inhibitor (SNRI) may be considered, and some of them are less likely to interact with ARV medications.See chapter Anxiety for descriptions of these medications.
SSRI antidepressants approved for panic disorder include the following:
- Fluoxetine (Prozac), recommended dosage 20 mg PO once daily (usual starting dosage 10 mg daily)
- Paroxetine (Paxil), recommended dosage 40 mg PO once daily (usual starting dosage 10 mg daily)
- Sertraline (Zoloft), recommended dosage 50-200 mg PO once daily (usual starting dosage 25 mg daily)
Benzodiazepines approved for panic disorder include the following:
- Clonazepam (Klonopin), recommended dosage 0.5-2 mg PO BID
- Alprazolam (Xanax), recommended dosage 0.5-3 mg PO TID or Xanax XR at a recommended dosage of 3-6 mg PO once daily.Start at low dosage, may increase every 3-4 days in increments of ≤1 mg/day if tolerated.
Section 8: Neuropsychiatric
# Disorders
# Potential ARV Interactions
Interactions may occur between certain ARVs and agents used to treat panic.Some combinations may be contraindicated and others may require dosage adjustment.Refer to medication interaction resources or consult with an HIV expert or pharmacist before prescribing.Some ARV medications (particularly protease inhibitors ) may affect the metabolism of some SSRIs via cytochrome P450 interactions.These generally are not clinically significant, but SSRIs used concomitantly with PIs should be started at low dosages and titrated cautiously to prevent antidepressant adverse effects and toxicity.On the other hand, some PIs may decrease levels of paroxetine and sertraline, and efavirenz also lowers sertraline levels; these antidepressants may require upward titration if used concurrently with interacting ARVs.PIs can significantly elevate the levels of clonazepam and alprazolam, resulting in the potential for severe sedation or respiratory depression.For patients receiving clonazepam or alprazolam, it is recommended that these medications be used at the lowest dosages for the shortest duration possible. |
# Patient Education
- Inform patients that behavioral interventions can help to reduce the frequency and severity of panic attacks.
- Some antidepressants and antianxiety medications can prevent or reduce the severity of panic attacks.
- Advise patients that they may develop problems with sexual function because of the medications.Patients should report any problems to their prescribers. (Note: Providers should let the patient know that sexual well-being is fundamental to quality of life and can be talked about and addressed in the clinical setting.)
# Background
Symptoms of posttraumatic stress disorder (PTSD) can develop after exposure to a traumatic event.A traumatic event may be a single instance, such as a car accident or experience of a natural disaster, or an ongoing pattern of events, such as continuous neglect, physical or sexual abuse, or chronic exposure to war or violent conflict.PTSD causes intrusive memories, hyperarousal, and psychological numbing or avoidance, among other symptoms.It may impair an individual's psychological and physical functioning, decreasing immune system function and increasing susceptibility to illness.Untreated PTSD can increase the risk of HIV transmission or acquisition and worsen the course of HIV treatment.
Individuals with PTSD may experience depression, anxiety, social isolation, impairments in trust and attachments, and feelings of anger, and PTSD often coexists with depression, anxiety, or other psychiatric illnesses.PTSD may be associated with increased risk-taking behavior (e.g., substance abuse, unsafe sex).
The rate of PTSD among individuals with HIV infection (in whom the lifetime prevalence is possibly as high as 42%) is higher than that of the general population (1.3%-7.8%).Women experience PTSD at a higher rate than men.The likelihood of developing PTSD increases in relation to the severity of or proximity to the traumatic event.A history of traumatic experiences may increase an individual's risk of developing PTSD after a new trauma.Although a diagnosis of HIV may trigger PTSD symptoms, a history of trauma or abuse often is present as well.A personal or family psychiatric history may increase the likelihood of developing PTSD.
PTSD is diagnosed, as in HIV-uninfected individuals, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV (see "References," below).It is treatable through diverse therapies and psychopharmacology.
# S: Subjective
The following reflect DSM-IV diagnostic criteria; include them in the history.
- The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death, serious injury, or a threat to the physical integrity of self or others.
- The person's response involved intense fear, helplessness, or horror.
- The patient complains of persistently reexperiencing the event in one or more of the following ways:
- Recurrent and intrusive distressing recollections of the event, including images, thoughts or perceptions
- Recurring distressing dreams of the event
- Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations and dissociative flashback episodes, including those that occur when awakening or intoxicated)
- Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event
- Physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event Section 8: Neuropsychiatric
# Disorders
Other complaints may include the following:
- Overwhelming emotions caused by memories of the event - Emotional numbness
- Disruptions in consciousness, memory, or identity
- Depersonalization (i.e., a feeling of watching oneself act, while having no control over a situation)
- Derealization (i.e., alteration in the perception or experience of the external world so that it seems strange or unreal)
- Feelings of estrangement from others
- Episodes of lost time
The patient may experience the following:
- Recurrent distressing recollections of the event
# O: Objective
- Check vital signs, with particular attention to heart rate (tachycardia) and respiratory rate (shortness of breath, hyperventilation).
- Perform a physical examination, including mental status and neurologic examination (tremor, hyperreflexia, focal abnormalities).
- Look for signs of physical trauma or sexual assault.
# A: Assessment
A differential diagnosis may include the following:
- Substance use (e.g., amphetamines, cocaine)
- Substance withdrawal (e.g., alcohol, benzodiazepines)
- Electrolyte imbalances
# Psychotherapy
Options include individual cognitivebehavioral therapy, dialectical-behavioral therapy, interpersonal therapy, exposure therapy, a stress-management group, relaxation therapy, visualization, guided imagery, supportive psychotherapy, and psychodynamic psychotherapy.Long-term psychotherapy may be indicated if experienced professionals are available and the patient is capable of forming an ongoing relationship.If possible, refer to an HIV-experienced therapist.The specific psychotherapy often depends on the skills and training of the practitioners available in a given health care system or region.In addition, refer the patient to available community-based support.
# Pharmacotherapy
Antidepressants Most antidepressants should be started at low dosages and gradually titrated upward to avoid unpleasant side effects.Therapeutic effects may not be noticed until 2-4 weeks after starting a medication.If there is no improvement in symptoms in 2-4 weeks, and there are no significant adverse effects, the dosage may be increased.Before prescribing a medication, always remember to check for drug-drug interactions, particularly with concurrent antiretrovirals (ARVs).See "Potential ARV Interactions," below, and chapter Depression for further information about antidepressants, including possible adverse effects and interactions with ARVs.
- Selective serotonin reuptake inhibitors (SSRIs) have the strongest evidence for efficacy and tolerability for PTSD and are first-line medication treatment. Benzodiazepines can reduce anxiety rapidly, often within hours, but may have counterbalancing side effects early in the course of their use that include sedation and incoordination.In addition, physical dependency may develop in patients who use them for more than a few weeks.Benzodiazepines are not recommended for people who have a history of alcohol abuse or dependence.Benzodiazepines ideally would be used only briefly and intermittently to quell acute and severe anxiety symptoms.
Buspirone (BuSpar) is a nonaddictive anxiolytic.It usually must be taken for at least 1-2 weeks before anxiety symptoms begin to lessen.Starting dosage is 5 mg PO TID.If symptoms persist, the dosage can be increased by 5 mg per dose each week to a maximum of 10-15 mg PO TID (for a total daily dosage of 30-45 mg).Low-dose benzodiazepines may be used during the initial weeks of buspirone therapy, until the effects of buspirone are felt.The major potential adverse effects of buspirone are dizziness and lightheadedness.
# Anticonvulsants
Mood stabilizers such as valproate (Depakote), carbamazepine (Tegretol), lamotrigine (Lamictal), and topiramate (Topamax) may be added for patients with a partial response to an antidepressant.They may be particularly helpful for those who have considerable irritability, anger, or hostility, as well as those with reexperiencing symptoms (e.g., flashbacks, intrusive memories).Gabapentin (Neurontin) 200-400 mg BID or QID sometimes helps to diminish anxiety.
Treatment with these agents usually should be done by or in consultation with a psychiatrist.
# Antipsychotics
Older and newer antipsychotics (aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) may be suitable for individuals with psychotic features of PTSD or those who have a comorbid psychotic illness.These medications also may be helpful for some individuals who have not benefited from medications indicated for PTSD.Adverse effects may include dyslipidemia, hyperglycemia, weight gain, and sudden cardiac death.Consultation with a psychiatrist is recommended.
# Other medications
A variety of other medications have been used as adjunctive treatment when insomnia and nightmares persist despite adequate use of psychotropic medications.Research is still quite limited, but suggests that the antihypertensive drugs clonidine (Catapres) and prazosin (Minipress) may help with the insomnia and nightmares of PTSD.
Patients with advanced HIV disease, as with geriatric patients, may be particularly vulnerable to the CNS effects of certain medications.Medications that affect the CNS should be started at low dosage and titrated slowly.Similar precautions should apply to patients with liver dysfunction.
- Inform patients that both behavioral interventions and medication can be very helpful in treating PTSD.If one strategy is not successful, many others are available.
- Advise patients that psychiatric medications are often given for a long time, usually for a year or longer.
- Advise patients that, when they start taking an antidepressant medication for PTSD, they should expect that it will take 2-4 weeks for them to notice any improvement.
Their symptoms should continue to decrease over the following weeks.If they do not have much improvement in symptoms, providers may choose to adjust the dosage of the medication or to change medications.Patients must continue taking their medications so that symptoms do not return.
- Advise patients that they may develop problems with sexual function because of psychiatric medications.They should report any problems to their prescribers.
# Insomnia
# Background
Insomnia is a common accompaniment to HIV infection, especially as the disease progresses and complications worsen.Once present, insomnia tends to be chronic, unlike the transient disturbances of sleep that are a normal part of life.Most insomnia related to HIV can be characterized by the amount, quality, or timing of sleep.Insomnia may cause progressive fatigue and diminished functioning.
# S: Subjective
The patient may complain of the following:
- Difficulty initiating sleep
- Early-morning awakening
- Mind-racing thoughts (e.g., "I can't turn off my thoughts.")
- Difficulty maintaining sleep
- Nonrestorative sleep (i.e., although the amount of sleep is adequate, the patient does not feel rested upon awakening)
- Nighttime restlessness Ask about the symptoms above, and about the following:
- Determine the patient's bedtime sleep habits; request additional history from a sleep partner, if possible.
- Try to quantify how long the patient actually sleeps each night.
- Ask about the following:
- Alcohol and recreational drug use
- Caffeine intake (quantity, times of day)
- Nightmares, life stressors
- Concurrent medications that may cause insomnia as an adverse effect (e.g., efavirenz, corticosteroids, pseudoephedrine, and decongestants)
- Medications (prescription or over-the-counter) or supplements used to promote sleep - Shift work, exercise, nighttime reflux or heartburn, snoring, and periods of apnea (not breathing)
- Collar size (size >16 more often associated with sleep apnea)
- Screen for depression and anxiety.
# O: Objective
Perform a general symptom-directed physical examination, including evaluation of body habitus, neurologic status, and mental status.
# A: Assessment
A partial differential diagnosis includes the following:
- Alcohol intake (interferes with sleep 2-4 hours after ingestion, may cause nocturnal awakening)
- Caffeine intake
# Pain
Underlying systemic medical conditions that can interfere with sleep, such as delirium, lung disease, congestive heart failure, renal failure, diarrhea, and incontinence
# P: Plan Evaluation
The diagnosis usually is based on history.A sleep evaluation (including polysomnography) may be indicated when a physiologic cause (e.g., obstructive sleep apnea) is suspected or insomnia is severe.
# Treatment
Treat underlying illnesses that may be causing or contributing to insomnia.
- Manage correctible medical conditions that may interfere with sleep.
- Treat depression and anxiety disorders.These are very common contributors to insomnia among people with HIV infection.See chapters Depression, Anxiety, and Panic Disorder.
- If the patient is suspected of having sleep apnea, periodic limb movements in sleep, or restless limb syndrome, refer to a specialist in sleep medicine for evaluation.
The following options are available for treatment:
# Behavioral strategies
- To correct deleterious sleep habits, patients should do the following:
- Establish a bedtime routine.
- Avoid stimuli before bedtime.
- Avoid vigorous exercise within 3-4 hours of bedtime.
- Reduce or eliminate daytime napping.
- Avoid eating, reading, watching TV, or working in bed.
- Wake up at the same time each day regardless of total hours of sleep.
- Have a dark, cool, quiet, comfortable environment conducive to sleep.
- Place the bedroom clock out of sight.
- If unable to fall sleep after 15-20 minutes, the patient should get up, go into another room for nonstimulating activity in dim light (such as reading), and not go back to bed until sleepy.
- The patient should discontinue use of caffeine, central nervous system stimulants, alcohol, and tobacco, with tapering if necessary, to avoid withdrawal symptoms.
- Teach or refer the patient for relaxation techniques.
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# Disorders
# Pharmacotherapy
Choosing a pharmacologic agent for insomnia A number of medications may be effective in treating insomnia.In selecting a medication for an individual patient, consider the following about a specific medication:
- Is it likely to improve symptoms that may be contributing to the patient's insomnia (e.g., depression, anxiety, psychosis, neuropathic pain)?
- Does it pose risks to the patient based on comorbid medical conditions (e.g., benzodiazepines should not be given to patients with sleep apnea, tricyclic antidepressants should not be given to patients with cardiac conduction problems)?
- Does it have adverse interactions with other medications, (e.g., zolpidem , zaleplon , and eszopiclone should be used with caution in patients taking protease inhibitors )?
- Is it the optimal agent for a patient with a current or past history of alcohol or sedative abuse/dependence?
- Is it affordable (e.g., formulary or co-pay issues)?
# Treatment considerations
There are limited data to guide the frequency (nightly, intermittently, as needed) and duration (brief, intermediate, long-term) of hypnotic medications.Hypnotics generally should be prescribed at the lowest effective dosage for the shortest possible period.The greater the degree of physical illness, the more likely the patient will need a low dosage of a hypnotic agent.When long-term treatment is necessary, benzodiazepines pose the greatest risk of tolerance, abuse, and dependence.
Possible adverse effects of all hypnotics include excess sedation, daytime grogginess, and disruption of the sleep architecture (e.g., causing sleepwalking).
Interactions may occur between certain antiretrovirals (ARVs) and agents used to treat insomnia.Some combinations may be contraindicated and others may require dosage adjustment.Refer to medication interaction resources or consult with an HIV expert, psychiatrist, or pharmacist before prescribing.
# Oral Health Background
Examination of the oral cavity should be included in both the initial and interim physical examination of all HIV-infected patients.Patients with lesions suspected to be oral manifestations of HIV disease should be referred to a dental health expert with experience in treating oral lesions associated with HIV/AIDS.Other oral lesions may be a sign of a systemic disease, a side effect of medications, or a result of poor oral hygiene.
# Xerostomia (Dry Mouth)
# S: Subjective
The chief complaint may be a dry, "sticky," or possibly a burning sensation in the mouth, or an inability to "taste" food.The patient may present with difficulty swallowing.
# O: Objective
The oral mucosal tissues appear dry and sometimes "shiny" in appearance.The lips may be dry and cracked, and the tongue is dry.Dental decay may be present on the cervical portion of the teeth (near the gingival margin or "gumline").Oral candidiasis (thrush) may or may not be present.
# A: Assessment
The differential diagnosis for the cause of xerostomia includes medication side effects (e.g., from anticholinergics), systemic diseases (e.g., Sjögren syndrome), adverse effects of radiation therapy, and salivary gland diseases.
# P: Plan
# Burning Mouth Syndrome; Atrophic Glossitis
# S: Subjective
The patient may complain of a constant burning sensation in the mouth or a numbness or tingling feeling of the tongue.Eating certain foods or spices may trigger the burning sensation.The patient also may complain of dry mouth or a metallic taste in the mouth.
# O: Objective
The tongue and oral mucosal tissues may be normal in appearance or there may be a slight redness on the tip and lateral margins of the tongue.In other cases, the tongue may appear "bald," owing to the loss of papillae on the Section 9: Oral Health dorsal surface, and it may be "beef red" in color.
# A: Assessment
Possible systemic etiologies include nutritional and vitamin deficiencies (atrophic glossitis), chronic alcoholism, medication adverse effects, diabetes mellitus, and gastric reflux.Local etiologies include denture irritation, oral habits such as tongue or cheek biting, and excessive use of certain toothpastes or mouthwashes.Psychological factors and nerve damage also may cause burning mouth.Erythematous candidiasis also can present as a burning sensation.
# P: Plan
Identify the cause of the burning sensation, if possible, by review of the medical history and by performing diagnostic tests as indicated (e.g., complete blood count, biopsy, or oral cytological smears).Once the underlying cause is identified, treatment may be as simple as changing a dentifrice or eliminating the identified irritant, or the condition may require systemic treatment.
# Recurrent Aphthous Ulceration (RAU)
# S: Subjective
The patient complains of a painful ulcer or ulcers in the mouth that recur.
# O: Objective
The typical appearance of an aphthous ulcer is a "red raised border with a depressed, necrotic (white-to-yellow pseudomembrane) center."Aphthous ulcers tend to present on nonkeratinized or nonfixed tissues such as the buccal mucosa or posterior oropharynx and may be small or large, solitary or in clusters, and can resemble intraoral herpetic lesions (although herpetic lesions tend to present on keratinized tissues such as the roof of the mouth and gingival tissues).
# A: Assessment
The differential diagnosis includes traumatic ulcers and herpes simplex virus ulcers.
# P: Plan
The diagnosis usually is based on appearance.For further information, see chapter Oral Ulceration.
# Recurrent Herpes Simplex
# S: Subjective
The patient complains of a locally painful ulcer or ulcers on the lips or intraoral areas.
# O: Objective
Herpes lesions are located on the lips, gingival tissues, or the hard palate.They may appear as small vesicular lesions that rupture, forming small ulcers.They may rupture and coalesce into larger lesions.
# A: Assessment
The differential diagnosis includes aphthous ulcer and traumatic ulcer.
# P: Plan
The diagnosis usually is based on appearance.For further information, see chapters Oral Ulceration and Herpes Simplex, Mucocutaneous.
# Periodontal Disease
The medical evaluation of patients with HIV infection should include assessment of periodontal health. |
Whereas the same type of plaque-induced periodontal diseases can be seen in both immunocompetent and immunosuppressed individuals, periodontal disease in HIV-infected patients can be a marker of HIV disease progression.In the HIV-infected patient with periodontal disease, it is important to distinguish whether the periodontitis represents an aggressive or chronic presentation unique to those with HIV disease.In addition, it is important to determine whether the patient has an inflammatory oral disease process that may further compromise his or her health.
Various illnesses and systemic factors (e.g., diabetes mellitus, hormonal abnormalities, medications, and malnutrition) can complicate the clinical presentation of periodontal disease.If significant periodontal disease is suspected, refer to an experienced dentist for diagnosis and treatment.Gingivitis, a milder form of periodontal disease, usually is reversible with proper professional and home oral health care.For further information on necrotizing ulcerative periodontitis or necrotizing ulcerative gingivitis, see chapter Necrotizing Ulcerative Periodontitis and Gingivitis.
# S: Subjective
The patient may complain of red, swollen, or painful gums, which may bleed spontaneously or with brushing; chronic bad breath or bad taste in the mouth; loose teeth or teeth that are separating; or a "bite" that feels abnormal.
# O: Objective
Examine the gingival tissues.Periodontitis appears as localized or generalized gingival inflammation.The gingivae appear bright red or reddish-purple, ulcerated, or necrotic.Spontaneous gingival hemorrhage and purulent discharge may be evident around the teeth, especially if pressure is applied to the gingivae.Fetor oris may be present.
# A: Assessment
The differential diagnosis includes gingivitis, periodontitis, trench mouth, and oral abscesses.Diagnosis usually is based on appearance.Patients with severe or recalcitrant disease should be referred to a dental care provider for definitive diagnosis and treatment.
# P: Plan
Treatment may include:
- Warm saline rinses
- Daily brushing and flossing
- Antimicrobial mouth rinse (e.g., Listerine, chlorhexidine)
- Antibiotic therapy For further information, see chapter Necrotizing Ulcerative Periodontitis and Gingivitis.
# Dental Caries Caused by Methamphetamine and Cocaine Use
Dental decay seen in individuals who smoke methamphetamine or crack cocaine, or use cocaine orally, often is referred to as "meth mouth."
# S: Subjective
The chief complaint may be pain in one or more teeth.However, if the condition is chronic, the patient may not complain of pain.
# O: Objective
In meth mouth, the enamel on all teeth or multiple teeth is grayish-brown to black in color (owing to decay), and appears "soft" (this has been described as a "texture less like that of hard enamel and more like that of a piece of ripened fruit").Oral mucosal tissues appear dry as a result of decreased salivary flow.The gingiva appears red or inflamed, and there may be spontaneous bleeding of the gingiva around the teeth.
Another pattern of dental decay can be seen in cocaine users who rub the drug along the gingiva in order to test its strength or purity.This can lead to localized dryness of the gingival tissues.Consequently, plaque sticks to the cervical portion of the teeth in the area where the cocaine is rubbed, resulting in Section 9: Oral Health dental caries along the cervical portion of the teeth.
# A: Assessment
The differential diagnosis includes other causes of caries.
# P: Plan
Refer to a dentist for appropriate care, which may involve restorative, endodontic therapy, periodontal care, and oral surgery.In severe cases, extraction of the involved teeth and replacement with a partial or complete denture may be necessary.Encourage proper oral hygiene; evaluate sucrose intake.
# Oral Cancer
# S: Subjective
Oral malignancies may be symptomatic or asymptomatic.Data suggest two distinct pathways for the development of oropharyngeal cancer: one driven predominantly by the carcinogenic effects of tobacco or alcohol (or both), another by genomic instability induced by human papillomavirus.
The patient may complain of a mouth sore that fails to heal or that bleeds easily, or a persistent white or red (or mixed) patch.The patient may note a lump, thickening, or soreness in the mouth, throat, or tongue; difficulty chewing or swallowing food; difficulty moving the jaw or tongue; chronic hoarseness; numbness of the tongue or other areas of the mouth; or a swelling of the jaw, causing dentures to fit poorly or become uncomfortable.
# O: Objective
Perform a thorough evaluation of the oropharynx, as well as lymph nodes in the head and neck.Suspicious lesions may occur on the lips, tongue, floor of the mouth, palate, gingiva, or oral mucosa, and may appear as an ulcer or a soft-tissue mass or masses that can be pink, reddish, purple, white, or mixed red and white.The lesion typically is indurated and may be painful.It may enlarge rapidly between examinations.
# A: Assessment
The differential diagnosis includes oral squamous cell carcinoma, lymphoma, Kaposi sarcoma, traumatic ulcer, hyperplasia, and hyperkeratosis.
# P: Plan
An ulcerated lesion or symptom described above that is present for 2 weeks or longer should be evaluated promptly by a dentist or physician.If cancer is suspected, a biopsy should be obtained to make a definitive diagnosis.Treatment will be based on the specific diagnosis.
# Bruxism
# S: Subjective
The patient may complain of chronic facial or jaw pain, sensitive teeth, earache, or waking up with a headache or facial pain.Often, the patient is not aware that he or she is clenching or grinding the teeth.Bruxism very often is a result of increased stress or anxiety, causing the patient consciously or unconsciously to clench or grind the teeth.However, some people may be "nighttime bruxers" and grind their teeth while sleeping, often loudly enough to wake others sleeping in the same room.
# O: Objective
Perform a focused evaluation of the oropharynx, jaw, and facial muscles.The teeth may appear shortened, flattened, or worn down as a result of chronic grinding or clenching of the teeth.There may be hyperkeratotic lesions on the inside of cheeks as a result of chronic grinding or biting.There may be tenderness with palpation of facial muscles.
# Oral Ulceration Background
Oral ulcerations appear as necrotic or eroded areas on the oral mucosa, including the tongue.Most such lesions are idiopathic (aphthous) or of viral etiology (e.g., herpes simplex virus ; rarely herpes zoster ).Oral ulcerations may be caused by fungal, parasitic, or bacteriologic pathogens; malignancy; or other systemic processes.This chapter will focus on herpetic and aphthous ulcers.
Herpetic ulcerations tend to appear on keratinized tissues such as the hard palate or gingiva.Recurrent aphthous ulcers tend to manifest on nonkeratinized tissues such as buccal mucosa, soft palate, and lingual (bottom) surface of the tongue, and, by definition, recur.
# S: Subjective
The patient complains of painful ulcerated areas in mouth.He or she may have difficulty eating, drinking, swallowing, or opening the mouth, and may complain of sore throat.
Inquire about previous occurrences of oral ulcerative disease as well as ulcerative gastrointestinal diseases, including HSV, cytomegalovirus (CMV), or histoplasmosis.Ask about recent sexual exposures.Inquire about recent trauma or burns.Note current medications and any recent changes in medications; obtain history of tobacco (smoked and chewed) and alcohol use.
# O: Objective
Look for red or white-bordered erosions or ulcerations varying in size from 1 mm to 2 cm on the buccal mucosa, oropharynx, tongue, lips, gingiva, and hard or soft palate.Lesions caused by HSV tend to be shallow and occur on keratinized tissues.HSV lesions may appear as clusters of vesicles that may coalesce into ulcerations with scalloped borders.Aphthous ulcers present with a white or gray pseudomembrane surrounded by a halo of inflammation.
# A: Assessment
Rule out syphilis and other suspected pathogens as well as trauma, seizure, and other physical injury.
# P: Plan
# Diagnostic Evaluation
The diagnosis of HSV and aphthous ulcers usually is made on the basis of characteristic lesions.Location, duration, and recurrence are key elements in determining the nature of the oral ulcer.As mentioned previously, HSV-related ulcers most often present on keratinized fixed tissues; aphthous ulcers appear on nonfixed tissues such as buccal mucosa, and have a tendency to recur.Check the absolute neutrophil count (ANC), as a low count (72 hours old usually will not yield a positive culture.
If other diagnoses are suspected, perform culture or biopsy as indicated.Also perform biopsy for ulcers that do not respond to therapy (in nonneutropenic patients).
Note that syphilis is very common among some HIV-infected populations.For patients in whom primary syphilis (manifested by an oral chancre) is suspected, perform (or refer for) darkfield examination; check Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) results (note that VDRL or RPR results may be negative in primary syphilis); see chapter Syphilis for further information.It is worth noting that, whereas chancres are described as painless, open sores in the mouth usually are associated with some degree of pain.
# Treatment
If HSV culture is positive, or if HSV is strongly suspected owing to the appearance of the lesions or the patient's history, treat with HSV antiviral medication (e.g., valacyclovir, famciclovir, or acyclovir) while waiting for results of culture.Do not use topical steroids without a concomitant oral HSV antiviral if the lesion is of possible herpetic etiology.Refer to chapter Herpes Simplex, Mucocutaneous for more information regarding management and treatment of HSV lesions.
Recalcitrant minor aphthous ulcerations should be treated with topical corticosteroids (e.g., fluocinonide 0.05% or clobetasol 0.05% ointments mixed 1:1 with Orabase).For multiple small lesions or lesions in areas where topical ointments are difficult to apply, consider dexamethasone elixir (0.5 mg/5 mL); the patient is to rinse TID with 5 mL for 1 minute, then expectorate.As with all oral topical steroids, patients should not drink or eat for 30 minutes after rinsing.Continue treatment for 1 week or until lesions resolve.
In some cases, recurrent aphthous ulcers may respond to one of the various "magic mouthwashes" that contain combinations of antibiotic, antifungal, corticosteroid, antihistamine, and anesthetic medication.The inclusion of an antihistamine (e.g., diphenhydramine) or an anesthetic (e.g., lidocaine) may be helpful in treating pain associated with these ulcers.
For large or extensive aphthous ulcers, systemic corticosteroids may be needed: prednisone 40-60 mg PO daily for 1 week followed by a taper should prove beneficial.If this is ineffective, refer for biopsy to rule out CMV, other infection, or neoplastic disease.
For patients with major oral aphthous ulcers that are recalcitrant to other therapies, thalidomide 200 mg daily for 2 weeks may be considered.Thalidomide is teratogenic and should not be used for women of childbearing potential without thorough patient education and two concomitant methods of birth control.
Consult with an expert.
Pain control may be needed in order for the patient to maintain food intake and prevent weight loss.Most of the topical treatments noted above will ease pain as well as treat the ulcer.Additional considerations for pain control include the following:
- Oral anesthetics: Various products are available, including gels (eg, Gelclair, an adherent oral rinse that acts as an oral bandage), viscous liquids, and sprays (e.g., benzocaine, lidocaine).These may be applied topically or swished and expectorated.They will provide temporary relief, but may lead to a temporary loss of taste sensation.
- Systemic: If topical treatments are inadequate, consider systemic analgesics (e.g., nonsteroidal antiinflammatory drugs or opiates).Refer to chapter Pain Syndrome and Peripheral Neuropathy.
Assess nutritional status and consider adding liquid food supplements, if indicated.Suggest soft, nonspicy, or salty foods if the ulcer is interfering with food intake.Refer to a registered dietitian if client is experiencing pain, problems eating, or weight loss.
Refer to an oral health specialist or an HIVexperienced dentist as needed.
# Patient Education
- Advise patients to report any oral pain or difficulty swallowing to their health care provider.
- Instruct patients in the application of topical ointments, and indicate that they may require assistance if the lesion is difficult for them to see on their own.
- It is important for patients to maintain good nutrition and food intake while their oral ulcers heal.Advise them to eat soft, bland foods, and refer to a nutritionist if they have difficulty.
# Oral Warts Background
Oral warts are caused by human papillomavirus (HPV) and may appear anywhere within the oral cavity or on the lips.They occur more frequently and more extensively in people with HIV infection than in those with normal immune function, especially in patients with advancing immune suppression (CD4 counts of <200-300 cells/µL).Oral warts may be refractory to therapy.The frequency of oral warts may increase, at least temporarily, in patients treated with antiretroviral therapy.
It should be noted that HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use, although oral warts normally are not caused by the HPV types that are associated with oncogenic changes.One analysis of stored samples suggests that the percentage of all oropharyngeal cancers that are HPVpositive has increased from about 20% to 60% since about 1980.Researchers also have reported that HPV-related oral cancers were among the most responsive to chemotherapy and radiation.
# S: Subjective
The patient notices raised lesions in the mouth or on the lips.Warts are not painful unless they have been traumatized.
# O: Objective
Examine the oral cavity carefully for abnormalities.Wart lesions may vary in appearance from smooth, small, and slightly raised lesions to cauliflower-like or spiked masses with prominent folds or projections.They may be single or multiple.
Review recent CD4 counts.In patients with oral warts, the CD4 count usually is <300 cells/µL.
# A: Assessment
A partial differential diagnosis includes: squamous cell carcinoma, lichen planus, and traumatic hyperkeratinized areas resulting from cheek biting or tongue thrusting.
# P: Plan
# Diagnostic Evaluation
- The diagnosis of oral warts usually is based on the appearance of the lesions.If lesions are unusual in appearance, are ulcerated, or have grown rapidly, perform biopsy to rule out cancer.If there is suspicion of other causes, perform other diagnostic evaluations as indicated.
- HPV may be demonstrated with electron micropsy or in situ hybridization; this testing is not routinely required.
- Observation of these lesions is important because of the potential, however minimal, for development of squamous cell carcinoma.
# Treatment
- Treatment is difficult, as these lesions tend to recur.Treatment options include cryosurgery and surgical or laser excision.Care must be taken when using laser excision, as HPV can survive in an aerosol.Extraoral lesions (lip or corner of mouth) may be treated with topical agents such as podofilox topical solution (Condylox) or fluorouracil 5% topical (Efudex).Imiquimod 5% cream (Aldara) may help to prevent recurrence once the lesions have resolved.
- Refer to an oral health specialist or dentist for treatment.
# Oral Hairy Leukoplakia
# Background
Oral hairy leukoplakia (OHL) is an oral infection caused by Epstein-Barr virus (EBV).It appears as white corrugated lesions (sometimes "hairy" in appearance) primarily on the lateral aspects of the tongue.This infection may spread across the entire dorsal surface onto the ventral surface of the tongue, and occasionally may be found on buccal mucosa.It is common in people with HIV infection, particularly in those with advanced immunosuppression (CD4 count <200 cells/µL).
# S: Subjective
The patient notices new, white lesions on the tongue that cannot be wiped off or removed by scraping or brushing.The OHL lesions usually are asymptomatic, but occasionally may cause alteration in taste, discomfort, or other symptoms.
# O: Objective
Perform a focused examination of the oropharynx.OHL appears as unilateral or bilateral white plaques or papillary lesions on the lateral, dorsal, or ventral surfaces of the tongue or on buccal mucosa.The lesions may vary in appearance from smooth, flat, small lesions to irregular, "hairy" or "verrucous" lesions with prominent vertical folds or projections.
# A: Assessment
A partial differential diagnosis for OHL includes:
- Oral candidiasis
# P: Plan Diagnostic Evaluation
A presumptive diagnosis of OHL usually is made on the basis of the clinical appearance of the lesions.OHL often is confused with candidiasis; the diagnosis of OHL should be considered for lesions that do not wipe away, as would be the case for pseudomembranous candidiasis.Definitive diagnosis of OHL requires biopsy and demonstration of EBV.
- Perform biopsy of lesions only if they are ulcerated or unusual in appearance, to distinguish OHL from cancer or other causes.
# Treatment
- Because OHL usually is asymptomatic, specific treatment generally is not necessary.
# Necrotizing Ulcerative Periodontitis and Gingivitis
# Background
Necrotizing ulcerating periodontitis (NUP) is a marker of severe immunosuppression that affects gingival tissues (gums) and extends to the underlying bone or periodontium.It may or may not be distinct from necrotizing ulcerative gingivitis (NUG), which is considered to be confined to the gingiva.This discussion will focus primarily on NUP, but the microbial profiles and treatment recommendations for these two periodontal diseases are similar.
NUP in HIV-infected individuals is believed to be an endogenous infection that progresses to necrosis of the gingiva.Pathogens may include anaerobic bacteria and fungi.NUP usually presents as "blunting" or ulceration of the interdental papillae, but rapidly progresses to destruction of underlying alveolar bone.It usually is associated with severe pain and spontaneous bleeding.Several case reports have described extensive destruction leading to exfoliation of teeth within 3-6 months of onset, with sequestration of necrotic alveolar bone and necrotic involvement of the adjacent mandible and maxilla.Patients may present with concomitant malnutrition resulting from inability to take food by mouth.The prevalence of NUP in the HIV-infected population has been reported as 0-5%.NUP is the most serious form of periodontal disease associated with HIV.
# S: Subjective
The patient complains of painful, spontaneously bleeding gums, diminished or metallic taste, bad breath, or loose teeth (with a prevalence toward anterior teeth and first molars). "Deep jaw pain" is a common complaint and may reflect extension to adjacent mucosa. |
# O: Objective
Examine the oral cavity carefully.NUP and NUG present with fiery red, ulcerated gingival tissues, and grayish exudate.Teeth may be very loose or missing and there will be a fetid odor from the mouth.The ulcerated tissues can extend past the attached gingiva to the adjacent mucosa.Necrosis of adjacent bone also is common.
# A: Assessment
The differential diagnosis includes other causes of gingival ulceration, such as herpes simplex virus, herpes zoster, and cytomegalovirus. (See relevant chapters on these conditions.)
# P: Plan Treatment
Treatment usually is divided into the acute phase and the maintenance phase.The primary concern in the acute phase is pain control.For the maintenance phase, treatment is directed toward reducing the burden of potential pathogens, preventing further tissue destruction, and promoting healing.
- For uncomplicated NUP or NUG, the primary care provider should prescribe an antimicrobial rinse (see below), antibiotic therapy (see below), medications for pain management, and nutritional supplementation; the patient should be referred to a dental health care professional.
Section 9: Oral Health
- Chlorhexidine gluconate rinse (0.12%) twice daily after brushing and flossing (an alcoholfree preparation is preferred).
- Antibiotic therapy (preferably narrow spectrum, to leave gram-positive aerobic flora unperturbed).
- Metronidazole is the drug of choice, 500 mg PO BID for 7-10 days.
- If the patient cannot tolerate metronidazole: clindamycin 150 mg QID or amoxicillin-clavulanate (Augmentin) 875 mg PO BID for 7-10 days, if no hypersensitivity or allergy to either drug exists.
- Refer to a dentist for the following:
- Removal of plaque and debris from the site of infection and inflammation.
- Debridement of necrotic hard and soft tissues, with a 0.12% chlorhexidine gluconate or povidone-iodine lavage.
# Patient Education
- Advise the patient of the following: Good oral hygiene is critical for arresting gingival infection and tooth loss.Avoid smoking and try to eliminate emotional stress.When primary stabilization is achieved, resume daily brushing and flossing after every meal.This may be difficult during the acute phase, but it is very important to keep the mouth as clean as possible.Nutrition education and supplements (liquid diet, plus vitamins/ minerals) are recommended.
- Frequent professional cleaning (every 3 months) may be needed during the maintenance phase.
- Patients taking metronidazole should not drink alcohol for at least 24-48 hours after taking the last dose, in order to avoid severe nausea and vomiting from a disulfiram-like reaction.
- Instruct patients not to drink or eat for 30 minutes after rinsing with chlorhexidine.
- Bleeding gums may (rarely) transmit HIV (or hepatitis C) during "deep kissing" or other activities (oral-genital contact).Advise patients/clients to avoid exposing partners to HIV by taking all necessary precautions, including abstinence from risky activities until this condition is healed and stable (no oozing of oral fluids).
Section 10: Resources and References
# Web-Based Resources Background
The care and management of HIV-infected patients is a rapidly evolving field.Keeping up to date with clinical information about HIV care has in the past required attendance at national and international conferences.With the increasing availability of the Internet, clinicians and patients are able to access the most current advances through Web coverage, without requiring travel or time away from work.
The challenge of using Internet resources is in determining which websites are accurate and current.Check for dates of authorship, the credentials of the site sponsors and authors, and how well supported any recommendations or analysis may be.Be aware of any possible commercial bias.Finally, it is important to remember that information on these sites does not replace clinical judgment or consultation with HIV experts.
Listed below is a selection of useful and accurate Internet sites.Many of these websites also link out to additional information resources, and many allow users to subscribe to receive updates via email.Many providers find it helpful to review sites geared toward patients, in order to maintain familiarity with patients' concerns and patient-based information resources.
# Sulfa Desensitization Background
Trimethoprim-sulfamethoxazole (TMP-SMX), also known as Septra, Bactrim, and cotrimoxazole, is a key antibiotic for prophylaxis and treatment of several HIV-related illnesses.It is the most effective prophylaxis and the first-line treatment for Pneumocystis jiroveci pneumonia (PCP).In addition, it is effective in preventing toxoplasmosis encephalitis in severely immunocompromised patients who have evidence of previous exposure (see chapter Opportunistic Infection Prophylaxis), and it is effective against certain bacterial infections.TMP-SMX is quite inexpensive, which is a rarity in the field of HIV treatment.Because of its effectiveness and availability, it is used widely throughout the world.However, adverse reactions to TMP-SMX and other sulfa drugs occur in a high proportion of HIV-infected patients (roughly 25%), and such reactions may limit treatment options.
Desensitization to TMP-SMX should be considered when there are no reasonable or available alternatives and the patient has not experienced severe reactions (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis) to sulfa drugs.Several methods of desensitizing patients with previous reactions to TMP-SMX have been tried.These methods vary in starting dosage and length of dosage escalation, but success rates are around 80% in most cases and may be higher in patients with CD4 counts of <200 cells/µL.
# S: Subjective
The patient reports a previous adverse reaction to sulfa drugs, such as erythema, pruritus, or rash.The patient has no history of anaphylaxis, Stevens-Johnson syndrome, or toxic epidermal necrolysis, and no reaction involving vesiculation, desquamation, ulceration, exfoliative dermatitis, etc.
# O: Objective
CD4 count <200 cells/µL, or other important indication for TMP-SMX.
# A: Assessment
Reaction to sulfa, possibly reversible with desensitization protocol.
# P: Plan
Begin 9-to 13-day desensitization protocol, starting with pediatric oral suspension, which contains 40 mg of TMP and 200 mg of SMX per 5 mL (1 teaspoon).Gradually increase the dosage according to the protocol.
If there is any concern about the severity of a previous reaction, have the patient take the initial morning dose in the clinic so that the patient may be monitored for 3-4 hours before going home. (This assumes that emergency treatment, including IV access materials, IV fluids, epinephrine, antihistamines, and steroids, are readily available.)Many experts recommend treatment with an antihistamine medication starting 1 day before initiation of the desensitization regimen and continuing daily until the dosage escalation is completed.
More rapid desensitization protocols are available (see "References," below) for patients urgently needing treatment with TMP-SMX.
# Desensitization Regimen
Use commercially available pediatric suspension (containing TMP 8 mg and SMX 40 mg per mL ), followed by double-strength tablets, as follows:
16 mg/80 mg 2 mL 7-9 40 mg/200 mg 5 mL (or 1/2 single-strength tablet)
9-12 80 mg/400 mg 1/2 double-strength tablet (or 1 single-strength tablet)
13 and thereafter 160 mg/800 mg 1 double-strength tablet Note: These day ranges are approximate; patients can be advanced more quickly or more slowly, depending on their reactions to the dosages.
In the event of mild reaction: If the patient experiences a mild reaction or itching (i.e., mild morbilliform rash without fever, systemic symptoms, or mucosal involvement), the dose can be reduced to the last tolerated step or continued at the same dosage for an additional day, while simultaneously treating the rash or reaction.Antihistamines or antipyretics may be used to treat symptoms of mild reactions.If the reaction diminishes, the patient may advance to the next dosage (consider more gradual increase of dosages); if the reaction worsens or if systemic symptoms develop, TMP-SMX should be discontinued.
In the event of severe reaction: The desensitization regimen should be discontinued and the patient should be treated appropriately for the reaction.
# Patient Education
For home desensitization regimen
- Explain the benefits of using TMP-SMX.Be sure the patient understands and is able to follow these instructions:
- The patient should measure the dose carefully and take it each morning, followed by a glass (6-8 oz) of water. (The patient should do a demonstration, if possible, using an oral syringe that will be used for the actual measuring at home.)
- TMP-SMX can cause severe illness unless close attention is paid to any problems that may occur.It is extremely important for the patient to check his/her body temperature each afternoon.If the temperature is more than 100.5°F by mouth, the patient should stop taking the drug and contact the clinic.Note: If shaking chills occur, the body temperature should be checked as soon as the shaking stops, and the patient should contact the clinic.
- If the patient develops a rash, blisters on the skin or in the mouth, or vomiting, he or she should stop taking TMP-SMX and go the clinic or emergency room immediately.The skin should be checked each evening, and any time itching occurs.
- If mild itching or a faint rash occurs, diphenhydramine (Benadryl) 25-50 mg PO can be taken Q4H as needed.If itching or rash persists, continue with the same dosage for an additional day; the patient should contact the clinic if there are questions or concerns.
- The patient should contact the clinic for alternative dosage instructions in the event of persistent itching without rash.
- Other adverse events should be reported immediately.
# For all desensitized patients
- Desensitization may be effective only as long as the allergic individual is continuously exposed to the drug.After desensitization is complete, continue with the daily dosage.If the drug is stopped (even for a few days), the entire regimen may have to be repeated, as patients may have a recurrence of the adverse reaction.
# A: Assessment
The differential diagnosis of TB is extensive and depends in part on the degree of immunosuppression (as indicated by the CD4 cell count) of the individual.It includes a broad range of bacterial, mycobacterial, viral, and fungal infections in addition to noninfectious causes.A partial differential diagnosis of pulmonary TB includes the following:
- Bacterial pneumonia
- Pulmonary Mycobacterium pneumonia (nontuberculous)
- Pneumocystis jiroveci pneumonia (PCP)
- Cryptococcus neoformans pneumonia/ pneumonitis
- Pulmonary Kaposi sarcoma
# Diagnostic Evaluation
# Initial evaluation
Suspected TB should be evaluated aggressively.
- During the initial evaluation, check complete blood count (CBC) and differential, sputum gram stain, sputum acid-fast bacilli (AFB) stain, culture and nucleic acid amplification (NAA) (see below), blood cultures, and chest X ray.
- For patients with lymphadenopathy, consider fine-needle aspiration biopsy for bacterial and AFB stains and culture, and cytologic evaluation.
- For patients with meningitis or central nervous system abnormalities, perform lumbar puncture (LP) and cerebral spinal fluid (CSF) analysis including cell count, protein, glucose, AFB smear and culture, and bacterial and fungal cultures.
- If focal neurologic abnormalities are present, obtain computed tomography (CT) scan of the head to rule out mass lesion before doing the LP.
- Perform other diagnostic tests as suggested by the clinical presentation.
# Imaging
Pulmonary TB can be associated with any chest X-ray appearance, including a normal X-ray image.However, the chest X ray classically demonstrates upper-lobe infiltrates with or without cavities.Patients with HIV infection (especially advanced HIV) are more likely to have atypical chest X-ray presentations, including absence of cavities, presence of lower-lobe disease, hilar or mediastinal adenopathy, and pleural effusions.
In disseminated TB, the chest X ray may show a miliary pattern with small nodules ("millet seeds") scattered throughout both lungs.
# AFB testing
TB should be diagnosed by identification of the organism in stained sputum smears or stains of tissue by biopsy and confirmed by culture or NAA test.All positive cultures should undergo drug susceptibility testing.Proof of the diagnosis is important because other opportunistic diseases can mimic TB, and mycobacterial infections other than TB can Section 6: Comorbidities, Coinfections, and Complications In HIV-infected persons with a CD4 count ≤100 cells/µL, twice-weekly regimens should not be used.For these patients, most experts recommend daily treatment during the induction phase. #For patients who experience slow responses, and those in whom sputum cultures are still positive after the initial 2 months of treatment, the continuation phase may be extended to 7 months, for a total of 9 months of treatment.Pediatric patients should be treated for 7 months in the continuation phase, for a total of 9 months of treatment.TB meningitis caused by susceptible organisms should be treated for 9-12 months.Bone and joint TB should be treated for 9-12 months; the longer time may be prudent when multiple bones and joints are involved or when it is difficult to document a response to treatment.Extrapulmonary disease in other sites should be treated for 6-9 months.
Adapted from American Thoracic Society, CDC, and Infectious Disease Society of America.Treatment of Tuberculosis.Morb Mort Weekly Rpts Recommendations and Reports.June 20, 2003, 52(RR11);1-77.
# Potential adverse effects:
- With all topical products: skin burning, stinging, dryness; allergic or contact dermatitis.Tar shampoos may discolor light hair, leave an oily film on hair, and leave an odor.Coal tar may be carcinogenic; use shampoo no more than twice a week, leave on skin or hair for 5 minutes, and rinse well.
- Topical corticosteroids may cause skin atrophy, telangiectasias, folliculitis, striae, and excessive hair growth.Risk of adverse effects is low and can be mediated by using product infrequently, diluting the product, or limiting the amount of time the product is on the skin (shampoos are ideal).
- With oral therapy, monitor for hepatotoxicity.
# Patient Education
- Although topical and oral medicines can relieve symptoms, recurrence is common.Effective antiretroviral therapy should be considered to control the effects of HIV on the immune system and thereby treat the underlying cause of seborrheic dermatitis.
# References
- Bikowski J.
# Patient Education
- Instruct patients to go to clinic for treatment at the intervals recommended.If patients are given oral antibiotics (penicillin-allergic individuals), instruct them to take their medications exactly as prescribed.
- Warn patients about the possibility of a Jarisch-Herxheimer reaction and advise them about self-management of associated symptoms (e.g., acetaminophen or aspirin at usual doses, fluids, and rest).
- Instruct patients about the required followup laboratory and clinical evaluations necessary to document adequate treatment.Emphasize the need for regular evaluation of treatment efficacy.
- Sex partners from the previous 3-6 months (sometimes longer, depending on the stage of syphilis) need to be evaluated and treated as soon as possible, even if they have no symptoms.Advise patients to inform their partners that they need to be tested and treated.
- Syphilis is a reportable communicable disease in the United States.Patients will be contacted to assist with partner tracing and to ensure appropriate treatment.
- Provide education about sexual risk reduction.Review sexual practices and support patients in using condoms with every sexual contact to prevent becoming reinfected with syphilis or infected with other STIs, and to prevent passing HIV to sex partners.
# References
# Disorders
Patients should be assessed carefully before the introduction of a potentially neurotoxic medication (including stavudine or didanosine), and the use of these medications for patients at high risk of developing peripheral neuropathy should be avoided.
Pain is significantly undertreated, especially among HIV-infected women, because of factors ranging from providers' lack of knowledge about the diagnosis and treatment of pain to patients' fear of addiction to analgesic medications.Pain, as the so-called fifth vital sign, should be assessed at every patient visit.
# S: Subjective
Self-report is the most reliable method to assess pain.
The patient complains of pain.The site and character of the pain will vary with the underlying cause.Ascertain the following from the patient:
- Duration, onset, progression Note: "Adjuvants" refers either to medications that are coadministered to manage an adverse effect of an opioid or to so-called adjuvant analgesics that are added to enhance analgesia.
Step 1: Nonopiates for mild pain (pain scale 1-3)
- The most common agents in this step include acetaminophen (650-1,000 mg PO Q6H as needed) and nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen 600-800 mg PO TID with food, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib.
- A proton-pump inhibitor (such as omeprazole) can decrease the risk of gastrointestinal bleeding when using NSAIDs.
- Acetaminophen has no effect on platelets and no antiinflammatory properties; avoid use in patients with hepatic insufficiency, and in general limit to 4 g per day in acute use (or 2 g per day for patients with liver disease).Monitor liver function tests in chronic use.
- NSAIDs and acetaminophen can be used together for synergism.
- Note that COX-2 inhibitors have been associated with an increased risk of cardiovascular events and should be used with caution.
# Disorders
Ask about the following symptoms:
# MCMD HAD
# O: Objective
- Check temperature and other vital signs (MCMD and HAD are not associated with fever).
- Perform a complete physical examination with special attention to signs of opportunistic illnesses.
- Perform a thorough neurological examination, including funduscopy.Rule out focal neurologic deficits.
- Perform Mini-Mental State Examination (note that this is not sensitive for HIVassociated neurocognitive disorders; negative results do not rule out these conditions).
- Consider a neuropsychological screening test such as the Modified HIV Dementia Scale (see Figure 1).Others are noted in "Laboratory and Diagnostic Evaluation," below.
# Disorders
Perform the following tests:
- Laboratory tests: Complete blood count, electrolytes and creatinine, liver function, thyroid function, vitamin B12, rapid plasma regain (RPR) or Venereal Disease Research Laboratory (VDRL).
- Toxicology tests if substance use is suspected (e.g., opioids, ethanol, amphetamines).
- Brain imaging studies (computed tomography scan or magnetic resonance imaging ); rule out spaceoccupying masses and other lesions; cortical atrophy may be seen in advanced HAD; this finding is not specific.
- Cerebral spinal fluid (CSF) tests if CNS infection is suspected.
- Consider tests for neurocognitive impairment as noted in the table below; most of these can be found on the website of the New York State Department of Health AIDS Institute (www.hivguidelines.org).
- Refer to an HIV-experienced neuropsychologist, neurologist, or psychiatrist, if available. |
# Tests for Identifying and Staging HIV-Related Neurocognitive Impairment
HIV Dementia Scale - Screens for the memory and attention deficits and psychomotor slowing that are typical of HAD - Requires training to administer and, therefore, may not be ideal for a clinic setting
# Modified HIV Dementia Scale
- Designed specifically for use by non-neurologists and, therefore, may be more useful than the HIV Dementia Scale for a primary care setting - Requires approximately 5 minutes to administer - See Figure 1, above.
# Mental Alternation Test
- Useful for assessing patients with early dementia, who will show impairments in timed trials
# Memorial Sloan-Kettering (MSK) Scale
- Can be used for assessing severity - Combines the functional impact of both cerebral dysfunction (dementia) and spinal cord dysfunction (myelopathy); the two entities can be separated and staged independently
# Trail Making Test, Parts A and B (from the Halstead-Reitan Neuropsychological Battery)
- May be used as a screening tool, but results require interpretation by a neuropsychologist - May be used at the bedside to track a patient's response to ART over time
# Grooved Pegboard (dominant and nondominant hand)
- May be used as a screening tool and does not require literacy
# Disorders
# References
- American Academy of Neurology.Section 8: Neuropsychiatric
# Disorders
The available antidepressant medications (SSRIs and SNRIs), including therapeutic dosages and possible positive and negative effects, are listed in Table 1.
# S: Subjective
The criteria for a diagnosis of generalized anxiety disorder include unrealistic or excessive worry about two or more life circumstances for >6 months, and at least three of the following subjective complaints:
- Restlessness or feeling keyed-up or on edge - Benzodiazepines generally should be used only for acute, short-term management because of the risk of tolerance and physiologic dependence.These risks are even more problematic for patients with a history of addiction.
# Potential ARV Interactions
Interactions may occur between certain ARVs and agents used to treat anxiety.Some combinations may be contraindicated and others may require dosage adjustment.Refer to medication interaction resources or consult with an HIV expert, psychiatrist, or pharmacist before prescribing.
# Antidepressants
# Disorders
# Patient Education
- Behavioral interventions can help to reduce anxiety, but may take practice.Patients should seek help from a therapist or another experienced source.
- Advise patients that misuse of alcohol or illicit drugs can cause or substantially worsen anxiety symptoms; advise patients to decrease or eliminate use.Refer for substance abuse treatment if indicated.
- Inform patients that they may develop problems with sexual function because of antianxiety medications.Patients should report any problems to their prescribers. (Note: Providers should let patients know that sexual well-being is fundamental to quality of life and can be talked about and addressed in the clinical setting.)
# Disorders
# Potential ARV Interactions
Interactions may occur between certain antiretrovirals and agents used to treat PTSD.Some combinations may be contraindicated and others may require dosage adjustment.
Refer to medication interaction resources or consult with an HIV expert or pharmacist before prescribing.
# Antidepressants
# Patient Education
- Explain to patients that illness (physical or emotional) is not a character flaw or a moral or spiritual weakness.
# Non-benzodiazepine hypnotics (agonists of the benzodiazepine receptor)
- Zolpidem (Ambien) 5-10 mg, zolpidem-CR (Ambien-CR) 6.25-12.5 mg, zaleplon (Sonata) 5-10 mg, and eszopiclone (Lunesta) 2-3 mg QHS.
- These newer hypnotic agents are benzodiazepine receptor agonists with shorter half-lives than benzodiazepines and are not likely to result in day-after drowsiness.They may have decreased addiction potential compared with benzodiazepine hypnotics.Patients should be advised to use these hypnotics on an as-needed basis rather than nightly; it is easier for patients to discontinue a drug that they are not taking every day.The inhibition of CYP 3A4 enzyme activity by PIs may increase levels of these benzodiazepine receptor agonists, particularly eszopiclone; this may cause excessive sedation or respiratory depression.
# Melatonin agonists
- Ramelteon (Rozerem), 8 mg QHS.
- The first of a new class of melatonin agonists to receive FDA approval, ramelteon may have some advantages over sedative/hypnotic agents, such as reduced dependence and overuse.However, it may have severe adverse reactions, including hypersensitivity reactions such as anaphylaxis and angioedema.Long-term interactions with ARV agents are unknown.
# Benzodiazepine hypnotics
- A number of benzodiazepines have FDA-approved indications for the short-term treatment of insomnia.They carry a risk of addiction and residual drowsiness the following day. -Metabolized by glucuronidation; predicted to have few drug interactions with ARVs:
- Temazepam (Restoril) 7.5-30 mg; intermediate half-life - Lorazepam (Ativan), 2-4 mg; intermediate half-life - Metabolized by CYP 34A; PIs may prolong their duration, resulting in excessive daytime somnolence.
These may be most beneficial for use with patients whose insomnia is associated with anxiety:
- Flurazepam (Dalmane) 15-30 mg - Quazepam (Doral) 7.5-15 mg - Estazolam (ProSom) 1-2 mg - Clonazepam (Klonopin) at a dose of 0.5-2 mg has been approved for treatment of periodic leg movements.PIs may prolong its duration and increase risk of adverse effects; start at low dosage and titrate slowly. -Triazolam (Halcion), another approved agent for insomnia, is contraindicated for use with all PIs and some nonnucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz) because of potentially life-threatening reactions (e.g., respiratory depression).
# Disorders
Agents Used for Sedating Side Effects (no FDA indication for insomnia)
# Antidepressants
- Tricyclic antidepressants at doses of 10-50 mg can be beneficial for sleep, but they have longer halflives than short-acting hypnotic agents, and potential adverse effects include cardiac dysrhythmias and pulmonary complications.Also, levels of tricyclics are elevated by ritonavir and lower dosages may be needed for patients taking ritonavir or ritonavir-boosted PIs.Routine testing of tricyclic blood levels should be performed on patients receiving higher doses (eg, 100 mg per day; 50 mg for nortriptyline), those on concurrently on ritonavir, and those with risk factors for cardiac conduction abnormalities.
A routine electrocardiogram should be performed before prescribing tricyclics, and this class of drugs should not be prescribed to patients with cardiac conduction problems.However, tricyclic antidepressants also have characteristics that may benefit some patients, including treatment of chronic pain, promotion of weight gain, and reduction of diarrhea.Amitriptyline (Elavil) and doxepin (Sinequan) are the most sedating of the tricyclic antidepressants and therefore are the drugs in this class most often used for sleep. -The tetracyclic antidepressant mirtazapine (Remeron) is sedating and has been effective in treating insomnia at low dosages (7.5-15 mg).Higher dosages may result in increased activation owing to increased NE receptor antagonism. -The selective serotonin reuptake inhibitor (SSRI) antidepressants are not sufficiently sedating to be used as sleeping agents, but when insomnia is caused by depression, sleep will improve as the depression lifts.
# Anticonvulsants
- Gabapentin (Neurontin) can be useful for patients with insomnia and has been demonstrated to be particularly beneficial for patients with alcohol and other substance-use disorders; it is widely prescribed for neuropathic pain.Tiagabine (Gabitril) has demonstrated efficacy in adults with insomnia.
# Patient Education
- Instruct patients in behavioral interventions that can help to reduce insomnia.
- Additional interventions are available when behavioral interventions are not sufficient.
- Patients should report new or worsening symptoms to their health care provider.These may be not only signs of worsening insomnia, but also symptoms of anxiety, depression, medications, or changes in medical conditions.
# A: Assessment
The differential diagnosis includes other causes of facial or jaw pain, including caries, dental abscesses, and trauma.
# P: Plan
Refer the patient to a dentist for treatment.
Treatment may include wearing a bite guard or psychological or behavioral management therapy.
# Oral Piercing
# S/O/A: Subjective/Objective/ Assessment
Jewelry worn in piercings in the tongue, lips, or cheeks can chip or fracture the teeth.Chronic rubbing of jewelry against the gingiva can cause the gingiva to recede, leading to periodontal problems. (These complications occur apart from procedure-or techniqueassociated complications associated with body piercing, such as inflammation and infection, bleeding, and transmission of bloodborne pathogens.)
# P: Plan
Refer the patient to a dentist for treatment.
Recommend plastic tongue jewelry as opposed to metal to prevent fracture of teeth.Removal of the jewelry may be warranted.
# Maxillary Tori; Mandibular Tori
# S: Subjective
The patient may complain of a "lump" in the roof or floor of the mouth, or behind the lower front teeth.
# O: Objective
Exostosis of normal bone (covered by oral mucosal tissue) can appear as a nodular or lobulated protuberance centrally located on the hard palate (maxillary tori) or unilaterally or bilaterally located behind the mandibular incisors (mandibular tori).This develops slowly and the patient may become aware of exophytic growth only if the area is inadvertently traumatized.
# A: Assessment
Differential diagnosis includes other benign or malignant lesions, including oral cancer.
# P: Plan
No treatment is indicated unless the exostosis interferes with speech or swallowing, or removal is needed for fabrication of dentures or a partial denture.Tori are a variation of normal anatomy.
Section 9: Oral Health
# Patient Education
- Instruct patients to comply with regular dental and medical care regimens.
- Instruct patients to use medications exactly as prescribed.
Section 9: Oral Health
- Immune system reconstitution through antiretroviral therapy will resolve OHL; consider initiation of HIV treatment if otherwise indicated.
- If specific treatment is required, the following options may be considered.
Relapse is common after discontinuation of treatment.
- Acyclovir 800 mg PO 5 times per day for 2 weeks; famciclovir and valacyclovir may be considered.
- Topical tretinoin (Retin-A) 0.025-0.05% solution, podophyllin 25% in tincture of benzoin, and other treatments also have been used.
- For relapse of severe OHL, consider maintenance therapy with high-dose acyclovir, famciclovir, or valacyclovir.
- For severe symptomatic cases, surgical treatment (e.g., cryosurgery, excision) may provide temporary resolution.
- Candidiasis may be present concurrently; treat candidiasis if it is present (see chapter Candidiasis, Oral and Esophageal).
# Patient Education
- Advise patients that OHL rarely is a problem in itself, but may be a marker of HIV progression.
- If treatment is given, review possible drug side effects and interactions, and advise patients to contact their care providers if new symptoms develop.
- Instruct patients to comply with regular dental and medical care regimens. - Women, Children, and HIV www.womenchildrenhiv.org/ Expert-selected, evidence-based information on prevention of mother-to-child transmission of HIV, care of women and children with HIV, and related topics.
# Resources for Clinicians
# Resources for Patients and the Community
- AIDS.gov / AIDS.gov provides access to Federal HIV/ AIDS information through a variety of new media channels, and supports the use of new media tools by Federal and community partners to improve domestic HIV programs serving minority and other communities most at-risk of, or living with, HIV.
- AIDS.org www.aids.org/ Online home of AIDS Treatment News.
- AIDS InfoNet www.aidsinfonet.org/ Comprehensive collection of fact sheets on clinical topics, available in English and Spanish, in print-friendly and downloadable formats.Regularly updated.
- AIDSmeds aidsmeds.com Information regarding HIV-related medications for patients, including drug interactions calculator.
- AIDS Project Los Angeles www.apla.org/ Fact sheets, newsletters, and program information.Some information in Spanish.
# Web-Based Resources | 597
Section 10: Resources and References
- The Body thebody.com Major HIV information resource geared toward patients and the community.
- Gay Men's Health Crisis www.gmhc.org/ Patient and program information from one of the oldest community organizations.Some information in Spanish.
- Project Inform projectinform.org Comprehensive information and advocacy information geared toward individuals infected and affected by HIV.
- San Francisco AIDS Foundation www.sfaf.org/ AIDS 101, BETA treatment newsletter, and prevention and program information.Some information in Spanish.
# Comments
# EFV:
- Should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.ATV/r:
- Should not be used in patients who require >20mg omeprazole equivalent per day.Refer to Table 15a for dosing recommendations regarding interactions between ATV/r and acid-lowering agents.
Alternative Regimens (Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens.An alternative regimen may be the preferred regimen for some patients.)
# NNRTI-based Regimens (in alphabetical order)
- EFV + (ABC or ZDV)/3TC 1 (BI)
- NVP + ZDV/3TC 1 (BI)
# PI-based Regimens (in alphabetical order)
- ATV/r + (ABC or ZDV)/3TC 1 (BI)
- FPV/r (once or twice daily) + either or TDF/FTC 1 (BI) - LPV/r (once or twice daily) + either or TDF/FTC 1 (BI)
# Comments
# NVP:
- Should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C) 3 - Should not be used in women with pre-ARV CD4 >250 cells/ mm 3 or men with pre-ARV CD4 >400 cells/mm 3 ABC:
- Should not be used in patients who test positive for HLA-B - 5701 - Use with caution in patients with high risk of cardiovascular disease or with pretreatment HIV-RNA >100,000 copies/mL (see text) Once-daily LPV/r is not recommended in pregnant women.
1 3TC may substitute for FTC or vice versa.Selection of a regimen should be individualized based on virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions.Refer to Table 6 for a list of advantages and disadvantages, and Appendix B, Tables 1-6 for dosing information for individual antiretroviral agents listed below.The regimens in each category are listed in alphabetical order. |
F o r s a le b y th e S u p e rin te n d e n t of D o c u m e n ts , U .S .G o v e rn m e n t P rin tin g O ffic e , W a sh in g to n , D .C .2 0 402# DISCLAIMER
Mention of company name or product does not constitute endorsement by the National In s titu te for Occupational Safety and Health.
# DHEW (NIOSH) Publication No.80-109
# PREFACE
The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exposed to an everincreasing number of p oten tial hazards in th e ir workplace.Consequently, the National In s titu te for Occupational Safety and Health (NIOSH) has implemented a program to evaluate the adverse health effects of widely used chemical and physical agents.This program includes the development of Special Hazard Reviews that serve to support and complement the other major health assessment a c tiv itie s of the In s titu te .
The intent of a Special Hazard Review is to analyze and document, from a health standpoint, the problems associated with a given in d u strial chemical, process, or physical agent.Generally, a Special Hazard Review is concerned with those hazards of a chronic nature such as cancer, mutagenicity, terato gen icity, or effects on reproduction.However, they may also deal with other effects that have been id en tified as being harmful to workers when these effects re su lt from exposure to substances found in the workplace.Special Hazard Reviews also recommend control measures, work p ractices, or other appropriate action to a s s is t employers in protecting the health and w ell-being of workers.This Special Hazard Review evaluates available information concerning the carcinogenicity and metabolism of benzidine-based dyes and concludes that a ll these dyes should be recognized as p o tential human carcinogens.This conclusion is based on evidence that four of the dyes have rapidly induced tumors in animals; that two studies of dye workers demonstrate an association between benzidine-based dye exposure and bladder cancer in workers; that a ll of the benzidine-based dyes thus far tested have been metabolized in animals to the carcinogen, benzidine; and that the enzyme (azoreductase) which breaks down these dyes to benzidine is found in both animals and humans.This enzyme acts upon a m ultitude of azo compounds to chemically reduce and break the azo linkage and, therefore, i t is highly probable that the azo-linkage in the as yet untested benzidine-based dyes is also cleaved forming benzidine.In addition, two carcinogenic im purities, 4-aminobiphenyl (an OSHA regulated carcinogen) and 2,4diaminoazobenzene (an animal carcinogen) have been id en tified in one commercial sampling of a benzidine-based dye and may contribute to the carcinogenic p otential of these dyes.
Anthony
Dyes con stitu te a large and diverse group of chemicals that have many applications for imparting color to diverse products.More than 1,200 chemically unique and stru c tu ra lly d ifferen t dyes are manufactured in the United S tates, and an additional 800 are imported.Dyes are c lassified according to th e ir chemical stru ctu re as well as by the method of application in the dyeing process.
A major class of dyes are those derived from benzidine, an aromatic amine acknowledged by both industry and government as causing bladder cancer in humans.
These recommendations include those dyes containing an unsubstituted benzidine structure in th e ir makeup.Such dyes are largely cla ssifie d as d irect dyes, since they may be applied d irec tly to fabrics or other substrates without pretreatm ent or subsequent processing.
Of some 200 benzidine-based dyes, about 30 are now marketed in the United S tates.The most recent estim ate of employee exposure is about 79,000 workers in 63 occupations.Market trends show a decreased usage from over 7 m illion pounds in 1976 to about 3.3 m illion pounds in 1978.All but one US company has phased out the manufacture of these dyes, but imports have increased to 1.6 m illion pounds in 1978 indicating continued worker exposure.Benzidine-based dyes are used prim arily to color te x tile s , leather, and paper.However, diverse industries consume 20% of the to ta l. Dyes constitute a large and diverse group of chemicals that have diverse applications for imparting color to many types of products.They may be broadly defined as w ater-soluble chemical substances that contain chromophoric structures and thus may be used to color another substance by becoming attached to i t by molecular bonding, adsorption, absorption, or mechanical adherence.
Pigments, in contrast to dyes, are insoluble and impart th eir color to another substance by being physically attached to or incorporated into i t .Detailed information on dyes and pigments may be found in the Colour Index , a compendium of technical information on dyes and th e ir use.
The use of dyes dates as far back as p reh isto ric man, but the synthetic dye industry began in 1856 when William H. Perkin f i r s t synthesized the dye mauve .Since that time, the synthetic dye industry has grown extensively in the United States as well as in other countries.
More than 1,200 chemically unique and stru c tu ra lly d ifferen t dyes are manufactured in the United S tates, and an additional 800 dyes are imported .Dyes are c la ssified according to th e ir chemical stru ctu re as well as by the method of application in the dyeing process.The dyes evaluated in th is review are those containing the benzidine moiety without any su bstitution on the diphenyl portion of the molecule, ie , those having a para diamino diphenyl grouping in th e ir stru c tu ra l configuration.They are hereafter referred to as benzidine-based dyes.Benzidine-based dyes are largely classifie d as d irec t dyes, since they may be applied d irec tly to fabrics or other substrates without pretreatm ent or without subsequent processes that firm ly attach the dye to the substrate (mordanting) .More than 200 benzidine-based dyes are lis te d in the Colour Index or are used commercially (see Appendix I I ) .Over 30 benzidine-based dyes have commercial importance in the United S tates, according to the US International Trade Commission .Seventeen are manufactured in th is country, a ll by a single company; the remaining dyes are a ll imported (see Appendix I I I ) .Benzidine-based dyes are used chiefly in the leather, te x tile , and paper ind u stries , but they are also used by beauticians, cra ft workers, and the general public .
The common sta rtin g m aterial for the manufacture of these dyes, benzidine, is acknowledged by both industry and government (Federal Register 39 (20):3756-97, January 29, 1974) to cause bladder cancer.This is based on considerable evidence from studies with humans as well as with animals.The carcinogenicity of benzidine was reviewed by Clayson and by Haley .The evidence presented in those reviews demonstrates that both b rief and prolonged exposures to benzidine have been associated with the development of bladder cancer in workers .Aromatic amines, as a class of chemicals, are generally carcinogenic.Benzidine is an outstanding carcinogen w ithin th is class; i t causes cancer in humans, ra ts , hamsters, and mice .The stru c tu re -a c tiv ity relationship between aromatic amines and carcinogenic potency has been reviewed in d e ta il .In addition, benzidine has also been used as a reference mutagen (a known positive control) for several years by the Huntingdon Research Center .In lig h t of a ll the extensive evidence in both humans and experimental animals, NIOSH recommended in 1973 that benzidine be regulated as a carcinogen; in 1974, the Occupational Safety and Health Administration of the Department of Labor promulgated a regulatory standard for benzidine.
U ntil recently there had been l i t t l e concern regarding the dyes derived from and which contain benzidine as an integ ral portion of th e ir chemical stru ctu re.Benzidine chemically united to other substances was not considered dangerous; in 1959, Billiard-Duchesne stated there was "no danger in using the finished dyes."Only recently has there been serious consideration given to the likelihood that processes in the body could free the benzidine that was o rig in ally used in the manufacture of the dyes .The process of metabolizing or converting a substance back to a sta rtin g component or to another compound is commonly referred to as biotransform ation.
In A pril 1978, NIOSH and the National Cancer In s titu te (NCI) jo in tly recommended that three widely used benzidine-based dyes (Direct Black 38, D irect Blue 6, and Direct Brown 95) be handled as if they were carcinogens.The NIOSH/NCI recommendation was based on two major findings.F irs t, NCI had determined in a short-term animal feeding study that rats administered the above dyes developed a high incidence of hepatocarcinomas and neoplastic nodules in 5-13 weeks.No sim ilar lesions developed in control animals .Second, NIOSH field studies demonstrated that some workers who had been exposed to these dyes had benzidine in th e ir urine .The amount found in the urine was greater than could be expected from benzidine contamination in the dyes.This demonstrated that the dye its e lf had broken down, releasing benzidine.
Since that time, NIOSH has examined and evaluated the available lite ra tu re concerning these and related dyes.This Special Hazard Review appraises the carcinogenic p o tential of those dyes known to contain the unsubstituted benzidine moiety.
# II.CHARACTERISTICS OF BENZIDINE-BASED DYES
# Chemical and Physical C haracteristics
At room temperature, benzidine-based dyes are a ll colored solids with negligible vapor pressure.The specific water so lu b ility varies from dye to dye, but a ll are su ffic ien tly w ater-soluble to be used for dyeing in an aqueous solution.They are a ll re lativ e ly stable in a ir or solution at ambient temperatures, and possess considerable fastness to lig h t. Unlike some of the anthraquinone vat dyes, benzidine-based dyes do not accelerate the tendering of cellu lo sic type fabrics under the influence of lig h t .They exhaust onto (combine with) cellu lo sic fib ers from a s a lt bath without other treatm ent.Based on th is property, these dyes are called substantive .They usually contain two or three azo groups.D irect dyes give excellent coverage and generally do not otherwise a lte r the appearance or character of the m aterial to be colored.They cover a wide hue range .Many d irect dyes now on the market do not contain the benzidine moiety and, therefore, are not considered in th is review.These nonbenzidine-derived d irect dyes provide industry with a wide range of colors and hues which may be considered for use as su b stitu tes for benzidine-based dyes ,
The chemical stru ctu res of benzidine-based dyes currently of commerical importance are shown in Appendix II I; a ll have the ch a ra c teristic diazotized benzidine nucleus as shown in Figure I I -l and d iffe r only in the substituents attached at eith er diazo linkage, ie, -N=N-.This linkage is considered the most la b ile portion of each of these dyes, and, in each case, enzymatic or thermal breakdown re su lts in the production of benzidine.
#N = N DIAZOTIZED BENZIDINE MOIETY FIGURE n-1
# Purity and Stability
Benzidine and other carcinogenic substances such as 4-amino biphenyl and 2 ,4-diaminoazobenzene may be present in benzidine-based dyes both as the resu lt of im purities introduced in manufacturing processes or may be present in benzidine-based dyes as products of thermal or enzymatic decomposition.NIOSH has measured the amount of benzidine present in d irect dyes from imported and domestic sources .For 26 samples of 11 types of dyes imported from seven countries, the benzidine concentration ranged from less than 1 ppm to 224 ppm.Only six samples contained greater than 10 ppm of benzidine.Similar re su lts were found for 26 samples from domestic sources.No single type of dye accounted for the high re su lts.Few investigators have attempted to analyze im purities other than benzidine present in d irect dyes.However, in one commercially produced lo t of Direct Black 38 (a benzidine-based dye), 150 ppm of 4-amino biphenyl and 9,200 ppm of 2 ,4-diaminoazobenzene (Basic Orange 2) were found even though only 0.1 ppm of benzidine was detected .
The concentration of im purities such as benzidine can be increased by decomposition of dyes containing benzidine as a portion of the stru ctu re.A measurable increase in the concentration of benzidine and 4-amino biphenyl im purities was found when D irect Black 38 in aqueous solution was stored at 25 or 37.5 C for 48 hours .In hamster urine stored at room temperature, su b stan tial increases in the concentrations of benzidine, 4amino biphenyl, and 2 ,4-diaminoazobenzene were found 48 and 96 hours a fter the addition of D irect Black 38 to the urine; at 5 C the dye in hamster urine was stable at lea st 96 hours .
Although a ll decomposition products have not been id en tified , benzidine-based dyes have been shown to break down in aqueous solution at elevated temperatures .Mel'nikov and K irillova examined a number of technical grade d irect dyes, including some that were benzidine-based.They found that the rate of decomposition of the dyes was accelerated by increased temperature and greatly accelerated in the presence of iron.For example, at 140 C a fte r 6 hours, 17.3% of Congo Red (Direct Red 28) decomposed, and, under the same conditions in the presence of iron, 83/i decomposed.When a 0.1% aqueous solution of Congo Red (Direct Red 28) was stored at 100 C for 1 hour, no decomposition was observed.The presence of te x tile additives such as urea, triethanolam ine, and cellosolve also increased the rate of decomposition.
# III.CHARACTERISTICS OF EXPOSURE
# Manufacture and Uses
The synthesis of dyes is b rie fly described in the Colour Index .Generally, the diazotized benzidine is reacted (coupled) with suitable secondary components such as hydroxylated aromatics or aromatic amines .Since the manufacture of dyes is directed toward producing a p articu lar color and not to producing a specific chemical e n tity , im purities such as benzidine, 4-amino biphenyl, 2,4-diaminoazobenzene, diphenyline, and semidine find th e ir way into the fin a l dye product.If these substances do not in te rfe re with the dyeing process, o rdinarily they are not removed .Additional substances, including other dyes, may be required to produce the p articu lar shade or hue desired in a product.Thus, dyes in general represent mixtures of substances rather than a p articu lar chemical e n tity .This is further complicated by the fact that manufacturers may use d iffering conditions of synthesis, startin g m aterials of d ifferen t purity, and even d ifferen t methods to manufacture dyes .These facts are important since each dye is depicted as a d efin itiv e chemical stru ctu re in textbooks and in the Colour Index .
More than 30 manufacturers in the United States now produce various d irect dyes.Only one of the nine US manufacturers that produced benzidine-based dyes in 1974 s t i l l does so in 1979 .Some d istrib u to rs import the benzidine-based dyes for resale in the United States .The 1979 Buyer's Guide published by the American Association of T extile Chemists and C olorists (AATCC) lis ts 20 unsubstituted benzidinebased dyes for sale in the United States .Not a ll dyes sold in the United States, however, are lis te d in the Buyer's Guide (W M artin, verbal communication, July 1979).
Since 1974, the eight US manufacturers that phased out the synthesis of benzidine-based dyes have replaced them with phthalocyanine, oto lid in e, o-dianisidine, phenylenediamine, and dioxyazine-type dyes .Nonbenzidine-based su b stitu tes appear to be in demand; five manufacturers now s e ll nonbenzidine-based su b stitu tes for Direct Black 38 .A suitable su b stitu te for D irect Blue 6 in the leather dyeing industry has been d iffic u lt to find .NIOSH considers the need for appropriate toxicologic testin g of a ll dye su b stitu tes to be essen tial before they are used in the workplace.
Benzidine-based dyes are used extensively to color te x tile s , leather, and paper.Ease of application has been a major asset to th e ir general a v a ila b ility and widespread usage.Of the to ta l use, 40% is used to color paper, 25% to color te x tile s , 15% for leather, and 20% for diverse applications in the petroleum, rubber, p la stic s , wood, soap, fu r, and hair dye ind u stries .
# Production Volume
Seventeen benzidine-based dyes are produced in the United States by one manufacturer, Fabricolor, In c .,of New Jersey.Table I I I -l gives the US production figures for benzidine dyestuffs manufactured during 1978. |
These figures were provided to NIOSH through the courtesy of Fabricolor (E Angstadt, w ritten communication, January 1979).
# IV.BIOLOGIC EFFECTS OF BENZIDINE-BASED DYES
# Human Cancer Studies
Two epidemiological studies have reported that exposure to benzidinebased dyes produces cancer in humans .Yoshida et al examined the p o ssib ility of a relationship between employment in the dyeing industry and an increased risk of developing bladder cancer.Occupational h isto rie s were available for 200 male p atien ts, a ll of whom had bladder cancer and who resided in Kyoto, Japan.One control group consisted of 148 men, at lea st 45 years old, who had been admitted to hospitals in the area with urinary disorders other than malignant tumors.Of the 200, 17 had worked in the dyeing industry.Bladder cancer p atien ts were 6.8 times more lik ely to have been employed as dyers than p atien ts with other urinary disorders.Ten of the 17 had been Kimono p ain ters.In a subsequent survey of Kimono painters in the Kyoto area, Yoshida and Miyakawa found that the practice of wetting the brush or spatula on the tongue was common.Of 141 persons interviewed, 47% admitted to th is p ractice.This indicated that ingestion of benzidine-based dyes was lik e ly .No information on specific dyes to which the bladder cancer p atien ts were exposed was available.However, Yoshida and Miyakawa referred to four benzidine-based dyes, D irect Black 38, Direct Green 1, D irect Red 17, and D irect Red 28, that had widespread use in Japan in the early 1970's .
Genin also studied worker exposure to benzidine-based dyes.A fter prelim inary work in which benzidine or dianisidine had been found in the urine of ra ts given dyes based on these substances, Genin examined the urine of 22 workers engaged in the drying and grinding of d irect azo dyes .Benzidine was present in the urine of eight persons and dianisidine was present in three.The q uantities varied from what were described as trace amounts to 0.3 jig/ml.Although the dyes being worked with at the time of urine sample collection were not described, Genin referred to two benzidine-based dyes, D irect Black 38 and D irect Blue 2, as being of greatest commercial importance in the USSR.Genin then examined the company records and found five cases of bladder tumors.Three had occurred between 1965 and 1968 among workers engaged in drying and grinding of d irect azo dyes.The persons were 68, 70, and 72 years old; had laten t periods of 18, 33, and 43 years; and had been exposed 24, 3, and 18 years, respectively.
Genin concluded that exposure to d irect azo dyes, synthesized from diphenyl amino d erivatives, is p o ten tially a cancer hazard.A dose-response relation sh ip could not be established, since the in ten sity of exposure to the dyes was not measured.
# Animal Cancer Studies
The National Cancer In s titu te (NCI) conducted a 93-day study with mice and ra ts that were fed three commercially available benzidine-based dyesi D irect Black 38, D irect Blue 6, and D irect Brown 95 .The three dyes were technical grade, factory-strength d irect dyes.
The molecular structures are shown in Appendix I I I , and the benzidine moiety can be iden tified in each stru ctu re.D irect Blue 6 was 66% pure, D irect Black 38 was 86% pure, and D irect Brown 95 was 79% pure, according to the manufacturer.Midwest Research In s titu te confirmed sim ilar values upon reanalysis of the m aterials.The balance of the constituents was mostly s a lt and w ater, but analyses by thin-layer chromatography (TLC), which used two d ifferen t solvent systems, demonstrated the presence of 8-15 minor im purities in each dye.No attempt was made to iden tify or quantitate these individual im purities.A specific analysis by high-pressure liquid chromatography was done to determine the presence or absence of benzidine.No benzidine was detected at the lowest detectable lim it of 0.004% (40 ppm) in any of the dyes.Corn o il was added to the dyes at 1.3% to suppress dust formation.While no specific analyses were done for benzidine in the food, spectrophotometric analyses of extracts of the d iet showed that each of the dyes was stable in feed for up to 2 weeks at temperatures up to 45 C.
For the bioassay in Fischer 344 ra ts , each dye was fed to 10 male and 10 female ra ts at 190, 375, 750, 1,500 or 3,000 ppm .Each dye was fed to 10 B6C3F1 mice of each sex at 750, 1,500, 3,000, 6,000, or 12,500 ppm, except that females were given D irect Brown 95 only up to 6,000 ppm.Ten matched mice and ra ts of each sex served as controls at each dose level.All animals except controls received one of the three dyes in th e ir feed for approximately 13 weeks.
The f i r s t observed tumor in the ra ts given dye occurred before 5 weeks in each case, regardless of the type of dye fed .This time-to-tumor interv al is the shortest encountered in the NCI bioassay program thus fa r. Dibromoethane has the next shortest time-to-tumor in te rv a l, which was 10 weeks .The shortest time-to-tumor for benzidine its e lf that has been observed in adult ra ts is 6 months .Tumor incidences in the ra ts given 1,500 ppm of a benzidine-based dye in the food are shown in Table IV
The single most important aspect of th is study was that sig n ifican t numbers of cancerous and precancerous lesions developed in the ra ts w ithin 93 days; hepatocarcinomas and/or neoplastic nodules developed in a sig n ifican t number of ra ts , except in the males exposed to Direct Brown 95.With th is dye the lesions found in male ra ts were lim ited to those described in the NCI report as precancerous.Neither cancerous nor precancerous lesions occurred in any of the control animals, nor had such lesions ever been observed in any of the controls in previous studies w ithin a 93-day time period.
The investigators concluded that the cancer observed was caused by the dyes themselves or a m etabolite and was not due to benzidine as an impurity.Since the benzidine concentration in each dye was less than 40 ppm, and since the time-to-tumor interv al for benzidine in ra ts at even higher levels has always been much longer than that observed for the dyes , th is conclusion appears to be ju s tifie d .The possible role of other im purities in the demonstrated carcinogenicity of the dyes cannot be established from the information contained in the re p o rt. Matched Controls
*At 3,000 ppm in female ra ts, the incidence of hepatocellular carcinoma was 4/10.
# Adapted from reference 29
The Clearinghouse on Environmental Carcinogens, a group representing industry, government, and the public, makes fin a l evaluation of the experimental re su lts on substances tested by the NCI bioassay program.The group concluded that Direct Blue 6 and D irect Black 38 dyes caused cancer in both sexes of Fischer 344 ra ts under the conditions of th is bioassay procedure, and that D irect Brown 95 dye caused cancer only in female ra ts .The Clearinghouse on Environmental Carcinogens concluded that testin g at lower levels for longer durations was unnecessary because of the rapid appearance of the tumors.The premature term ination of the study, originally contracted to be carried out over the normal lifetim es of the ra ts and mice and at nontoxic lev els, precluded demonstration of any carcinogenic effect in the mouse or a dose-response relationship in the ra t.
In contrast to the NCI study, two other investigations of the carcinogenic properties of benzidine-based dyes have given equivocal re su lts.In a 270-day study by F u jita et al , D irect Blue 6 was injected subcutaneously into 20 male and 20 female ra ts of an unspecified stra in .Total doses were 170 and 180 mg, respectively, given at weekly or biweekly in terv als.The daily dose was 1 ml of an aqueous 1% solution of the dye.Total survival at 270 days was 50%.In 2 of the 20 females, injection s ite sarcomas developed at 211 and 216 days, respectively.While atrophy of the parenchymal c e lls of the liv e r and d ila ta tio n of the liv er sinusoids were found during pathological examination of.the ra ts , no pre neoplastic or neoplastic lesions were reported.This study did not support the NCI findings of a rapid neoplastic response.The appearance of local sarcomas at injection site s may or may not indicate carcinogenicity in this study since no tumors were observed at remote site s .
N iitsu studied the carcinogenicity of two benzidine-based dyes, D irect Blue 6 and D irect Black 38 (sources unspecified).Wistar ra ts were given the dyes via th e ir drinking water (0.04%).Twenty male and twentyfive female ra ts were used to te s t D irect Black 38.Because Direct Blue 6 was found to be p artic u larly toxic to male ra ts , the assay of th is dye was lim ited to 20 female ra ts.The observation period was lim ited to only 14 months, since by that time a large number of animals had developed infections and died.The author concluded that the immunological competence of the ra ts had been compromised.With D irect Black 38 adm inistration, 14-month survival was 4/20 for males and 2/25 for females.One of the two surviving females had cancer of the breast (pathological designation not specified).With Direct Blue 6 adm inistration, 12/20 female ra ts were aliv e at 12 months; 1 of the 12 surviving Wistar female ra ts had a glandular tumor of the outer ear.No tumors were found in the controls.
N iitsu concluded that the carcinogenicity or lack of carcinogenicity of these two d irect dyestuffs could not be determined from the re su lts of the experiment .D ifferent stra in s of ra ts and d ifferen t sources of dye were used in the N iitsu and the NCI studies.Also, the NCI re su lts were found using concentrations of 1,500 and 3,000 ppm in the food , while the N iitsu study used 400 ppm in the drinking water .The marked su sc e p tib ility of the ra ts to infection noted in the N iitsu 14-month study was not found in the shorter 93-day NCI study, except for one ra t that died of b acterial infection.The 93-day period may have been too short a time to expect the type of infection noted by N iitsu .
Marshall , in 1953, reported that V ital Red (a benzidine-based dye) injected in trap erito n eally (ip) into 27 Wister albino ra ts , aged 3-4 months, at a dosage of 1 ml of a 2% aqueous solution of the dye every 2 weeks for 7 months, produced no pathological changes.A detailed pathology description was not given in the report.Twenty animals maintained on the same d iet were the negative controls for th is study.In contrast, ra ts injected with Trypan Blue or Evans Blue (o-tolidine-based dyes) developed lymphomatous tumors.While th is study cannot be considered a negative lifetim e study, i t is apparent that ip-in jected V ital Red did not, under the experimental conditions stated , rapidly produce liv e r tumors as did oral adim inistration of Direct Black 38, Brown 95, and Blue 6 in the NCI study.Korosteleva et al reported a study in 1977 designed to te s t the carcinogenicity of D irect Red 10.They u tiliz e d a to ta l of 75 white ra ts of unspecified stra in without statin g the number used as controls.The purity of D irect Red 10 was not described.The dye was administered to the ra ts at 500 mg per ra t daily in the food.Nephrotoxic and hepatotoxic effects were evident by the 100th day of observation.More severe kidney effects were noted at a s t i l l la te r stage.Direct Red 10, a benzidinebased dye, produced tumors in 10 of the 18 male ra ts that had survived 500 days.
The type of neoplasms found in the study were four microcholangiomas (malignancy of mixed masses of liv e r cord c e lls and b ile d u c ts), three leukemias (malignant transform ation at white bood c e lls ) , two plasmacytomas (m ultiple myeloma, a neoplasm of plasma c e lls ) , and one hypernephroma (kidney neoplasm with stru ctu re that resembles c o rtical tissue at the adrenal gland).These types of tumors, which are rare in ra ts , were markedly d ifferen t from the hepatocarcinomas found in the NCI study .Korosteleva et al also designed the study to determine whether D irect Red 10 could be metabolized to benzidine (see section on Animal Metabolic S tu dies).
Another chronic te s t of the carcinogenicity of Deep D irect Black EX (Direct Black 38) was reported by Okajima et al in 1975 .The dye was administered to male W istar ra ts in the drinking water for 60 weeks.At that time a ll were k illed since a sig n ifican t number had developed neoplasms.Results are given in Table IV-2.This report confirmed that D irect Black 38 is carcinogenic in ra ts when administered at lower doses over a longer period of time than used in the NCI study , Because the 60-week experimental period is much shorter than the r a t 's normal lif e span, a more extended experiment would be expected to re su lt in s t i l l more tumors.As in the NCI bioassay , i t would appear as though i t was not necessary to continue th is experiment over the lifetim e of the ra ts since a sig n ifican t number of tumors has resulted by 60 weeks. Okajima et al and N iitsu both adm inistered D irect Black 38 to ra ts in the drinking water a t sim ilar concentrations (500 and 400 ppm, resp ectiv ely ).I t is not apparent why carcinogenicity was established only in the study by Okajima et a l .Undoubtedly, the low survival ra te in the N iitsu study was a major facto r, since early deaths may have precluded the development of cancer in th is study.The m ortality ra te in the N iitsu study was 97% for D irect Black 38, while the m ortality ra te in the Okajima study was 13% for the same dye.
# Human Metabolic Studies
Humans as well as other mammals can change (metabolize) the benzidinebased dyes back to benzidine .The major organ in which benzidine-based dyes are metabolized to benzidine is the liv e r, but other organs also can do th is to a greater or lesser degree .
Various bacteria and yeast normally found in the small and large in testin e can also reduce the azo bond in benzidine-based dyes and release benzidine .This occurs both in vivo and in v itro ,
The major enzyme capable of lysing (breaking) the azo linkage of benzidine-based dyes is a cytochrome oxidase.This enzyme, termed azoreductase, is associated with the cytochrome P-450 microsomal fraction of the ce llu la r homogenate.The enzyme was extensively studied with relatio n to the azo dye prontosil , and has been described as an "enzyme par excellance" for lysing the azo linkage of dyes .Azoreductase is an extremely nonspecific enzyme found in a ll mammals tested so far , as well as in various microorganisms .I t is not necessary that the substance be a dye for th is enzyme to exert its action.The only requirement is the diazo linkage, ie , -N=N-.No exceptions have been reported .Knowledge of th is enzymatic capability in humans led to the following study .
In 1977, a NIOSH investigation was undertaken to survey in d u strial hygiene practices in the dye industry and to examine urine samples from workers exposed to benzidine-based dyes .The study protocol included prior n o tifica tio n of the benzidine-based dye manfacturer and team sampling of environmental levels of to ta l p artic u la te .In most cases, i t also included determ ination of the amount of dye present in the p articu late and analysis of the dye samples for residual benzidine.In addition, determination of the urinary levels of benzidine through, in most cases, controlled dual analytical procedures was also performed.These procedures were developed through the e ffo rts of the C linical and Biomedical Support Section, Division of Biomedical and Behavioral Science, and the Measurement Services Section, Division of Physical Sciences and Engineering, NIOSH.Both procedures are described in the report .One of the procedures is also given in Appendix I of th is Special Hazard Review. |
The lowest detectable lim it for nonspecific primary aromatic amines by th is method was 1 ppb with the provision that at le a st 100 ml of urine be available for analysis.This method required confirm ation of the nonspecific primary aromatic amines as benzidine or monoacetyl benzidine by TLC.The other procedure used to confirm the s p lit samples was electron-capture gas chromatography as developed by Nony and Bowman .The lowest detectable concentration of benzidine in urine stated by these authors was 1.4 ppb; for monoacetyl benzidine, i t was 5.8 ppb.
Environmental and urinary samples were collected at six fa c ilitie s where workers were p o ten tially exposed to benzidine-based dyes.These f a c ilitie s were: two benzidine-based dye m anufacturers, two te x tile dyeing p lan ts, a leather tanning plan t, and a specialty paper m ill .
In the f i r s t dye manufacturing fa c ility , two of eight workers p oten tially exposed to benzidine-based dyes had monoacetyl benzidine in th eir urine.The concentration of primary amines was 3 ppb in one case and 7 ppb in the other.These spot samples of urine were positive despite the fact that the workers observed were using cartridge-type face resp irato rs at the time of the sampling and that the environment appeared to be dust free.This fa c ility has since discontinued the manufacture of benzidinebased dyes .
In the other dye manufacturing fa c ility , four workers were monitored for exposure to benzidine-based dyes.The average environmental exposure levels of four of the workers were 4.3, 5.2, 11.7, and 17.4 mg to ta l p articu late/cu m. The corresponding urinary concentrations of benzidine averaged 52, 11, 10, and 112 ppb, respectively.The worker having 112 ppb benzidine in his urine (spray dry operator) also had 590 ppb monoacetyl benzidine in the same sample.This fa c ility has also taken measures since then to control dyestuff exposures and to monitor the urine of workers for benzidine .
Three of the above four workers had benzidine congeners other than monoacetyl and diacetyl benzidine in th e ir urine.Two of these workers had o -tolidin e in th e ir urine at 15 and 50 ppb.The third had o-dianisidine in his urine at 1 ppb.At the time of the inv estig atio n, these three workers were not exposed to o -to lid in e, o-dianisidine, or to dyes derived from these two substances.However, prior exposure to any of these substances could not be ruled out.Therefore, the source of o -tolidin e and odianisidine in the urine of these workers could not be established.Many workers, who were monitored and found to have short-term environmental exposures as high as 92.7 mg to ta l p articu late/cu m, did not provide urine samples to the investigators and thus th e ir urine could not be evaluated for the presence of benzidine .
In one te x tile dye manufacturing fa c ility , 7 p oten tially exposed workers were compared with 23 nonindustrially exposed office workers who were used as controls.D irect Black 38 and Direct Blue 2, both benzidinebased dyes, were being used at th is fa c ility .No benzidine was detected in the urine of any control.Urinary concentrations of benzidine in the seven p oten tially exposed workers ranged from below the lim it of detection to 39 ppb; three had both benzidine and monoacetyl benzidine in the urine (one dye tub operator and two dye-weighers).The four other p oten tially exposed workers had no benzidine or monoacetyl benzidine in the urine.The to ta l airborne p articu late m aterial (measured gravim etrically) ranged from 1 to A mg/cu m. Neither the dye concentration nor the types of dye in the p articu lates were determined.
In the other te x tile plan t, 10 workers were also monitored in the same way.The dyes used were D irect Blue 6, D irect Black 38, D irect Brown 95, and Direct Red 8.All airborne concentrations were less than 2 mg to ta l particu late/cu m. Some exposures were equivalent to those in the f ir s t te x tile dye fa c ility .At th is fa c ility , the amount of benzidine-based dye in the p articu late samples was measured colorm etrically.The amount ranged from 0 to 29% by weight in the d ifferen t samples.Presence of benzidine in the urine was expected but not found .
Dye exposure in the leather finishing fa c ility was lim ited to Direct Black 38 and D irect Brown 95.Time-weighted average (TWA) environmental concentrations were 0.69, 5.79, and 10.65 mg/cu m (three samples each).Each of the three workers p o ten tially exposed wore NIOSH-approved half-face cartridge re sp irato rs.No benzidine was found in the urine of the three workers .
In the sp eciality paper processing fa c ility , 23 environmental samples and 47 urine samples were analyzed.The environmental samples were a ll less than 6 mg/cu m (range, 0.17-5.10 mg to ta l p articu late m atter/cu m).In th is fa c ility , management had recently in itia te d a program in which resp irato r use was s tr ic tly enforced.Approximately 1,667 kg (3,000 lb) of D irect Black 38 were consumed during the 3-day survey.Despite th is heavy consumption, no urine samples contained benzidine .Time lim itatio ns prevented extended and repeated monitoring of the environment and the workers under a v ariety of conditions .The time of day for urine collection , for example, may be c r itic a l, because exposure is most lik e ly during work hours and a major portion of the benzidine m etabolites may have been elim inated in the urine before spot sampling the following day.This p o ssib ility of a cyclic type of excretion pattern is made more apparent by work in experimental animals showing that the benzidine m etabolites of D irect Black 38 were largely excreted w ithin the f i r s t 16 hours a fte r dye intake .Since spot samples were taken during the w orkshift, the peak excretion phase may have been missed.
This study demonstrated that benzidine can be found in the urine of workers who have contact only with the finished dyes under the present working conditions of the industry.No dye samples contained more than 25 ppm benzidine.C alculations provided in the NIOSH report demonstrated that the amount of benzidine found in urine of the workers was too great to have come only from benzidine impurity in the dye, and thus was a metabolic breakdown product of the dye.Even when i t appeared that standard protective equipment such as cartridge resp irato rs were used, the occurrence of benzidine in the urine was not necessarily prevented.One pulverizer operator who was observed to be using a h alf-face resp irato r had 52 ppb benzidine in his urine.However, th is worker was only observed a short time and i t is not known whether he used the resp irato r throughout the day.
Following id e n tifica tio n of 2,4-diaminoazobenzene (at 9,200 ppm) and 4amino biphenyl as contaminants in D irect Black 38, the National Center for Technical Research (NCTR) reanalyzed some of the the urine samples from workers studied in the above NIOSH investigation .Although q uantitative data were not given, 2,4-diaminoazobenzene was reported to be present in some urine samples but not 4-amino biphenyl .The International Agency for Research on Cancer (IARC) has reviewed the carcinogenic effect of 2,4-diaminoazobenzene, and designated i t an animal carcinogen .OSHA regulates 4-amino biphenyl as a carcinogen in the same manner as benzidine.
Genin analyzed the urine of 22 workers who had p o ten tial long-term contact with benzidine-based dyes during the manufacture of the d irect azo dyes D irect Black 38, D irect Blue 2, Direct Blue 15, and Direct Blue 218.He found benzidine in the urine of 8 of the 22 workers p o ten tially exposed and dianisidine in 3.The concentrations of benzidine or dianisidine in the urine ranged from what were described as "trace amounts" to 300 ppb, but the individual levels were not reported.Although th is study demonstrated that workers exposed to benzidine-based or dianisidine-based dyes may have benzidine or dianisidine in th e ir urine, q uantitative exposure could not be measured under the conditions p resen t, and doseresponse data were not reported.Korosteleva et al , in studies from 1966 to 1977, id en tified a benzidine complex in the serum of workers in a te x tile factory.The amount of the benzidine complex in the serum depended on the extent and duration of exposure to d irect dyestuffs in the workplace .In th is study, the author compared the blood serum of female te x tile m ill workers (18-60 years old) with that of nonindustrially-exposed blood donors.He found 22 of 77 workers p o ten tially exposed to any type of dye had benzidine complexed to albumin in the serum, compared with no instances of th is complex in 24 nonindustrially-exposed blood donors.Further, those workers exposed only to d irect dyes showed an incidence of 19 of 40, while 21 workers exposed to dyes that were not d irect dyes, or to other in d u stria l substances, had no benzidine-albumin complex in th e ir serum.Since the major d irect dyes reported were benzidine-based , and the benzidine-albumin complex was only found in the workers exposed to d irect dyes, the only reasonable source of the benzidine in the blood was from the benzidine-based dyes.
Thus, two Russian studies and one US study have demonstrated that benzidine or benzidine complexes are present in the body flu id s of humans exposed to benzidine-based dyes.
# Animal Metabolic Studies
As early as 1911, i t was known that azo dyes could be metabolized to simpler components.Sisley and Porcher reported that when dogs received oral doses of Orange 1, a monoazo dye, the dye was reductively cleaved at the azo linkage, resu ltin g in su lfa n ilic acid production in the urine.Sisley and Porcher further demonstrated that i t was necessary for Orange 1 to pass through the in te stin a l tra c t to be lysed.They suggested at that time that the m icrobial flo ra of the digestive tra c t was essen tial for the reduction of th is dye .In 1970, Walker reviewed the metabolism of azo compounds and concluded that many species of animals, yeast, and bacteria could reduce the azo linkage .The nonspecificity of azoreductase has been repeatedly demonstrated .This enzyme rapidly and e ffic ie n tly breaks the double bond in the N=N linkage regardless of the other e n titie s in the substrate.
The National Cancer In s titu te found that both ra ts and mice can metabolize benzidine-based dyes to benzidine .P rior to feeding Direct Black 38, D irect Brown 95, and D irect Blue 6 in the d ie t, the investigators analyzed each batch of dye, and detected no free benzidine (detection lim it was 0.004%).The amounts of benzidine found in urine of the animals are given in Tables IV-3 and IV-4.
Although there was no d irect correlation between the amount of benzidine excreted in the urine and the incidence of tumors in ra ts , each animal fed dye excreted benzidine, and the amount excreted was dose-related in most cases to the amount of dye administered .Since food consumption was not reported, individual dose-excretion ra tio s could not be calcu lated .
Benzidine was measured in the urine of mice and ra ts 3 and 11 and 4 and 12 weeks, respectively, a fte r the experiment began .The mice excreted approximately the same amount of benzidine at 3 weeks as the ra ts did at 4 weeks, and, in general, the mice excreted considerably more at 11 weeks than ra ts excreted at 12 weeks.There were no tumors found in mice by 93 days, while high incidences were found in ra ts exposed for the same period.Since benzidine alone did not produce tumors in ra ts u n til approximately 6 months of exposure at high doses , the production of tumors in ra ts by 93 days suggested that the parent dye (or a m etabolite other than benzidine) was the active carcinogen and that carcinogenicity did not depend exclusively on the presence of benzidine, per se.The NCI report concluded that the benzidine found in urine was a product of dye biotransform ation and not from a benzidine contaminant in the dye .The role of other known carcinogens in these dyes, such as 4-amino biphenyl or 2,4-diaminoazobenzene , was not examined; since they were not suspected contaminants at that time, no analysis was carried out to estab lish th eir presence or absence.I t should be noted that the analytical techniques used in the NCI study were colorim etric assays sim ilar to the one described in Appendix I. These methods are not specific for benzidine, and i t is possible that m etabolites and/or other aromatic amines were responsible for the colorim etric response . *Samples from untreated controls taken at weeks 3 and 11 showed no benzidine when spotted on TLC p lates.Numbers in parentheses are standard deviations.If fewer than three samples were averaged, the number of samples is given in parentheses instead.
# Adapted from reference 29
Aromatic amines, such as benzidine, produce tumors only ind irectly .They are f ir s t converted by the body to a more reactive substance, which has been termed the ultim ate (or proximate) carcinogen .The NCI investigators did not attempt to iden tify specific m etabolites of benzidine, and i t is not known if N-hydroxy diacetyl benzidine (one m etabolite suggested as the ultim ate carcinogen ) was among the m etabolites in eith er the ra t or mouse urine.
Rinde and Rinde and Troll reported that when any of four benzidine-based dyes, D irect Blue 6, D irect Black 38, D irect Brown 95, and Direct Red 28 (Congo Red), was administered to rhesus monkeys by gavage, benzidine and its monoacetyl derivative could be detected in the urine on an average of 1.25% of the benzidine moiety in the dyes studied.When benzidine its e lf was fed, free benzidine and its monoacetyl derivative were detected in the urine on the average of 1.45% of the original benzidine fed.The authors concluded on the basis of the above evidence that nearly to ta l conversion of the dye to benzidine took place.However, th is may not be the case because w ater-soluble m etabolites of benzidine or the dye may con stitu te a d ifferin g proportion of the m etabolites than the sparingly-soluble portion .
Because each dye was administered in dimethyl sulfoxide (DMSO), absorption of the dye from the in te stin e would be expected to be greater than when administered in aqueous solution, since DMSO enhances so lu b ility and absorption.Since no other m etabolites were investigated, NIOSH does not consider the re p o rt's conclusion of complete conversion of benzidinebased dyes to benzidine as appropriate.N evertheless, the fact was established that there is at lea st p a rtia l conversion of each of the four dyes to benzidine under the conditions of the experiment.Black 38 were found to be susceptible to azo reduction in th is study.Thus, b acte rial ly sis of the azo bond in the in te stin e is probably a basic means of producing benzidine from the benzidine-based dyes.This benzidine is then available to be absorbed into the body and excreted by the kidney to produce an effect on the bladder.An increase in the b acterial azoreductase enzyme level in the in te stin e was brought about in Fischer 344 ra ts by feeding a meat-based d iet in place of the normal grain-based diet .I t is not known whether ra ts given benzidine-based dyes together with a meat-based d iet would excrete more benzidine in the urine than when fed the dyes together with a grain-based d iet (such as used in the NCI study), but such an effect would not be unexpected.This is sig n ifican t, since man generally consumes a d iet high in meat protein.
A review a rtic le on benzidine metabolism called attention to re su lts from various investigations that showed that a v ariety of azo dyes including benzidine-based dyes were reducible at the azo linkage.In the case of azonaphthols, reduction occurred far more readily in the b acterial system than the liv e r preparation .Direct Blue 6, however, while reducible in vivo , was not reported to be reducible by the in te stin a l bacteria of female mice of a stra in designated as dd .
Yoshida et al reported in 1973 that Direct Black 38 (Direct Deep Black EX) was reducible both by E co li and common so il bacteria .
The I£ coli used were isolated from humans.The common so il bacteria were those taken from so il as well as from raw riv er w ater. |
Thin-layer chromatography was used for benzidine detection, and adequate negative and positive controls were used.Benzidine was found to be a reduction product from a ll b acterial samples used.In addition, Yoshida et al demonstrated that 3 g of cotton cloth dyed with D irect Black 38 yielded benzidine when incubated with the b acterial flo ra of raw riv er water for 72 hours.The color of the fabric faded under the action of the bacteria but not when incubated for 2 weeks with d is tille d water.This is the only investigation found in the lite ra tu re that dealt with b ac te rial breakdown of benzidine-based dyes once the dye is attached to a fab ric.The importance of th is investigation can also be appreciated by considering that while in tact benzidine-based dyes may not penetrate the skin , the benzidine portion of the molecule is readily absorbed through the skin 11,14,16,17,45].Since E coli is a b acteria commonly found on the skin, i t is lik e ly that the dye attached to a benzidine-based dyed fabric that contacts the skin w ill break down to benzidine.Since benzidine can be absorbed d irec tly through the skin, fabric with benzidine-based dyes can be a source of th is compound.II coli is unusually re sista n t to the b a c te rio sta tic effect of dyes in general and grows at temperatures as low as 20 C .
In 1977, Korosteleva et al demonstrated that ra ts of an unspecified stra in , given 500 mg of D irect Red 10 orally each day, could metabolize th is benzidine-based dye to benzidine, which then acted as a hapten forming a complex with protein in the liv e r and kidney w ithin 4 days after the in itia l dose.By the 30th day, the benzidine complex was present in the blood.The investigators reported a correlation between the carcinogenicity of D irect Red 10 and its a b ility to form antigens containing the benzidine moiety in vivo.
Metabolism studies on Direct Black 38 were recently completed for NIOSH at the National Center for Toxicological Research, in Jefferson, Arkansas .Sensitive as well as sp ecific analytical chemical methods were developed for assay of the known and the proposed im purities in D irect Black 38 as well as i ts known and proposed m etabolites.Similar studies were carried out for possible m etabolites of the substance Pigment Yellow 12, a pigment containing and deri-ved from 3 ,3 '-dichlorobenzidine.This pigment was not metabolized to benzidine, dichlorobenzidine, 2,4diaminoazobenzene, or 4-amino biphenyl, confirming prior studies in other species .
F ifteen male Syrian golden hamsters weighing approximately 110 g were administered D irect Black 38 at 100 mg/kg by g astric lavage .Urine was collected for analysis at in terv als up to 7 days.Three hamsters were used as controls.The dry, purified dye was analyzed and found to contain 3 ppm benzidine, 6 ppm 4-amino biphenyl, and 670 ppm 2,4-diaminoazobenzene.Further attempts a t p u rificatio n to elim inate the 2,4-diaminoazobenzene were unsuccessful.
The major portion of a ll m etabolites of Direct Black 38 was excreted w ithin 16 hours a fter adm inistration.The average to ta ls of m etabolites excreted by 16 hours are shown in Table IV
# Hydrolyzable benzidine- 257
Hydrolyzable 4-amino biphenyl- 5.1 *Hydrolyzable means that these substances were o rig in ally present as conjugates and were divided by adding sodium hydroxide.Adapted from reference 37 This analysis would account for approximately 10% of the benzidine moiety available in the D irect Black 38 o rigin ally fed to these animals.
The presence of 4-amino biphenyl as a m etabolite in the hamster urine is sig n ifican t in th at 4-amino biphenyl is a substance regulated by OSHA as a carcinogen in the same manner as benzidine .In addition, the presence of re la tiv e ly high concentrations of monoacetyl benzidine and hydrolyzable benzidine in the urine means that at some point the to ta l exposure of each animal to benzidine in th is experiment must have been several orders of magnitude greater than that indicated by the concentration of benzidine its e lf in the urine .In monkeys, Rinde was able to recover approximately 1.5% of the benzidine contained in each of four benzidine-based dyes as benzidine or monoacetyl benzidine.A major portion of benzidine would be expected to be excreted in a conjugated form and would not be detected unless the urine is f i r s t treated with an a lk a li to hydrolyze the conjugates of benzidine.Methods developed up to th is point have not included a hydrolysis step.Future methods for monitoring human urine should u tiliz e a hydrolysis step to provide the most sensitive indicator of exposure to benzidine-based dyes .
The In ternatio n al Business Machines Corporation recently reported preliminary data to the Environmental Protection Agency on a te st to determine possible skin absorption of Direct Black 38 in rabbits .The diphenyl portion of D irect Black 38 was f i r s t labeled with carbon-14.A proprietary mixture of D irect Black 38 was then applied to the skin of two rab bits.At the end of 144 hours, 91% of the rad io activ ity was recovered in the urine and feces of the rab bits.This indicates that D irect Black 38 or a portion of the molecule had penetrated the skin.Previous work by Rinde in monkeys had not shown skin absorption in that species .
# In another prelim inary study, Matthews examined the following benzidine-based dyes:
Direct Blue 2, D irect Black 4, D irect Brown 2, D irect Red 28, D irect Orange 8, and D irect Green 1.Each was fed to one of six female mongrel dogs at 100 mg/kg.Benzidine its e lf was fed to a seventh dog as a positive control.The treated dogs were held in individual metabolism cages, where they received food and water ad libitum .The urine was collected daily for 3 days, and analyzed for benzidine.The amount of benzidine measured in each urine varied from 320 to 1,675 /ig, but, in every case, dye adm inistration resulted in the excretion of benzidine.In the case of D irect Brown 2, benzidine excretion after adm inistration of the dye exceeded to ta l urinary benzidine excretion observed in the positive control dog given pure benzidine.
These re su lts increase to 11 the number of dyes that have been demonstrated to be metabolized to benzidine in humans, monkeys, ra ts , hamsters, mice, or dogs .
# V. EVALUATION AND CONCLUSIONS
Benzidine, an interm ediate in the synthesis of most benzidine-based dyes, is controlled as a human carcinogen in the workplace.When a Federal standard for benzidine (29 CFR 1910.1010) was promulgated in 1974, there was l i t t l e evidence to suggest that dyes prepared from benzidine were carcinogenic.Since then, a number of cases of bladder cancer have been reported in two groups of workers with exposure to benzidine-based dyes .These reports are meaningful in that they provide evidence that man is susceptible to the carcinogenic action of these dyes.However, the major evidence for the carcinogenic action of benzidine-based dyes is found in controlled animal studies.Rats fed Direct Blue 6, D irect Black 38, and Direct Brown 95 developed tumors in as l i t t l e time as 5 weeks .By 13 weeks, many exposed ra ts developed hepatocarcinomas or neoplastic nodules.In a separate study in which ra ts were fed D irect Red 10, carcinogenic a c tiv ity was also demonstrated , In yet another study, D irect Black 38 was found to be carcinogenic in ra ts when given at lower doses over a longeri period of time .Since the re su lts in animals support the findings in humans, i t must be concluded that benzidine-based dyes may cause cancer in humans.
Studies on ligated in te stin e and b acteria commonly present in the in testin e have shown that the azo linkage can be broken to yield benzidine from Direct Black 38, Direct Red 10, D irect Red 17, D irect Red 28, and D irect Orange 8.While inhalation is a major route of employee exposure to benzidine-based dyes , many of the inhaled dye p articles may be too large to reach and be retained in the lung.They then would be returned to the e p ig lo ttis by the c ilia l action of the bronchial mucosa or trapped by nasal impaction, and then swallowed so that they become available for absorption by the body.In addition, hand to mouth tran sfer, contamination of foods, or poor work p ractices would lead to oral ingestion of the dyes.B acterial reduction in the in te stin e would represent one source of benzidine in such cases.
Other available evidence suggests that cleavage of the azo linkage of the dye also occurs a fte r absorption of the dye, resu ltin g in the release of benzidine in vivo.Benzidine has been found in the urine of workers who handled benzidine-based dyes in the dye manufacturing and te x tile industries .In a Russian study, about h alf of the te x tile m ill workers examined who handled d irect dyes had benzidine-albumin complexes in the blood .In another Russian study, 8 Further research is needed to c la rify the issue of skin absorption of the dyes.However, i t is known that D irect Black 38 can be reduced to benzidine by b acteria commonly found on the skin .This suggests that the dermal route could be a source of employee exposure since benzidine is readily absorbed through the skin .Preliminary work in rabbits supports th is as a possible route of exposure .
The evidence presented above demonstrates that benzidine is a metabolic product of at least .11 benzidine-based dyes.The azoreductase enzyme that breaks down these dyes to benzidine is ubiquitous and generic.I t acts on a m ultitude of azo compounds, containing a large v ariety of individual components and has been observed to cleave the N=N linkage common to these compounds.The a b ility to be metabolized in vivo to a known carcinogen is su fficien t evidence to necessitate regulation of a ll benzidine-based dyes.In addition, animal experiments have suggested that these dyes could have a greater p otential for carcinogenicity than benzidine alone, since the dyes have been reported to form tumors much more quickly than benzidine .Therefore, benzidine-based dyes may be a more robust source of the ultim ate carcinogen.Im purities introduced in the manufacture of the dye may also be a factor.For example, 4-amino biphenyl and 2 ,4-diaminoazobenzene were id en tified in commercially prepared D irect Black 38 .
Both contaminants are important because 2,4-diaminoazobenzene is considered a carcinogen by IARC and 4-amino biphenyl is regulated as a human carcinogen (29 CFR 1910.1011).Mutagenesis te s ts using the Salmonella typhimurium (TA-98 and TA-100) assay with activation were positive for the following substances: the urine of hamsters fed D irect Black 38, the major m etabolites of th is dye (benzidine, monoacetyl benzidine, diacetyl benzidine, and 4-amino biphenyl), and the dye its e lf .
Studies have reported that four benzidine-based dyes rapidly induce cancer in experimental animals, suggesting that these substances may have a greater carcinogenic p otential than can be attrib u ted to th e ir m etabolite benzidine alone.Other studies have reported a number of cases of bladder cancer in two groups of workers exposed to benzidine-based dyes, but not to benzidine.In addition, a ll of the 11 benzidine-based dyes thus far tested have consistently been metabolized in animals to the carcinogen benzidine.The azoreductase enzyme responsible for formation of benzidine in the body is known to be nonspecific in i ts action and is found in b acteria, animals, and humans.Occupational exposure to benzidine-based dyes has also resulted in benzidine formation in the bodies of workers.This then indicates that there is an extremely high probability that those yet untested benzidine-based dyes can be metabolized to benzidine also.Based on a combination of the above facto rs, NIOSH concludes that a ll benzidinebased dyes, regardless of th e ir physical sta te or proportion in a mixture, should be recognized as p oten tial human carcinogens.In addition, NIOSH recommends that the production, use, storage, packaging, and d istrib u tio n of a ll benzidine-based dyes be discontinued in lig h t of present evidence o p o tential carcinogenic risk s. The replacement of benzidine-based dyes with less toxic su bstitutes should be in itia te d immediately.As an interim measure, stringent controls and work p ractices are recommended to minimize exposure to any of the benzidine-based dyes.
During th is interim period, since the carcinogens benzidine, 4-amino biphenyl, and 2 ,4-diaminoazobenzene have been id en tified as contaminants or breakdown products of a commercially prepared benzidine-based dye , p articu lar attention should be given to the possible increase in concentration of these im purities in the cleanup of sp ills or leaks, waste disposal, and hot dyeing processes.
A number of reports have considered or referred to the use of su b stitu tes to replace benzidine-based dyes .In the absence of additional inform ation, NIOSH recommends that the benzidine congener dyes be handled with extreme care in the workplace and that exposure to these dyes be minimized.Substitution of noncarcinogenic dyes for those that are benzidine-based is e ssen tial.However, i t must be recognized that the stru ctu ral requirements for a compound to impart color leads to the use of dyes containing m oieties that tend to be chemically reactive and toxic.Thus, the p o ssib ility of metabolic conversion to even more toxic compounds, as well as the effects of the dye its e lf , must be considered.In addition, toxic im purities can be introduced in manufacture.Information on the toxic effects of possible su b stitu tes should be taken into account during replacement of benzidine-based dyes.If such information is incomplete or suggests that the dye might also have carcinogenic p o ten tial, other su b stitu tes must be used.
# VI.WORK.PRACTICES AND CONTROL RECOMMENDATIONS
This section evaluates the conditions under which employee exposure to benzidine-based dyes is lik e ly .I t also delineates those operations in which the most intense exposures would be predicted in the absence of controls.Emphasis is placed on work practices and control recommendations to lim it excessive employee exposure to benzidine-based dyes in operations that can be p artic u la rly hazardous.The employer should, in addition, evaluate existing programs for labeling and posting, employee education, cleanup of s p ills , disposal of waste, emergencies, and general plant san itatio n to ensure their adequacy in lig h t of evidence of carcinogenicity of the benzidine-based dyes.If present programs are inadequate, new ones should be implemented to ensure a clean and healthful workplace and to ensure that employees are aware of the hazards involved and of th e ir role in maintaining a safe working environment.
During manufacture, the dyes are generally prepared in a closed system in which benzidine is formed by the reaction of the sta rtin g m aterial, hydrazobenzene, with hydrochloric acid .One dye manufacturer has developed a process th at uses nitrobenzene as the sta rtin g m aterial, thus elim inating the need for employees to handle hydrazobenzene, which forms benzidine in the stomach if ingested .After the dye is p recip itated , however, generally i t is handled in open systems .The dye is filte re d in presses and the press cake is unloaded manually.The press cake is then dried, and the dried dye is ground into a fine powder.This fine powder is then transferred to ribbon blenders where other dyes are often admixed to obtain the desired colors.Sulfonated dedusting o il is usually added at th is point to reduce the tendency for the dye to produce an aerosol when poured or mixed.S alt or sugar is nearly always added to d ilu te the concentrated dye .The fin a l product is then weighed and packaged for marketing.
Processes in which dried dye is handled have the g reatest p otential for employee exposure during the manufacture or repackaging of benzidine-based dyes; such processes should be performed in closed systems.Access to such areas should be re stric te d to authorized employees.When such enclosure is not possible, each operation should be provided with continuous local exhaust v en tilatio n so that a ir movement is always from surrounding work areas to the operation and then through su itab le f ilte r s as described in OSHA safety and health standards (29 CFR 1910), so as to prevent the release of any benzidine-based dye to the work environment.
Handling of moist press cakes and solutions constitutes a lesser source of employee exposure to benzidine-based dyes than handling dry powders, since solutions and moist m aterials are less lik ely to be dispersed into the a ir or d istrib u ted over large areas.N evertheless, closed systems should be used to further lim it employee exposure to benzidine-based dyes. |
F ilte r presses that can be emptied and decontaminated without opening the f ilte r s have been used for preparation of benzidine su lfate , and the use of th is type of f i l t e r should also be applicable in the manufacture of the dyes.
Various methods of elim inating the dust hazard associated with dyes have been used.In addition to the treatment with sulfonated o ils referred to above, two other methods are presently employed .One method is to form the dye into p ellets so that dusting is minimized.The other procedure is to make up the dyes in unitized double packages.The outer package, which is used for protection during shipment, contains an inner package that dissolves in water.Thus, the worker making up a dye bath would add the appropriate number of units of dye to the bath without opening the inner package.These procedures may be combined for added safety (a dye package of p ellets in double packets).
Pastes rather than dried dyes have been used by the paper industry for some time .In th is case, the paste is added to a large container of an aqueous solution and that solution is metered to each batch of paper as i t is dyed.
Benzidine-based dyes are used in the paper, te x tile , and leather finishing ind u stries.Since the industries are diverse, i t would be expected that the conditions of p o tential exposure to benzidine-based dyes are equally diverse.At le a st 63 occupational categories have been found to be associated with p o tential exposure to benzidine-based dyes .In the f a c ilitie s surveyed by NIOSH , a three-step process for handling the benzidine-based dyes was c h aracteristic of a ll three ind u stries.F irs t, a dye weigher dispensed the m aterial into a vessel.In some cases the weigher also dissolved the dry dyestuffs.Next, the m aterial to be dyed and the dissolved dye were placed in a dyeing v at.F inally, the dyed m aterial was dried and finished.The degree of worker exposure in areas where paper, te x tile s , or leather are being dyed would be expected to vary widely depending on conditions such as the temperature of the dye solution, the amount of manual handling of the dyed m aterial, and the design of the dye v ats.Employees who handle paper, te x tile s , or leather a fte r i t is dyed could also be exposed to benzidine-based dyes since excess dye retained on the finished m aterial would be available for release as dried powder.
During use of benzidine-based dyes, the g reatest p o ten tial for exposure would be expected to be among dye-weighers who handle dry powders .Their operations should be carried out in a hood designed and maintained so as to draw a ir inward at an average linear face velocity of 150 feet per minute (0.76 m/s) with a minimum of 125 feet per minute (0.64 m /s).P articular attention should be paid to the design of such hoods to ensure that the employee can transfer the m aterial from its o rigin al container to the weighing scale without taking any dye outside the enclosure or inserting any part of the body other than hands and arms inside the hood.Containers of benzidine-based dyes should be opened only during the weighing operation.Once opened, they should remain w ithin the hood u n til disposal or u n til a ll the contents have been used.The use of pastes or liquids rather than dried dyes should be considered as a control measure.
The dye weigher should prepare the dye solutions to be placed in the vats.This procedure would elim inate the need to tran sfer the more hazardous dry m aterial from one statio n to another.The dye weighing area should be regulated, and access should be lim ited to authorized employees who are wearing adequate personal protective equipment adequate to prevent skin contact with or inhalation of the dyes.If workers must handle the m aterial in the vats manually, or if adjustments to machinery are necessary while benzidine-based dye is present, the worker must wear impervious clothing and resp irato ry protection to prevent exposure to the dyes.
T extiles are dyed at various stages in th e ir manufacture, including unspun fib ers, unwoven yarn, and finished fab ric.Workers who prepare fabrics from unspun fib ers are of p artic u la r concern, since they could be p oten tially exposed to benzidine-based dyes contained on dusts generated during manufacture.In addition, some benzidine-based dyes possess much poorer fastness to wet treatment than do others; persons who launder such clothing are p o ten tially exposed to the dyes.Employees and employers should be aware that those who launder, weave, or sew fabrics dyed with benzidine-based dyes are p o ten tially exposed to the dyes.If exposure is considered lik e ly , the employer should in s titu te stringent control measures and work p ractices to prevent such exposure.
Several generally acceptable p ractices for the control of hazardous m aterials are recommended wherever there is p o ten tial for exposure .For example, pressure fa ilu re alarms for closed systems and exhaust v en tilatio n can rapidly indicate a system fa ilu re that might re su lt in the release of substan tial q uan tities of benzidine-based dyes.Continuous flow indicators, such as water or o il manometers properly mounted at the juncture of a fume hood and duct throat and marked to indicate acceptable airflow , w ill give a readily observable indication of decreased efficiency in the v en tilatio n system for the hood.Wet methods, vacuum cleaning, or other methods that do not lead to redispersion of se ttle d dust should be used for plant maintenance and san itatio n .Dry sweeping or blowing with compressed a ir should be prohibited.In the cleanup of leaks or s p ills and in maintenance or rep air operations on contaminated systems or equipment, employees should wear clean impervious garments, including at least gloves, boots, and an air-supplied resp irato r with positive pressure in the facepiece.
Benzidine is readily absorbed through the skin, and reuse of protective equipment or work clothing contaminated with benzidine can lead to its dermal absorption .However, evidence for dermal absorption of the benzidine-based dyes is conflicting , As a prudent measure, absorption of benzidine-based dyes through the skin must be considered a real p o ssib ility , Thus, employee exposure through contaminated clothing may be as serious a problem for benzidine-based dyes as i t is for benzidine .P articu late m aterial containing the dyes can be released into the external environment, including the employee's home, unless clothing p oten tially contaminated with the dyes is removed before the employee leaves the exposure area.If an employee's skin is p oten tially contaminated with benzidine-based dyes, the employee should wash or shower as appropriate before leaving the exposure area.
# Workplace Air
At th is time, NIOSH is unaware of a p ra ctic al method for identifying each sp ecific benzidine-based dye workers may be exposed to.I t should be possible to identify classes of azo dyes such as the benzidine-based dyes by the use of high performance liquid chromatography or gas chromatography a fte r reduction of the azo linkage.Additional research is generally needed in th is area.
Although methods to measure the concentration of an individual benzidine-based dye in a ir are not available, a screening method for diazonium sa lts and azo dyes in air has been developed by NIOSH and is described in Appendix 1(A).The range of the method is lis te d as 0.01-0.4 mg/cu m in a 500-lite r sample of a ir.If only one benzidine-based dye is present and other positive interferences are absent, a q uantitative estim ate of the concentration of the dye present in the a ir can be made.If more than one azo dye of any type is present, the method is not quan titative and the concentration of to ta l azo dye present must be given as a range.However, the method can indicate the adequacy of work practices and engineering controls employed to minimize the concentration of airborne benzidine-based dyes during the period required to phase in su b stitu te dyes.
# Urinary Levels
Aromatic diamines, such as benzidine, are not normally found in the body.However, benzidine, a metabolic product of benzidine-based dyes, has appeared in the urine of employees exposed to the dyes but not to benzidine.This demonstrates systemic absorption of the dye or a portion thereof.Currently, the measurement of urinary benzidine is used more as a diagnostic practice than for use in compliance.The presence of benzidine in the urine of a worker p o ten tially exposed to a benzidine-based dye would v erify that such exposure had, in fa c t, occurred, but its absence cannot be considered v e rific a tio n that no exposure has occurred.
The method recommended in Appendix 1(B) can detect the presence of aromatic amines at 100 ng/100 ml of urine, although recovery efficiency at the lim it of detection is poor.If aromatic amines are found in the urine, thin-layer chromatography (TLC) can be used to confirm (though not rigorously prove) the presence of benzidine.The to ta l volume of the sample must be no less than 100 ml; the minimum detection lim it in such a volume is 300 ng.An Rf value iden tical to th at of benzidine constitutes th is confirm ation.If benzidine is detected by u rin a ly sis, i t would demonstrate that employee exposure to benzidine or benzidine-based dyes has occurred and would suggest inadequacies in eith er engineering controls or work p ractices.Thus, u rinalysis in addition to environmental monitoring is necessary to assure the employer that exposure of employees to benzidine-based dyes has been minimized.
Specific methods for the detection of benzidine in human and hamster urine and in in d u stria l effluents have been developed.Two are based on electron-capture gas chromatography, one is based on high performance liquid chromatography , and one is a spectrophotofluorim etric technique .Unlike the fluorescamine method or the method given in Appendix 1(B), they can measure benzidine in the presence of other aromatic amines.While a ll these methods should be readily adaptable to detection of benzidine in an employee's urine, they involve considerably more elaborate instrum entation and analytical techniques than the routine screening method described in Appendix 1(B).Several points need further c la rific a tio n before the amount of benzidine in the urine can be correlated precisely with the concentration of benzidinebased dyes in the a ir.For example, the optimum conditions for sample collection are not known.The NCTR study recommended alkaline hydrolysis of the urine to measure both free and conjugated benzidine.Since u rin aly sis is presently useful as a q u alitativ e index of exposure only, the less elaborate screening method constitutes the best approach at th is time. Duplicate samples of airborne p artic u la te m aterial are collected on cellulose acetate membrane f il te r s .One f i l t e r is extracted with d ilu te hydrochloric acid and analyzed for diazonium sa lts spectrophotom etrically at 375 nm.The second f i l t e r is extracted with an appropriate solvent and a spectrophotometric scan of the solution is made in the 400-to 700-nm range.The absorbance maxima are compared with the absorbance maxima of standard solutions prepared from bulk samples of the azo dyes. c h a r a c t e r i s t i c a b s o r p t i v i t y , the c o n c e n t r a t io n o f t o t a l diazonium s a l t s must be g iv e n as a ra n g e . (2) Connect the cassette to the vacuum pump.No tubing should be placed in front of the f i l t e r .
# D irect
# The s a l t h avin g the h ig h e s t a b s o r p t i v i t y d eterm in es the upper l i m i t o f the ran ge and th e s a l t h avin g the lo w e st a b s o r p t i v i t y d eterm in es the
(3) Turn on the pump to begin sample collection .Measure the flowrate and time, or volume, as accurately as possible.Sample 500 lite r s or more at 1.5-2 liters/m in .
(4) Take duplicate samples at each sampling s ite .One is for the diazonium s a lt analysis; the other for the azo dye analysis.P rotect the f ilte r s from lig h t to prevent photodecomposition of the diazonium s a lts .
(5) Ship the f ilte r s in a su itab le container designed by NI0SH to minimize contamination and to prevent damage in tra n sit.Include two or more blank f il te r s , which are handled in the same manner as the sample f ilte r s except that no a ir is sampled through them.
(c) Analysis of Samples (1) Diazonium Salts Extract one of the duplicate sample f ilte r s from each s ite with 40 ml of 0.1 N HCl in a 100-ml beaker.A gitate the mixture in an u ltraso nic bath for 5 minutes.Allow the f i l te r and any suspended solids to s e ttle .Extract a blank f i l t e r in the same manner.Perform the extractions with minimum exposure to lig h t. Transfer a portion of each solution to a 1-, 5-, or 10-cm fused s ilic a c e ll, depending on the anticipated diazonium s a lt concentration.Determine the absorbance of the blank and the sample of 375 nm.Use 0.1 N HCl as the reference solution.
(2) Azo Dyes Select an appropriate solvent by experimentation with the bulk samples. (See Advantages and Disadvantages, section (f).)Extract one of the duplicate sample f ilte r s and a blank f i l t e r with the solvent using the extraction procedure outlined in section (1) on Diazonium S alts.Tranfer a portion of each solution to a 1-, 5-, or 10-cm fused s ilic a c e ll, depending on the anticipated concentration.Using the solvent as a reference, scan the 400-to 700-nm range to locate the absorbance maxima.Measure the absorbance at each wavelength where the bulk azo dyes absorb. (2) Transfer a portion of each solution to a 1-, 5-, or 10-cm fused s ilic a c e ll.
(3) Using the 0.1 N HCl solution as the reference solution, determine the absorbance of each standard a t 375 nm.
(4) Construct a standard curve for each diazonium s a lt by plo ttin g the absorbance against the amount (in micrograms) of the individual diazonium s a lt in the corresponding standard.
yielding the largest value.The lower lim it of the range is taken from the curve yielding the lowest value.
(c) Correct the calculated amount or range of amounts of the appropriate diazonium salt(.s) or azo dye(s) for any corresponding value found by the analysis of blank f ilte r s .
(d) The concentration or range of concentrations of diazonium sa lts and azo dyes may be expressed in mg/cu m: mg/cu m = Amount ((ug)g) Vs (in lite rs )
where: Vs = volume (lite rs ) of a ir sampled.
# APPENDIX I -ANALYSIS (CONTINUED) (B) METHOD FOR MONITORING FOR BENZIDINE IN URINE
NIOSH has reviewed the various methods of biological monitoring for benzidine and related chemicals.There are two acceptable methods: the recommended method that follows and the fluorescamine method given in the o -tolidin e c rite ria document .The recommended method presented here is less expensive and more sen sitive than the fluorescamine method; however, i t requires a longer working time.Neither method is specific for benzidine.
Any other method of at least equal se n sitiv ity and precision may be substituted for the recommended method [37, 59,78 100-20,000 ng/ 100 ml urine Precision:
Not determined C lassificatio n: D (opera tional) Date Issued: 8/3/79 P rinciple of the Method Aromatic amines, including benzidine, are extracted from urine with chloroform a fte r pH adjustment.The chloroform extract is back extracted into 0.1 N HC1 and derivatized with 2 ,4 ,6-trinitrobenzene sulfonic acid (TNBS).The TNBS derivatives are extracted with chloroform to remove in terferin g chromophores and the fin a l chloroform extract quantitated spectrophotom etrically at 400 nm while using benzidine as a standard.The resu ltin g chloroform extract is concentrated to droplet volume for benzidine id e n tific a tio n by thin-layer chromatography (TLC).A ttention is called to the poor s ta b ility of the chloroform solution of the TNBS derivative of benzidine.Q uantitation of th is derivative by colorimetry should be performed w ithin 30-45 minutes a fte r preparation of the fin al chloroform solution. |
(a) The detection lim it of th is spectrophotometric procedure is 100 ng of benzidine (aromatic amine) per 100 ml of urine.The detection lim it for benzidine by TLC is 300 ng/100 ml urine.
(b) The range is from the detection lim it up to.20,000 ng/100 ml of urine.
(c) The UV and/or v isib le detector (maximum absorbance, 400 nm) has a lin ear response up to 0.02 mg of benzidine per 100 ml of urine.
# Range and Sensitivity
Interferences (a) Any other aromatic amine having an absorbance maximum at 400 nm and an Rf value iden tical to that of benzidine when chromatographed by TLC would in te rfe re .
(b) Aromatic amines in substances that are normally present, ingested, or produced by metabolic processes in the worker w ill produce a chromophore (false p o sitiv e ).
(c) Extraction at pH 5 with chloroform and subsequent back extraction into HC1 reduce interference from other compounds.
# Precision and Accuracy
(a) Recovery studies conducted on benzidine indicate 70% at the 500 ng/100 ml level and a marked decrease (about 20%) at the 100 ng/100 ml le v e l.
(b) The precision has not been evaluated at th is time.
Advantages and Disadvantages (a) The principal advantage is that the method is specific for aromatic amines in the nanogram range.
(b) Another advantage is that benzidine at 300 ng/100 ml can be confirmed by TLC in conjunction with the method.I t should be noted that the TLC confirmation data does not prove that the chromophore is benzidine.More rigorous methods must be used for absolute confirm ation.
(c) The disadvantages of the method are the com plexities of the procedure (emulsions and losses in e x tra c tio n s), nonspecificity for benzidine, and the increased time for confirmation by TLC.
(3) The urine is extracted with 10 ml of chloroform for 2 minutes.If an emulsion is formed, then centrifuge to separate the two phases.The chloroform fractio n (organic phase) is collected and saved.
(4) The urine is extracted twice more with chloroform (10 ml), and a ll three of the chloroform fractions are combined.
(5) Reextract the combined chloroform mixture with 2 ml of 0.1 N HC1 for 30 minutes on a ro tato r.
(6) Transfer the aqueous phase (about 2 ml) into a culture tube (16x125 mm) using a Pasteur pipet.
(7) Add 2 ml of pH 5.5 buffer and 0.7 ml of TNBS reagent, mix w ell, and le t stand for 15 minutes at room temperature.A reagent blank is prepared by adding 2 ml of 0.1 N HC1 to 2 ml of pH 5.5 sodium acetate buffer and 0.7 ml TNBS reagent and is treated as a sample.
(8) Add 2 ml of CHC13 and shake for 1 minute.
(9) Measure the absorbance of the organic phase at 400 nm on a spectrophotometer.
(10) Retain the organic phase for the benzidine-TLC confirmation, (c) TLC Confirmation of Benzidine (1) The TNB-derivative (chloroform extract) is concentrated by evaporating with nitrogen to about 0.2-ml aliquot.
(2) Ten m icro liters of the aliquot is spotted on a silic a -g e l TLC plate that was activated at 110 C for 30 minutes.
(3) The p late is then developed in chloroform-formic acid 90:10, volume to volume (prepared d a ily ).
(4) The Rf of the unknown amine derivative is compared with that of a benzidine spiked deriv ativ e, which should always be run as a standard.Benzidine produces a spot on the TLC p late having an Rf = 0.41, visualized by both v isib le and UV lig h t. The spot is yellow in v isib le lig h t and appears as a dark spot under UV lig h t.
# C alibration and Standardization
(a) CAUTION: Benzidine is a known human carcinogen and appropriate precautions should be u tiliz e d to minimize exposure.All wastes including acetone rinsed d irty glassware should be collected and disposed by approved methods.
# (b)
Prepare a working standard solution containing 10 fig of benzidine per ml of methyl alcohol.A series of benzidine spiked urine samples are prepared from a urine pool sample that was previously shown to have less than 100 ng benzidine per 100 ml of urine.The spiked urine samples serve as standards and are analyzed by the colorim etric method.The calibratio n curve is established by plo ttin g benzidine concentration (ng per 100 ml of urine) vs the absorbance at 400 nm.
# Calculations
(a) The concentration of the analyte in the urine sample is compared with a standard curve prepared with benzidine spiked urine samples as described in C alibrations and Standardization.
All samples are read against a reagent blank as described in Procedure. (c) If the calculated concentration exceeds 300 ng/100 ml, the chloroform extract should be analyzed by TLC to ten tativ ely confirm the presence of benzidine.
(d) In th is laboratory, normal rangds of urine specimens from NIOSH employees not exposed to benzidine or aromatic amines are reported below:
# Number of Urine Specimens
Cone, (ng/100 ml) Aromatic Amine
# D ise a se C o n tr o l, N a tio n a l I n s t i t u t e f o r O cc u p a tio n a l S a f e t y and
(4) Determine the absorbance of each standard at the wavelength of its maximum. (5) Construct a standard curve for each azo dye by p lo ttin g the absorbance against the amount (in micrograms) of the individual azo dye in the corresponding standard.
# Calculations
(a) Diazonium Salts (1) If only one diazonium s a lt is present in the sample, read from the appropriate calib ratio n curve the amount (in micrograms) corresponding to the absorbance of the sample.
(2) If more than one diazonium s a lt is present, the re su lts must be given as a range. (See Advantages and Disadvantages (f).)From the calibratio n curve for each diazonium s a lt, read the amount (in micrograms) corresponding to the absorbance of the sample.The upper lim it of the range is taken from the curve yielding the larg est value.The lower lim it of the range is taken from the curve yielding the lowest value. (b) Azo Dyes (1) If only one azo dye is present in the sample, read from the appropriate calib ratio n curve the amount (in micrograms) corresponding to the absorbance of the sample at the wavelength of maximum absorption.
(2) If more than one azo dye is present, the re su lts must be given as a range. (See Advantages and Disadvantages (h).)From the calibratio n curve for each azo dye absorbing at the same wavelength as the sample, read the amount (in micrograms) of azo dye corresponding to the absorbance of the sample.The upper lim it of the range is taken from the curve (d)
A rigorous specific method for benzidine in urine has recently been published .I t uses fluoroanhydride deriv atizatio n and electron capture gas chromatography, but requires considerable more time and equipment to perform.
# Apparatus
(a) Spectrophotometer capable of measuring absorbance at 400 nm and accommodating semimicrocuvettes (1-ml capacity ).
(b) Centrifuge with speed range to 4000 rpm. (c) Rotator for mixing te s t tubes (25x200 mm).
(d) pH meter.
(e) TLC plates precoated with s ilic a gel and without fluorescence indicator (0.5-mm thickness, E. Merck, Darmstadt, Germany).
(f) Chromatographic tank for thin -lay er chromatography.
(g) UV source for reading TLC p lates. (h) Graduated cylinders (100 ml). (2) Samples of "spot" urine (150 ml) are collected following 6 hours of suspected exposure to benzidine-based azo dyes.
(3) Samples should be collected in polyethylene b o ttle s and, if not analyzed on the same day, should be frozen u n til analysis can be done.
# (b) Analysis of Samples
(1) One hundred m illilite r s of well mixed urine is adjusted to pH 5.0 to 6.0 (1 N HC1 or 1 N NaOH) in a glass b o ttle (180-ml capacity).A control urine sample (100 ml) and a control urine sample (.100 ml) spiked with benzidine (300-1000 ng) should be analyzed concurrently with the unknown samples.
(2) Add 0.2 g NaCl cry stals to the pH adjusted urine. and reported as produced or imported by the US International Trade Commission (ITC) or those*$o which potential exposure was found f441.
If less than three manufacturers make a dye, ITC does not publish the production figures.A discussion of limitations of the estimation of worker exposure is contained in reference 44. *This dye may also be synthesized with cresotic acid in place of salicylic acid.
The Colour Index designates both dyes as Direct Orange 1.
# D E P A R T M E N T O F H E A L T H .E D U C A T I O N , A N D W E L F A R E PUBLIC HEALTH SERVICE C E N T E R F O R D I S E A S E C O N T R O L
# T H IR D C L A SS N A T I O N A L I N S T I T U T E F O R O C C U P A T I O N A L S A F E T Y A N D H E A L T H R O B E R T A .T A F T L A B O R |
These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013.The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 201059 ).These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection.Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs.#Introduction
The term sexually transmitted diseases (STDs) refers to a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity.Physicians and other health-care providers play a critical role in preventing and treating STDs.These guidelines for the treatment of STDs are intended to assist with that effort.Although these guidelines emphasize treatment, prevention strategies and diagnostic recommendations also are discussed.
This document updates CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010 (1).These recommendations should be regarded as a source of clinical guidance rather than prescriptive standards; health-care providers should always consider the clinical circumstances of each person in the context of local disease prevalence.These guidelines are applicable to any patient-care setting that serves persons at risk for STDs, including family-planning clinics, HIV-care clinics, correctional health-care settings, private physicians' offices, Federally Qualified Health Centers (FQHCs), and other primary-care facilities.These guidelines focus on treatment and counseling and do not address other community services and interventions that are essential to STD/HIV prevention efforts.
# Methods
These guidelines were developed by CDC staff and an independent workgroup for which members were selected on the basis of their expertise in the clinical management of STDs.Members of the multidisciplinary workgroup included representatives from federal, state, and local health departments; public-and private-sector clinical providers; clinical and basic science researchers; and numerous professional organizations.All workgroup members disclosed potential conflicts of interest; several members of the workgroup acknowledged receiving financial support for clinical research from commercial companies.All potential conflicts of interest are listed at the end of the workgroup member section.
In 2012, CDC staff and workgroup members were charged with identifying key questions regarding treatment and clinical management that were not addressed in the 2010 STD Treatment Guidelines (1).To answer these questions and synthesize new information available since publication of the 2010 Guidelines, workgroup members collaborated with CDC staff to conduct a systematic literature review using an extensive MEDLINE database evidence-based approach (e.g., using published abstracts and peer-reviewed journal articles).These reviews also focused on four principal outcomes of STD therapy for each individual disease or infection: 1) treatment of infection based on microbiologic eradication; 2) alleviation of signs and symptoms; 3) prevention of sequelae; 4) prevention of transmission, including advantages such as cost-effectiveness and other advantages (e.g., single-dose formulations and directly observed therapy) and disadvantages (e.g., side effects) of specific regimens.The outcome of the literature review informed development of background materials, including tables of evidence from peer-reviewed publications summarizing the type of study (e.g., randomized controlled trial or case series), study population and setting,
# Sexually Transmitted Diseases Treatment Guidelines, 2015
treatments or other interventions, outcome measures assessed, reported findings, and weaknesses and biases in study design and analysis.
In April 2013, the workgroup's research was presented at an in-person meeting of the multidisciplinary workgroup members.Each key question was discussed, and pertinent publications were reviewed in terms of strengths, weaknesses, and relevance.The workgroup evaluated the quality of evidence, provided answers to the key questions, and rated the recommendations based on the United Services Preventive Services Task Forces (USPSTF) modified rating system (http:// www.uspreventiveservicestaskforce.org/uspstf/grades.htm).The discussion culminated in a proposal of recommendations to be adopted for consideration by CDC. (More detailed description of the key questions, search terms, and systematic search and review process is available at / std/tg2015/evidence.htm).Following the April meeting, the literature was searched periodically by CDC staff to identify subsequently published articles warranting consideration by the workgroup either through e-mail or conference calls.
CDC developed draft recommendations based on the workgroup's proposal.To ensure development of evidencebased recommendations, a second independent panel of public health and clinical experts reviewed the draft recommendations.The recommendations for STD screening during pregnancy, cervical cancer screening, and HPV vaccination were developed after CDC staff reviewed the published recommendations from other professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), USPSTF, American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and the Advisory Committee on Immunization Practices (ACIP) as part of the initial review process.The sections on hepatitis B virus (HBV) and hepatitis A virus (HAV) infections are based on previously published recommendations (2)(3)(4).
Throughout this report, the evidence used as the basis for specific recommendations is discussed briefly.More comprehensive, annotated discussions of such evidence will appear in background papers that will be available in a supplement issue of the journal Clinical Infectious Diseases after publication of these treatment guidelines.When more than one therapeutic regimen is recommended, the recommendations are listed alphabetically unless prioritized based on efficacy, tolerance, or costs.For infections with more than one recommended regimen, listed regimens have similar efficacy and similar rates of intolerance or toxicity unless otherwise specified.Recommended regimens should be used primarily; alternative regimens can be considered in instances of notable drug allergy or other medical contraindications to the recommended regimens.
# Clinical Prevention Guidance
The prevention and control of STDs are based on the following five major strategies (5):
- accurate risk assessment and education and counseling of persons at risk on ways to avoid STDs through changes in sexual behaviors and use of recommended prevention services; - pre-exposure vaccination of persons at risk for vaccinepreventable STDs; - identification of asymptomatically infected persons and persons with symptoms associated with STDs; - effective diagnosis, treatment, counseling, and follow up of infected persons; and - evaluation, treatment, and counseling of sex partners of persons who are infected with an STD.
# STD/HIV Risk Assessment
Primary prevention of STDs includes performing an assessment of behavioral risk (i.e., assessing the sexual behaviors that may place persons at risk for infection) as well as biologic risk (i.e., testing for risk markers for HIV acquisition or transmission).As part of the clinical encounter, health-care providers should routinely obtain sexual histories from their patients and address risk reduction as indicated in this report.Guidance for obtaining a sexual history is available on the CDC Division of STD Prevention resource page () and in the curriculum provided by CDC's STD/HIV Prevention Training Centers ().Effective interviewing and counseling skills characterized by respect, compassion, and a nonjudgmental attitude toward all patients are essential to obtaining a thorough sexual history and delivering effective prevention messages.Effective techniques for facilitating rapport with patients include the use of 1) open-ended questions (e.g., "Tell me about any new sex partners you've had since your last visit," and "What has your experience with using condoms been like?");2) understandable, nonjudgmental language ("Are your sex partners men, women, or both?""Have you ever had a sore or scab on your penis?");and 3) normalizing language ("Some of my patients have difficulty using a condom with every sex act.How is it for you?").The "Five P's" approach to obtaining a sexual history is one strategy for eliciting information concerning five key areas of interest (Box 1).For additional information about gaining cultural competency when working with certain populations (e.g., gay, bisexual, or other men who have sex with men , women who have sex with women , or transgender men and women) see MSM, WSW, and Transgender Men and Women.
In addition to obtaining a behavioral risk assessment, a comprehensive STD/HIV risk assessment should include STD screening, because STDs are biologic markers of risk, particularly for HIV acquisition and transmission among some MSM.STD screening is an essential and underutilized component of an STD/HIV risk assessment in most clinical settings.Persons seeking treatment or evaluation for a particular STD should be screened for HIV and other STDs as indicated by community prevalence and individual risk factors (see prevention section and sections on chlamydia, gonorrhea, and syphilis).Persons should be informed about all the STDs for which they are being tested and notified about tests for common STDs (e.g., genital herpes and human papillomavirus ) that are available but not being performed.Efforts should be made to ensure that all persons receive care regardless of individual circumstances (e.g., ability to pay, citizenship or immigration status, language spoken, or specific sex practices).
# STD/HIV Prevention Counseling
After obtaining a sexual history from their patients, all providers should encourage risk reduction by providing prevention counseling.Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the patient's culture, language, gender, sexual orientation, age, and developmental level.Prevention counseling for STD/HIV should be offered to all sexually active adolescents and to all adults who have received an STD diagnosis, have had an STD in the past year, or have multiple sexual partners.
USPSTF recommends high-intensity behavioral counseling for all sexually active adolescents and for adults at increased risk for STDs and HIV (6,7).Such interactive counseling, which can be resource intensive, is directed at a person's risk, the situations in which risk occurs, and the use of personalized goal-setting strategies.One such approach, known as clientcentered STD/HIV prevention counseling, involves tailoring a discussion of risk reduction to the individual situation.While one large study in STD clinics (Project RESPECT) demonstrated that this approach was associated with lower acquisition of curable STDs (e.g., trichomoniasis, chlamydia, gonorrhea, and syphilis) (8), another study conducted 10 years later in the same settings but different contexts (Project AWARE) did not replicate this result (9).Briefer providerdelivered prevention messages have been shown to be feasible and to decrease subsequent STDs in HIV primary-care settings (10).Other approaches use motivational interviewing to move clients toward achievable risk-reduction goals.Client-centered counseling and motivational interviewing can be used effectively by clinicians and staff trained in these approaches.CDC provides additional information on these and other effective behavioral interventions at .Training in client-centered counseling is available through the CDC STD/HIV National Network of Prevention Training Centers ().
# Partners
- "Do you have sex with men, women, or both?"
- "In the past 2 months, how many partners have you had sex with?" - "In the past 12 months, how many partners have you had sex with?" - "Is it possible that any of your sex partners in the past 12 months had sex with someone else while they were still in a sexual relationship with you?"2.Practices
- "To understand your risks for STDs, I need to understand the kind of sex you have had recently." - "Have you had vaginal sex, meaning 'penis in vagina sex'?"If yes, "Do you use condoms: never, sometimes, or always?" - "Have you had anal sex, meaning 'penis in rectum/ anus sex'?"If yes, "Do you use condoms: never, sometimes, or always?" - "Have you had oral sex, meaning 'mouth on penis/ vagina'?" -For condom answers: - If "never": "Why don't you use condoms?" -If "sometimes": "In what situations (or with whom) do you use condoms?"3.Prevention of pregnancy
- "What are you doing to prevent pregnancy?"4.Protection from STDs
- "What do you do to protect yourself from STDs and HIV?"5.Past history of STDs
- "Have you ever had an STD?"
- "Have any of your partners had an STD?"Additional questions to identify HIV and viral hepatitis risk include:
- "Have you or any of your partners ever injected drugs?" - "Have your or any of your partners exchanged money or drugs for sex?" - "Is there anything else about your sexual practices that I need to know about?"
In addition to one-on-one STD/HIV prevention counseling, videos and large-group presentations can provide explicit information concerning STDs and reducing disease transmission (e.g., how to use condoms correctly and the importance of routine screening).Group-based strategies have been effective in reducing the occurrence of STDs among persons at risk, including those attending STD clinics (11).
Because the incidence of some STDs, notably syphilis, is higher in persons with HIV infection, the use of clientcentered STD counseling for persons with HIV infection continues to be strongly encouraged by public health agencies and other health organizations.A recent federal guideline recommends that clinical and nonclinical providers assess an individual's behavioral and biologic risks for acquiring or transmitting STD and HIV, including having sex without condoms, recent STDs, and partners recently treated for STDs.This guideline also recommends that clinical and nonclinical providers offer or make referral for 1) regular screening for several STDs, 2) onsite STD treatment when indicated, and 3) risk-reduction interventions tailored to the individual's risks (12).Brief risk-reduction counseling delivered by medical providers during HIV primary-care visits coupled with routine STD screening has been shown to reduce STD incidence in persons with HIV infection (10).Several other specific methods have been designed for the HIV care setting () (13)(14)(15).
# Prevention Methods
# Pre-exposure Vaccination
Pre-exposure vaccination is one of the most effective methods for preventing transmission of human papillomavirus (HPV), HAV, and HBV.HPV vaccination is recommended routinely for boys and girls aged 11 or 12 years and can be administered beginning at 9 years of age.Either bivalent, quadrivalent, or 9-valent HPV vaccine is recommended for females, whereas quadrivalent vaccine or 9-valent vaccine is recommended for males (16) / vacc-specific/hpv.html.Vaccination is recommended through age 26 years for all females and through age 21 years for all males that have not received any or all of the vaccine doses.For persons with HIV infection and for MSM, vaccination is recommended through age 26 years (16).Further details regarding HPV vaccination are available in another section of this document (see HPV Vaccine), at / std/hpv, and at / vacc-specific/hpv.html.
Hepatitis B vaccination is recommended for all unvaccinated, uninfected persons being evaluated or treated for an STD (3,4).
In addition, hepatitis A and B vaccines are recommended for MSM, injection-drug users (IDUs), persons with chronic liver disease (CLD), and persons with HIV infection who have not yet been infected with one or both types of hepatitis virus (3,4,17).Details regarding hepatitis A and B vaccination are available at .
# Abstinence and Reduction of Number of Sex Partners
The most reliable way to avoid transmission of STDs is to abstain from oral, vaginal, and anal sex or to be in a long-term, mutually monogamous relationship with a partner known to be uninfected.For persons who are being treated for an STD other than HIV (or whose partners are undergoing treatment), counseling that encourages abstinence from sexual intercourse until completion of the entire course of medication is crucial.A recent trial conducted among women on the effectiveness of counseling messages demonstrated that women whose sexual partners have used condoms may benefit from a hierarchical message that includes condoms, whereas women without such experience might benefit more from an abstinence-only message (18).A more comprehensive discussion of abstinence and other sexual practices than can help persons reduce their risk for STDs is available in Contraceptive Technology, 20th Edition (19).
# Male Condoms
When used consistently and correctly, male latex condoms are highly effective in preventing the sexual transmission of HIV infection.In heterosexual HIV serodiscordant relationships (i.e., those involving one infected and one uninfected partner) in which condoms were consistently used, HIV-negative partners were 80% less likely to become infected with HIV compared with persons in similar relationships in which condoms were not used (20,21).Moreover, studies demonstrate that consistent condom use reduces the risk for other STDs, including chlamydia, gonorrhea, and trichomoniasis (22)(23)(24).By limiting lower genital tract infections, condoms also might reduce the risk of developing pelvic inflammatory disease (PID) in women (25).In addition, consistent and correct use of latex condoms reduces the risk for HPV infection and HPVassociated diseases, genital herpes, hepatitis B, syphilis, and chancroid when the infected area or site of potential exposure is covered (26)(27)(28)(29)(30)(31)(32).
Condoms are regulated as medical devices and are subject to random sampling and testing by the U.S. Food and Drug Administration (FDA).Each latex condom manufactured in the United States is tested electronically for holes before packaging.Rate of condom breakage during sexual intercourse and withdrawal is approximately two broken condoms per 100 condoms used in the United States.Rates of breakage and slippage may be slightly higher during anal intercourse (33,34).The failure of condoms to protect against STD or unintended pregnancy usually results from inconsistent or incorrect use rather than condom breakage (35).Users should check the expiration or manufacture date on the box or individual package.Latex condoms should not be used beyond their expiration date or more than 5 years after the manufacturing date.Male condoms made of materials other than latex are available in the United States and can be classified in two general categories: 1) polyurethane and other synthetic and 2) natural membrane.
Polyurethane male condoms provide comparable protection against STDs/HIV and pregnancy to that of latex condoms (19,24).These can be substituted for latex condoms by persons with latex allergy, are generally more resistant to deterioration, and are compatible with use of both oil-based and water-based lubricants. |
The effectiveness of other synthetic male condoms to prevent sexually transmitted infections has not been extensively studied, and FDA-labeling restricts their recommended use to latex-sensitive or allergic persons.Natural membrane condoms (frequently called "natural skin" condoms or "lambskin" condoms) are made from lamb cecum and can have pores up to 1,500 nm in diameter.Although these pores do not allow the passage of sperm, they are more than 10 times the diameter of HIV and more than 25 times that of HBV.Moreover, laboratory studies demonstrate that sexual transmission of viruses, including hepatitis B, herpes simplex, and HIV, can occur with natural membrane condoms (19).While natural membrane condoms are recommended for pregnancy prevention, they are not recommended for prevention of STDs and HIV.
Providers should advise that condoms must be used consistently and correctly to be effective in preventing STDs and HIV infection; providing instructions about the correct use of condoms can be useful.Communicating the following recommendations can help ensure that patients use male condoms correctly:
- Use a new condom with each sex act (i.e., oral, vaginal, and anal). -Carefully handle the condom to avoid damaging it with fingernails, teeth, or other sharp objects. -Put the condom on after the penis is erect and before any genital, oral, or anal contact with the partner. -Use only water-based lubricants (e.g., K-Y Jelly, Astroglide, AquaLube, and glycerin) with latex condoms.Oil-based lubricants (e.g., petroleum jelly, shortening, mineral oil, massage oils, body lotions, and cooking oil) can weaken latex and should not be used; however, oil-based lubricants can generally be used with synthetic condoms.
- Ensure adequate lubrication during vaginal and anal sex, which might require the use of exogenous water-based lubricants. -To prevent the condom from slipping off, hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect.Additional information about male condoms is available at .
# Female Condoms
Several condoms for females are globally available, including the FC2 Female Condom, Reddy condom, Cupid female condom, and Woman's condom (36).Use of female condoms can provide protection from acquisition and transmission of STDs, although data are limited (36).Although female condoms are more costly compared with male condoms, they offer the advantage of being a female-controlled STD/HIV prevention method, and the newer versions may be acceptable to both men and women.Although the female condom also has been used during receptive anal intercourse, efficacy associated with this practice remains unknown (37).Additional information about the female condom is available at http:// www.ashasexualhealth.org/sexual-health/all-about-condoms/ female-condoms.
# Cervical Diaphragms
In observational studies, diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis (38).However, a trial examining the effect of a diaphragm plus lubricant on HIV acquisition among women in Africa showed no additional protective effect when compared with the use of male condoms alone.Likewise, no difference by study arm in the rate of acquisition of chlamydia, gonorrhea, or herpes occurred (39,40).Diaphragms should not be relied on as the sole source of protection against HIV or other STDs.
# Topical Microbicides and Spermicides
Nonspecific topical microbicides are ineffective for preventing HIV (41)(42)(43)(44)(45).Spermicides containing N-9 might disrupt genital or rectal epithelium and have been associated with an increased risk for HIV infection.Condoms with N-9 are no more effective than condoms without N-9; therefore, N-9 alone or in a condom is not recommended for STD or HIV prevention (41).N-9 use has also been associated with an increased risk for bacterial urinary tract infections in women (46,47).No proven topical antiretroviral agents exist for the prevention of HIV, though trials are underway to evaluate several candidates for vaginal and rectal microbicides using tenofovir and other antiretroviral drugs.
# Nonbarrier Contraception, Surgical Sterilization, and Hysterectomy
Contraceptive methods that are not mechanical barriers offer no protection against HIV or other STDs.Sexually active women who use hormonal contraception (i.e., oral contraceptives, patch, ring, implants, injectables, or intrauterine hormonal methods), have nonhormonal intrauterine devices (IUDs), have been surgically sterilized, or have had hysterectomies should be counseled to use condoms to reduce the risk for STDs, including HIV infection.Women who take oral contraceptives and are prescribed certain antimicrobials should be counseled about potential interactions (19).
Whether hormonal contraception raises a woman's risk for acquiring HIV or another STD is unclear.A systematic review of epidemiologic evidence found that most studies showed no association between use of oral contraceptives and HIV acquisition among women.Studies examining the association between progestin-only injectables and HIV acquisition have had mixed results; some studies show a higher risk of acquisition among women using depo-medroxyprogesterone acetate (DMPA), while other studies do not (48).The World Health Organization (WHO) and CDC reviewed the evidence on hormonal contraception and HIV acquisition and concluded that data are insufficient to recommend that women modify their hormonal contraceptive practices, but that women using progestin-only injectables should be strongly advised to also use condoms as an HIV prevention strategy (49,50).
# Male Circumcision
Male circumcision reduces the risk for HIV and some STDs in heterosexual men.Three randomized, controlled trials performed in regions of sub-Saharan Africa where generalized HIV epidemics involving predominantly heterosexual transmission were occurring demonstrated that male circumcision reduced the risk for HIV acquisition among men by 50%-60% (51)(52)(53).In these trials, circumcision was also protective against other STDs, including high-risk genital HPV infection and genital herpes (54)(55)(56).Follow up studies have demonstrated sustained benefit of circumcision for HIV prevention (57) and that the effect is not mediated solely through a reduction in herpes simplex virus type 2 (HSV-2) infection or genital ulcer disease (58).WHO and the Joint United Nations Programme on HIV/ AIDS (UNAIDS) have recommended that male circumcision efforts be scaled up as an effective intervention for the prevention of heterosexually acquired HIV infection (59).These organizations also recommend that countries with hyperendemic and generalized HIV epidemics and low prevalence of male circumcision expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support.In the United States, the American Academy of Pediatrics (AAP) recommends that newborn male circumcision be available to families that desire it, as the benefits of the procedure, including prevention of penile cancers, urinary tract infections, genital ulcer disease, and HIV outweigh the risks (60).ACOG has also endorsed the AAP's policy statement (60).In light of these benefits, the American Urological Association states that male circumcision should be considered an option for risk reduction, among other strategies (61).
No definitive data exist to determine whether male circumcision reduces HIV acquisition in MSM, although one randomized trial is ongoing in China (62).A review found a modest protective effect among men who were the insertive partner for anal intercourse, but the evidence was rated as poor.Further higher quality studies are needed to confirm any potential benefit of male circumcision for this population (62).
# Emergency Contraception
Unprotected intercourse exposes women to risks for STDs and unplanned pregnancy.Providers managing such women should offer counseling about the option of emergency contraception (EC) if pregnancy is not desired.The options for EC in the United States include the copper IUD and emergency contraceptive pills (ECPs) (63).ECPs are available in the following formulations: ulipristal acetate in a single dose (30 mg), levonorgestrel in a single dose (1.5 mg) or as a split dose (0.75 mg each taken 12 hours apart), or combined estrogen and progestin (Yuzpe regimen).Some ECPs can be obtained over the counter; ECPs can also be provided through advance prescription or supply from providers (64,65).Emergency insertion of a copper IUD up to 5 days after sex can reduce pregnancy risk by more than 99% (66).ECPs are most efficacious when initiated as soon as possible after unprotected sex but have some efficacy up to 5 days later.ECPs are ineffective (but not harmful) if the woman is already pregnant (67).A 2012 Cochrane review summarized the efficacy, safety, and convenience of various methods of emergency contraception (67).More information about EC is available in the 20th edition of Contraceptive Technology (19) or .
# Postexposure Prophylaxis for HIV and STD
Guidelines for the use of postexposure prophylaxis (PEP) aimed at preventing HIV infection and other STDs as a result of sexual exposure are discussed in another section of this report (see Sexual Assault and STDs).Genital hygiene methods (e.g., vaginal washing and douching) after sexual exposure are ineffective in protecting against HIV and STDs and might increase the risk for bacterial vaginosis (BV), some STDs, and HIV infection (68).
# Antiretroviral Treatment of Persons with HIV Infection to Prevent HIV Infection in Partners
The randomized controlled trial HPTN 052 demonstrated that in HIV serodiscordant, heterosexual couples, HIV antiretroviral therapy in the infected partner decreases the risk for transmission to the uninfected partner by 96% (69).Therefore, antiretroviral therapy not only is beneficial to the health of persons with HIV infection, but also reduces the risk for continued transmission.For these reasons, treatment should be offered to all persons with HIV infection.Detailed guidance for prescribing antiretroviral regimens can be found in the U.S. Department of Health and Human Services' HIV treatment guidelines at (70).
# HSV Treatment of Persons with HIV and HSV Infections to Prevent HIV Infection in Uninfected Partners
Providing HSV treatment to persons co-infected with HIV and HSV has not been demonstrated to be beneficial in reducing HIV acquisition in uninfected partners.A large randomized, controlled trial evaluated 3,408 serodiscordant heterosexual couples enrolled at 14 Africa sites in which the partner with HIV infection was also seropositive for HSV-2.The co-infected partner was randomized to receive either placebo or acyclovir 400-mg twice per day, and the primary outcome was HIV transmission to the uninfected partner.Use of acyclovir had no effect on HIV transmission (71).These findings are consistent with those from a previous trial that found no benefit of acyclovir in preventing HIV-1 acquisition in persons who were seropositive for HSV-2 (72).
# Preexposure Prophylaxis for HIV
Certain large, randomized, placebo-controlled trials examining daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) have demonstrated safety (73) and a substantial reduction in the rate of HIV acquisition for MSM (74), HIV-discordant heterosexual couples (75), and heterosexual men and women recruited as individuals (76).In addition, one clinical trial involving IDUs (77) and one involving heterosexual HIV-discordant couples (75) demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone when combined with repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of STDs.High adherence to oral PrEP with TDF alone or in a fixed-dose combination with FTC was strongly associated with protection from infection.
Data suggest that when administered orally, levels of TDF are lower in vaginal tissue than rectal tissue, potentially explaining why high levels of adherence were needed to yield benefits among women in these trials (78).Despite initial concerns about PrEP fostering antiretroviral resistance among persons who become infected, standard tests employed in these studies detected emergence of resistance only in persons inadvertently started on PrEP during acute HIV infection, not in persons who were initially uninfected but later became infected while taking PrEP medication (79).
The U.S. Public Health Service (USPHS) has issued recommendations on the basis of these trial results and the FDA approval of an indication for the use of TDF/FTC for PrEP.USPHS recommends that clinicians evaluate HIV-negative men and women who are sexually active or injecting illicit drugs and consider PrEP as a prevention option for persons whose sexual or injection behaviors and epidemiologic context place them at substantial risk for acquiring HIV infection.Comprehensive guidance for the use of daily PrEP to reduce the risk for acquiring HIV infection can be found at http:// www.cdc.gov/hiv/prevention/research/prep/index.html.
# HIV Seroadaptation Strategies
Seroadaptive strategies for HIV prevention have largely originated within communities of MSM.They are predicated on knowledge of self and partner HIV-infection status.One specific seroadaptive practice is serosorting, which includes limiting anal sex without a condom to partners with the same HIV status as their own, or choosing to selectively use condoms only with HIV serodiscordant partners.Another practice among serodiscordant couples is seropositioning, in which the person with HIV infection is the receptive partner for anal intercourse.Observational studies have consistently found that serosorting confers greater risk of HIV infection than consistent condom use, but is lower risk compared with anal intercourse without a condom and without serosorting (80)(81)(82).Serosorting practices have been associated with increased risk of STDs including chlamydia and gonorrhea (83,84).
Serosorting is not recommended for the following reasons: 1) too many MSM who have HIV do not know they are infected because they have not been tested for HIV recently, 2) men's assumptions about the HIV status of their partners might be wrong, and 3) some men with HIV infection might not disclose or may misrepresent their HIV status.All of these factors increase the risk that serosorting could lead to HIV infection.Additional information is available at .cdc.gov/msmhealth/serosorting.htm or / hiv/pub/guidelines/msm_guidelines2011/en.
# Retesting After Treatment to Detect Repeat Infections
Retesting several months after diagnosis of chlamydia, gonorrhea, or trichomoniasis can detect repeat infection and potentially can be used to enhance population-based prevention (85,86).Any person who tests positive for chlamydia or gonorrhea, along with women who test positive for trichomonas, should be rescreened 3 months after treatment.Any person who receives a syphilis diagnosis should undergo follow-up serologic syphilis testing per current recommendations (see Syphilis).Further details on retesting can be found in the specific sections on chlamydia, gonorrhea, syphilis, and trichomonas within this report.
# Partner Services
The term "partner services" refers to a continuum of clinical evaluation, counseling, diagnostic testing, and treatment designed to increase the number of infected persons brought to treatment and to disrupt transmission networks.This continuum includes efforts undertaken by health departments, medical providers, and patients themselves.The term "public health partner services" refers to efforts by public health departments to identify the sex-and needle-sharing partners of infected persons to assure their medical evaluation and treatment.
Clinicians can provide partner services by counseling infected persons and providing them with written information and medication to give to their partners (if recommended and allowable by state law), directly evaluating and treating sex partners, and cooperating with state and local health departments.Clinicians' efforts to ensure the treatment of a patient's sex partners can reduce the risk for reinfection and potentially diminish transmission of STDs (87).Therefore, clinicians should encourage all persons with STDs to notify their sex partners and urge them to seek medical evaluation and treatment.Timespent counseling patients on the importance of notifying partners is associated with improved notification outcomes (88).When possible, clinicians should advise persons to bring their primary sex partner along with them when returning for treatment and should concurrently treat both persons.Although this approach can be effective for a main partner (89,90), it might not be feasible approach for additional sex partners.Some evidence suggests that providing patients with written information to share with sex partners can increase rates of partner treatment (87).
The types and comprehensiveness of public health partner services and the specific STDs for which they are offered vary by public health agency and the geographic burden of STDs.In most areas of the United States, health departments routinely attempt to provide partner services to all persons with early syphilis (primary, secondary, and early latent syphilis) and persons with a new diagnosis of HIV infection.It is also recommended that health departments provide partner services for persons who might have cephalosporin-resistant gonorrhea.In contrast, relatively few U.S. health departments routinely provide partner services to persons with gonorrhea, chlamydial infection, trichomonas, or other STDs (91).Clinicians should familiarize themselves with public health practices in their area, but in most instances, providers should understand that responsibility for ensuring the treatment of partners of persons with STDs other than syphilis and HIV rests with the diagnosing provider and the patient.
Many health departments now use the internet to notify the sex partners of persons with STDs (92), especially MSM and in cases where no other identifying information is available ().Clinical providers are unlikely to participate directly in internet partner notification.Internet sites allowing patients to send anonymous e-mail or text messages advising partners of their exposure to an STD are operational in some areas; anonymous notification via the internet is considered better than no notification at all and might be an option in some instances.However, because the extent to which these sites affect partner notification and treatment is uncertain, patients should be encouraged either to notify their partners in person or by telephone, personal e-mail, or text message; alternatively, patients can authorize a medical provider or public health professional to do so.
# Expedited Partner Therapy
Expedited Partner Therapy (EPT), also termed patientdelivered partner therapy (PDPT), is the clinical practice of treating the sex partners of persons who receive chlamydia or gonorrhea diagnoses by providing medications or prescriptions to the patient.Patients then provide partners with these therapies without the health-care provider having examined the partner (see ).Unless prohibited by law or other regulations, medical providers should routinely offer EPT to heterosexual patients with chlamydia or gonorrhea infection when the provider cannot confidently ensure that all of a patient's sex partners from the prior 60 days will be treated.If the patient has not had sex in the 60 days before diagnosis, providers should attempt to treat a patient's most recent sex partner.EPT is legal in most states.However, providers should visit to obtain updated information for their state.Providing patients with appropriately packaged medication is the preferred approach to PDPT because data on the efficacy of PDPT using prescriptions is limited and many persons do not fill the prescriptions given to them by a sex partner. |
Medication or prescriptions provided for PDPT should be accompanied by treatment instructions, appropriate warnings about taking medications (if the partner is pregnant or has an allergy to the medication), general health counseling, and a statement advising that partners seek medical evaluation for any symptoms of STD, particularly PID.
The evidence supporting PDPT is based on three U.S. clinical trials involving heterosexual men and women with chlamydia or gonorrhea (93)(94)(95).All three trials reported that more partners were treated when patients were offered PDPT: two reported statistically significant declines in the rate of reinfection and one observed a lower risk of persistent or recurrent infection that was statistically nonsignificant.A fourth trial in the United Kingdom did not demonstrate a difference in the risk of reinfection or in the numbers of partners treated between persons offered PDPT and those advised to notify their sex partners (96).
U.S. trials and a meta-analysis of PDPT revealed that the magnitude of reduction in reinfection of index case-patients compared with patient referral differed according to the STD and the sex of the index case-patient (87,(93)(94)(95).However, across trials, reductions in chlamydia prevalence at follow-up were approximately 20%; reductions in gonorrhea at follow-up were approximately 50%.Existing data suggest that PDPT also might have a role in partner management for trichomoniasis; however, no single partner management intervention has been shown to be more effective than any other in reducing trichomoniasis reinfection rates (97,98).No data support use of PDPT in the routine management of patients with syphilis.Data on the use of PDPT for gonorrhea or chlamydial infection among MSM are limited (99,100).Published studies suggest that >5% of MSM without a previous HIV diagnosis have a new diagnosis of HIV infection when evaluated as partners of patients with gonorrhea or chlamydial infection (101,102).As a result, PDPT should not be used routinely in MSM.All persons who receive bacterial STD diagnoses and their sex partners, particularly MSM, should be tested for HIV infection.
# Reporting and Confidentiality
The accurate and timely reporting of STDs is integral to public health efforts to assess morbidity trends, allocate limited resources, and assist local health authorities in partner notification and treatment.STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with state and local statutory requirements.Syphilis (including congenital syphilis), gonorrhea, chlamydia, chancroid, HIV infection, and AIDS are reportable diseases in every state.Because the requirements for reporting other STDs differ by state, clinicians should be familiar with the reporting requirements applicable within their jurisdictions.
Reporting can be provider-or laboratory-based or both.Clinicians who are unsure of state and local reporting requirements should seek advice from state or local health department STD programs.STDs and HIV reports are kept strictly confidential.In most jurisdictions, such reports are protected by statute or regulation.Before conducting a follow-up of a positive STD-test result, public health professionals should consult the patient's health-care provider if possible to verify the diagnosis and determine the treatments being received.
# Special Populations Pregnant Women
Intrauterine or perinatally transmitted STDs can have severely debilitating effects on pregnant women, their partners, and their fetuses.All pregnant women and their sex partners should be asked about STDs, counseled about the possibility of perinatal infections, and provided access to screening and treatment, if needed.
Recommendations to screen pregnant women for STDs are based on disease severity and sequelae, prevalence in the population, costs, medico-legal considerations (e.g., state laws), and other factors.The screening recommendations in this report are generally broader (i.e., more pregnant women will be screened for more STDs than would by following other screening recommendations) and are consistent with other CDC guidelines.
# Recommended Screening Tests
- All pregnant women in the United States should be screened for HIV infection at the first prenatal visit, even if they have been previously tested (103,104).Screening should be conducted after the woman is notified of the need to be screened for HIV as part of the routine panel of prenatal tests, unless she declines (i.e., opt-out screening).For women who decline HIV testing, providers should address their objections, and when appropriate, continue to encourage testing.Women who decline testing because they have had a previous negative HIV test should be informed of the importance of retesting during each pregnancy.Testing pregnant women and treating those who are infected are vital not only to maintain the health of the woman, but to reduce perinatal transmission of HIV through available antiretroviral and obstetrical interventions.Retesting in the third trimester (preferably before 36 weeks' gestation) is recommended for women at high risk for acquiring HIV infection (e.g., women who use illicit drugs, have STDs during pregnancy, have multiple sex partners during pregnancy, live in areas with high HIV prevalence, or have partners with HIV infection).Rapid HIV screening should be performed on any woman in labor who has not been screened for HIV during pregnancy unless she declines.If a rapid HIV test result is positive in these women, antiretroviral prophylaxis should be administered without waiting for the results of the confirmatory test (105). -A serologic test for syphilis should be performed for all pregnant women at the first prenatal visit (106).When access to prenatal care is not optimal, rapid plasma reagin (RPR) card test screening (and treatment, if that test is reactive) should be performed at the time that a pregnancy is confirmed.Women who are at high risk for syphilis or live in areas of high syphilis morbidity should be screened again early in the third trimester (at approximately 28 weeks' gestation) and at delivery.Some states require all women to be screened at delivery.Neonates should not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least one time during pregnancy and preferably again at delivery if at risk.Any woman who delivers a stillborn infant should be tested for syphilis. -All pregnant women should be routinely tested for hepatitis B surface antigen (HBsAg) at the first prenatal visit even if they have been previously vaccinated or tested (107).Women who were not screened prenatally, those who engage in behaviors that put them at high risk for infection (e.g., having had more than one sex partner in the previous 6 months, evaluation or treatment for an STD, recent or current injection-drug use, and an HBsAgpositive sex partner) and those with clinical hepatitis should be retested at the time of admission to the hospital for delivery.Pregnant women at risk for HBV infection also should be vaccinated. (110).
# Other Tests
- Evidence does not support routine screening for BV in asymptomatic pregnant women at high risk for preterm delivery (111). (111).
# Adolescents
In the United States, prevalence rates of many sexually acquired infections are highest among adolescents and young adults (117,118).For example, the reported rates of chlamydia and gonorrhea are highest among females during their adolescent and young adult years, and many persons acquire HPV infection at this time.
Persons who initiate sex early in adolescence are at higher risk for STDs, along with adolescents residing in detention facilities, those who use injection drugs, adolescents attending STD clinics, and young men who have sex with men (YMSM).Factors contributing to this increased risk during adolescence include having multiple sexual partners concurrently, having sequential sexual partnerships of limited duration, failing to use barrier protection consistently and correctly, having increased biologic susceptibility to infection, and facing multiple obstacles to accessing health care (118).
All 50 states and the District of Columbia explicitly allow minors to consent for their own health services for STDs.No state requires parental consent for STD care, although some states restrict a minor's ability to provide consent on the basis of age or type of service (i.e., prevention, diagnosis, or treatment only).No state requires that providers notify parents that an adolescent minor has received STD services, except in limited or unusual circumstances.However, many states authorize parental notification of a minor's receipt of STD services, even where the minor can legally provide his or her own consent to the service (/ spib_OMCL.pdf; ).Protecting confidentiality for such care, particularly for adolescents enrolled in private health insurance plans, presents multiple problems.After a claim has been reported, many states mandate that health plans provide a written statement to the beneficiary indicating the service performed, the charges covered, what the insurer allows, and the amount for which the patient is responsible (i.e., explanation of benefit ) (119).In addition, federal laws obligate notices to beneficiaries when claims are denied, including alerting beneficiaries who need to pay for care until the allowable deductible is reached.For STD detection-and treatment-related care, an EOB or medical bill that is received by a parent might disclose services provided and list STD laboratory tests performed or treatment given.
Despite the high rates of infections documented in the adolescent population, providers frequently fail to inquire about sexual behaviors, assess STD risks, provide risk-reduction counseling, and ultimately, screen for asymptomatic infections during clinical encounters.Discussions concerning sexual behavior should be appropriate for the patient's developmental level and should be aimed at identifying risk behaviors (e.g., multiple partners; unprotected oral, anal, or vaginal sex; and drug-use behaviors).Careful, nonjudgmental, and thorough counseling is particularly vital for adolescents who might not feel comfortable acknowledging their engagement in behaviors that place them at high risk for STDs.
# Screening Recommendations
Routine laboratory screening for common STDs is indicated for sexually active adolescents.The following screening recommendations summarize published federal agency and medical professional organizations' clinical guidelines for sexually active adolescents.
- (124)(125)(126).This recommendation is based on the low incidence of cervical cancer and limited utility of screening for cervical cancer in adolescents (127).
# Primary Prevention Recommendations
Primary prevention and anticipatory guidance to recognize symptoms and behaviors associated with STDs are strategies that can be incorporated into any or all types of healthcare visits for adolescents and young adults.The following recommendations for primary prevention of STDs (i.e., vaccination and counseling) are based on published federal agency and medical professional organizations' clinical guidelines for sexually active adolescents and young adults.
- The HPV vaccine, bivalent, quadrivalent, or 9-valent, is recommended routinely for females aged 11 and 12 years and can be administered beginning at 9 years of age ( 16
# Children
Management of children who have STDs requires close cooperation between clinicians, laboratorians, and childprotection authorities.Official investigations, when indicated, should be initiated promptly.Certain diseases (e.g., gonorrhea, syphilis, and chlamydia), if acquired after the neonatal period, strongly suggest sexual contact.For other diseases (e.g., HPV infections and vaginitis), the association with sexual contact is not as clear (see Sexual Assault and STDs).
# Persons in Correctional Facilities
Multiple studies have demonstrated that persons entering correctional facilities have high rates of STDs (including HIV) and viral hepatitis (/ corrections.htm), especially those aged ≤35 years (118).Incarcerated persons are more likely to have low socioeconomic status, live in urban areas, and be ethnic and racial minorities.Risk behaviors for contracting STDs (e.g., having unprotected sex; having multiple sexual partners; using drugs and alcohol; and engaging in commercial, survival, or coerced sex) are common among incarcerated populations.Before incarceration, many have had limited access to medical care.
Although no comprehensive national guidelines regarding STD care and management have been developed for correctional populations, growing evidence demonstrates the utility of expanded STD screening and treatment services in correctional settings.For example, in jurisdictions with comprehensive, targeted jail screening, more chlamydial infections among females (and males if screened) are detected and subsequently treated in the correctional setting than any other single reporting source (118,129) and might represent the majority of reported cases in certain jurisdictions (130).
Both men and women ≤35 years of age in juvenile and adult detention facilities have been reported to have higher rates of chlamydia (131) and gonorrhea (118) than their nonincarcerated counterparts in the community, and across many studies, rates have been consistently higher among women than men.Syphilis seroprevalence rates, which can indicate previous or current infection, are considerably higher among adult men and women than in adolescents, consistent with the overall national syphilis trends (132).Detection and treatment of early syphilis in correctional facilities might impact rates of transmission (133).
In short-term facilities, including jails and juvenile detention facilities that commonly house entrants for <1 year, up to half of entrants are released back in the community within 48 hours.As a result, treatment completion rates for those screened for STDs and who receive STD diagnoses in short-term facilities might not be optimal.However, because of the mobility of incarcerated populations in and out of the community, the impact of screening in correctional facilities on the prevalence of infections among detainees and subsequent transmission in the community after release might be considerable (134).Moreover, treatment completion rates of ≥95% can be achieved by offering screening at or shortly after intake, facilitating earlier receipt of test results; follow-up of untreated persons can be conducted through public health outreach (130).
Universal screening for chlamydia and gonorrhea in women ≤35 years entering juvenile and adult correctional facilities has been a long-standing recommendation.However, no such recommendation existed for men until 2006, when CDC convened a consultation on male chlamydia screening (121) that resulted in recommendations to screen men <30 years for chlamydia at intake into jails.
Whereas several studies have shown a high prevalence of trichomonas among incarcerated persons, none have demonstrated the impact of trichomonas screening in correctional facilities (135)(136)(137).Women who report vaginal discharge should be evaluated and treated appropriately.
# Chlamydia and Gonorrhea Screening
Women ≤35 and men <30 years in correctional facilities should be screened for chlamydia and gonorrhea.Chlamydia and gonorrhea screening should be conducted at intake.
# Syphilis Screening
Universal screening should be conducted on the basis of the local area and institutional prevalence of early (primary, secondary, and early latent) infectious syphilis.Correctional facilities should stay apprised of syphilis prevalence as it changes over time.
# Men Who Have Sex with Men
The term "men who have sex with men" (MSM) describes a heterogeneous group of men who have varied behaviors, identities, and health-care needs (138).Some MSM are at high risk for HIV infection and other viral and bacterial STDs - STI is the term used by USPSTF to describe the syndromes caused by various pathogens that can be acquired and transmitted through sexual activity.
because MSM may practice anal sex, and the rectal mucosa is uniquely susceptible to certain STD pathogens.In addition, multiple sex partners, substance use, and sexual network dynamics of MSM increase risk for HIV and STDs in this population.The frequency of unsafe sexual practices and the reported rates of bacterial STDs and incident HIV infection declined substantially in MSM from the 1980s through the mid-1990s.However, since that time, increased rates of early syphilis (primary, secondary, or early latent), gonorrhea, and chlamydial infection and higher rates of sexual risk behaviors have been documented among MSM in the United States and virtually all industrialized countries.Approximately two thirds of the cases of primary and secondary syphilis diagnoses in the United States are in MSM, particularly those in ethnic minority groups (118,139,140).Increased syphilis screening in MSM demonstrated a doubling of early syphilis detection; however, 71% of the syphilis diagnoses occurred when the patient sought care for symptoms (141).Acute HIV infection has been associated with a recent or concurrent STD, including syphilis, among men at a municipal STD clinic (142) and in the multisite iPrex study (143), and several studies have demonstrated that early syphilis is associated with HIV infection among MSM (144,145).Factors associated with increases in syphilis among MSM have included substance abuse (e.g., methamphetamine), having multiple anonymous partners, and seeking sex partners through the internet (146,147).One study found that 5.9% of MSM had repeat primary or secondary syphilis infection within 2 years of an initial infection; factors associated with repeat syphilis infection were HIV infection, black race, and having ≥10 recent sexual partners (148).Because of this risk for repeat infection, these data suggest that prevention efforts should include follow up serologic testing.
Gonococcal infection in MSM has been associated with similar risk factors, including having multiple anonymous partners and abuse of substances, particularly crystal methamphetamine (149).Rectal gonococcal rates are increasing among MSM with HIV infection, underscoring the importance of obtaining an accurate, current sexual history and asking about correlates of increased risk (e.g., anonymous sex and substance use) (150).Insertive oral sex has been associated with urethral gonorrhea acquisition (151,152); the prevalence of pharyngeal gonorrhea and pharyngeal chlamydia has been demonstrated to be 7.3% and 2.3%, respectively (153).In a multicity study, rectal gonorrhea and rectal chlamydia prevalence rates among MSM were 5.4% and 8.9%, respectively (154).Rectal gonorrhea and chlamydia infections, especially those that are recurrent, have been associated with increased risk for HIV seroconversion among MSM (155,156).MSM with new HIV infection diagnoses are more likely than HIV-uninfected MSM to receive a diagnosis of asymptomatic gonorrhea (25.9% versus 10.9%, p<0.001) and chlamydia (18.5% vs 7.8%, p<0.001) (157).Thus, rectal gonorrhea and chlamydia screening in MSM might be a cost-effective intervention in certain urban settings (158).
MSM remain at disproportionate risk for HIV acquisition and transmission in the United States, particularly those who are black or Hispanic.Factors that increase the risk for HIV infection in MSM include either receptive or insertive anal sex without a condom, having another STD, having sex with anonymous partners without a condom, and using methamphetamines or drugs that enhance sexual performance (159).
Substantial numbers of MSM remain unaware of their serostatus (up to 44% in one recent survey of young men in minority populations) (160).Unfortunately, many men are not asked about STD-related risks, including the gender of sex partners. |
Even if gender of sex partners is ascertained, many MSM, including those with HIV infection, are neither asked about risky sexual behaviors nor provided with routine STD testing (especially at anatomic sites of exposure for gonorrhea or chlamydia), often because of the discomfort associated with these discussions (161)(162)(163).Clinicians should routinely ask sexually active MSM about symptoms consistent with common STDs, including urethral discharge, dysuria, genital and perianal ulcers, regional lymphadenopathy, skin rash, and anorectal symptoms consistent with proctitis (e.g., discharge and pain on defecation or during anal intercourse) and then perform appropriate diagnostic testing.In addition, providers should offer evidence-based counseling on safer sex using interventions that have been demonstrated to decrease STD incidence in clinical-care settings (10).
Clinicians should be familiar with local resources available to assist MSM with syphilis and HIV partner services as well as HIV linkage and retention in care.In addition, interventions promoting behavior change also might be appropriate.In recent years, medical educational materials have been developed in print (164) and through electronic media () to increase primary-care provider knowledge and cultural competency regarding the diagnosis and management of STDs and other clinical conditions in the lesbian, gay, bisexual, and transgender populations.Electronic media is also an important tool for disseminating and collecting information to and from MSM.Because many MSM meet partners online and seek health information from websites, increased use of the internet for STD prevention might be warranted.MSM are amenable to receiving HIV and STD risk-reduction messages online (165) and willing to respond to requests for partner identification from public health authorities through the internet (166).
The following screening tests should be performed at least annually for sexually active MSM, including those with HIV infection.
- HIV serology, if HIV status is unknown or negative and the patient himself or his sex partner(s) has had more than one sex partner since most recent HIV test. -Syphilis serology to establish whether persons with reactive tests have untreated syphilis, have partially treated syphilis, are manifesting a slow serologic response to appropriate prior therapy, or are serofast. -A test for urethral infection † with N. gonorrhoeae and C. trachomatis in men who have had insertive intercourse § during the preceding year (testing of the urine using NAAT † is the preferred approach). -A test for rectal infection † with N. gonorrhoeae and C. trachomatis in men who have had receptive anal intercourse § during the preceding year (NAAT of a rectal specimen is the preferred approach). -A test for pharyngeal infection † with N. gonorrhoeae in men who have had receptive oral intercourse § during the preceding year (NAAT of a pharyngeal specimen is the preferred approach).Testing for C. trachomatis pharyngeal infection is not recommended.MSM with HIV infection are also at risk for STDs.Data from a study of 557 adults with HIV infection receiving primary care in four U.S. cities demonstrate that 13% had STD at study enrollment, and 7% had incident STD at 6 months; among MSM with HIV infection, STD incidence was 20% (10).Excluding trichomoniasis, 94% of incident STDs were diagnosed in MSM.All MSM with HIV infection entering care should be screened for gonorrhea and chlamydia at appropriate anatomic sites of exposure, as well as for syphilis (17).The frequency of follow-up testing might be dictated by subsequent behavior; screening is recommended annually, at a minimum, to include syphilis serologic testing and chlamydia and gonorrhea screening at exposed anatomic sites (138).STD screening rates in HIV clinics have been suboptimal.In one study involving eight U.S. cities, although syphilis testing was provided to most MSM with HIV infection, <10% were screened for extra-genitourinary gonorrhea or chlamydia, and <20% provided the urine or urethral specimens needed for testing (162).More frequent STD screening (i.e., for syphilis, gonorrhea, and chlamydia) at 3-6-month intervals is indicated for MSM, including those with HIV infection if risk behaviors persist or if they or their sexual partners have multiple partners.Evaluation for HSV-2 infection with type-specific serologic tests also can be considered if infection status is unknown in persons with previously undiagnosed genital tract infection.
HPV infection and HPV-associated conditions (e.g., anogenital warts and anal squamous intraepithelial lesions) are highly prevalent among MSM.The quadrivalent vaccine is recommended routinely for MSM through age 26 years (16,167,168); the efficacy of this vaccine in preventing HPV associated diseases in men aged >26 years is unknown.
Data are insufficient to recommend routine anal-cancer screening with anal cytology in persons with HIV infection or HIV-negative MSM.More evidence is needed concerning the natural history of anal intraepithelial neoplasia, the best screening methods and target populations, safety of and response to treatments, and other programmatic considerations before screening can be routinely recommended.However, some clinical centers perform anal cytology to screen for anal cancer among high-risk populations (e.g., persons with HIV infection and MSM), followed by high-resolution anoscopy for those with abnormal cytologic results (e.g., ASC-US).
All MSM should be tested for HBsAg to detect chronic HBV infection.Prompt identification of chronic infection with HBV is essential to ensure necessary care and services to prevent transmission to others (169).Screening among past or current drug users should include HCV and HBV testing.Vaccination against hepatitis A and B is recommended for all MSM in whom previous infection or vaccination cannot be documented (2,3).Preimmunization serologic testing might be considered to reduce the cost of vaccinating MSM who are already immune to these infections, but this testing should not delay vaccination.Vaccinating persons who are immune to HAV or HBV infection because of previous infection or vaccination does not increase the risk for vaccine-related adverse events (see Hepatitis A and Hepatitis B).
Sexual transmission of HCV can occur, especially among MSM with HIV infection (see Emerging Issues, Hepatitis C).Serologic screening for HCV is recommended at initial evaluation of persons with newly diagnosed HIV infection.Because of accumulating evidence of acute HCV infection acquisition among persons with HIV infection (especially MSM with HIV infection ) and because regular screening for HCV infection is cost effective (176,177), MSM with HIV infection should be regularly screened for HCV.Screening should be performed at least yearly and more frequently depending on specific circumstances (e.g., local HCV prevalence and incidence, high-risk sexual behavior, and concomitant ulcerative STDs or STD-related proctitis).Screening should be performed using HCV antibody assays † Regardless of condom use during exposure. §Commercially available NAATs have not been cleared by FDA for these indications, but they can be used by laboratories that have met all regulatory requirements for an off-label procedure.Source: CDC.Recommendations for the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae -2014.MMWR Recomm Rep 2014;63(No RR-2):1-19.followed by HCV RNA testing for those with a positive antibody result (178).
# Women Who Have Sex with Women
Women who have sex with women (WSW) are a diverse group with variations in sexual identity, sexual behaviors, sexual practices, and risk behaviors.Recent studies indicate that some WSW, particularly adolescents and young women as well as women with both male and female partners, might be at increased risk for STDs and HIV based on reported risk behaviors (179)(180)(181)(182)(183).Certain studies have highlighted the wide diversity of sexual practices and examined use of protective/risk reduction strategies among populations of WSW (184)(185)(186).Use of barrier protection with female partners (gloves during digital-genital sex, condoms with sex toys, and latex or plastic barriers ) was infrequent in all studies.Despite this, few comprehensive and reliable resources of sexual health information for WSW are available (187).
Few data are available on the risk for STDs conferred by sex between women, but transmission risk probably varies by the specific STD and sexual practice (e.g., oral-genital sex; vaginal or anal sex using hands, fingers, or penetrative sex items; and oral-anal sex) (188,189).Practices involving digital-vaginal or digital-anal contact, particularly with shared penetrative sex items, present a possible means for transmission of infected cervicovaginal or anal secretions.This possibility is most directly supported by reports of shared trichomonas infections (190,191) and by concordant drug resistance genotype testing and phylogenetic linkage analysis identifying HIV transmitted sexually between women (192,193).Most self-identified WSW (53%-97%) have had sex with men in the past and might continue this practice, with 5%-28% of WSW reporting male partners within the past year (189,(194)(195)(196).
HPV, which can be transmitted through skin-to-skin contact, is common among WSW, and sexual transmission of HPV likely occurs between female sex partners (197)(198)(199).HPV DNA has been detected through polymerase chain reaction (PCR)-based methods from the cervix, vagina, and vulva in 13%-30% of WSW (197,198).Among WSW who reported never having had a male sexual partner, 26% had antibodies to HPV-16, and 42% had antibodies to HPV-6 (197).High-and low-grade squamous intraepithelial lesions (SIL) have been detected on Pap tests in WSW who reported no previous sex with men (197,198,200,201).WSW are at risk for acquiring HPV from both their female partners and from current or prior male partners, and thus are at risk for cervical cancer.Therefore, routine cervical cancer screening should be offered to all women, regardless of sexual orientation or sexual practices, and women should be offered HPV vaccine as per current guidelines (16).
Genital transmission of HSV-2 between female sex partners is inefficient, but can occur.A U.S. population-based survey among women aged 18-59 years demonstrated an HSV-2 seroprevalence of 30% among women reporting same-sex partners in the past year, 36% among women reporting samesex partners in their lifetime, and 24% among women reporting no lifetime same-sex behavior (195).HSV-2 seroprevalence among women self-identifying as "homosexual or lesbian" was 8%, similar to a prior clinic-based study of WSW (195,196).The relatively frequent practice of orogenital sex among WSW might place them at higher risk for genital infection with HSV-1, a hypothesis supported by the recognized association between HSV-1 seropositivity and previous number of female partners among WSW.Thus, sexual transmission of HSV-1 and HSV-2 can occur between female sex partners.This information should be communicated to women as part of a larger sexual health counseling and evaluation effort.
Less is known regarding transmission of bacterial STDs between female partners.Transmission of syphilis between female sex partners, probably through oral sex, has been reported.Although the rate of transmission of C. trachomatis between women is unknown, infection also might be acquired from past or current male partners.More recent data suggests that C. trachomatis infection among WSW might be more common than previously believed (179,202).Reports of same-sex behavior in women should not deter providers from offering and providing screening for STDs, including chlamydia, according to current guidelines.
BV is common among women in general and even more so among women with female partners (203,204).Sexual behaviors that facilitate the transfer of vaginal fluid and bacteria between partners may be involved in the pathogenesis of BV.A study including monogamous couples demonstrated that female sex partners frequently share identical genital Lactobacillus strains (205).Within a community-based cohort of WSW, extravaginal (i.e., oral and rectal) reservoirs of BV-associated bacteria were a risk factor for incident BV (206).Several new studies have examined the impact of specific sexual practices on the vaginal microflora (207)(208)(209) and on recurrent (210) or incident (211,212) BV among WSW and non-WSW.These studies have continued to support, though have not proven, the hypothesis that sexual behaviors, specific BV-associated bacteria, and possibly exchange of vaginal or extravaginal microbiota (e.g., oral bacterial communities) between partners might be involved in the pathogenesis of BV in WSW.
Although BV is common in WSW, routine screening for BV is not recommended.Results of a randomized trial using a behavioral intervention to reduce persistent BV among WSW through reduced sharing of vaginal fluid on hands or sex toys has been published (213).Although women randomized to the intervention were 50% less likely to report receptive digitalvaginal contact without gloves than controls and reported sharing sex toys infrequently, these women had no reduction in persistent BV at 1 month post-treatment and no reduction in incident episodes of recurrent BV.To date, no reported trials have examined the potential benefits of treating female partners of women with BV; thus, no recommendation can be made regarding partner therapy in WSW.Increasing awareness of signs and symptoms of BV in women and encouraging healthy sexual practices (e.g., avoiding shared sex toys, cleaning shared sex toys, and barrier use) might benefit women and their partners.WSW are at risk for acquiring bacterial, viral, and protozoal STDs from current and prior partners, both male and female.WSW should not be presumed to be at low or no risk for STDs based on sexual orientation.Report of same sex behavior in women should not deter providers from considering and performing screening for STDs and cervical cancer according to current guidelines.Effective screening requires that care providers and their female patients engage in a comprehensive and open discussion of sexual and behavioral risks that extends beyond sexual identity.
# Transgender Men and Women
Persons who are transgender identify with a sex that differs from that they were assigned at birth.Transgender women ("trans-women" or "transgender male to female") identify as women but were born with male anatomy.Similarly, transgender men (also referred to as "trans-men" or "transgender female to male") identify as men but were born with female anatomy.However, transgender persons might use different and often fluid terminology to refer to themselves through their life course.Gender identity is independent from sexual orientation.Persons who are transgender might have sex with men, women, or both and consider themselves to be heterosexual, gay, lesbian, or bisexual.Prevalence studies of transgender persons in the overall population have been limited and often based on small convenience samples.
# Transgender Women
A systematic review of studies of HIV among transgender women suggests that the prevalence of HIV in the United States is 27.7% among all transgender women and 56.3% among black transgender women (214).Data also suggests high rates of HIV among transgender women globally (215).Bacterial STD prevalence varies among transgender women, but is based largely on convenience samples.Providers caring for transgender women should have knowledge of their patients' current anatomy and patterns of sexual behavior before counseling them about STD and HIV prevention (216).Most transgender women have not undergone genital affirmation surgery and may retain a functional penis (217)(218)(219); in this instance, they might engage in insertive oral, vaginal, or anal sex with men and women.
# Transgender Men
The few studies of HIV prevalence and incidence in transgender men suggest that although some transgender men engage in risky behaviors, they have a lower prevalence of HIV than transgender women (220).Providers should consider the anatomic diversity among transgender men, because many still have a vagina and cervix and are at risk for bacterial STDs, cervical HPV, and cervical cancer (221).
# Recommendations
Clinicians should assess STD-and HIV-related risks for their transgender patients based on current anatomy and sexual behaviors.Because of the diversity of transgender persons regarding surgical affirming procedures, hormone use, and their patterns of sexual behavior, providers must remain aware of symptoms consistent with common STDs and screen for asymptomatic STDs on the basis of behavioral history and sexual practices.
# Emerging Issues
# Hepatitis C
HCV infection is the most common chronic bloodborne infection in the United States, with an estimated 2.7 million persons living with chronic infection (222).HCV is not efficiently transmitted through sex (170,223).Studies of HCV transmission between heterosexual or homosexual couples have yielded mixed results, but generally have found either no or very minimally increased rates of HCV infection in partners of persons with HCV infection compared with those whose partners are not HCV-infected (223)(224)(225)(226)(227)(228)(229)(230).However, data indicate that sexual transmission of HCV can occur, especially among persons with HIV infection.Increasing incidence of acute HCV infection among MSM with HIV infection has been reported in New York City (231,232) and Boston (175,177), along with multiple European cities (233)(234)(235).These men usually engage in high-risk and traumatic sexual practices and might have concurrent genital ulcerative disease or STD-related proctitis (233,235).Other common practices associated with new cases of HCV infection include group sex and use of cocaine and other nonintravenous drugs during sex.
Certain studies have revealed that risk increases commensurate with increasing numbers of sex partners among heterosexual persons with HIV infection (225,226,(236)(237)(238) and MSM (239)(240)(241)(242), especially if their partners are also coinfected with HIV (234,235,(239)(240)(241)(242)(243).
Persons newly infected with HCV typically are either asymptomatic or have a mild clinical illness.HCV RNA can be detected in blood within 1-3 weeks after exposure.The average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8-9 weeks, and anti-HCV can be detected in >97% of persons by 6 months after exposure.Chronic HCV infection develops in 70%-85% of HCV-infected persons; 60%-70% of chronically infected persons develop evidence of active liver disease.Most infected persons remain unaware of their infection because they are not clinically ill.However, infected persons serve as a source of transmission to others and are at risk for CLD and other HCV-related chronic diseases decades after infection.
HCV is primarily transmitted parenterally, usually through shared drug-injection needles and paraphernalia.HCV also can be transmitted through exposures in health-care settings as a consequence of inadequate infection-control practices (244).Transmission following receipt of blood, tissues, and organs from donors with HCV infection has occurred only rarely since 1992, when routine screening of these donated products was mandated in the United States.Tattoos applied in regulated settings have not been associated with HCV transmission, although those obtained in unregulated settings have been linked to such transmission (224).Occupational and perinatal exposures also can result in transmission of HCV, but such transmission is uncommon.
Acute hepatitis C is a reportable condition in 49 states, and matching viral hepatitis and HIV surveillance registries can facilitate early detection of social networks of HCV transmission among MSM with HIV infection. |
Suspected clusters of acute HCV infection should be reported to the appropriate public health authorities.
HCV screening is recommended by CDC and USPSTF for all persons born during 1945-1965 and others based on their risk for infection or on a recognized exposure, including past or current injection drug use, receiving a blood transfusion before 1992, long-term hemodialysis, being born to a mother with HCV infection, intranasal drug use, receipt of an unregulated tattoo, and other percutaneous exposures (109,224,245).
# Diagnosis
Testing for HCV infection should include use of an FDA-cleared test for antibody to HCV (i.e., immunoassay, EIA, or enhanced chemiluminescence immunoassay and, if recommended, a supplemental antibody test) followed by NAAT to detect HCV RNA for those with a positive antibody result (178).Persons with HIV infection with low CD4-positive cell count might require further testing by NAAT because of the potential for a false-negative antibody assay.
Persons determined to be anti-HCV positive should be evaluated (by referral or consultation, if appropriate) for the presence of acute infection; presence, severity, or development of CLD; and eligibility for treatment.Nucleic acid testing, including reverse transcriptase polymerase chain reaction (RT-PCR) to detect HCV RNA, is necessary to confirm the diagnosis of current HCV infection, and testing of liver function (alanine aminotransferase level) provides biochemical evidence of CLD.
# Treatment
Providers should consult with specialists knowledgeable about management of hepatitis C infection.Further, they can consult existing guidelines to learn about the latest advances in the management of hepatitis C ().
# Management of Sex Partners
Because incident HCV has not been demonstrated to occur in heterosexual couples followed over time (223,(227)(228)(229), condom use might not be necessary in such circumstances.Persons with HCV infection with one long-term, steady sex partner do not need to change their sexual practices.However, they should discuss the low but present risk for transmission with their partner and discuss the need for testing (170,245).Heterosexuals and MSM with HCV infection and more than one partner, especially those with concurrent HIV infection, should protect their partners against HCV and HIV acquisition by using male latex condoms (231,234,235).Partners of persons with HCV and HIV infection should be tested for HCV and HIV, if not known to be infected.
# Other Management Considerations
All persons with HCV for whom HIV and HBV infection status is unknown should be tested for these infections.Those who have HIV or HBV should be referred for or provided with appropriate care and treatment.
# Prevention
Reducing the burden of HCV infection and disease in the United States requires implementation of both primary and secondary prevention activities.Primary prevention reduces or eliminates HCV transmission, whereas secondary prevention activities are aimed at reducing CLD and other chronic diseases in persons with HCV infection by first identifying them and then providing medical management and antiviral therapy, if appropriate.No vaccine for hepatitis C is available, and prophylaxis with immune globulin is not effective in preventing HCV infection after exposure.
Persons with HCV infection should be provided information regarding how to protect their liver from further harm (i.e., hepatotoxic agents); for instance, persons with HCV infection should be advised to avoid drinking alcohol and taking any new medicines (including over-the-counter and herbal medications) without checking with their clinician.In addition, a determination for the need of hepatitis A and B vaccination should be made; persons who are not immune should be vaccinated.
To reduce the risk for transmission to others, persons with HCV infection should be advised 1) not to donate blood, body organs, other tissue, or semen; 2) not to share any personal items that might have blood on them (e.g., toothbrushes and razors); and 3) to cover cuts and sores on the skin to keep the virus from spreading by blood or secretions.Women with HCV infection do not need to avoid pregnancy or breastfeeding.
Persons who use or inject drugs should be counseled about the importance of stopping drug-use behaviors and provided with assistance to enter and complete substanceabuse treatment (including relapse prevention).Persons who continue to inject drugs despite counseling should be encouraged to take the following additional steps to reduce personal and public health risks:
- never reuse or share syringes, water, or drug preparation equipment; - only use syringes obtained from a reliable source (e.g., pharmacies); - use a new, sterile syringe to prepare and inject drugs; - if possible, use sterile water to prepare drugs; otherwise, use clean water from a reliable source (e.g., fresh tap water); - use a new or disinfected container (i.e., cooker) and a new filter (i.e., cotton) to prepare drugs; - clean the injection site before injection with a new alcohol swab; and - safely dispose of syringes after one use.
# Postexposure Follow-Up
No postexposure prophylaxis has been demonstrated to be effective against HCV.HCV testing is recommended for health-care workers after percutaneous or permucosal exposures to HCV-positive blood.Children born to women with HCV infection also should be tested for HCV.Prompt identification of acute infection is important, because outcomes are improved when treatment is initiated early in the course of illness.
# Special Considerations Pregnancy
Routine screening for HCV infection is not recommended for all pregnant women.Pregnant women with a known risk factor for HCV infection should be offered screening.Although the rate for transmission is highly variable, up to six of every 100 infants born to HCV-infected women become infected; this infection occurs predominantly during or near delivery, and no treatment or delivery method-such as caesarian section-has been demonstrated to decrease this risk (246).However, the risk is increased by the presence of maternal HCV viremia at delivery and is two-to threefold greater if the woman is coinfected with HIV.HCV has not been shown to be transmitted through breast milk, although mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding.Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended (/ preview/mmwrhtml/mm6218a5.htm?s_cid=mm6218a5_w).
# HIV Infection
All persons with HIV infection should undergo serologic screening for HCV at initial evaluation (17,247).Providers should be aware of the likelihood that MSM with HIV infection will acquire HCV after initial screening.Because of accumulating evidence of acute HCV infection acquisition in persons with HIV infection, especially MSM, and costeffectiveness of regular screening (176,177), periodic HCV screening should be considered (170)(171)(172)(173)(174)(175).For persons with HIV infection, HCV screening with HCV antibody assays can be considered at least yearly in those at high risk for infection and more frequently depending on specific circumstances (e.g., community HCV prevalence and incidence, high-risk sexual behavior, and concomitant ulcerative STDs and STD-related proctitis).Indirect testing (e.g., ALT) is not recommended for detecting incident HCV infections because such testing, especially if performed once a year, can miss many persons who have reverted after acute HCV infection to a normal ALT level at the time of testing (175,177).Conversely, ALT can be elevated by antiretroviral and other medications, alcohol, and toxins.If ALT levels are being monitored, persons with HIV infection who experience new and unexplained increases in ALT should be tested for acute HCV infection and evaluated for possible medication toxicity or excessive alcohol use.
Continued unprotected sexual contact between partners with HIV infection can facilitate spread of HCV, as the virus can be recovered from the semen of men with HIV (248).Specific prevention practices (e.g., barrier precautions that limit contact with body fluids during sexual contact with other MSM) should be discussed.
Because a minimal percentage of persons with HIV infection fail to develop HCV antibodies, HCV RNA testing should be performed in persons with unexplained liver disease who are anti-HCV negative.The course of liver disease is more rapid in HIV/HCV coinfected persons, and the risk for cirrhosis is nearly twice that of persons with HCV infection alone.Coinfected persons receiving HIV antiviral regimens are now being treated for HCV after their CD4+ cell counts increase, optimizing their immune response.
# Mycoplasma genitalium
M. genitalium was first identified in the early 1980s (249) and has become recognized as a cause of male urethritis, responsible for approximately 15%-20% of nongonococcal urethritis (NGU) cases, 20%-25% of nonchlamydial NGU, and approximately 30% of persistent or recurrent urethritis (250).In most settings, it is more common than N. gonorrhoeae but less common than C. trachomatis.While M. genitalium is often the sole pathogen detected, coinfection with C. trachomatis is not uncommon in selected areas (251)(252)(253).
Although strong and consistent evidence has linked M. genitalium to urethritis in men, it remains unknown whether this infection can cause male infertility or other male anogenital tract disease syndromes.The organism has been detected in men with epididymitis in a limited number of cases, but this has not been extensively investigated.Similarly, M. genitalium has been found in the rectum, but detection is infrequently accompanied by rectal symptoms, and its presence does not appear to cause a syndrome of clinical proctitis.
The pathogenic role of M. genitalium is less definitive in women than it is in men.M. genitalium can be found in the vagina, cervix, and endometrium and, like chlamydial and gonococcal infections, M. genitalium infections in women are commonly asymptomatic.M. genitalium can be detected in 10%-30% of women with clinical cervicitis, and most (253)(254)(255)(256)(257)(258)(259) studies have found that this organism is more common among women with cervicitis than those without this syndrome (251,260,261).
M. genitalium is found in the cervix and/or endometrium of women with PID more often than in women without PID (262)(263)(264)(265)(266)(267)(268)(269)(270)(271), and endosalpingitis develops in nonhuman primates after inoculation with M. genitalium, suggesting that this organism can cause PID.M. genitalium has been detected in 2%-22% of PID cases (median: 10%) depending on the setting, but the frequency with which M. genitalium-infected women experience PID has been under studied.Although one study in Sweden reported a substantial increase in risk for postabortal PID among women with M. genitalium (262), the proportion of M. genitalium-positive women who subsequently experienced PID in two other studies was relatively low (<5%) (272,273), and evidence from serologic studies assessing the association of PID with antibody to M. genitalium is inconsistent.Overall, evidence suggests that M. genitalium can cause PID, but that this occurs less frequently than it does with C. trachomatis (271,273).
A few seroepidemologic studies have found that women with tubal factor infertility are more likely to have antibodies to M. genitalium than fertile women, suggesting that this organism might cause female infertility.However, more research is needed.On the basis of certain reports, M. genitalium was uncommonly identified in women who experience adverse pregnancy outcomes, but was associated with increased risk for preterm delivery in one U.S. and another Peruvian study (274,275).Data are scarce regarding M. genitalium and ectopic pregnancy.
# Diagnostic Considerations
M. genitalium is a slow-growing organism.Culture can take up to 6 months, and only a few laboratories in the world are able to recover clinical isolates.Therefore, NAAT is the preferred method for M. genitalium detection.In research settings, M. genitalium is diagnosed by NAAT testing of urine, urethral, vaginal, and cervical swabs and through endometrial biopsies, typically using in-house PCR or assays intended for research use only.NAAT tests (polymerase chain reaction or transcription mediated amplification) for M. genitalium are available in some large medical centers and commercial laboratories, but there is no diagnostic test for M. genitalium that is cleared by the FDA for use in the United States.In the absence of validated tests, M. genitalium should be suspected in cases of persistent or recurrent urethritis and may be considered in persistent or recurrent cases of cervicitis and PID.
# Treatment
M. genitalium lacks a cell wall, and thus antibiotics targeting cell-wall biosynthesis (e.g., beta-lactams including penicillins and cephalosporins) are ineffective against this organism.Given the diagnostic challenges, treatment of most M. genitalium infections will occur in the context of syndromic management for urethritis, cervicitis, and PID.
# Urethritis and Cervicitis
The 7-day doxycycline regimen recommended for treatment of urethritis is largely ineffective against M. genitalium with a median cure rate of approximately 31% (276)(277)(278).The 1-g single dose of azithromycin was significantly more effective against M. genitalium than doxycycline in two randomized urethritis treatment trials (276,277) and is preferred over doxycycline.However, resistance to azithromycin appears to be rapidly emerging.The median cure rate for both men and women is approximately 85%, but was only 40% in the most recent trial (278).Persons with treatment failures after the 1-g azithromycin regimen frequently have macrolide-resistant strains, suggesting that single-dose azithromycin therapy might select for resistance.A longer course of azithromycin (an initial 500-mg dose followed by 250 mg daily for 4 days) might be marginally superior to the single dose regimen (279)(280)(281).However, in some settings, approximately 50% of all M. genitalium infections are caused by organisms that are already resistant to azithromycin (282), and persons who do not respond to the 1-g azithromycin regimen generally do not benefit from retreatment with the extended dose regimen.
Moxifloxacin (400 mg daily x 7, 10 or 14 days) has been successfully used to treat M. genitalium in men and women with previous treatment failures, with cure rates of 100% in initial reports (280,283).However, moxifloxacin has been used in only a few cases, and the drug has not been tested in clinical trials.Although generally considered effective, studies in Japan, Australia, and the United States have reported moxifloxacin treatment failures after the 7 day regimen (284)(285)(286)(287).
# PID
Recommended PID treatment regimens are based on antibiotics that are not effective against M. genitalium.Therefore, clinicians might consider M. genitalium in cases that do not respond to therapy within 7-10 days.Where validated M. genitalium testing is available, clinicians might test women with PID for M. genitalium.When M. genitalium is detected, a regimen of moxifloxacin 400 mg/day for 14 days has been effective in eradicating the organism (288).Nevertheless, no data have been published that assess the benefits of testing women with PID for M. genitalium, and the importance of directing treatment against this organism is currently unknown.
# Follow-up
In settings where validated M. genitalium testing is available, persons with persistent urethritis, cervicitis, or PID accompanied by persistent detection of M. genitalium might be treated with moxifloxacin.However, routine tests-of-cure in asymptomatic persons are not recommended.
# Management of Sex Partners
Sex partners should be managed according to guidelines for patients with nongonococcal urethritis (NGU), cervicitis, and PID.In settings with access to validated M. genitalium tests, partner testing and treatment of identified infections might be considered.
# Special Considerations HIV Infection
Persons who have an M. genitalium infection and HIV infection should receive the same treatment regimen as those who are HIV negative.Treatment of most M. genitalium infections will occur in the context of syndromic management for urethritis, cervicitis, and PID (See Mycoplasma genitalium, Treatment).
# HIV Infection: Detection, Counseling, and Referral
HIV infection typically begins with a brief acute retroviral syndrome, transitions to a multi-year chronic illness that progressively depletes CD4 T-lymphocytes critical for maintenance of effective immune function, and ends with symptomatic, life-threatening immunodeficiency.This late stage of infection, known as acquired immunodeficiency syndrome (AIDS), develops over months to years with an estimated median time of approximately 11 years (289).In the absence of treatment, virtually all persons with AIDS will die from AIDS-related causes; however with antiretroviral therapy, persons provided early effective treatment can expect to live a near normal lifespan (290)(291)(292).Early diagnosis of HIV infection and linkage to care are essential not only for the patients' own health but also to reduce the risk for transmitting HIV to others.As of March 2012, U.S. guidelines recommend all persons with HIV infection diagnoses be offered effective antiretroviral therapy (70).
As of 2011, approximately 16% of the estimated 1.2 million persons with HIV infection in the United States are unaware of their infection (/ pdf/2011_Monitoring_HIV_Indicators_HSSR_FINAL.pdf ).Knowledge of HIV-infection status has important clinical implications, because HIV infection alters the immune system and thereby affects the diagnosis, evaluation, treatment, and follow-up of some other STDs.Diagnosing HIV infection during the acute phase of disease is particularly important (see Acute HIV Infection).Persons with acute HIV infection are highly infectious, because HIV concentrations are extremely high in plasma and genital secretions following initial infection (293)(294)(295)(296).However, tests for HIV antibodies are often negative during this phase of infection, causing persons to mistakenly believe they are uninfected and unknowingly continue to engage in behaviors associated with HIV transmission.Of persons with acute HIV infection, 50%-90% are symptomatic, many of whom seek medical care (297,298).Because persons with no HIV-associated symptoms might present for assessment or treatment of a concomitantly acquired STD, providers serving persons at risk for STDs are in a position to diagnose HIV infection in persons during the acute phase of infection.
Despite the availability of effective antiretroviral therapy, many cases of HIV infection continue to be diagnosed at advanced stages, as evidenced by low CD4 cell counts.Nationally, the proportion of patients who receive AIDS diagnoses at or within 12 months of their HIV diagnosis in 2010 was 32% (299).Since 2006, CDC has recommended efforts to increase HIV testing by streamlining the consent process and expanding opt-out testing to all health-care settings, including those serving persons at risk for STDs (122).HIV testing facilitates early diagnosis, which reduces the spread of disease, extends life expectancy, and reduces costs of care.However, rates of testing remain low: CDC estimates that in 2008, only 45% of adults aged 18-64 years had ever been tested (300), and that during 2006-2009 approximately 41% of persons with newly diagnosed HIV infection had never been previously tested (301).
Comprehensive HIV treatment services are usually not available in facilities focusing primarily on STD treatment (e.g., STD clinics). |
In such settings, patients with a new diagnosis of HIV infection or those with an existing diagnosis of HIV infection who are not engaged in regular on-going care should be linked promptly to a health-care provider or facility experienced in caring for HIV-infected patients (70).Providers working in STD clinics should be knowledgeable about the treatment options available in their communities, educate HIVinfected persons about their illness, and link these patients to HIV-related care and support services.Provision of care also should include behavioral and psychosocial services, especially for alcohol and drug addiction and for mental health problems.
A detailed discussion of the complex issues required for the management of HIV infection is beyond the scope of this report; however this information is available elsewhere (17,70,247).These HIV care and management resources are updated frequently, and the most current versions are available online (see URLs accompanying each reference).These resources provide additional information about the diagnosis, medical management, and counseling of persons with HIV infection, referral for support services, and management of sex and injection-drug partners in STD-treatment facilities.In addition, subsequent sections of this report briefly discuss HIV infection during pregnancy and among infants and children.
# Detection of HIV Infection: Screening
All persons who seek evaluation and treatment for STDs should be screened for HIV infection.Screening should be routine, regardless of whether the patient reports any specific behavioral risks for HIV infection.Persons at high risk for HIV infection with early syphilis, gonorrhea, or chlamydia should be screened at the time of the STD diagnosis, even if an HIV test was recently performed.Some STDs, especially rectal gonorrhea and syphilis, are a risk marker for HIV acquisition (142,145,156).
CDC recommends HIV screening for patients aged 13-64 years in all health-care settings (122).Persons should be notified that testing will be performed, but retain the option to decline or defer testing (an opt-out approach) (302).Consent for HIV screening should be incorporated into the general informed consent for medical care in the same manner as other screening or diagnostic tests.A separate consent form for HIV testing is not recommended.
Providing prevention counseling in conjunction with HIV diagnostic testing or as part of HIV screening programs should not be required in health-care settings.However, some persons might be more likely to think about HIV and consider their risk-related behavior when undergoing an HIV test.HIV testing presents providers with an opportunity to conduct HIV/STD prevention counseling and communicate riskreduction messages.
# Diagnosing HIV Infection
HIV infection can be diagnosed by serologic tests that detect antibodies against HIV-1 and HIV-2 and by virologic tests that detect HIV antigens or ribonucleic acid (RNA).Testing begins with a sensitive screening test, usually an antigen/antibody combination or antibody immunoassay (IA).Available serologic tests are both highly sensitive and specific and can detect all known subtypes of HIV-1.Most can also detect HIV-2 and uncommon variants of HIV-1 (e.g., group O and group N).Rapid HIV tests enable clinicians to make a preliminary diagnosis of HIV infection within 30 minutes.However, most rapid antibody assays become reactive later than conventional laboratory-based antibody or combination antigen/antibody serologic assays, and thus can produce negative results in recently infected persons.
The recommended diagnostic algorithm for HIV infection consists of a laboratory-based immunoassay, which if repeatedly reactive is followed by a supplemental test (e.g., an HIV-1/ HIV-2 antibody differentiation assay, Western blot, or indirect immunofluorescence assay).However, available HIV laboratory antigen/antibody immunoassays detect HIV infection earlier than these supplemental tests.Therefore, during very early stages of HIV infection, discordant HIV test results (reactive immunoassay results with negative supplemental test results) have been erroneously interpreted as negative (303).This problem is minimized by use of a combination HIV-1/HIV-2 antigen-antibody (Ag/Ab) immunoassay, which if reactive is followed by an HIV-1/HIV-2 antibody differentiation assay (304).This algorithm confers an additional advantage, as it can detect HIV-2 antibodies after the initial immunoassay.Although HIV-2 is uncommon in the United States, accurate identification is important because monitoring and therapy for HIV-2 differs from that for HIV-1 (305).RNA testing is performed on all specimens with reactive immunoassay but negative supplemental antibody test results to determine whether the discordance represents acute HIV infection.
The following are specific recommendations that apply to testing for HIV infection.
# Acute HIV Infection
Health-care providers should be knowledgeable about the symptoms and signs of acute retroviral syndrome, which develops in 50%-90% of persons within the first few weeks after they become infected with HIV (298).Acute retroviral syndrome is characterized by nonspecific symptoms, including fever, malaise, lymphadenopathy, and skin rash.Suspicion of acute retroviral syndrome should prompt urgent assessment with an antigen/antibody immunoassay or HIV RNA in conjunction with an antibody test.If the immunoassay is negative or indeterminate, then testing for HIV RNA should follow.Clinicians should not assume that a laboratory report of a negative HIV antibody test result indicates that the necessary RNA screening for acute HIV infection has been conducted.Further, HIV home-testing kits only detect HIV antibodies and therefore will not detect acute HIV infection.
Persons with acute HIV infection are highly infectious because the concentration of virus in plasma and genital secretions is extremely elevated during this stage of infection (294,306).Antiretroviral therapy during acute HIV infection is recommended, because it substantially reduces infectiousness to others, improves laboratory markers of disease, may decrease severity of acute disease, lowers viral set-point, reduces the size of the viral reservoir, decreases rate of viral mutation by suppressing replication, and preserves immune function (70).Persons who receive an acute HIV infection diagnosis should be referred immediately to an HIV clinical-care provider, provided prevention counseling (e.g., advised to reduce number of partners and to use condoms correctly and consistently), and screened for STDs.Information should be provided on the availability of postexposure prophylaxis for sexual and needle-sharing partners not known to have HIV infection if the most recent contact was within the 72 hours preceding HIV diagnosis ().
# After Establishing a New HIV Diagnosis
Persons with newly diagnosed HIV infection should be informed about 1) the importance of promptly initiating medical care for their own health and to reduce further transmission of HIV, 2) the effectiveness of HIV treatments, and 3) what to expect as they enter medical care for HIV infection (70).They should be linked promptly to a health-care provider or facility experienced in caring for patients with HIV.Persons with symptoms or signs that suggest advanced HIV infection (e.g., fever, weight loss, diarrhea, cough, shortness of breath, and oral candidiasis) should be immediately evaluated or referred for evaluation.Persons experiencing psychologic distress should be referred accordingly (see Counseling for Persons with HIV Infection and Referral to Support Services).Detailed and regularly updated recommendation for the initial management of persons with HIV infection can be found elsewhere (17,70,247).
# Counseling for Persons with HIV Infection and Referral to Support Services
Providers should expect persons with HIV infection to be distressed when first informed of a positive test result.Such persons face multiple major adaptive challenges, including coping with the reactions of others to a stigmatizing illness, developing and adopting strategies for maintaining physical and emotional health, initiating changes in behavior to prevent HIV transmission to others, and reducing the risk for acquiring additional STDs.Many persons will require assistance with making reproductive choices, gaining access to health services, and coping with changes in personal relationships.Therefore, behavioral and psychosocial services are an integral part of health care for persons with HIV infection.
Persons testing positive for HIV infection have unique needs.Some require referral for specific behavioral interventions (e.g., a substance abuse program), mental health disorders (e.g., depression), and emotional distress, while others require assistance with securing and maintaining employment and housing.Women should be counseled or appropriately referred regarding reproductive choices and contraceptive options, and persons with multiple psychosocial problems might be candidates for comprehensive risk-reduction counseling and other support services.
The following are specific recommendations for HIV counseling and linkage to services that should be offered to patients before they leave the testing site.
- (12,15,(307)(308)(309)(310).Involvement of nongovernment and community-based organizations might complement such efforts in the clinical setting.
# Management of Sex Partners and Injection-Drug Partners
Clinicians providing services to persons with HIV infection should determine whether any partners should be notified concerning possible exposure to HIV (122,311)
# STD Testing During HIV Care
At the initial HIV care visit, providers should test all sexually active persons with HIV infection for curable STDs (e.g., syphilis, gonorrhea, and chlamydia) and perform testing at least annually during the course of HIV care (12).Specific testing includes syphilis serology and NAAT for N. gonorrhoeae and C. trachomatis at the anatomic site of exposure, as the preferred approach.Women with HIV infection should also be screened for trichomonas at the initial visit and annually thereafter.Women should be screened for cervical cancer precursor lesions by cervical Pap tests per existing guidelines (247).
More frequent screening for curable STDs might be appropriate depending on individual risk behaviors and the local epidemiology of STDs.Many STDs are asymptomatic, and their diagnosis might indicate risk behavior that should prompt referral for partner services and prevention counseling (10).Pathogen-specific sections of this document provide more detailed information on screening, testing, and treatment.
# Special Considerations Pregnancy
All pregnant women should be tested for HIV infection during the first prenatal visit.A second test during the third trimester, preferably at <36 weeks' gestation, should be considered for all pregnant women and is recommended for those known to be at high risk for acquiring HIV, those who receive health care in jurisdictions with elevated incidence of HIV or AIDS among women, and women seen in clinical settings in which prenatal screening identifies at least one pregnant women with HIV infection per 1,000 women screened (122).Diagnostic algorithms for HIV infection in pregnant women are not different than those for nonpregnant women (See Diagnosis, HIV Infection).Pregnant women should be informed about being tested for HIV as part of the panel of prenatal tests (103,122); for women who decline, providers should address concerns that pose obstacles to testing and encourage testing at subsequent prenatal visits.Women who decline testing because they have had a previous negative HIV test result should be informed about the importance of retesting during each pregnancy.Women with no prenatal care should be tested for HIV at the time of delivery.
Testing pregnant women is important not only because knowledge of infection status can help maintain the health of the woman, but because it enables receipt of interventions (i.e., antiretroviral and obstetrical) that can substantially reduce the risk for perinatal transmission of HIV.After a pregnant woman has been identified as having HIV infection, she should be educated about the benefits of antiretroviral treatment for her health and for reducing the risk for transmission to her infant.In the absence of antiretroviral treatment, a mother's risk of transmitting HIV to her neonate is approximately 30% but can be reduced to <2% through antiretroviral treatment, obstetrical interventions (i.e., elective cesarean section at 38 weeks of pregnancy), and breastfeeding avoidance (105).Pregnant women who have HIV infection should be linked to an HIV care provider and given appropriate antenatal and postpartum treatment and advice.Detailed and regularly updated recommendations for the initial management of persons with HIV infection and pregnancy are available in existing guidance at .
# HIV Infection Among Neonates, Infants, and Children
Diagnosis of HIV infection in a pregnant woman indicates the need to evaluate and manage the HIV-exposed neonate and consider whether the woman's other children might be infected.Detailed recommendations regarding diagnosis and management of HIV in neonates and children of mothers with HIV infection are beyond the scope of this report and can be found at .Exposed neonates and children with HIV infection should be referred to physicians with such expertise.
# Diseases Characterized by Genital, Anal, or Perianal Ulcers
In the United States, most young, sexually active patients who have genital, anal, or perianal ulcers have either genital herpes or syphilis.The frequency of each condition differs by geographic area and population; however, genital herpes is the most prevalent of these diseases.More than one etiologic agent (e.g., herpes and syphilis) can be present in a genital, anal, or perianal ulcer.Less common infectious causes of genital, anal, or perianal ulcers include chancroid and donovanosis.Genital herpes, syphilis, and chancroid have been associated with an increased risk for HIV acquisition and transmission.Genital, anal, or perianal lesions can also be associated with infectious as well as noninfectious conditions that are not sexually transmitted (e.g., yeast, trauma, carcinoma, aphthae, fixed drug eruption, and psoriasis).
A diagnosis based only on medical history and physical examination frequently is inaccurate.Therefore, all persons who have genital, anal, or perianal ulcers should be evaluated; in settings where chancroid is prevalent, a test for Haemophilus ducreyi also should be performed.Specific evaluation of genital, anal, or perianal ulcers includes 1) syphilis serology, darkfield examination, or PCR testing if available; 2) culture or PCR testing for genital herpes; and 3) serologic testing for typespecific HSV antibody.
No FDA-cleared PCR test to diagnose syphilis is available in the United States, but two FDA-cleared PCR tests are available for the diagnosis of HSV-1 and HSV-2 in genital specimens.Some clinical laboratories have developed their own syphilis and HSV PCR tests and have conducted Clinical Laboratory Improvement Amendment (CLIA) verification studies in genital specimens.Type-specific serology for HSV-2 might be helpful in identifying persons with genital herpes (see Genital Herpes, Type-Specific Serologic Tests).In addition, biopsy of ulcers can help identify the cause of ulcers that are unusual or that do not respond to initial therapy.HIV testing should be performed on all persons with genital, anal, or perianal ulcers not known to have HIV infection (see Diagnostic Considerations, sections on Syphilis, Chancroid, and Genital Herpes Simplex Virus).
Because early treatment decreases the possibility of transmission, public health standards require health-care providers to presumptively treat any patient with a suspected case of infectious syphilis at the initial visit, even before test results are available.Presumptive treatment of a patient with a suspected first episode of genital herpes also is recommended, because successful treatment depends on prompt initiation of therapy.The clinician should choose the presumptive treatment on the basis of clinical presentation (i.e., HSV lesions begin as vesicles and primary syphilis as a papule) and epidemiologic circumstances (e.g., high incidence of disease among populations and communities and travel history).For example, syphilis is so common in MSM that any man who has sex with men presenting with a genital ulcer should be presumptively treated for syphilis at the initial visit after syphilis and HSV tests are performed.After a complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis (313).
# Chancroid
The prevalence of chancroid has declined in the United States (118).When infection does occur, it is usually associated with sporadic outbreaks.Worldwide, chancroid appears to have declined as well, although infection might still occur in some regions of Africa and the Caribbean.Like genital herpes and syphilis, chancroid is a risk factor in the transmission and acquisition of HIV infection (314).
# Diagnostic Considerations
A definitive diagnosis of chancroid requires the identification of H. ducreyi on special culture media that is not widely available from commercial sources; even when these media are used, sensitivity is <80% (315).No FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and have conducted CLIA verification studies in genital specimens.
The combination of a painful genital ulcer and tender suppurative inguinal adenopathy suggests the diagnosis of chancroid (316).For both clinical and surveillance purposes, a probable diagnosis of chancroid can be made if all of the following criteria are met: 1) the patient has one or more painful genital ulcers; 2) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; 3) the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers; and 4) an HSV PCR test or HSV culture performed on the ulcer exudate is negative.
# Treatment
Successful treatment for chancroid cures the infection, resolves the clinical symptoms, and prevents transmission to others.In advanced cases, scarring can result despite successful therapy.
# Recommended Regimens
Azithromycin 1 g orally in a single dose OR Ceftriaxone 250 mg IM in a single dose OR Ciprofloxacin 500 mg orally twice a day for 3 days OR Erythromycin base 500 mg orally three times a day for 7 days Azithromycin and ceftriaxone offer the advantage of singledose therapy.Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported.However, because cultures are not routinely performed, data are limited regarding the current prevalence of antimicrobial resistance.
# Other Management Considerations
Men who are uncircumcised and patients with HIV infection do not respond as well to treatment as persons who are circumcised or HIV-negative.Patients should be tested for HIV infection at the time chancroid is diagnosed.If the initial test results were negative, a serologic test for syphilis and HIV infection should be performed 3 months after the diagnosis of chancroid.
# Follow-Up
Patients should be re-examined 3-7 days after initiation of therapy.If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy.If no clinical improvement is evident, the clinician must consider whether 1) the diagnosis is correct, 2) the patient is coinfected with another STD, 3) the patient is infected with HIV, 4) the treatment was not used as instructed, or 5) the H. ducreyi strain causing the infection is resistant to the prescribed antimicrobial. |
The time required for complete healing depends on the size of the ulcer; large ulcers might require >2 weeks.In addition, healing is slower for some uncircumcised men who have ulcers under the foreskin.Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and might require needle aspiration or incision and drainage, despite otherwise successful therapy.Although needle aspiration of buboes is a simpler procedure, incision and drainage might be preferred because of reduced need for subsequent drainage procedures.
# Management of Sex Partners
Regardless of whether symptoms of the disease are present, sex partners of patients who have chancroid should be examined and treated if they had sexual contact with the patient during the 10 days preceding the patient's onset of symptoms.
# Special Considerations Pregnancy
Data suggest ciprofloxacin presents a low risk to the fetus during pregnancy, with a potential for toxicity during breastfeeding (317).Alternate drugs should be used during pregnancy and lactation.No adverse effects of chancroid on pregnancy outcome have been reported.
# HIV Infection
Persons with HIV infection who have chancroid should be monitored closely because they are more likely to experience treatment failure and to have ulcers that heal slowly.Persons with HIV infection might require repeated or longer courses of therapy, and treatment failures can occur with any regimen.Data are limited concerning the therapeutic efficacy of the recommended single-dose azithromycin and ceftriaxone regimens in persons with HIV infection.
# Genital HSV Infections
Genital herpes is a chronic, life-long viral infection.Two types of HSV can cause genital herpes: HSV-1 and HSV-2.Most cases of recurrent genital herpes are caused by HSV-2, and approximately 50 million persons in the United States are infected with this type of genital herpes (318).However, an increasing proportion of anogenital herpetic infections have been attributed to HSV-1 infection, which is especially prominent among young women and MSM (319)(320)(321).
Most persons infected with HSV-2 have not had the condition diagnosed.Many such persons have mild or unrecognized infections but shed virus intermittently in the anogenital area.As a result, most genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs.Management of genital HSV should address the chronic nature of the disease rather than focusing solely on treatment of acute episodes of genital lesions.
# Diagnostic Considerations
The clinical diagnosis of genital herpes can be difficult, because the painful multiple vesicular or ulcerative lesions typically associated with HSV are absent in many infected persons.Recurrences and subclinical shedding are much more frequent for genital HSV-2 infection than for genital HSV-1 infection (322,323).A patient's prognosis and the type of counseling needed depend on the type of genital herpes (HSV-1 or HSV-2) causing the infection; therefore, the clinical diagnosis of genital herpes should be confirmed by type-specific laboratory testing (321,324).Both type-specific virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care to persons with or at risk for STDs.Persons with genital herpes should be tested for HIV infection.
# Virologic Tests
Cell culture and PCR are the preferred HSV tests for persons who seek medical treatment for genital ulcers or other mucocutaneous lesions.The sensitivity of viral culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal.Nucleic acid amplification methods, including PCR assays for HSV DNA, are more sensitive and are increasingly available (325)(326)(327).PCR is the test of choice for diagnosing HSV infections affecting the central nervous system and systemic infections (e.g., meningitis, encephalitis, and neonatal herpes).Viral culture isolates and PCR amplicons should be typed to determine which type of HSV is causing the infection.Failure to detect HSV by culture or PCR, especially in the absence of active lesions, does not indicate an absence of HSV infection because viral shedding is intermittent.Cytologic detection of cellular changes associated with HSV infection is an insensitive and nonspecific method of diagnosing genital lesions (i.e., Tzanck preparation) and therefore should not be relied on.Although a direct immunofluorescence (IF) assay using fluorescein-labeled monoclonal antibodies is also available to detect HSV antigen from genital specimens, this assay lacks sensitivity (328).
# Type-Specific Serologic Tests
Both type-specific and type-common antibodies to HSV develop during the first several weeks after infection and persist indefinitely.Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1).Providers should only request type-specific glycoprotein G (gG)-based serologic assays when serology is performed for their patients (329)(330)(331).
Both laboratory-based assays and point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit are available.The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80%-98%; false-negative results might be more frequent at early stages of infection (330,332,333).The most commonly used test, HerpeSelect HSV-2 Elisa might be falsely positive at low index values (1.1-3.5) (334)(335)(336).Such low values should be confirmed with another test, such as Biokit or the Western blot (337).The HerpeSelect HSV-2 Immunoblot should not be used for confirmation, because it uses the same antigen as the HSV-2 Elisa.Repeat testing is indicated if recent acquisition of genital herpes is suspected.The HerpeSelect HSV-1 Elisa is insensitive for detection of HSV-1 antibody.IgM testing for HSV 1 or HSV-2 is not useful, because IgM tests are not type-specific and might be positive during recurrent genital or oral episodes of herpes (337).
Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection.In this instance, education and counseling appropriate for persons with genital HSV infections should be provided.The presence of HSV-1 antibody alone is more difficult to interpret.Many persons with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic.However, acquisition of genital HSV-1 is increasing, and genital HSV-1 also can be asymptomatic (318)(319)(320)(321)338).Lack of symptoms in a person who is HSV-1 seropositive does not distinguish anogenital from orolabial or cutaneous infection, and regardless of site of infection, these persons remain at risk for acquiring HSV-2.
Type-specific HSV serologic assays might be useful in the following scenarios: 1) recurrent genital symptoms or atypical symptoms with negative HSV PCR or culture; 2) clinical diagnosis of genital herpes without laboratory confirmation; and 3) a patient whose partner has genital herpes.HSV serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition.Screening for HSV-1 and HSV-2 in the general population is not indicated.
# Management of Genital Herpes
Antiviral chemotherapy offers clinical benefits to most symptomatic patients and is the mainstay of management.Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management.
Systemic antiviral drugs can partially control the signs and symptoms of genital herpes when used to treat first clinical and recurrent episodes or when used as daily suppressive therapy.However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued.Randomized trials have indicated that three antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (339)(340)(341)(342)(343)(344)(345)(346)(347).Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration.Famciclovir also has high oral bioavailability.Topical therapy with antiviral drugs offers minimal clinical benefit and is discouraged.
# First Clinical Episode of Genital Herpes
Newly acquired genital herpes can cause a prolonged clinical illness with severe genital ulcerations and neurologic involvement.Even persons with first-episode herpes who have mild clinical manifestations initially can develop severe or prolonged symptoms.Therefore, all patients with first episodes of genital herpes should receive antiviral therapy.
# Recommended Regimens*
Acyclovir 400 mg orally three times a day for 7-10 days OR Acyclovir 200 mg orally five times a day for 7-10 days OR Valacyclovir 1 g orally twice a day for 7-10 days OR Famciclovir 250 mg orally three times a day for 7-10 days - Treatment can be extended if healing is incomplete after 10 days of therapy.
# Established HSV-2 Infection
Almost all persons with symptomatic first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection.Intermittent asymptomatic shedding occurs in persons with genital HSV-2 infection, even in those with longstanding or clinically silent infection.Antiviral therapy for recurrent genital herpes can be administered either as suppressive therapy to reduce the frequency of recurrences or episodically to ameliorate or shorten the duration of lesions.Some persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed.Many persons prefer suppressive therapy, which has the additional advantage of decreasing the risk for genital HSV-2 transmission to susceptible partners (348,349).
# Suppressive Therapy for Recurrent Genital Herpes
Suppressive therapy reduces the frequency of genital herpes recurrences by 70%-80% in patients who have frequent recurrences (345)(346)(347)(348); many persons receiving such therapy report having experienced no symptomatic outbreaks.Treatment also is effective in patients with less frequent recurrences.Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year (350,351).Quality of life is improved in many patients with frequent recurrences who receive suppressive therapy rather than episodic treatment (352).
The frequency of genital herpes recurrences diminishes over time in many persons, potentially resulting in psychological adjustment to the disease.Therefore, periodically during suppressive treatment (e.g., once a year), providers should discuss the need to continue therapy.However, neither treatment discontinuation nor laboratory monitoring in a healthy person is necessary.
Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection (349).Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences.Suppressive antiviral therapy also is likely to reduce transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes.Acyclovir, famciclovir, and valacyclovir appear equally effective for episodic treatment of genital herpes (342)(343)(344)(345)(346), but famciclovir appears somewhat less effective for suppression of viral shedding (353).Ease of administration and cost also are important considerations for prolonged treatment.
# Recommended Regimens
# Episodic Therapy for Recurrent Genital Herpes
Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks.The patient should be provided with a supply of drug or a prescription for the medication with instructions to initiate treatment immediately when symptoms begin.
# Recommended Regimens
Acyclovir 400 mg orally three times a day for 5 days OR Acyclovir 800 mg orally twice a day for 5 days OR Acyclovir 800 mg orally three times a day for 2 days OR Valacyclovir 500 mg orally twice a day for 3 days OR Valacyclovir 1 g orally once a day for 5 days OR Famciclovir 125 mg orally twice daily for 5 days OR Famciclovir 1 gram orally twice daily for 1 day OR Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days
# Severe Disease
Intravenous (IV) acyclovir therapy should be provided for patients who have severe HSV disease or complications that necessitate hospitalization (e.g., disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis).The recommended regimen is acyclovir 5-10 mg/kg IV every 8 hours for 2-7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy.HSV encephalitis requires 21 days of intravenous therapy.Impaired renal function warrants an adjustment in acyclovir dosage.
# Counseling
Counseling of infected persons and their sex partners is critical to the management of genital herpes.The goals of counseling include helping patients cope with the infection and preventing sexual and perinatal transmission.Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides.Multiple resources, including websites () and printed materials, are available to assist patients, their partners, and clinicians who become involved in counseling (354,355).
Although the psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears minimal and transient (356,357), some HSV-infected persons might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection can be substantial.Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children.The misconception that HSV causes cancer should be dispelled.
The following topics should be discussed when counseling persons with genital HSV infection:
- the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission; - the effectiveness of suppressive therapy for persons experiencing a first episode of genital herpes in preventing symptomatic recurrent episodes; - use of episodic therapy to shorten the duration of recurrent episodes; - importance of informing current sex partners about genital herpes and informing future partners before initiating a sexual relationship; - potential for sexual transmission of HSV to occur during asymptomatic periods (asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2); - importance of abstaining from sexual activity with uninfected partners when lesions or prodromal symptoms are present; - effectiveness of daily use of valacyclovir in reducing risk for transmission of HSV-2, and the lack of effectiveness of episodic or suppressive therapy in persons with HIV and HSV infection in reducing risk for transmission to partners who might be at risk for HSV-2 acquisition; - effectiveness of male latex condoms, which when used consistently and correctly can reduce (but not eliminate) the risk for genital herpes transmission (27,358,359); - HSV infection in the absence of symptoms (type-specific serologic testing of the asymptomatic partners of persons with genital herpes is recommended to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists); - risk for neonatal HSV infection; and
- increased risk for HIV acquisition among HSV-2 seropositive persons who are exposed to HIV (suppressive antiviral therapy does not reduce the increased risk for HIV acquisition associated with HSV-2 infection) (75,347).Asymptomatic persons who receive a diagnosis of HSV-2 infection by type-specific serologic testing should receive the same counseling messages as persons with symptomatic infection.In addition, such persons should be educated about the clinical manifestations of genital herpes.
Pregnant women and women of childbearing age who have genital herpes should inform the providers who care for them during pregnancy and those who will care for their newborn infant about their infection.More detailed counseling messages are described in Special Considerations, Genital Herpes in Pregnancy.
# Management of Sex Partners
The sex partners of persons who have genital herpes can benefit from evaluation and counseling.Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital herpes.Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions and offered type-specific serologic testing for HSV infection.
# Special Considerations Allergy, Intolerance, and Adverse Reactions
Allergic and other adverse reactions to oral acyclovir, valacyclovir, and famciclovir are rare.Desensitization to acyclovir has been described (360).
# HIV Infection
Immunocompromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes.Lesions caused by HSV are common among persons with HIV infection and might be severe, painful, and atypical.HSV shedding is increased in persons with HIV infection.Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs (361,362).Clinical manifestations of genital herpes might worsen during immune reconstitution early after initiation of antiretroviral therapy.
Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among persons with HIV infection (363)(364)(365).HSV typespecific serologic testing can be offered to persons with HIV infection during their initial evaluation if infection status is unknown, and suppressive antiviral therapy can be considered in those who have HSV-2 infection.Suppressive anti-HSV therapy in persons with HIV infection does not reduce the risk for either HIV transmission or HSV-2 transmission to susceptible sex partners (71,366).
# Recommended Regimens for Daily Suppressive Therapy in Persons with HIV
Acyclovir 400-800 mg orally twice to three times a day OR Valacyclovir 500 mg orally twice a day OR Famciclovir 500 mg orally twice a day
# Recommended Regimens for Episodic Infection in Persons with HIV
Acyclovir 400 mg orally three times a day for 5-10 days OR Valacyclovir 1 g orally twice a day for 5-10 days OR Famciclovir 500 mg orally twice a day for 5-10 days For severe HSV disease, initiating therapy with acyclovir 5-10 mg/kg IV every 8 hours might be necessary.
# Antiviral-resistant HSV
If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate obtained for sensitivity testing (367).Such persons should be managed in consultation with an infectious-disease specialist, and alternate therapy should be administered.All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir.Foscarnet (40-80 mg/kg IV every 8 hours until clinical resolution is attained) is often effective for treatment of acyclovir-resistant genital herpes (368,369).Intravenous cidofovir 5 mg/kg once weekly might also be effective. |
Imiquimod is a topical alternative (370), as is topical cidofovir gel 1%; however, cidofovir must be compounded at a pharmacy (371).These topical preparations should be applied to the lesions once daily for 5 consecutive days.
Clinical management of antiviral resistance remains challenging among persons with HIV infection, necessitating other preventative approaches.However, experience with another group of immunocompromised persons (hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to develop acyclovir-resistant HSV compared with those who received episodic therapy for outbreaks (372).
# Genital Herpes in Pregnancy
Most mothers of newborns who acquire neonatal herpes lack histories of clinically evident genital herpes (373,374).The risk for transmission to the neonate from an infected mother is high (30%-50%) among women who acquire genital herpes near the time of delivery and low (<1%) among women with prenatal histories of recurrent herpes or who acquire genital HSV during the first half of pregnancy (375,376).
Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the neonate to herpetic lesions and viral shedding during delivery.Because the risk for herpes is highest in newborn infants of women who acquire genital HSV during late pregnancy, these women should be managed in consultation with maternal-fetal medicine and infectiousdisease specialists.
Women without known genital herpes should be counseled to abstain from vaginal intercourse during the third trimester with partners known or suspected of having genital herpes.In addition, pregnant women without known orolabial herpes should be advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes.Type-specific serologic tests may be useful for identifying pregnant women at risk for HSV infection and guiding counseling regarding the risk for acquiring genital herpes during pregnancy.For example, such testing could be offered to women with no history of genital herpes whose sex partner has HSV infection.However, the effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by infected partners has not been studied.Routine HSV-2 serologic screening of pregnant women is not recommended.
All pregnant women should be asked whether they have a history of genital herpes.At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions.Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally.Although cesarean delivery does not completely eliminate the risk for HSV transmission to the neonate, women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean delivery to reduce the risk for neonatal HSV infection.
Many infants are exposed to acyclovir each year, and no adverse effects in the fetus or newborn attributable to the use of this drug during pregnancy have been reported.Acyclovir can be safely used to treat women in all stages of pregnancy, along with those who are breastfeeding (317,377).Although data regarding prenatal exposure to valacyclovir and famciclovir are limited, data from animal trials suggest these drugs also pose a low risk in pregnant women.Acyclovir can be administered orally to pregnant women with first-episode genital herpes or recurrent herpes and should be administered IV to pregnant women with severe HSV infection.Suppressive acyclovir treatment late in pregnancy reduces the frequency of cesarean delivery among women who have recurrent genital herpes by diminishing the frequency of recurrences at term (378)(379)(380).However, such treatment may not protect against transmission to neonates in all cases (381).No data support use of antiviral therapy among HSV-seropositive women without a history of genital herpes.
Recommended regimen for suppressive therapy of pregnant women with recurrent genital herpes *
# Neonatal Herpes
Newborn infants exposed to HSV during birth, as documented by maternal virologic testing of maternal lesions at delivery or presumed by observation of maternal lesions, should be followed carefully in consultation with a pediatric infectious-disease specialist.Guidance is available on management of neonates who are delivered vaginally in the presence of maternal genital HSV lesions (382).
Surveillance cultures or PCR of mucosal surfaces of the neonate to detect HSV infection might be considered before the development of clinical signs of neonatal herpes to guide initiation of treatment.In addition, administration of acyclovir might be considered for neonates born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants.All infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir.The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg IV every 8 hours for 14 days if disease is limited to the skin and mucous membranes, or for 21 days for disseminated disease and that involving the central nervous system.
# Granuloma Inguinale (Donovanosis)
Granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis).The disease occurs rarely in the United States, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa (383)(384)(385).Clinically, the disease is commonly characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudobuboes) also might occur.The lesions are highly vascular (i.e., beefy red appearance) and bleed.Extragenital infection can occur with extension of infection to the pelvis, or it can disseminate to intra-abdominal organs, bones, or the mouth.The lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens.
# Diagnostic Considerations
The causative organism of granuloma inguinale is difficult to culture, and diagnosis requires visualization of darkstaining Donovan bodies on tissue crush preparation or biopsy.No FDA-cleared molecular tests for the detection of K. granulomatis DNA exist, but such an assay might be useful when undertaken by laboratories that have conducted a CLIA verification study.
# Treatment
Several antimicrobial regimens have been effective, but only a limited number of controlled trials have been published (383).Treatment has been shown to halt progression of lesions, and healing typically proceeds inward from the ulcer margins; prolonged therapy is usually required to permit granulation and re-epithelialization of the ulcers.Relapse can occur 6-18 months after apparently effective therapy.
# Recommended Regimen
Azithromycin 1 g orally once per week or 500 mg daily for at least 3 weeks and until all lesions have completely healed Alternative Regimens Doxycycline 100 mg orally twice a day for at least 3 weeks and until all lesions have completely healed OR Ciprofloxacin 750 mg orally twice a day for at least 3 weeks and until all lesions have completely healed OR Erythromycin base 500 mg orally four times a day for at least 3 weeks and until all lesions have completely healed OR Trimethoprim-sulfamethoxazole one double-strength (160 mg/800 mg) tablet orally twice a day for at least 3 weeks and until all lesions have completely healed
The addition of another antibiotic to these regimens can be considered if improvement is not evident within the first few days of therapy.Addition of an aminoglycoside to these regimens is an option (gentamicin 1 mg/kg IV every 8 hours).
# Other Management Considerations
Persons should be followed clinically until signs and symptoms have resolved.All persons who receive a diagnosis of granuloma inguinale should be tested for HIV.
# Follow-up
Patients should be followed clinically until signs and symptoms resolve.
# Management of Sex Partners
Persons who have had sexual contact with a patient who has granuloma inguinale within the 60 days before onset of the patient's symptoms should be examined and offered therapy.However, the value of empiric therapy in the absence of clinical signs and symptoms has not been established.
# Special Considerations Pregnancy
Doxycycline should be avoided in the second and third trimester of pregnancy because of the risk for discoloration of teeth and bones, but is compatible with breastfeeding (317).Data suggest that ciprofloxacin presents a low risk to the fetus during pregnancy (317).Sulfonamides are associated with rare but serious kernicterus in those with G6PD deficiency and should be avoided in third trimester and during breastfeeding (317).For these reasons, pregnant and lactating women should be treated with a macrolide regimen (erythromycin or azithromycin).The addition of an aminoglycoside (gentamicin 1 mg/kg IV every 8 hours) can be considered if improvement is not evident within the first few days of therapy.
# HIV Infection
Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who do not have HIV infection.The addition of an aminoglycoside (gentamicin 1 mg/kg IV every 8 hours) can be considered if improvement is not evident within the first few days of therapy.
# Lymphogranuloma Venereum
Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3 (386,387).The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral.A self-limited genital ulcer or papule sometimes occurs at the site of inoculation.However, by the time patients seek care, the lesions have often disappeared.Rectal exposure in women or MSM can result in proctocolitis mimicking inflammatory bowel disease, and clinical findings may include mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus (388,389).Outbreaks of LGV protocolitis have been reported among MSM (390)(391)(392).
LGV can be an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic colorectal fistulas and strictures; reactive arthropathy has also been reported.However, reports indicate that rectal LGV can be asymptomatic (393).Persons with genital and colorectal LGV lesions can also develop secondary bacterial infection or can be coinfected with other sexually and nonsexually transmitted pathogens.
# Diagnostic Considerations
Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies for proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers.Genital lesions, rectal specimens, and lymph node specimens (i.e., lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection (394).NAATs for C. trachomatis perform well on rectal specimens, but are not FDA-cleared for this purpose.Many laboratories have performed the CLIA validation studies needed to provide results from rectal specimens for clinical management.MSM presenting with protocolitis should be tested for chlamydia; NAAT performed on rectal specimens is the preferred approach to testing.
Additional molecular procedures (e.g., PCR-based genotyping) can be used to differentiate LGV from non-LGV C. trachomatis in rectal specimens.However, they are not widely available, and results are not available in a timeframe that would influence clinical management.
Chlamydia serology (complement fixation titers ≥1:64 or microimmunofluorescence titers >1:256) might support the diagnosis of LGV in the appropriate clinical context.Comparative data between types of serologic tests are lacking, and the diagnostic utility of these older serologic methods has not been established.Serologic test interpretation for LGV is not standardized, tests have not been validated for clinical proctitis presentations, and C. trachomatis serovar-specific serologic tests are not widely available.
# Treatment
At the time of the initial visit (before diagnostic tests for chlamydia are available), persons with a clinical syndrome consistent with LGV, including proctocolitis or genital ulcer disease with lymphadenopathy, should be presumptively treated for LGV.As required by state law, these cases should be reported to the health department.
Treatment cures infection and prevents ongoing tissue damage, although tissue reaction to the infection can result in scarring.Buboes might require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/ femoral ulcerations.
# Recommended Regimen Doxycycline 100 mg orally twice a day for 21 days
# Alternative Regimen
Erythromycin base 500 mg orally four times a day for 21 days Although clinical data are lacking, azithromycin 1 g orally once weekly for 3 weeks is probably effective based on its chlamydial antimicrobial activity.Fluoroquinolone-based treatments also might be effective, but the optimal duration of treatment has not been evaluated.
# Other Management Considerations
Patients should be followed clinically until signs and symptoms have resolved.Persons who receive an LGV diagnosis should be tested for other STDs, especially HIV, gonorrhea, and syphilis.Those who test positive for another infection should be referred for or provided with appropriate care and treatment.
# Follow-up
Patients should be followed clinically until signs and symptoms resolve.
# Management of Sex Partners
Persons who have had sexual contact with a patient who has LGV within the 60 days before onset of the patient's symptoms should be examined and tested for urethral, cervical, or rectal chlamydial infection depending on anatomic site of exposure.They should be presumptively treated with a chlamydia regimen (azithromycin 1 g orally single dose or doxycycline 100 mg orally twice a day for 7 days).
# Special Considerations Pregnancy
Pregnant and lactating women should be treated with erythromycin.Doxycycline should be avoided in the second and third trimester of pregnancy because of risk for discoloration of teeth and bones, but is compatible with breastfeeding (317).Azithromycin might prove useful for treatment of LGV in pregnancy, but no published data are available regarding an effective dose and duration of treatment.
# HIV Infection
Persons with both LGV and HIV infection should receive the same regimens as those who are HIV negative.Prolonged therapy might be required, and delay in resolution of symptoms might occur.
# Syphilis
Syphilis is a systemic disease caused by Treponema pallidum.The disease has been divided into stages based on clinical findings, helping to guide treatment and follow-up.Persons who have syphilis might seek treatment for signs or symptoms of primary syphilis infection (i.e., ulcers or chancre at the infection site), secondary syphilis (i.e., manifestations that include, but are not limited to, skin rash, mucocutaneous lesions, and lymphadenopathy), or tertiary syphilis (i.e., cardiac, gummatous lesions, tabes dorsalis, and general paresis).Latent infections (i.e., those lacking clinical manifestations) are detected by serologic testing.Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are late latent syphilis or syphilis of unknown duration.T. pallidum can infect the central nervous system and result in neurosyphilis, which can occur at any stage of syphilis.Early neurologic clinical manifestations (i.e., cranial nerve dysfunction, meningitis, stroke, acute altered mental status, and auditory or ophthalmic abnormalities) are usually present within the first few months or years of infection.Late neurologic manifestations (i.e., tabes dorsalis and general paresis) occur 10-30 years after infection.
# Diagnostic Considerations
Darkfield examinations and tests to detect T. pallidum directly from lesion exudate or tissue are the definitive methods for diagnosing early syphilis (395).Although no T. pallidum detection tests are commercially available, some laboratories provide locally developed and validated PCR tests for the detection of T. pallidum DNA.A presumptive diagnosis of syphilis requires use of two tests: a nontreponemal test (i.e., Venereal Disease Research Laboratory or Rapid Plasma Reagin ) and a treponemal test (i.e., fluorescent treponemal antibody absorbed tests, the T. pallidum passive particle agglutination assay, various enzyme immunoassays , chemiluminescence immunoassays, immunoblots, or rapid treponemal assays).Although many treponemal-based tests are commercially available, only a few are approved for use in the United States.Use of only one type of serologic test is insufficient for diagnosis and can result in false-negative results in persons tested during primary syphilis and false-positive results in persons without syphilis.
False-positive nontreponemal test results can be associated with various medical conditions and factors unrelated to syphilis, including other infections (e.g., HIV), autoimmune conditions, immunizations, pregnancy, injection-drug use, and older age (395,396).Therefore, persons with a reactive nontreponemal test should always receive a treponemal test to confirm the diagnosis of syphilis.
Nontreponemal test antibody titers might correlate with disease activity and are used to follow treatment response.Results should be reported quantitatively.A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results obtained using the same serologic test.Sequential serologic tests in individual patients should be performed using the same testing method (VDRL or RPR), preferably by the same laboratory.The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers frequently are slightly higher than VDRL titers.Nontreponemal test titers usually decline after treatment and might become nonreactive with time; however, in some persons, nontreponemal antibodies can persist for a long period of time, a response referred to as the "serofast reaction."Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity.However, 15%-25% of patients treated during the primary stage revert to being serologically nonreactive after 2-3 years (397).Treponemal antibody titers do not predict treatment response and therefore should not be used for this purpose.Some clinical laboratories are screening samples using treponemal tests, typically by EIA or chemiluminescence immunoassays (398,399).This reverse screening algorithm for syphilis testing can identify persons previously treated for syphilis, those with untreated or incompletely treated syphilis, and persons with false-positive results that can occur with a low likelihood of infection.Persons with a positive treponemal screening test should have a standard nontreponemal test with titer performed reflexively by the laboratory to guide patient management decisions.If the nontreponemal test is negative, the laboratory should perform a different treponemal test (preferably one based on different antigens than the original test) to confirm the results of the initial test.If a second treponemal test is positive, persons with a history of previous treatment will require no further management unless sexual history suggests likelihood of re-exposure.In this instance, a repeat nontreponemal test in 2-4 weeks is recommended to evaluate for early infection.Those without a history of treatment for syphilis should be offered treatment. |
Unless history or results of a physical examination suggest a recent infection, previously untreated persons should be treated for late latent syphilis.If the second treponemal test is negative and the epidemiologic risk and clinical probability for syphilis are low, further evaluation or treatment is not indicated.Two studies demonstrate that high quantitative index values from treponemal EIA/CIA tests correlate with TPPA positivity; however, the range of optical density values varies among different treponemal immunoassays, and the clinical significance of these findings warrant further investigation (400,401).
For most persons with HIV infection, serologic tests are accurate and reliable for diagnosing syphilis and following a patient's response to treatment.However, atypical nontreponemal serologic test results (i.e., unusually high, unusually low, or fluctuating titers) might occur regardless of HIV-infection status.When serologic tests do not correspond with clinical findings suggestive of early syphilis, presumptive treatment is recommended for persons with risk factors for syphilis, and use of other tests (e.g., biopsy and PCR) should be considered.
Further testing is warranted for persons with clinical signs of neurosyphilis (e.g., cranial nerve dysfunction, auditory or ophthalmic abnormalities, meningitis, stroke, acute or chronic altered mental status, and loss of vibration sense).Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances.The diagnosis of neurosyphilis depends on a combination of cerebrospinal fluid (CSF) tests (CSF cell count or protein and a reactive CSF-VDRL) in the presence of reactive serologic test results and neurologic signs and symptoms.CSF laboratory abnormalities are common in persons with early syphilis and are of unknown significance in the absence of neurologic signs or symptoms (402).CSF-VDRL is highly specific but insensitive.In a person with neurologic signs or symptoms, a reactive CSF-VDRL (in the absence of blood contamination) is considered diagnostic of neurosyphilis.When CSF-VDRL is negative despite the presence of clinical signs of neurosyphilis, reactive serologic test results, and abnormal CSF cell count and/or protein, neurosyphilis should be considered.In this instance, additional evaluation using FTA-ABS testing on CSF may be warranted.The CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive.Neurosyphilis is highly unlikely with a negative CSF FTA-ABS test, especially among persons with nonspecific neurologic signs and symptoms (403).
Among persons with HIV infection, CSF leukocyte count usually is elevated (>5 white blood cell count /mm 3 ).Using a higher cutoff (>20 WBC/ mm 3 ) might improve the specificity of neurosyphilis diagnosis (404).
# Treatment
Penicillin G, administered parenterally, is the preferred drug for treating persons in all stages of syphilis.The preparation used (i.e., benzathine, aqueous procaine, or aqueous crystalline), dosage, and length of treatment depend on the stage and clinical manifestations of the disease.Treatment for late latent syphilis and tertiary syphilis require a longer duration of therapy, because organisms theoretically might be dividing more slowly (the validity of this rationale has not been assessed).Longer treatment duration is required for persons with latent syphilis of unknown duration to ensure that those who did not acquire syphilis within the preceding year are adequately treated.
Selection of the appropriate penicillin preparation is important, because T. pallidum can reside in sequestered sites (e.g., the CNS and aqueous humor) that are poorly accessed by some forms of penicillin.Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis.Reports have indicated that practitioners have inadvertently prescribed combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product (Bicillin L-A) widely used in the United States.Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products to avoid using the inappropriate combination therapy agent for treating syphilis (405).
The effectiveness of penicillin for the treatment of syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized.Therefore, nearly all recommendations for the treatment of syphilis are based not only on clinical trials and observational studies, but many decades of clinical experience.
# Special Considerations Pregnancy
Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy.Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin (see Management of Persons Who Have a History of Penicillin Allergy).
# Jarisch-Herxheimer Reaction
The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, fever, and other symptoms that can occur within the first 24 hours after the initiation of any therapy for syphilis.Patients should be informed about this possible adverse reaction and how to manage it if it occurs.The Jarisch-Herxheimer reaction occurs most frequently among persons who have early syphilis, presumably because bacterial burdens are higher during these stages.Antipyretics can be used to manage symptoms, but they have not been proven to prevent this reaction.The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this should not prevent or delay therapy (see Syphilis During Pregnancy).
# Management of Sex Partners
Sexual transmission of T. pallidum is thought to occur only when mucocutaneous syphilitic lesions are present.Such manifestations are uncommon after the first year of infection.Persons exposed sexually to a person who has primary, secondary, or early latent syphilis should be evaluated clinically and serologically and treated according to the following recommendations:
# Primary and Secondary Syphilis Treatment
Parenteral penicillin G has been used effectively to achieve clinical resolution (i.e., the healing of lesions and prevention of sexual transmission) and to prevent late sequelae.However, no comparative trials have been conducted to guide the selection of an optimal penicillin regimen.Substantially fewer data are available for nonpenicillin regimens.Available data demonstrate that use of additional doses of benzathine penicillin G, amoxicillin, or other antibiotics do not enhance efficacy when used to treat primary and secondary syphilis, regardless of HIV status (406,407).
# Recommended Regimen for Infants and Children
Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose Infants and children aged ≥1 month who receive a diagnosis of syphilis should have birth and maternal medical records reviewed to assess whether they have congenital or acquired syphilis (see Congenital Syphilis).Infants and children aged ≥1 month with primary and secondary syphilis should be managed by a pediatric infectious-disease specialist and evaluated for sexual abuse (e.g., through consultation with childprotection services) (see Sexual Assault or Abuse of Children).
# Other Management Considerations
All persons who have primary and secondary syphilis should be tested for HIV infection.In geographic areas in which the prevalence of HIV is high, persons who have primary or secondary syphilis should be retested for acute HIV in 3 months if the first HIV test result was negative.
Persons who have syphilis and symptoms or signs suggesting neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, and hearing loss) or ophthalmic disease (e.g., uveitis, iritis, neuroretinitis, and optic neuritis) should have an evaluation that includes CSF analysis, ocular slit-lamp ophthalmologic examination, and otologic examination.Treatment should be guided by the results of this evaluation.
Invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common among adults who have primary or secondary syphilis (402).In the absence of clinical neurologic findings, no evidence supports variation from the recommended treatment regimen for primary and secondary syphilis.Symptomatic neurosyphilis develops in only a limited number of persons after treatment with the penicillin regimens recommended for primary and secondary syphilis.Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, routine CSF analysis is not recommended for persons who have primary or secondary syphilis.
# Follow-Up
Clinical and serologic evaluation should be performed at 6 and 12 months after treatment; more frequent evaluation might be prudent if follow-up is uncertain or if repeat infection is a concern.Serologic response (i.e., titer) should be compared with the titer at the time of treatment.However, assessing serologic response to treatment can be difficult, and definitive criteria for cure or failure have not been well established.In addition, nontreponemal test titers might decline more slowly for persons previously treated for syphilis (408,409).
Persons who have signs or symptoms that persist or recur and those with at least a fourfold increase in nontreponemal test titer persisting for >2 weeks likely experienced treatment failure or were re-infected.These persons should be retreated and reevaluated for HIV infection.Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed; treatment should be guided by CSF findings.
Failure of nontreponemal test titers to decline fourfold within 6-12 months after therapy for primary or secondary syphilis might be indicative of treatment failure.However, clinical trial data have demonstrated that 15%-20% of persons with primary and secondary syphilis treated with the recommended therapy will not achieve the fourfold decline in nontreponemal titer used to define response at 1 year after treatment (406,409).Serologic response to treatment appears to be associated with several factors, including the person's stage of syphilis (earlier stages are more likely to decline fourfold and become negative) and initial nontreponemal antibody titers (lower titers are less likely to decline fourfold than higher titers) (409).Optimal management of persons who have less than a fourfold decline in titers after treatment of syphilis is unclear.At a minimum, these persons should receive additional clinical and serologic follow-up and be evaluated for HIV infection.If additional follow-up cannot be ensured, retreatment is recommended.Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in such situations.
For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis).Serologic titers might not decline despite a negative CSF examination and a repeated course of therapy (410).In these circumstances, although the need for additional therapy or repeated CSF examinations is unclear, it is not generally recommended.
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
Data to support use of alternatives to penicillin in the treatment of primary and secondary syphilis are limited.However, several therapies might be effective in nonpregnant, penicillin-allergic persons who have primary or secondary syphilis.Regimens of doxycycline 100 mg orally twice daily for 14 days (411,412) and tetracycline (500 mg four times daily for 14 days) have been used for many years.Compliance is likely to be better with doxycycline than tetracycline, because tetracycline can cause gastrointestinal side effects and requires more frequent dosing.Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone (1-2 g daily either IM or IV for 10-14 days) is effective for treating primary and secondary syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined (413).Azithromycin as a single 2 g oral dose has been effective for treating primary and secondary syphilis in some populations (414)(415)(416).However, T. pallidum chromosomal mutations associated with azithromycin and other macrolide resistance and treatment failures have been documented in multiple geographical areas in the United States (417)(418)(419).Accordingly, azithromycin should not be used as first-line treatment for syphilis and should be used with caution only when treatment with penicillin or doxycycline is not feasible.Azithromycin should not be used in MSM, persons with HIV, or pregnant women.Careful clinical and serologic follow-up of persons receiving any alternative therapies is essential.
Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin.Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Persons Who Have a History of Penicillin Allergy).
# Pregnancy
Pregnant women with primary or secondary syphilis who are allergic to penicillin should be desensitized and treated with penicillin.For more information, see Management of Persons Who Have a History of Penicillin Allergy and Syphilis During Pregnancy.
# HIV Infection
Persons with HIV infection who have primary or secondary syphilis should be treated as those without HIV infection.For more information on treatment and management, see Syphilis in Persons with HIV infection.
# Latent Syphilis
Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of primary, secondary, or tertiary disease.Persons who have latent syphilis and who acquired syphilis during the preceding year are classified as having early latent syphilis, a subset of latent syphilis.Persons can receive a diagnosis of early latent syphilis if, during the year preceding the diagnosis, they had 1) a documented seroconversion or a sustained (>2 week) fourfold or greater increase in nontreponemal test titers; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis.In addition, for persons with reactive nontreponemal and treponemal tests whose only possible exposure occurred during the previous 12 months, early latent syphilis can be assumed.In the absence of these conditions, an asymptomatic person should be considered to have latent syphilis.Nontreponemal serologic titers usually are higher early in the course of syphilis infection.However, early latent syphilis cannot be reliably diagnosed solely on the basis of nontreponemal titers.All persons with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, perianal area, perineum and vagina in women, and underneath the foreskin in uncircumcised men) to evaluate for mucosal lesions.
# Treatment
Because latent syphilis is not transmitted sexually, the objective of treating persons in this stage of disease is to prevent complications and transmission from a pregnant woman to her fetus.Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available to guide choice of specific regimens or duration.Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early latent syphilis do not enhance efficacy, regardless of HIV infection (406,407).
# Recommended Regimens for Infants and Children
Early Latent Syphilis Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose Late Latent Syphilis Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as 3 doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units)
Infants and children aged ≥1 month diagnosed with latent syphilis should be managed by a pediatric infectious-disease specialist and receive a CSF examination.In addition, birth and maternal medical records should be reviewed to assess whether these infants and children have congenital or acquired syphilis.For those with congenital syphilis, treatment should be undertaken as described in the congenital syphilis section in this document.Those with acquired latent syphilis should be evaluated for sexual abuse (e.g., through consultation with child protection services) (see Sexual Assault or Abuse of Children).These regimens are for penicillin nonallergic children who have acquired syphilis and who have normal CSF examination results.
# Other Management Considerations
All persons who have latent syphilis should be tested for HIV infection.Persons who receive a diagnosis of latent syphilis and have neurologic signs and symptoms (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis or stroke) should be evaluated for neurosyphilis (see Neurosyphilis).
If a person misses a dose of penicillin in a course of weekly therapy for latent syphilis, the appropriate course of action is unclear.Clinical experience suggests that an interval of 10-14 days between doses of benzathine penicillin for latent syphilis might be acceptable before restarting the sequence of injections (i.e., if dose 1 is given on day 0, dose 2 is administered between days 10 and 14).Pharmacologic considerations suggest that an interval of 7-9 days between doses, if feasible, might be more optimal (420)(421)(422).Missed doses are not acceptable for pregnant women receiving therapy for latent syphilis (423).
Pregnant women who miss any dose of therapy must repeat the full course of therapy.
# Follow-Up
Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months.A CSF examination should be performed if 1) a sustained (>2 weeks) fourfold increase or greater in titer is observed, 2) an initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months of therapy, or 3) signs or symptoms attributable to syphilis develop.In such circumstances, patients with CSF abnormalities should be treated for neurosyphilis.If the CSF examination is negative, retreatment for latent syphilis should be administered.Serologic titers might fail to decline despite a negative CSF examination and a repeated course of therapy, especially if the initial nontreponemal titer is low (<1:8); in these circumstances, the need for additional therapy or repeated CSF examinations is unclear but is generally not recommended.Serologic and clinical monitoring should be offered along with a reevaluation for HIV infection.
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented.Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to antibiotics recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Primary and Secondary Syphilis, Treatment).The only acceptable alternatives for the treatment of latent syphilis are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), each for 28 days.The efficacy of these alternative regimens in persons with HIV infection has not been well studied.These therapies should be used only in conjunction with close serologic and clinical follow-up, especially in persons with HIV infection.On the basis of biologic plausibility and pharmacologic properties, ceftriaxone might be effective for treating latent syphilis. |
However, the optimal dose and duration of ceftriaxone therapy have not been defined; treatment decisions should be discussed in consultation with a specialist.Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin.Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Persons Who Have a History of Penicillin Allergy).
# Pregnancy
Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin.For more information, see Management of Persons Who Have a History of Penicillin Allergy and Syphilis during Pregnancy.
# HIV Infection
Persons with HIV infection with latent syphilis should be treated as persons who do not have HIV infection.For more information on treatment and management of latent syphilis, see Syphilis in Persons with HIV Infection.
# Tertiary Syphilis
Tertiary syphilis refers to gummas and cardiovascular syphilis but not to neurosyphilis.Guidelines for all forms of neurosyphilis (e.g., early or late neurosyphilis) are discussed elsewhere in these recommendations (see Neurosyphilis).Persons who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen.
# Recommended Regimen Tertiary Syphilis with Normal CSF Examination
Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
# Other Management Considerations
All persons who have tertiary syphilis should be tested for HIV infection and should receive a CSF examination before therapy is initiated.Persons with CSF abnormalities should be treated with a neurosyphilis regimen.Some providers treat all persons who have cardiovascular syphilis with a neurosyphilis regimen.These persons should be managed in consultation with an infectious-disease specialist.Limited information is available concerning clinical response and follow-up of persons who have tertiary syphilis.
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
Providers should ask patients about known allergies to penicillin.Any person allergic to penicillin should be treated in consultation with an infectious-disease specialist.
# Pregnancy
Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin.For more information, see Management of Persons Who Have a History of Penicillin Allergy and Syphilis during Pregnancy.
# HIV Infection
Persons with HIV infection who have tertiary syphilis should be treated as described for persons without HIV infection.For more information on the management of tertiary syphilis in persons with HIV infection, see Syphilis in Persons with HIV Infection.
# Neurosyphilis Treatment
CNS involvement can occur during any stage of syphilis, and CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurologic findings.No evidence exists to support variation from recommended treatment for syphilis at any stage for persons without clinical neurologic findings, with the exception of tertiary syphilis.If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis or stroke), a CSF examination should be performed.
Syphilitic uveitis or other ocular manifestations (e.g., neuroretinitis and optic neuritis) can be associated with neurosyphilis.A CSF examination should be performed in all instances of ocular syphilis, even in the absence of clinical neurologic findings.Ocular syphilis should be managed in collaboration with an ophthalmologist and according to the treatment and other recommendations for neurosyphilis, even if a CSF examination is normal.In instances of ocular syphilis and abnormal CSF test results, follow-up CSF examinations should be performed to assess treatment response.
# Recommended Regimen Neurosyphilis and Ocular Syphilis
Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days
If compliance with therapy can be ensured, the following alternative regimen might be considered.
# Alternative Regimen
Procaine penicillin G 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times a day, both for 10-14 days
The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for latent syphilis.Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.
# Other Management Considerations
The following are other considerations in the management of persons who have neurosyphilis:
- All persons who have neurosyphilis should be tested for HIV. -Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be beneficial.
# Follow-Up
If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal.Follow-up CSF examinations also can be used to evaluate changes in the CSF-VDRL or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important (424,425).Leukocyte count is a sensitive measure of the effectiveness of therapy.If the cell count has not decreased after 6 months, or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered.Limited data suggest that in immunocompetent persons and persons with HIV infection on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters following neurosyphilis treatment (425).
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10-14 days can be used as an alternative treatment for persons with neurosyphilis (426,427).Cross-sensitivity between ceftriaxone and penicillin can occur, but the risk for penicillin cross-reactivity between third-generation cephalosporins is negligible (428-431) (see Management of Persons Who Have a History of Penicillin Allergy).If concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, penicillin desensitization in consultation with a specialist is recommended.Other regimens have not been adequately evaluated for treatment of neurosyphilis.
# Pregnancy
Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin.For more information, see Syphilis during Pregnancy.
# HIV Infection
Persons with HIV infection who have neurosyphilis should be treated as described for persons without HIV infection.For more information on neurosyphilis, see Syphilis in Persons with HIV infection.
# Persons with HIV Infection Diagnostic Considerations
Interpretation of treponemal and nontreponemal serologic tests for persons with HIV infection is the same as for the HIV-uninfected patient.Although rare, unusual serologic responses have been observed among persons with HIV infection who have syphilis; although most reports have involved post-treatment serologic titers that were higher than expected (high serofast) or fluctuated, false-negative serologic test results and delayed appearance of seroreactivity have also been reported (432).
When clinical findings are suggestive of syphilis but serologic tests are nonreactive or their interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, and PCR of lesion material) might be useful for diagnosis.Neurosyphilis should be considered in the differential diagnosis of neurologic signs and symptoms in persons with HIV infection.
# Treatment
Persons with HIV infection who have early syphilis might be at increased risk for neurologic complications (433) and might have higher rates of serologic treatment failure with recommended regimens.The magnitude of these risks is not defined precisely, but is likely small.Although longterm (>1 year) comparative data are lacking, no treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in persons with HIV infection than the syphilis regimens recommended for persons without HIV infection (406).Careful follow-up after therapy is essential.The use of antiretroviral therapy as per current guidelines might improve clinical outcomes in persons with HIV infection and syphilis (425,434,435).
# Primary and Secondary Syphilis among Persons with HIV Infection
# Recommended Regimen
Benzathine penicillin G, 2.4 million units IM in a single dose Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in primary and secondary syphilis do not result in enhanced efficacy (406,407).
# Other Management Considerations
Most persons with HIV infection respond appropriately to the recommended benzathine penicillin treatment regimen for primary and secondary syphilis.CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in persons with HIV infection, even in those without syphilis.The clinical and prognostic significance of such CSF laboratory abnormalities in persons with primary and secondary syphilis who lack neurologic symptoms is unknown.Certain studies have demonstrated that among persons with HIV infection and syphilis, CSF abnormalities are associated with a CD4 count of ≤350 cells/mL and/or an RPR titer of ≥1:32 (404,436,437); however, CSF examination has not been associated with improved clinical outcomes in the absence of neurologic signs and symptoms.All persons with HIV infection and syphilis should have a careful neurologic exam (425,434,435).
# Follow-Up
Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy; those who meet the criteria for treatment failure (i.e., signs or symptoms that persist or recur or persons who have a sustained fourfold increase or greater in titer) should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and retreatment guided by CSF findings).In addition, CSF examination and retreatment can be considered for persons whose nontreponemal test titers do not decrease fourfold within 12-24 months of therapy.If CSF examination is normal, treatment with benzathine penicillin G administered as 2.4 million units IM each at weekly intervals for 3 weeks is recommended.Serologic titers might not decline despite a negative CSF examination and a repeated course of therapy (410).In these circumstances, the need for additional therapy or repeated CSF examinations is unclear, but is not generally recommended.Serologic and clinical monitoring should be provided.
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
Persons with HIV infection who are penicillin-allergic and have primary or secondary syphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative persons.Persons with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Persons Who Have a History of Penicillin Allergy).The use of alternatives to penicillin has not been well studied in persons with HIV infection; azithromycin is not recommended in persons with HIV infection and primary and secondary syphilis.Alternative therapies should be used only in conjunction with close serologic and clinical follow-up.
# Latent Syphilis among Persons with HIV Infection Recommended Regimen for Early Latent Syphilis
Benzathine penicillin G, 2.4 million units IM in a single dose
# Recommended Regimen for Late Latent Syphilis
Benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks
# Other Management Considerations
All persons with HIV infection and syphilis should undergo a careful neurologic examination; those with neurologic symptoms or signs should undergo immediate CSF examination.In the absence of neurologic symptoms, CSF examination has not been associated with improved clinical outcomes and therefore is not recommended.
# Follow-Up
Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy.If, at any time, clinical symptoms develop or a sustained (>2 weeks) fourfold or greater rise in nontreponemal titers occurs, a CSF examination should be performed and treatment administered accordingly.If the nontreponemal titer does not decline fourfold after 24 months, CSF examination can be considered and treatment administered accordingly, although initial low titers (<1:8) might not decline.Even after retreatment, serologic titers might fail to decline.In these circumstances, the need for repeated CSF examination or additional therapy is unclear but is generally not recommended.Serologic and clinical monitoring should be provided.
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
The efficacy of alternative nonpenicillin regimens in persons with HIV infection has not been well studied, and these therapies should be used only in conjunction with close serologic and clinical follow-up.Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (See Management of Persons Who Have a History of Penicillin Allergy).
# Neurosyphilis Among Persons with HIV Infection
All persons with HIV infection and syphilis should receive a careful neurologic examination.Persons with HIV infection and neurosyphilis should be treated according to the recommendations for HIV-negative persons with neurosyphilis (See Neurosyphilis).
# Follow Up
Persons with HIV infection and neurosyphilis should be managed according to the recommendations for HIV-negative persons with neurosyphilis (see Neurosyphilis).Limited data suggest that changes in CSF parameters might occur more slowly in persons with HIV infection, especially those with more advanced immunosuppression (424,434).
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations Penicillin Allergy
Persons with HIV infection who are penicillin-allergic and have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis (See Neurosyphilis).Several small observational studies conducted in persons with HIV infection with neurosyphilis suggest that ceftriaxone 1-2 g IV daily for 10-14 days might be effective as an alternate agent (438)(439)(440).The possibility of cross-sensitivity between ceftriaxone and penicillin exists, but the risk of penicillin cross-reactivity between third-generation cephalosporins is negligible (428-431) (see Management of Persons Who Have a History of Penicillin Allergy).If concern exists regarding the safety of ceftriaxone for a person with HIV infection and neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, penicillin desensitization in consultation with a specialist is recommended.Other regimens have not been adequately evaluated for treatment of neurosyphilis.
# Syphilis During Pregnancy
All women should be screened serologically for syphilis early in pregnancy (106).Most states mandate screening at the first prenatal visit for all women (441).In populations in which receipt of prenatal care is not optimal, RPR test screening and treatment (if the RPR test is reactive) should be performed at the time pregnancy is confirmed (442).Antepartum screening by nontreponemal antibody testing is typical, but treponemal antibody testing is being used in some settings.Pregnant women with reactive treponemal screening tests should have additional quantitative nontreponemal testing, because titers are essential for monitoring treatment response.For communities and populations in which the prevalence of syphilis is high and for women at high risk for infection, serologic testing should also be performed twice during the third trimester: once at 28-32 weeks' gestation and again at delivery.Any woman who has a fetal death after 20 weeks' gestation should be tested for syphilis.No mother or neonate should leave the hospital without maternal serologic status having been documented at least once during pregnancy, and if the mother is considered high risk, documented at delivery.
# Diagnostic Considerations
Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined appropriately for the stage of syphilis.In general, the risk for antepartum fetal infection or congenital syphilis at delivery is related to the stage of syphilis during pregnancy, with the highest risk occurring with the primary and secondary stage.Quantitative maternal nontreponemal titer, especially if >1:8, might be a marker of early infection and bacteremia.However, risk for fetal infection is still significant in pregnant women with late latent syphilis and low titers.Pregnant women with stable, serofast low antibody titers who have previously been treated for syphilis might not require additional treatment; however, rising or persistently high antibody titers might indicate reinfection or treatment failure, and treatment should be considered.
If a treponemal test (e.g., EIA or CIA) is used for antepartum syphilis screening, all positive EIA/CIA tests should be reflexed to a quantitative nontreponemal test (RPR or VDRL).If the nontreponemal test is negative, then the results are considered discrepant and a second treponemal test (TP-PA preferred) should be performed, preferably on the same specimen.If the second treponemal test is positive, current or past syphilis infection can be confirmed.For women with a history of adequately treated syphilis who do not have ongoing risk, no further treatment is necessary.Women without a history of treatment should be staged and treated accordingly with a recommended penicillin regimen.If the second treponemal test is negative, the positive EIA/CIA is more likely to represent a false-positive test result in low-risk women with no history of treated syphilis (400).If the woman is at low risk for syphilis, lacks signs or symptoms of primary syphilis, has a partner with no clinical or serologic evidence of syphilis, and is likely to follow up, repeat serologic testing within 4 weeks can be considered to determine whether the EIA/CIA remains positive or if the RPR/VDRL or the TP-PA becomes positive.If both the RPR and TP-PA remain negative, no further treatment is necessary.If follow-up is not possible, women without a history of treated syphilis should be treated according to the stage of syphilis.
# Treatment
Penicillin G is the only known effective antimicrobial for preventing maternal transmission to the fetus and treating fetal infection (443).Evidence is insufficient to determine optimal, recommended penicillin regimens (444).
# Recommended Regimen
Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection.
# Other Management Considerations
- Some evidence suggests that additional therapy is beneficial for pregnant women.For women who have primary, secondary, or early latent syphilis, a second dose of benzathine penicillin 2.4 million units IM can be administered 1 week after the initial dose (445-447). -When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for congenital syphilis.However, this evaluation should not delay therapy. |
Sonographic signs of fetal or placental syphilis (i.e., hepatomegaly, ascites, hydrops, fetal anemia, or a thickened placenta) indicate a greater risk for fetal treatment failure (448); cases accompanied by these signs should be managed in consultation with obstetric specialists.Evidence is insufficient to recommend specific regimens for these situations. -Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction (449).These women should be advised to seek obstetric attention after treatment if they notice any fever, contractions, or decrease in fetal movements.Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment.No data are available to suggest that corticosteroid treatment alters the risk for treatment-related complications in pregnancy. -Missed doses are not acceptable for pregnant women receiving therapy for late latent syphilis (423).Pregnant women who miss any dose of therapy must repeat the full course of therapy. -All women who have syphilis should be offered testing for HIV infection.
# Follow-Up
Coordinated prenatal care and treatment are vital.At a minimum, serologic titers should be repeated at 28-32 weeks' gestation and at delivery.Serologic titers can be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high.Providers should ensure that the clinical and antibody responses are appropriate for the patient's stage of disease, although most women will deliver before their serologic response to treatment can be assessed definitively.Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, clinical signs of infection are present at delivery, or the maternal antibody titer at delivery is fourfold higher than the pretreatment titer.
# Management of Sex Partners
See Syphilis, Management of Sex Partners.
# Special Considerations
# Penicillin Allergy
No proven alternatives to penicillin are available for treatment of syphilis during pregnancy.Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin.Skin testing or oral graded penicillin dose challenge might be helpful in identifying women at risk for acute allergic reactions (see Management of Persons Who Have a History of Penicillin Allergy).
Tetracycline and doxycycline are contraindicated in the second and third trimester of pregnancy (317).Erythromycin and azithromycin should not be used, because neither reliably cures maternal infection or treats an infected fetus (444).Data are insufficient to recommend ceftriaxone for treatment of maternal infection and prevention of congenital syphilis.
# HIV Infection
Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV.All women with HIV infection should be evaluated for syphilis and receive a penicillin regimen appropriate for the stage of infection.Data are insufficient to recommend any alternative regimens for pregnant women with HIV infection (see Syphilis Among Persons with HIV infection).
# Congenital Syphilis
Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit.Additional testing at 28 weeks' gestation and again at delivery is warranted for women who are at increased risk or live in communities with increased prevalence of syphilis infection (442,450).Moreover, as part of the management of pregnant women who have syphilis, information concerning ongoing risk behaviors and treatment of sex partners should be obtained to assess the risk for reinfection.Routine screening of newborn sera or umbilical cord blood is not recommended, as diagnosis at this time does not prevent symptomatic congenital syphilis in some newborns.No mother or newborn infant should leave the hospital without maternal serologic status having been documented at least once during pregnancy, and preferably again at delivery if at risk.
# Evaluation and Treatment of Neonates (Infants Aged <30 Days)
The diagnosis of congenital syphilis can be difficult, as maternal nontreponemal and treponemal IgG antibodies can be transferred through the placenta to the fetus, complicating the interpretation of reactive serologic tests for syphilis in neonates.Therefore, treatment decisions frequently must be made on the basis of 1) identification of syphilis in the mother; 2) adequacy of maternal treatment; 3) presence of clinical, laboratory, or radiographic evidence of syphilis in the neonate; and 4) comparison of maternal (at delivery) and neonatal nontreponemal serologic titers using the same test, preferably conducted by the same laboratory.Any neonate at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.
All neonates born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on the neonate's serum, because umbilical cord blood can become contaminated with maternal blood and yield a false-positive result, and Wharton's jelly within the umbilical cord can yield a false-negative result.Conducting a treponemal test (i.e., TP-PA, FTA-ABS, EIA, or CIA) on neonatal serum is not recommended because it is difficult to interpret.No commercially available immunoglobulin (IgM) test can be recommended.
All neonates born to women who have reactive serologic tests for syphilis should be examined thoroughly for evidence of congenital syphilis (e.g., nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, and pseudoparalysis of an extremity).Pathologic examination of the placenta or umbilical cord using specific staining (e.g., silver) or a T. pallidum PCR test using a CLIAvalidated test should be considered; DFA-TP reagents are not available.Darkfield microscopic examination or PCR testing of suspicious lesions or body fluids (e.g., bullous rash and nasal discharge) also should be performed.In addition to these tests, for stillborn infants, skeletal survey demonstrating typical osseous lesions might aid in the diagnosis of congenital syphilis.
The following scenarios describe the congenital syphilis evaluation and treatment of neonates born to women who have reactive serologic tests for syphilis during pregnancy.Maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the neonate for congenital syphilis in most scenarios, except when congenital syphilis is proven or highly probable (See Scenario 1).
# Scenario 1: Proven or highly probable congenital syphilis
Any neonate with: 1.an abnormal physical examination that is consistent with congenital syphilis; OR 2.a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer; ¶ OR 3.a positive darkfield test or PCR of lesions or body fluid(s).
# Recommended Evaluation
# Recommended Regimens
Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days
If more than 1 day of therapy is missed, the entire course should be restarted.Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin).When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis.The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy.
# Scenario 2: Possible Congenital Syphilis
Any neonate who has a normal physical examination and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and one of the following:
1.mother was not treated, inadequately treated, or has no documentation of having received treatment; OR 2.mother was treated with erythromycin or a regimen other than those recommended in these guidelines (i.e., a nonpenicillin G regimen); † † OR 3.mother received recommended treatment <4 weeks before delivery.
# Recommended Evaluation
- CSF analysis for VDRL, cell count, and protein - CBC, differential, and platelet count - Long-bone radiographs A complete evaluation is not necessary if 10 days of parenteral therapy is administered, although such evaluations might be useful.For instance, a lumbar puncture might document CSF abnormalities that would prompt close follow-up.Other tests (e.g., CBC, platelet count, and bone radiographs) can be performed to further support a diagnosis of congenital syphilis.
# Recommended Regimens
Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days OR Benzathine penicillin G 50,000 units/kg/dose IM in a single dose Before using the single-dose benzathine penicillin G regimen, the complete evaluation (i.e., CSF examination, long-bone radiographs, and CBC with platelets) must be normal, and follow-up must be certain.If any part of the infant's evaluation is abnormal or not performed, if the CSF analysis is uninterpretable because of contamination with blood, or if follow-up is uncertain, a 10-day course of penicillin G is required.If the neonate's nontreponemal test is nonreactive and the provider determines that the mother's risk of untreated syphilis is low, treatment of the neonate with a single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis can be considered without an evaluation.
Neonates born to mothers with untreated early syphilis at the time of delivery are at increased risk for congenital syphilis, and the 10-day course of penicillin G may be considered even if the complete evaluation is normal and follow-up is certain.
# Scenario 3: Congenital Syphilis less likely
Any neonate who has a normal physical examination and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following are true:
1.mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and 2.mother has no evidence of reinfection or relapse.
# Recommended Evaluation
No evaluation is recommended.
# Recommended Regimen
Benzathine penicillin G 50,000 units/kg/dose IM in a single dose- - Another approach involves not treating the infant, but rather providing close serologic follow-up every 2-3 months for 6 months for infants whose mother's nontreponemal titers decreased at least fourfold after appropriate therapy for early syphilis or remained stable for low-titer, latent syphilis (e.g., VDRL <1:2; RPR <1:4).
# Scenario 4: Congenital Syphilis unlikely
Any neonate who has a normal physical examination and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following are true:
1.mother's treatment was adequate before pregnancy and 2.mother's nontreponemal serologic titer remained low and stable (i.e., serofast) before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).
# Recommended Evaluation
No evaluation is recommended.
# Recommended Regimen
No treatment is required, but infants with reactive nontreponemal tests should be followed serologically to ensure the nontreponemal test returns to negative (see Follow-Up).Benzathine penicillin G 50,000 units/kg as a single IM injection might be considered, particularly if follow-up is uncertain and the neonate has a reactive nontreponemal test.
# Follow-Up
All neonates with reactive nontreponemal tests should receive careful follow-up examinations and serologic testing (i.e., a nontreponemal test) every 2-3 months until the test becomes nonreactive.In the neonate who was not treated because congenital syphilis was considered less likely or unlikely, nontreponemal antibody titers should decline by age 3 months and be nonreactive by age 6 months, indicating that the reactive test result was caused by passive transfer of maternal IgG antibody.At 6 months, if the nontreponemal test is nonreactive, no further evaluation or treatment is needed; if the nontreponemal test is still reactive, the infant is likely to be infected and should be treated.Treated neonates that exhibit persistent nontreponemal test titers by 6-12 months should be re-evaluated through CSF examination and managed in consultation with an expert.Retreatment with a 10-day course of a penicillin G regimen may be indicated.Neonates with a negative nontreponemal test at birth and whose mothers were seroreactive at delivery should be retested at 3 months to rule out serologically negative incubating congenital syphilis at the time of birth.Treponemal tests should not be used to evaluate treatment response because the results are qualitative and passive transfer of maternal IgG treponemal antibody might persist for at least 15 months.
Neonates whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal.A reactive CSF Venereal Disease Research Laboratory (VDRL) test or abnormal CSF indices that persist and cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis and should be managed in consultation with an expert.
# Special Considerations
# Penicillin Allergy
Infants and children who require treatment for congenital syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and then treated with penicillin (see Management of Persons with a History of Penicillin Allergy).Skin testing remains unavailable for infants and children because the procedure has not been standardized for this age group.Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone) for congenital syphilis in infants and children.If a nonpenicillin G agent is used, close clinical, serologic, and CSF follow-up is required in consultation with an expert.
# Penicillin Shortage
During periods when the availability of aqueous crystalline penicillin G is compromised, the following is recommended (see ).
1.For neonates with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium).If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days).If aqueous or procaine penicillin G is not available, ceftriaxone (in doses appropriate for birthweight) can be considered with careful clinical and serologic follow-up and in consultation with an expert, as evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis.Management might include a repeat CSF examination at age 6 months if the initial examination was abnormal.Ceftriaxone must be used with caution in infants with jaundice.
2.For neonates without any clinical evidence of congenital syphilis (Scenario 2 and Scenario 3), use a. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days OR b. benzathine penicillin G, 50,000 U/kg IM as a single dose.If any part of the evaluation for congenital syphilis is abnormal or was not performed, CSF examination is not interpretable, or follow-up is uncertain, procaine penicillin G is recommended.A single dose of ceftriaxone is inadequate therapy.
# For premature infants who have no clinical evidence
-f congenital syphilis (Scenario 2 and Scenario 3) and might not tolerate IM injections because of decreased muscle mass, IV ceftriaxone can be considered with careful clinical and serologic follow-up and in consultation with an expert.Ceftriaxone dosing must be adjusted according to birthweight.
# HIV Infection
Evidence is insufficient to determine whether neonates who have congenital syphilis and HIV or whose mothers have HIV infection require different therapy or clinical management than is recommended for all neonates.All neonates with congenital syphilis and HIV infection should be managed similarly as neonates with congenital syphilis who do not have HIV infection.
# Evaluation and Treatment of Infants and Children with Congenital Syphilis
Infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should be examined thoroughly and have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse of Children).Any infant or child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.
# Recommended Evaluation
- CSF analysis for VDRL, cell count, and protein - CBC, differential, and platelet count - Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, neuroimaging, and auditory brain-stem response)
# Recommended Regimen
Aqueous crystalline penicillin G 200,000-300,000 units/kg/day IV, administered as 50,000 units/kg every 4-6 hours for 10 days
If the infant or child has no clinical manifestations of congenital syphilis and the evaluation (including the CSF examination) is normal, treatment with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM can be considered.A single dose of benzathine penicillin G 50,000 units/kg IM up to the adult dose of 2.4 million units in a single dose can be considered after the 10-day course of IV aqueous penicillin to provide more comparable duration of treatment in those who have no clinical manifestations and normal CSF.All of the above treatment regimens also would be adequate for children who might have other treponemal infections.
# Follow-Up
Careful follow-up examinations and serologic testing (i.e., a nontreponemal test) of infants and children treated for congenital syphilis after the neonatal period (30 days of age) should be performed every 3 months until the test becomes nonreactive or the titer has decreased fourfold.The serologic response after therapy might be slower for infants and children than neonates.If these titers increase at any point for more than 2 weeks or do not decrease fourfold after 12-18 months, the infant or child should be evaluated (e.g., through CSF examination), treated with a 10-day course of parenteral penicillin G, and managed in consultation with an expert.Treponemal tests should not be used to evaluate treatment response, because the results are qualitative and persist after treatment; further, passive transfer of maternal IgG treponemal antibody might persist for at least 15 months after delivery.
Infants or children whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal.After 2 years of follow-up, a reactive CSF VDRL test or abnormal CSF indices that persists and cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis and should be managed in consultation with an expert. |
# Special Considerations
# Penicillin Allergy
Infants and children who require treatment for congenital syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and treated with penicillin (see Management of Persons with a History of Penicillin Allergy).Skin testing remains unavailable for infants and children because the procedure has not been standardized for this age group.Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone) for congenital syphilis in infants and children.If a nonpenicillin G agent is used, close clinical, serologic, and CSF follow-up is required in consultation with an expert.
# Penicillin Shortage
During periods when the availability of penicillin G is compromised, management options are similar to options for the neonate (see Evaluation and treatment of infants during the first month of life).
1.For infants and children with clinical evidence of congenital syphilis, procaine penicillin G (50,000 U/kg/ dose IM up to the adult dose of 2.4 million units a day in a single daily dose for 10 days) is recommended.A single dose of benzathine penicillin G 50,000 units/kg IM up to the adult dose of 2.4 million units in a single dose can be considered after the 10-day course of procaine penicillin.If procaine or benzathine penicillin G is not available, ceftriaxone (in doses appropriate for age and weight) can be considered with careful clinical and serologic follow-up.Infants and children receiving ceftriaxone should be managed in consultation with an expert, as evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis in infants or children.For infants aged ≥30 days, use 75 mg/kg IV/IM of ceftriaxone a day in a single daily dose for 10-14 days (dose adjustment might be necessary based on current weight).For children, the dose should be 100 mg/kg of ceftriaxone a day in a single daily dose.2.For infants and children without any clinical evidence of infection (see Scenario 2 and Scenario 3), use a. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days or b. benzathine penicillin G, 50,000 U/kg IM as a single dose.If any part of the evaluation for congenital syphilis is abnormal or not performed, CSF examination is not interpretable, or follow-up is uncertain, procaine penicillin G is recommended.
# HIV Infection
Evidence is insufficient to determine whether infants and children who have congenital syphilis and HIV or whose mothers have HIV infection require different therapy or clinical management than is recommended for all infants and children.All infants and children with congenital syphilis and HIV infection should be managed like infants and children without HIV infection.
# Management of Persons Who Have a History of Penicillin Allergy
No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women.Penicillin also is recommended, whenever possible, for persons with HIV infection.The prevalence of reported penicillin allergy in the United States is about 8%-10% (451)(452)(453) and might be higher in hospitalized persons (454).The prevalence of reported penicillin allergy in developing countries is unknown; however, limited data suggest that penicillin is one of the most frequently reported allergies in some developing countries (455,456).Of persons reporting penicillin allergy, 10%-15% have a positive skin test suggestive of a penicillin allergy; these persons are at risk for an immunoglobulin E (IgE)-mediated allergic response to penicillin such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension) (428)(429)(430)457,458).Re-administration of penicillin to patients with a history of IgE-mediated hypersensitivity reactions can cause severe, immediate reactions.Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic persons, unless they undergo induction of drug tolerance (also referred to as "desensitization") to temporarily eliminate IgE-mediated hypersensitivity.However, many persons with a reported history of penicillin allergy likely have had other types of adverse drug reactions or have lost their sensitivity to penicillin over time and can safely be treated with penicillin.
Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for IgE-mediated reactions to penicillin (458,459).Although the testing reagents are easily generated, only the major determinant (benzylpenicilloyl poly-L-lysine ) and penicillin G have been available commercially.These two tests identify an estimated 90%-99% of the allergic patients.However, because skin testing without the minor determinants would still fail to identify 1%-10% of allergic persons and because serious or fatal reactions can occur among these minordeterminant-positive persons, caution should be exercised when the full battery of skin-test reagents is not available (Box 2) (457-460).Manufacturers are working on a minor determinant mixture, but at the time of publication, no such product has been cleared by FDA for use in the United States.Penicillin skin testing has been used in a variety of settings to improve antibiotic use (453,(461)(462)(463).
Some studies have reported cross-reactivity rates as high as 10% among persons with a history of penicillin allergy who take cephalosporins.However, more recent studies indicate a lower rate (<2.5%) of cross reactivity between these drugs (428)(429)(430)(431)464).Risk is highest with first-generation cephalosporins and cephalosporins that have similar R-group side chains to specific penicillins (465,466).The risk for penicillin cross-reactivity between most second-generation (cefoxitin) and all third generation cephalosporins (cefixime and ceftriaxone) is negligible (428)(429)(430)(431); cefoxitin, cefixime, and ceftriaxone do not have an R group side chain similar to penicillin G.
# Recommendations
Persons with a history of severe non-IgE-mediated reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, and hemolytic anemia) are not candidates
# Penicillin Allergy Skin Testing
Persons at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphylaxis or other IgE-mediated reactions, asthma, or other diseases that would make anaphylaxis more dangerous or 2) are being treated with beta-adrenergic blocking agents should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents.In these situations, testing should be performed in a monitored setting in which treatment for an anaphylactic reaction is available.If possible, antihistamines (e.g., chlorpheniramine maleate, fexofenadine, diphenhydramine HCL, and hydroxyzine) should not have been taken within the 5 days before skin testing.
# Procedures
Dilute the antigens in saline either 100-fold for preliminary testing (if the patient has had a IgE-mediated reaction to penicillin) or 10-fold (if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year).Pre-Pen is provided full-strength (6 x 10-5 meq penicilloyl) in a single dose ampoule.Penicillin G is diluted to 10,000 IU/ml in saline and aliquoted in sterile vials that remain stable for at least 6 months if frozen.
# Epicutaneous (Prick) Tests
Duplicate drops of skin-test reagent are placed on the volar surface of the forearm.The underlying epidermis is pierced with a 26-gauge needle without drawing blood.An epicutaneous test is positive if the average wheal diameter after 15 minutes is ≥4 mm larger than that of negative controls; otherwise, the test is negative.The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs.
# Intradermal Test
If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26or 27-gauge needle on a syringe.The margins of the wheals induced by the injections should be marked with a ball point pen.An intradermal test is positive if the average wheal diameter 15 minutes after injection is >2 mm larger than the initial wheal size and also is >2 mm larger than the histamine controls.Otherwise, the tests are negative.If the duplicates are discordant, a second set of duplicate tests can be used to resolve the ambiguity.
# Desensitization
Persons who have a positive skin test to one of the penicillin determinants can be desensitized (Table 1).This is a for skin testing or challenge and should avoid penicillins indefinitely.If the full battery of skin-test reagents is available, including both major and minor determinants (see Penicillin Allergy Skin Testing), persons who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy.Persons with positive skin test results should be desensitized before initiating treatment.
If the full battery of skin-test reagents, including the minor determinants, is not available, skin testing should be conducted using the major determinant (Pre-Pen) and penicillin G. Those persons who have positive test results should be desensitized.For persons with negative skin tests, a subsequent observed challenge to the penicillin of choice is recommended.In addition, for persons with a history of severe or recent suspected IgE-mediated reactions to penicillin with negative skin testing, the penicillin of choice should be given by graded challenge.If the major determinant is not available for skin testing, all persons with a history suggesting IgE-mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting.In persons with reactions not likely to be IgE-mediated, outpatientmonitored graded challenges can be considered. straightforward, relatively safe procedure that can be performed orally or intravenously.Modified protocols might be considered based on an individual's symptoms, drug of choice, and route of administration (467)(468)(469).Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform.Desensitization should occur in a hospital setting because serious IgE-mediated allergic reactions can occur; the procedure can usually be completed in approximately 4-12 hours, after which time the first dose of penicillin is administered.After desensitization, penicillin should be maintained continuously for the duration of the course of therapy.Once the course is completed, if penicillin is required in the future, the desensitization procedure should be repeated.
# Diseases Characterized by Urethritis and Cervicitis Urethritis
Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions.Symptoms, if present, include dysuria; urethral pruritis; and mucoid, mucopurulent, or purulent discharge.Signs of urethral discharge on examination can also be present in persons without symptoms.Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis and, less commonly, prostatitis (470)(471)(472)(473)(474).If point-of-care diagnostic tools (e.g., Gram, methylene blue or gentian violet stain microscopy, first void urine with microscopy, and leukocyte esterase) are not available, drug regimens effective against both gonorrhea and chlamydia should be administered.Further testing to determine the specific etiology is recommended to prevent complications, re-infection, and transmission because a specific diagnosis might improve treatment compliance, delivery of risk reduction interventions, and partner notification.Both chlamydia and gonorrhea are reportable to health departments.NAATs are preferred for the detection of C. trachomatis and N. gonorrhoeae, and urine is the preferred specimen in males (394).NAAT-based tests for the diagnosis of T. vaginalis in men have not been cleared by FDA; however, some laboratories have performed the CLIA-compliant validation studies (475) needed to provide such testing.
# Etiology
Several organisms can cause infectious urethritis.The presence of Gram-negative intracellular diplococci (GNID) or MB/GV purple intracellular diplococci on urethral smear is indicative of presumed gonorrhea infection, which is frequently accompanied by chlamydial infection.NGU, which is diagnosed when microscopy of urethral secretions indicates inflammation without GNID or MB/GV purple intracellular diplococci, is caused by C. trachomatis in 15%-40% of cases; however, prevalence varies by age group, with a lower burden of disease occurring among older men (476).Documentation of chlamydial infection as the etiology of NGU is essential because of the need for partner referral for evaluation and treatment to prevent complications of chlamydia, especially in female partners.Complications of C. trachomatis-associated NGU among males include epididymitis, prostatitis, and reactive arthritis.
M. genitalium, which can be sexually transmitted, is associated with symptoms of urethritis as well as urethral inflammation and accounts for 15%-25% of NGU cases in the United States (470)(471)(472)(473).However, FDA-cleared diagnostic tests for M. genitalium are not available.
T. vaginalis can cause NGU in heterosexual men, but the prevalence varies substantially by region of the United States and within specific subpopulations.In some instances, NGU can be acquired by fellatio (i.e., oral penile contact), sometimes because of specific pathogens such as HSV, Epstein Barr Virus, and adenovirus (476); data supporting other Mycoplasma species and Ureaplasma as etiologic agents are inconsistent.Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis, urethral lesions, or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to recommended therapy.Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse (476).The importance of NGU not caused by defined pathogens is uncertain; neither complications (e.g., urethral stricture and epididymitis) nor adverse outcomes in sex partners have been identified in these cases.
# Diagnostic Considerations
Clinicians should attempt to obtain objective evidence of urethral inflammation.However, if point-of-care diagnostic tests (e.g., Gram, MB or GV, or Gram stain microscopy) are not available, all men should be tested by NAAT and treated with drug regimens effective against both gonorrhea and chlamydia.
In the setting of compatible symptoms, urethritis can be documented on the basis of any of the following signs or laboratory tests:
- Mucoid, mucopurulent, or purulent discharge on examination. -Gram stain of urethral secretions demonstrating ≥2 WBC per oil immersion field (477).The Gram stain is a pointof-care diagnostic test for evaluating urethritis that is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection.MB/GV stain of urethral secretions is an alternative point-of-care diagnostic test with performance characteristics similar to Gram stain; thus, the cutoff number for WBC per oil immersion field should be the same (478).Presumed gonococcal infection is established by documenting the presence of WBC containing GNID in Gram stain or intracellular purple diplococci in MB/GV smears; men should be presumptively treated and managed accordingly for gonorrhea (GC) infection (see Gonococcal Infections). -Positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun firstvoid urine demonstrating ≥10 WBC per high power field.In settings where Gram stain or MB/GV smear is available, men who meet criteria for urethritis (microscopy of urethral secretions with ≥2 WBC per oil immersion field and no intracellular gram negative or purple diplococci) should receive NAAT testing for C. trachomatis and N. gonorrhoeae and can be managed as recommended (see Nongonococcal Urethritis).Men evaluated in settings in which Gram stain or MB/GV smear is not available (i.e., gonococcal infection cannot be ruled out at the point of care) who meet at least one criterion for urethritis (i.e., urethral discharge, positive LE test on first void urine, or microscopic exam of first void urine sediment with ≥10 WBC per hfp) should be tested by NAAT and treated with regimens effective against gonorrhea and chlamydia.
If symptoms are present but no evidence of urethral inflammation is present, NAAT testing for C. trachomatis and N. gonorrhoeae might identify infections (479).If the results demonstrate infection with these pathogens, the appropriate treatment should be given and sex partners referred for evaluation and treatment.If none of these clinical criteria are present, empiric treatment of symptomatic men is recommended only for those men at high risk for infection who are unlikely to return for a follow-up evaluation or test results.Such men should be treated with drug regimens effective against gonorrhea and chlamydia.
# Nongonococcal Urethritis Diagnostic Considerations
NGU is a nonspecific diagnosis that can have many infectious etiologies.NGU is confirmed in symptomatic men when staining of urethral secretions indicates inflammation without Gram negative or purple diplococci.All men who have confirmed NGU should be tested for chlamydia and gonorrhea even if point-of-care tests are negative for evidence of GC.NAATs for chlamydia and gonorrhea are recommended because of their high sensitivity and specificity; a specific diagnosis can potentially reduce complications, re-infection, and transmission (394).Testing for T. vaginalis should be considered in areas or populations of high prevalence.
# Treatment
Presumptive treatment should be initiated at the time of NGU diagnosis.Azithromycin and doxycycline are highly effective for chlamydial urethritis.NGU associated with M. genitalium currently responds better to azithromycin than doxycycline, although azithromycin efficacy might be declining (See Mycoplasma genitalium).
# Recommended Regimens
Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days
# Alternative Regimens
Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days As a directly observed treatment, single-dose regimens might be associated with higher rates of compliance over other regimens.To maximize compliance with recommended therapies, medications should be dispensed onsite in the clinic, and regardless of the number of doses involved in the regimen, the first should be directly observed.
# Other Management Considerations
To minimize transmission and reinfection, men treated for NGU should be instructed to abstain from sexual intercourse until they and their partner(s) have been adequately treated (i.e., for 7 days after single-dose therapy or until completion of a 7-day regimen and symptoms resolved).Men who receive a diagnosis of NGU should be tested for HIV and syphilis.
# Follow-Up
Men should be provided results of the testing obtained as part of the NGU evaluation, and those with a specific diagnosis of chlamydia, gonorrhea, or trichomonas should be offered partner services and instructed to return 3 months after treatment for repeat testing because of high rates of reinfection, regardless of whether their sex partners were treated (480,481) (see Chlamydia, Follow-Up and Gonorrhea, Follow-Up).
If symptoms persist or recur after completion of therapy, men should be instructed to return for re-evaluation. |
Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for retreatment.Providers should be alert to the possible diagnosis of chronic prostatitis/chronic pelvic pain syndrome in men experiencing persistent perineal, penile, or pelvic pain or discomfort, voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months.Men with persistent pain should be referred to a urologist.
# Management of Sex Partners
All sex partners of men with NGU within the preceding 60 days should be referred for evaluation, testing, and presumptive treatment with a drug regimen effective against chlamydia.EPT is an alternative approach to treating female partners for CT in the absence of signs and symptoms of PID (95).If N. gonorrhea or T. vaginalis is documented, all partners should be evaluated and treated according to the management section for their respective pathogen.To avoid reinfection, sex partners should abstain from sexual intercourse until they and their partner(s) are adequately treated.
# Persistent and Recurrent NGU
The objective diagnosis of persistent or recurrent NGU should be made before considering additional antimicrobial therapy.In men who have persistent symptoms after treatment without objective signs of urethral inflammation, the value of extending the duration of antimicrobials has not been demonstrated.Men who have persistent or recurrent NGU can be retreated with the initial regimen if they did not comply with the treatment regimen or were re-exposed to an untreated sex partner.
Recent studies have shown that the most common cause of persistent or recurrent NGU is M. genitalium, especially following doxycycline therapy (277,278).Azithromycin 1 g orally in a single dose should be administered to men initially treated with doxycycline.Certain observational studies have shown that moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium.Therefore, men who fail a regimen of azithromycin should be retreated with moxifloxacin 400 mg orally once daily for 7 days.Higher doses of azithromycin have not been found to be effective for M. genitalium in cases of azithromycin failure (280).
T. vaginalis is also known to cause urethritis in men who have sex with women.Although no NAAT for T. vaginalis detection in men has been FDA-cleared in the United States, several large reference laboratories have performed the necessary CLIA validation of a urine-based T. vaginalis NAAT for men for clinical use.Trichomonas NAAT testing is more sensitive than culture (475).In areas where T. vaginalis is prevalent, men who have sex with women and have persistent or recurrent urethritis should be presumptively treated with metronidazole 2 g orally in a single dose or tinidazole 2 g orally in a single dose; their partners should be referred for evaluation and appropriate treatment.Persons with persistent or recurrent NGU after presumptive treatment for M. genitalium or T. vaginalis should be referred to a urologist.
# Special Considerations HIV Infection
NGU might facilitate HIV transmission.Persons with NGU and HIV should receive the same treatment regimen as those who are HIV negative.
# Cervicitis
Two major diagnostic signs characterize cervicitis: 1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis) and 2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os.Either or both signs might be present.Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse).A finding of leukorrhea (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix.In the absence of the major diagnostic signs of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (i.e., cervicitis is unlikely in the absence of leucorrhea) (482,483).The criterion of using an increased number of WBCs on endocervical Gram stain in the diagnosis of cervicitis has not been standardized and therefore is not helpful.In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in most clinical settings.Finally, although the presence of gram negative intracellular diplococci on Gram stain of endocervical fluid may be specific for the diagnosis of gonococcal cervical infection when evaluated by an experienced laboratorian, it is not a sensitive indicator of infection.
# Etiology
When an etiologic organism is isolated in the presence of cervicitis, it is typically C. trachomatis or N. gonorrhoeae.Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection).However, in most cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (e.g., women aged >30 years) (484).Limited data indicate that infection with M. genitalium or BV and frequent douching might cause cervicitis (257)(258)(259)261,265,(485)(486)(487).For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy.Because most persistent cases of cervicitis are not caused by recurrent or reinfection with C. trachomatis or N. gonorrhoeae, other factors (e.g., persistent abnormality of vaginal flora, douching , or idiopathic inflammation in the zone of ectopy) might be involved.
# Diagnostic Considerations
Because cervicitis might be a sign of upper-genital-tract infection (endometritis), women with a new episode of cervicitis should be assessed for signs of PID and should be tested for C. trachomatis and for N. gonorrhoeae with NAAT; such testing can be performed on either vaginal, cervical, or urine samples (394) (see Chlamydia and Gonorrhea Diagnostic Considerations).Women with cervicitis also should be evaluated for the presence of BV and trichomoniasis, and if these are detected, they should be treated.Because the sensitivity of microscopy to detect T. vaginalis is relatively low (approximately 50%), symptomatic women with cervicitis and negative microscopy for trichomonads should receive further testing (i.e., culture, NAAT or other FDA approved diagnostic test) (see Trichomoniasis, Diagnosis).A finding of >10 WBC per high power field in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae (488,489).Although HSV-2 infection has been associated with cervicitis, the utility of specific testing (i.e., PCR, culture or serologic testing) for HSV-2 is unknown.FDA-cleared diagnostic tests for M. genitalium are not available.
# Treatment
Several factors should affect the decision to provide presumptive therapy for cervicitis.Presumptive treatment with antimicrobials for C. trachomatis and N. gonorrhoeae should be provided for women at increased risk (e.g., those aged <25 years and those with a new sex partner, a sex partner with concurrent partners, or a sex partner who has a sexually transmitted infection), especially if follow-up cannot be ensured or if testing with NAAT is not possible.Trichomoniasis and BV should also be treated if detected (see Bacterial Vaginosis and Trichomoniasis).For women at lower risk of STDs, deferring treatment until results of diagnostic tests are available is an option.If treatment is deferred and NAATs for C. trachomatis and N. gonorrhoeae are negative, a follow-up visit to see if the cervicitis has resolved can be considered.
Recommended Regimens for Presumptive Treatment- Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days *Consider concurrent treatment for gonococcal infection if patient is at risk for gonorrhea or lives in a community where the prevalence of gonorrhea is high.
# Other Considerations
To minimize transmission and reinfection, women treated for cervicitis should be instructed to abstain from sexual intercourse until they and their partner(s) have been adequately treated (i.e., for 7 days after single-dose therapy or until completion of a 7-day regimen) and symptoms have resolved.Women who receive a diagnosis of cervicitis should be tested for HIV and syphilis.
# Follow-Up
Women receiving treatment should return to their provider for a follow-up visit, allowing the provider to determine whether cervicitis has resolved.For women who are not treated, a follow-up visit gives providers an opportunity to communicate results of tests obtained as part of the cervicitis evaluation.Additional follow-up should be conducted as recommended for the infections identified.Women with a specific diagnosis of chlamydia, gonorrhea, or trichomonas should be offered partner services and instructed to return in 3 months after treatment for repeat testing because of high rates of reinfection, regardless of whether their sex partners were treated (480).If symptoms persist or recur, women should be instructed to return for re-evaluation.
# Management of Sex Partners
Management of sex partners of women treated for cervicitis should be appropriate for the specific STD identified or suspected.All sex partners in the past 60 days should be referred for evaluation, testing, and presumptive treatment if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the women with cervicitis.EPT or other effective partner referral strategies (see Partner Services) are alternative approaches to treating male partners of women who have chlamydia or gonococcal infection (93)(94)(95).To avoid reinfection, sex partners should abstain from sexual intercourse until they and their partner(s) are adequately treated.
# Persistent or Recurrent Cervicitis
Women with persistent or recurrent cervicitis despite having been treated should be reevaluated for possible re-exposure or treatment failure to gonorrhea or chlamydia.If relapse and/ or reinfection with a specific STD have been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined; in addition, the utility of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis remains unknown.The etiology of persistent cervicitis including the potential role of M. genitalium (490) is unclear.M. genitalium might be considered for cases of clinically significant cervicitis that persist after azithromycin or doxycycline therapy in which re-exposure to an infected partner or medical nonadherence is unlikely.In settings with validated assays, women with persistent cervicitis could be tested for M. genitalium with the decision to treat with moxifloxacin based on results of diagnostic testing (491).In treated women with persistent symptoms that are clearly attributable to cervicitis, referral to a gynecologic specialist can be considered.
# Special Considerations HIV Infection
Women with cervicitis and HIV infection should receive the same treatment regimen as those who are HIV negative.Cervicitis increases cervical HIV shedding.Treatment of cervicitis in women with HIV infection reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners (492)(493)(494)(495)(496).
# Pregnancy
Diagnosis and treatment of cervicitis in pregnant women does not differ from that in women that are not pregnant.For more information, see Cervicitis, sections on Diagnostic Considerations and Treatment.
# Chlamydial Infections Chlamydial Infections in Adolescents and Adults
Chlamydial infection is the most frequently reported infectious disease in the United States, and prevalence is highest in persons aged ≤24 years (118).Several sequelae can result from C. trachomatis infection in women, the most serious of which include PID, ectopic pregnancy, and infertility.Some women who receive a diagnosis of uncomplicated cervical infection already have subclinical upper-reproductive-tract infection.
Asymptomatic infection is common among both men and women.To detect chlamydial infections, health-care providers frequently rely on screening tests.Annual screening of all sexually active women aged <25 years is recommended, as is screening of older women at increased risk for infection (e.g., those who have a new sex partner, more than one sex partner, a sex partner with concurrent partners, or a sex partner who has a sexually transmitted infection (108).Although CT incidence might be higher in some women aged ≥25 years in some communities, overall the largest burden of infection is among women aged <25 years.
Chlamydia screening programs have been demonstrated to reduce the rates of PID in women (497,498).Although evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men because of several factors (e.g., feasibility, efficacy, and cost-effectiveness), the screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics) or in populations with high burden of infection (e.g., MSM) (108,121).Among women, the primary focus of chlamydia screening efforts should be to detect chlamydia, prevent complications, and test and treat their partners, whereas targeted chlamydia screening in men should only be considered when resources permit, prevalence is high, and such screening does not hinder chlamydia screening efforts in women (499,500).More frequent screening for some women (e.g., adolescents) or certain men (e.g., MSM) might be indicated.
# Diagnostic Considerations
C. trachomatis urogenital infection can be diagnosed in women by testing first-catch urine or collecting swab specimens from the endocervix or vagina.Diagnosis of C. trachomatis urethral infection in men can be made by testing a urethral swab or first-catch urine specimen.NAATs are the most sensitive tests for these specimens and therefore are recommended for detecting C. trachomatis infection (394).NAATs that are FDA-cleared for use with vaginal swab specimens can be collected by a provider or self-collected in a clinical setting.Selfcollected vaginal swab specimens are equivalent in sensitivity and specificity to those collected by a clinician using NAATs (501,502), and women find this screening strategy highly acceptable (503,504).Optimal urogenital specimen types for chlamydia screening using NAAT include first catchurine (men) and vaginal swabs (women) (394).Rectal and oropharyngeal C. trachomatis infection in persons engaging in receptive anal or oral intercourse can be diagnosed by testing at the anatomic site of exposure.NAATs are not FDA-cleared for use with rectal or oropharyngeal swab specimens.However, NAATs have been demonstrated to have improved sensitivity and specificity compared with culture for the detection of C. trachomatis at rectal sites (505-507) and at oropharyngeal sites among men (505)(506)(507)(508).Some laboratories have established CLIA-defined performance specifications when evaluating rectal and oropharyngeal swab specimens for C. trachomatis, thereby allowing results to be used for clinical management.Most persons with C. trachomatis detected at oropharyngeal sites do not have oropharyngeal symptoms.However, when gonorrhea testing is performed at the oropharyngeal site, chlamydia test results might be reported as well because some NAATs detect both bacteria from a single specimen.Data indicate that performance of NAATs on self-collected rectal swabs is comparable to clinician-collected rectal swabs, and this specimen collection strategy for rectal C. trachomatis screening is highly acceptable (509-511).Self-collected rectal swabs are a reasonable alternative to clinician-collected rectal swabs for C. trachomatis screening by NAAT, especially when clinicians are not available or when self collection is preferred over clinician collection.Previous evidence suggests that the liquid-based cytology specimens collected for Pap smears might be acceptable specimens for NAAT testing, although test sensitivity using these specimens might be lower than that associated with use of cervical or vaginal swab specimens (512); regardless, certain NAATs have been FDA-cleared for use on liquid-based cytology specimens.
# Treatment
Treating persons infected with C. trachomatis prevents adverse reproductive health complications and continued sexual transmission, and treating their sex partners can prevent reinfection and infection of other partners.Treating pregnant women usually prevents transmission of C. trachomatis to neonates during birth.Chlamydia treatment should be provided promptly for all persons testing positive for infection; treatment delays have been associated with complications (e.g., PID) in a limited proportion of women (513).
# Recommended Regimens
Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days
# Alternative Regimens
Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days A meta-analysis of 12 randomized clinical trials of azithromycin versus doxycycline for the treatment of urogenital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively (514).These studies were conducted primarily in populations with urethral and cervical infection in which follow-up was encouraged, adherence to a 7-day regimen was effective, and culture or EIA (rather than the more sensitive NAAT) was used for determining microbiological outcome.More recent retrospective studies have raised concern about the efficacy of azithromycin for rectal C. trachomatis infection (515,516), however, these studies have limitations, and prospective clinical trials comparing azithromycin versus doxycycline regimens for rectal C. trachomatis infection are needed.
Although the clinical significance of oropharyngeal C. trachomatis infection is unclear and routine oropharyngeal screening for CT is not recommended, available evidence suggests oropharyngeal C. trachomatis can be sexually transmitted to genital sites (152,517); therefore, detection of C. trachomatis from an oropharyngeal specimen should be treated with azithromycin or doxycycline.The efficacy of alternative antimicrobial regimens in resolving oropharyngeal chlamydia remains unknown.
In a double-blinded randomized control trial, a doxycycline delayed-release 200 mg tablet administered daily for 7 days was as effective as generic doxycycline 100 mg twice daily for 7 days for treatment of urogenital C. trachomatis infection in men and women and had a lower frequency of gastrointestinal side effects.However, this regimen is more costly than those that involve multiple daily doses (518).Delayed-release doxycycline (Doryx) 200 mg daily for 7 days might be an alternative regimen to the doxycycline 100 mg twice daily for 7 days for treatment of urogenital C. trachomatis infection.Erythromycin might be less efficacious than either azithromycin or doxycycline, mainly because of the frequent occurrence of gastrointestinal side effects that can lead to nonadherence with treatment.Levofloxacin and ofloxacin are effective treatment alternatives, but they are more expensive and offer no advantage in the dosage regimen.Other quinolones either are not reliably effective against chlamydial infection or have not been evaluated adequately.
# Other Management Considerations
To maximize adherence with recommended therapies, onsite, directly observed single-dose therapy with azithromycin should always be available for persons for whom adherence with multiday dosing is a concern.In addition, for multidose regimens, the first dose should be dispensed on site and directly observed. |
To minimize disease transmission to sex partners, persons treated for chlamydia should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen and resolution of symptoms if present.To minimize risk for reinfection, patients also should be instructed to abstain from sexual intercourse until all of their sex partners are treated.Persons who receive a diagnosis of chlamydia should be tested for HIV, GC, and syphilis.
# Follow-Up
Test-of-cure to detect therapeutic failure (i.e., repeat testing 3-4 weeks after completing therapy) is not advised for persons treated with the recommended or alterative regimens, unless therapeutic adherence is in question, symptoms persist, or reinfection is suspected.Moreover, the use of chlamydial NAATs at <3 weeks after completion of therapy is not recommended because the continued presence of nonviable organisms (394,395,519) can lead to false-positive results.
A high prevalence of C. trachomatis infection has been observed in women and men who were treated for chlamydial infection during the preceding several months (480,481,(520)(521)(522).Most post-treatment infections do not result from treatment failure, but rather from reinfection caused by failure of sex partners to receive treatment or the initiation of sexual activity with a new infected partner, indicating a need for improved education and treatment of sex partners.Repeat infections confer an elevated risk for PID and other complications in women.Men and women who have been treated for chlamydia should be retested approximately 3 months after treatment, regardless of whether they believe that their sex partners were treated (480,481).If retesting at 3 months is not possible, clinicians should retest whenever persons next present for medical care in the 12-month period following initial treatment.
# Management of Sex Partners
Sexual partners should be referred for evaluation, testing, and presumptive treatment if they had sexual contact with the partner during the 60 days preceding the patient's onset of symptoms or chlamydia diagnosis.Although the exposure intervals defined for the identification of at-risk sex partners are based on limited data, the most recent sex partner should be evaluated and treated, even if the time of the last sexual contact was >60 days before symptom onset or diagnosis.
Among heterosexual patients, if health department partner management strategies (e.g., disease intervention specialists) are impractical or not available for persons with chlamydia and a provider is concerned that sex partners are unable to promptly access evaluation and treatment services, EPT should be considered as permitted by law (see Partner Services).Compared with standard patient referral of partners, this approach to therapy, which involves delivering the medication itself or a prescription, has been associated with decreased rates of persistent or recurrent chlamydia (93)(94)(95).Providers should also provide patients with written educational materials to give to their partner(s) about chlamydia in general, to include notification that partner(s) have been exposed and information about the importance of treatment.These materials also should inform partners about potential therapyrelated allergies and adverse effects, along with symptoms suggestive of complications (e.g., testicular pain in men and pelvic or abdominal pain in women).EPT is not routinely recommended for MSM with chlamydia because of a high risk for coexisting infections (especially undiagnosed HIV) among their partners, and because data are limited regarding the effectiveness of this approach in reducing persistent or recurrent chlamydia among MSM.Having partners accompany patients when they return for treatment is another strategy that has been used to ensure partner treatment (See Partner Services).To avoid reinfection, sex partners should be instructed to abstain from sexual intercourse until they and their sex partners have been adequately treated (i.e., for 7 days after a single-dose regimen or after completion of a 7-day regimen) and have resolved any symptoms.
# Special Considerations Pregnancy
Doxycycline is contraindicated in the second and third trimesters of pregnancy.Human data suggest ofloxacin and levofloxacin present a low risk to the fetus during pregnancy, with a potential for toxicity during breastfeeding; however, data from animal studies raise concerns about cartilage damage to neonates (317).Thus, alternative drugs should be used to treat chlamydia in pregnancy.Clinical experience and published studies suggest that azithromycin is safe and effective (523)(524)(525).Test-of-cure to document chlamydial eradication (preferably by NAAT) 3-4 weeks after completion of therapy is recommended because severe sequelae can occur in mothers and neonates if the infection persists.In addition, all pregnant women who have chlamydial infection diagnosed should be retested 3 months after treatment.Detection of C. trachomatis infection at repeat screening during the third semester is not uncommon in adolescent and young adult women, including in those without C. trachomatis detected at the time of initial prenatal screening (526,527).Women aged <25 years and those at increased risk for chlamydia (e.g., those who have a new sex partner, more than one sex partner, a sex partner with concurrent partners, or a sex partner who has a sexually transmitted infection) should be rescreened during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant (108).
# Recommended Regimens
Azithromycin 1 g orally in a single dose Alternative Regimens Amoxicillin 500 mg orally three times a day for 7 days OR Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin base 250 mg orally four times a day for 14 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 400 mg orally four times a day for 14 days
Because of concerns about chlamydia persistence following exposure to penicillin-class antibiotics that has been demonstrated in animal and in vitro studies, amoxicillin is now considered an alternative therapy for C. trachomatis in pregnant women (528,529).The frequent gastrointestinal side effects associated with erythromycin can result in nonadherence with these alternative regimens.The lower dose 14-day erythromycin regimens can be considered if gastrointestinal tolerance is a concern.Erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity.
# HIV Infection
Persons who have chlamydia and HIV infection should receive the same treatment regimen as those who do not have HIV infection.For more information, see Chlamydia, Treatment.
# Chlamydial Infections Among Neonates
Prenatal screening and treatment of pregnant women is the best method for preventing chlamydial infection among neonates.C. trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix.Although the efficacy of neonatal ocular prophylaxis with erythromycin ophthalmic ointments to prevent chlamydia ophthalmia is not clear, ocular prophylaxis with these agents prevents gonococcal ophthalmia and therefore should be administered (see Ophthalmia Neonatorum Caused by N. gonnorrhoeae).
Initial C. trachomatis neonatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum, although infection might be asymptomatic in these locations.Instead, C. trachomatis infection in neonates is most frequently recognized by conjunctivitis that develops 5-12 days after birth.C. trachomatis also can cause a subacute, afebrile pneumonia with onset at ages 1-3 months.Although C. trachomatis has been the most frequent identifiable infectious cause of ophthalmia neonatorum, neonatal chlamydial infections (including ophthalmia and pneumonia) have occurred less frequently since the institution of widespread prenatal screening and treatment of pregnant women.
# Ophthalmia Neonatorum Caused by C. trachomatis
A chlamydial etiology should be considered for all infants aged ≤30 days that have conjunctivitis, especially if the mother has a history of chlamydia infection.These infants should receive evaluation and appropriate care and treatment.
# Diagnostic Considerations
Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., direct fluorescence antibody tests and NAAT).DFA is the only nonculture FDA-cleared test for the detection of chlamydia from conjunctival swabs; NAATs are not FDA-cleared for the detection of chlamydia from conjunctival swabs, and clinical laboratories must verify the procedure according to CLIA regulations.Specimens for culture isolation and nonculture tests should be obtained from the everted eyelid using a dacron-tipped swab or the swab specified by the manufacturer's test kit; for culture and DFA, specimens must contain conjunctival cells, not exudate alone.Ocular specimens from neonates being evaluated for chlamydial conjunctivitis also should be tested for N. gonorrhoeae (see Ophthalmia Neonatorum Caused by N. gonnorrhoeae).
# Treatment of Ophthalmia Neonatorum
# Recommended Regimen
Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days*
# Alternative Regimen
Azithromycin suspension, 20 mg/kg/day orally, 1 dose daily for 3 days- - An association between oral erythromycin and azithromycin and infantile hypertrophic pyloric stenosis (IHPS) has been reported in infants aged <6 weeks.Infants treated with either of these antimicrobials should be followed for signs and symptoms of IHPS.
Although data on the use of azithromycin for the treatment of neonatal chlamydia infection are limited, available data suggest a short course of therapy might be effective (530).Topical antibiotic therapy alone is inadequate for treatment for ophthalmia neonatorum caused by chlamydia and is unnecessary when systemic treatment is administered.
# Follow-Up
Because the efficacy of erythromycin treatment for ophthalmia neonatorum is approximately 80%, a second course of therapy might be required (531).Data on the efficacy of azithromycin for ophthalmia neonatorum are limited.Therefore, follow-up of infants is recommended to determine whether initial treatment was effective.The possibility of concomitant chlamydial pneumonia should be considered (see Infant Pneumonia Caused by C. trachomatis).
# Management of Mothers and Their Sex Partners
Mothers of infants who have ophthalmia caused by chlamydia and the sex partners of these women should be evaluated and presumptively treated for chlamydia.For more information, see Chlamydial Infection in Adolescents and Adults.
# Infant Pneumonia Caused by C. trachomatis
Chlamydia pneumonia in infants typically occurs at 1-3 months and is a subacute pneumonia.Characteristic signs of chlamydial pneumonia in infants include 1) a repetitive staccato cough with tachypnea and 2) hyperinflation and bilateral diffuse infiltrates on a chest radiograph.In addition, peripheral eosinophilia (≥400 cells/mm 3 ) occurs frequently.Because clinical presentations differ, all infants aged 1-3 months suspected of having pneumonia (especially those whose mothers have a history of chlamydial infection) should be tested for C. trachomatis and treated if infected.
# Diagnostic Considerations
Specimens for chlamydial testing should be collected from the nasopharynx.Tissue culture is the definitive standard diagnostic test for chlamydial pneumonia.Nonculture tests (e.g., DFA and NAAT) can be used.DFA is the only nonculture FDA-cleared test for the detection of C. trachomatis from nasopharyngeal specimens, but DFA of nasopharyngeal specimens has a lower sensitivity and specificity than culture.NAATs are not FDA-cleared for the detection of chlamydia from nasopharyngeal specimens, and clinical laboratories must verify the procedure according to CLIA regulations (394).Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C. trachomatis.
# Treatment
Because test results for chlamydia often are not available at the time that initial treatment decisions must be made, treatment for C. trachomatis pneumonia must frequently be based on clinical and radiologic findings, age of the infant (i.e., 1-3 months), and risk of chlamydia in the mother (i.e., age <25, multiple partners, and history of chlamydial infection).The results of tests for chlamydial infection assist in the management of an infant's illness.
# Recommended Regimen
Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days
# Alternative Regimen
Azithromycin 20 mg/kg/day orally, 1 dose daily for 3 days
# Follow-Up
Because the effectiveness of erythromycin in treating pneumonia caused by C. trachomatis is approximately 80%, a second course of therapy might be required (532).Data on the effectiveness of azithromycin in treating chlamydial pneumonia are limited.Follow-up of infants is recommended to determine whether the pneumonia has resolved, although some infants with chlamydial pneumonia continue to have abnormal pulmonary function tests later in childhood.
# Management of Mothers and Their Sex Partners
Mothers of infants who have chlamydia pneumonia and the sex partners of these women should be evaluated, tested, and presumptively treated for chlamydia.For more information, see Chlamydial Infection in Adolescents and Adults.
# Neonates Born to Mothers Who Have Chlamydial Infection
Neonates born to mothers who have untreated chlamydia are at high risk for infection; however, prophylactic antibiotic treatment is not indicated, as the efficacy of such treatment is unknown.Infants should be monitored to ensure appropriate treatment if symptoms develop.
# Chlamydial Infections Among Infants and Children
Sexual abuse must be considered a cause of chlamydial infection in infants and children.However, perinatally transmitted C. trachomatis infection of the nasopharynx, urogenital tract, and rectum might persist for 2-3 years (see Sexual Assault or Abuse of Children).
# Diagnostic Considerations
NAAT can be used for vaginal and urine specimens from girls (see Sexual Assault or Abuse of Children), although data are insufficient to recommend the use of NAAT in boys.Data also are lacking regarding use of NAAT for specimens from extragenital sites (rectum and pharynx) in boys and girls (394); other nonculture tests (e.g., DFA) are not recommended because of specificity concerns.Culture is still the preferred method for detection of urogenital C. trachomatis in boys and at extragenital sites in boys and girls.
# Recommended Regimen for Infants and Children Who Weigh <45 kg
Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days Data are limited on the effectiveness and optimal dose of azithromycin for the treatment of chlamydial infection in infants and children who weigh <45 kg
# Recommended Regimen for Children Who Weigh ≥45 kg but Who Are Aged <8 Years Azithromycin 1 g orally in a single dose
# Recommended Regimens for Children Aged ≥8 years
Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days
# Other Management Considerations
See Sexual Assault or Abuse of Children.
# Follow-Up
A test-of-cure culture (repeat testing after completion of therapy) to detect therapeutic failure ensures treatment effectiveness.Therefore, a culture should be obtained at a follow-up visit approximately 2 weeks after treatment is completed.
# Gonococcal Infections Gonococcal Infections in Adolescents and Adults
In the United States, an estimated 820,000 new N. gonorrhoeae infections occur each year (533).Gonorrhea is the second most commonly reported communicable disease (118).Urethral infections caused by N. gonorrhoeae among men can produce symptoms that cause them to seek curative treatment soon enough to prevent sequelae, but often not soon enough to prevent transmission to others.Among women, gonococcal infections are commonly asymptomatic or might not produce recognizable symptoms until complications (e.g., PID) have occurred.PID can result in tubal scarring that can lead to infertility and ectopic pregnancy.
Annual screening for N. gonorrhoeae infection is recommended for all sexually active women aged <25 years and for older women at increased risk for infection (e.g., those who have a new sex partner, more than one sex partner, a sex partner with concurrent partners, or a sex partner who has an STI) (108).Additional risk factors for gonorrhea include inconsistent condom use among persons who are not in mutually monogamous relationships, previous or coexisting sexually transmitted infections, and exchanging sex for money or drugs.Clinicians should consider the communities they serve and might opt to consult local public health authorities for guidance on identifying groups at increased risk.Gonococcal infection, in particular, is concentrated in specific geographic locations and communities.Subgroups of MSM are at high risk for gonorrhea infection and should be screened at sites of exposure (see MSM).Screening for gonorrhea in men and older women who are at low risk for infection is not recommended (108).A recent travel history with sexual contacts outside of the United States should be part of any gonorrhea evaluation.
# Diagnostic Considerations
Specific microbiologic diagnosis of infection with N. gonorrhoeae should be performed in all persons at risk for or suspected to have gonorrhea; a specific diagnosis can potentially reduce complications, reinfections, and transmission.Culture and NAAT are available for the detection of genitourinary infection with N. gonorrhoeae (394); culture requires endocervical (women) or urethral (men) swab specimens.NAAT allows for the widest variety of FDA-cleared specimen types, including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women).However, product inserts for each NAAT manufacturer must be carefully consulted because collection methods and specimen types vary.Culture is available for detection of rectal, oropharyngeal, and conjunctival gonococcal infection, but NAAT is not FDA-cleared for use with these specimens.Some laboratories have met CLIA regulatory requirements and established performance specifications for using NAAT with rectal and oropharyngeal swab specimens that can inform clinical management.Certain NAATs that have been demonstrated to detect commensal Neisseria species might have comparable low specificity when testing oropharyngeal specimens for N. gonorrhoeae (394).The sensitivity of NAAT for the detection of N. gonorrhoeae in urogenital and nongenital anatomic sites is superior to culture, but varies by NAAT type (394,(505)(506)(507)(508).In cases of suspected or documented treatment failure, clinicians should perform both culture and antimicrobial susceptibility testing because nonculture tests cannot provide antimicrobial susceptibility results.Because N. gonorrhoeae has demanding nutritional and environmental growth requirements, optimal recovery rates are achieved when specimens are inoculated directly and when the growth medium is promptly incubated in an increased CO 2 environment (394).Several non-nutritive swab transport systems are available that might maintain gonococcal viability for up to 48 hours in ambient temperatures (534)(535)(536).
Because of its high specificity (>99%) and sensitivity (>95%), a Gram stain of urethral secretions that demonstrates polymorphonuclear leukocytes with intracellular Gramnegative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men.However, because of lower sensitivity, a negative Gram stain should not be considered sufficient for ruling out infection in asymptomatic men.Detection of infection using Gram stain of endocervical, pharyngeal, and rectal specimens also is insufficient and is not recommended.MB/GV stain of urethral secretions is an alternative point-of-care diagnostic test with performance characteristics similar to Gram stain.Presumed gonococcal infection is established by documenting the presence of WBC containing intracellular purple diplococci in MB/GV smears. |
# Antimicrobial-Resistant N. gonorrhoeae
Gonorrhea treatment is complicated by the ability of N. gonorrhoeae to develop resistance to antimicrobials (537).In 1986, the Gonococcal Isolate Surveillance Project (GISP), a national sentinel surveillance system, was established to monitor trends in antimicrobial susceptibilities of urethral N. gonorrhoeae strains in the United States (538).The epidemiology of antimicrobial resistance guides decisions about gonococcal treatment recommendations and has evolved because of shifts in antimicrobial resistance patterns.In 2007, emergence of fluoroquinolone-resistant N. gonorrhoeae in the United States prompted CDC to cease recommending fluoroquinolones for treatment of gonorrhea, leaving cephalosporins as the only remaining class of antimicrobials available for treatment of gonorrhea in the United States (539).Reflecting concern about emerging gonococcal resistance, CDC's 2010 STD treatment guidelines recommended dual therapy for gonorrhea with a cephalosporin plus either azithromycin or doxycycline, even if NAAT for C. trachomatis was negative at the time of treatment (1).However, during 2006-2011, the minimum concentrations of cefixime needed to inhibit in vitro growth of the N. gonorrhoeae strains circulating in the United States and many other countries increased, suggesting that the effectiveness of cefixime might be waning (118,540).In addition, treatment failures with cefixime or other oral cephalosporins have been reported in Asia (541-544), Europe (545-549), South Africa (550), and Canada (551,552).Ceftriaxone treatment failures for pharyngeal infections have been reported in Australia (553,554), Japan (555), and Europe (556,557).As a result, CDC no longer recommends the routine use of cefixime as a first-line regimen for treatment of gonorrhea in the United States (540).In addition, U.S. gonococcal strains with elevated MICs to cefixime also are likely to be resistant to tetracyclines but susceptible to azithromycin (540).Consequently, only one regimen, dual treatment with ceftriaxone and azithromycin, is recommended for treatment of gonorrhea in the United States.CDC () and state health departments can provide the most current information on gonococcal susceptibility.
Criteria for resistance to cefixime and ceftriaxone have not been defined by the Clinical and Laboratory Standards Institute (CLSI).However, isolates with cefixime or ceftriaxone MICs ≥0.5 µg/mL are considered to have decreased susceptibility (558).In the United States, the proportion of isolates in GISP demonstrating decreased susceptibility to ceftriaxone or cefixime has remained low; during 2013, no isolates with decreased susceptibility (MIC ≥0.5 µg/mL) to ceftriaxone or cefixime were identified (118).Because increasing MICs might predict the emergence of resistance, GISP established lower cephalosporin MIC breakpoints than those set by CLSI to provide greater sensitivity in detecting declining gonococcal susceptibility for surveillance purposes.The percentage of isolates with cefixime MICs ≥0.25 µg/mL increased from 0.1% in 2006 to 1.4% in 2011 (118,540), and declined to 0.4% in 2013 (118).The percentage of isolates with ceftriaxone MICs ≥0.125 µg/mL increased from <0.1% in 2006 to 0.4% in 2011 and decreased to 0.05% in 2013.Isolates with high-level cefixime and ceftriaxone MICs (cefixime MICs 1.5-8 µg/mL and ceftriaxone MICs 1.5-4 µg/mL) have been identified in Japan ( 555
# Dual Therapy for Gonococcal Infections
On the basis of experience with other microbes that have developed antimicrobial resistance rapidly, a theoretical basis exists for combination therapy using two antimicrobials with different mechanisms of action (e.g., a cephalosporin plus azithromycin) to improve treatment efficacy and potentially slow the emergence and spread of resistance to cephalosporins.Use of azithromycin as the second antimicrobial is preferred to doxycycline because of the convenience and compliance advantages of single-dose therapy and the substantially higher prevalence of gonococcal resistance to tetracycline than to azithromycin among GISP isolates, particularly in strains with elevated cefixime MICs (118,540).In addition, clinical trials have demonstrated the efficacy of azithromycin 1 g for the treatment of uncomplicated urogenital GC (561,562).
Limited data suggest that dual treatment with azithromycin might enhance treatment efficacy for pharyngeal infection when using oral cephalosporins (563,564).In addition, persons infected with N. gonorrhoeae frequently are coinfected with C. trachomatis; this finding has led to the longstanding recommendation that persons treated for gonococcal infection also be treated with a regimen that is effective against uncomplicated genital C. trachomatis infection, further supporting the use of dual therapy that includes azithromycin (565).
# Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum
# Recommended Regimen
Ceftriaxone 250 mg IM in a single dose PLUS Azithromycin 1g orally in a single dose As dual therapy, ceftriaxone and azithromycin should be administered together on the same day, preferably simultaneously and under direct observation.Ceftriaxone in a single injection of 250 mg provides sustained, high bactericidal levels in the blood.Extensive clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing 99.2% of uncomplicated urogenital and anorectal and 98.9% of pharyngeal infections in clinical trials (566,567).No clinical data exist to support use of doses of ceftriaxone >250 mg.
Single-dose injectable cephalosporin regimens (other than ceftriaxone 250 mg IM) that are safe and generally effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg IM), cefoxitin (2 g IM with probenecid 1 g orally), and cefotaxime (500 mg IM).None of these injectable cephalosporins offer any advantage over ceftriaxone for urogenital infection, and efficacy for pharyngeal infection is less certain (566,567).Several other antimicrobials are active against N. gonorrhoeae, but none have substantial advantages over the recommended regimen, and efficacy data (especially for pharyngeal infection) are limited.
# Alternative Regimens
If ceftriaxone is not available: Cefixime 400 mg orally in a single dose PLUS Azithromycin 1 g orally in a single dose A 400-mg oral dose of cefixime should only be considered as an alternative cephalosporin regimen because it does not provide as high, nor as sustained, bactericidal blood levels as a 250-mg dose of ceftriaxone; further, it demonstrates limited efficacy for treatment of pharyngeal gonorrhea (92.3% cure; 95% confidence interval = 74.9%-99.1%); in older clinical studies, cefixime cured 97.5% of uncomplicated urogenital and anorectal gonococcal infections (95% CI = 95.4%-99.8%) (566,567).The increase in the prevalence of isolates obtained through GISP with elevated cefixime MICs might indicate early stages of development of clinically significant gonococcal resistance to cephalosporins.CDC anticipates that rising cefixime MICs soon will result in declining effectiveness of cefixime for the treatment of urogenital gonorrhea.Furthermore, as cefixime becomes less effective, continued used of cefixime might hasten the development of resistance to ceftriaxone, a safe, well-tolerated, injectable cephalosporin and the last antimicrobial known to be highly effective in a single dose for treatment of gonorrhea at all anatomic sites of infection.Other oral cephalosporins (e.g., cefpodoxime and cefuroxime) are not recommended because of inferior efficacy and less favorable pharmacodynamics (566,568).
Because of the prevalence of tetracycline resistance among GISP isolates, particularly those with elevated cefixime MICs (118), the use of azithromycin as the second antimicrobial is preferred.However, in the case of azithromycin allergy, doxycycline (100 mg orally twice a day for 7 days) can be used in place of azithromycin as an alternative second antimicrobial when used in combination with ceftriaxone or cefixime.
In a recent clinical trial, dual treatment of uncomplicated, urogenital gonorrhea with single doses of oral gemifloxacin 320 mg plus oral azithromycin 2 g was associated with cure rates of 99.5% (lower one-sided 95% CI bound = 97.6%), and dual treatment with single doses of intramuscular gentamicin 240 mg plus oral azithromycin 2 g cured 100% of cases (lower one-sided 95% CI bound = 98.5%) (569).This trial was not powered to provide reliable estimates of the efficacy of these regimens for treatment of rectal or pharyngeal infection, but both regimens cured the few extragenital infections among study participants.Either of these regimens might be considered as alternative treatment options in the presence of cephalosporin allergy.However, gastrointestinal adverse events might limit their use: 7.7% of patients treated with gemifloxacin plus azithromycin and 3.3% of patients treated with gentamicin plus azithromycin vomited within 1 hour of medication administration, necessitating retreatment with a ceftriaxone and azithromycin.
Spectinomycin, which is useful in persons who cannot tolerate cephalosporins, is expensive, has poor efficacy against pharyngeal infection (51.8%; 95% CI = 38.7%-64.9%) (566), and is not being produced in the United States (570).However, it has been effective in clinical trials, curing 98.2% of uncomplicated urogenital and anorectal gonococcal infections (566).When available, spectinomycin is an effective alternative for the treatment of urogenital and anorectal infection.
Monotherapy with azithromycin 2 g orally as a single dose has been demonstrated to be 99.2% effective against uncomplicated urogenital gonorrhea (95% CI = 97.3%-99.9%) (567).However, monotherapy is no longer recommended because of concerns over the ease with which N. gonorrhoeae can develop resistance to macrolides, and because several studies have documented azithromycin treatment failures (546,(571)(572)(573)(574).Strains of N. gonorrhoeae circulating in the United States are not adequately susceptible to penicillins, tetracyclines, and older macrolides (e.g., erythromycin), and thus use of these antimicrobials cannot be recommended.
# Uncomplicated Gonococcal Infections of the Pharynx
Most gonococcal infections of the pharynx are asymptomatic and can be relatively common in some populations (505,506,575,576).Gonococcal infections of the pharynx are more difficult to eradicate than are infections at urogenital and anorectal sites (551).Few antimicrobial regimens, including those involving oral cephalosporins, can reliably cure >90% of gonococcal pharyngeal infections (566,567).Providers should ask their patients with urogenital or rectal GC about oral sexual exposure; if reported, patients should be treated with a regimen with acceptable efficacy against pharyngeal gonorrhea infection.
# Recommended Regimen
Ceftriaxone 250 mg IM in a single dose PLUS Azithromycin 1 g orally in a single dose
# Other Management Considerations
To maximize adherence with recommended therapies and reduce complications and transmission, medication for gonococcal infection should be provided on site and directly observed.If medications are not available when treatment is indicated, linkage to an STD treatment facility should be provided for same-day treatment.To minimize disease transmission, persons treated for gonorrhea should be instructed to abstain from sexual activity for 7 days after treatment and until all sex partners are adequately treated (7 days after receiving treatment and resolution of symptoms, if present).All persons who receive a diagnosis of gonorrhea should be tested for other STDs, including chlamydia, syphilis, and HIV.
# Follow-Up
A test-of-cure is not needed for persons who receive a diagnosis of uncomplicated urogenital or rectal gonorrhea who are treated with any of the recommended or alternative regimens; however, any person with pharyngeal gonorrhea who is treated with an alternative regimen should return 14 days after treatment for a test-of-cure using either culture or NAAT.If the NAAT is positive, effort should be made to perform a confirmatory culture before retreatment.All positive cultures for test-of-cure should undergo antimicrobial susceptibility testing.
Symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae (with or without simultaneous NAAT), and any gonococci isolated should be tested for antimicrobial susceptibility.Persistent urethritis, cervicitis, or proctitis also might be caused by other organisms (see Urethritis, Cervicitis, and Proctitis sections).
A high prevalence of N. gonorrhoeae infection has been observed among men and women previously treated for gonorrhea (86,480,481,577).Rather than signaling treatment failure, most of these infections result from reinfection caused by failure of sex partners to receive treatment or the initiation of sexual activity with a new infected partner, indicating a need for improved patient education and treatment of sex partners.Men or women who have been treated for gonorrhea should be retested 3 months after treatment regardless of whether they believe their sex partners were treated.If retesting at 3 months is not possible, clinicians should retest whenever persons next present for medical care within 12 months following initial treatment.
# Management of Sex Partners
Recent sex partners (i.e., persons having sexual contact with the infected patient within the 60 days preceding onset of symptoms or gonorrhea diagnosis) should be referred for evaluation, testing, and presumptive dual treatment.If the patient's last potential sexual exposure was >60 days before onset of symptoms or diagnosis, the most recent sex partner should be treated.To avoid reinfection, sex partners should be instructed to abstain from unprotected sexual intercourse for 7 days after they and their sexual partner(s) have completed treatment and after resolution of symptoms, if present.
For heterosexual men and women with gonorrhea for whom health department partner-management strategies are impractical or unavailable and whose providers are concerned about partners' access to prompt clinical evaluation and treatment, EPT with cefixime 400 mg and azithromycin 1 g can be delivered to the partner by the patient, a disease investigation specialist, or a collaborating pharmacy as permitted by law (see Partner Services).With this approach, provision of medication must be accompanied by written materials (93,95) to educate partners about their exposure to gonorrhea, the importance of therapy, and when to seek clinical evaluation for adverse reactions or complications.Educational materials for female partners should include information about the importance of seeking medical evaluation for PID (especially if symptomatic); undertreatment of PID in female partners and missed opportunities to diagnose other STDs in women are of concern.EPT should not be considered a routine partner management strategy in MSM with gonorrhea because of a high risk for coexisting infections (especially HIV infection) and because no data exist on efficacy in this population.
# Special Considerations Allergy, Intolerance, and Adverse Reactions
Allergic reactions to first-generation cephalosporins occur in <2.5% of persons with a history of penicillin allergy and are uncommon with third-generation cephalosporins (e.g., ceftriaxone and cefixime) (428,430,464).Use of ceftriaxone or cefixime is contraindicated in persons with a history of an IgE-mediated penicillin allergy (e.g., anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis) (428,431).Data are limited regarding alternative regimens for treating gonorrhea among persons who have either a cephalosporin or IgE-mediated penicillin allergy.Potential therapeutic options are dual treatment with single doses of oral gemifloxacin 320 mg plus oral azithromycin 2 g or dual treatment with single doses of intramuscular gentamicin 240 mg plus oral azithromycin 2 g (569).Spectinomycin for treatment of urogenital and anorectal gonorrhea can be considered when available.Providers treating persons with cephalosporin or IgE-mediated penicillin allergy should consult an infectiousdisease specialist.
# Pregnancy
Pregnant women infected with N. gonorrhoeae should be treated with dual therapy consisting of ceftriaxone 250 mg in a single IM dose and azithromycin 1 g orally as a single dose.When cephalosporin allergy or other considerations preclude treatment with this regimen and spectinomycin is not available, consultation with an infectious-disease specialist is recommended.
# HIV Infection
Persons who have gonorrhea and HIV infection should receive the same treatment regimen as those who are HIV negative.For more information, see appropriate treatment sections under Gonoccocal Infections.
# Suspected Cephalosporin Treatment Failure
Cephalosporin treatment failure is the persistence of N. gonorrhoeae infection despite appropriate cephalosporin treatment and is indicative of infection with cephalosporinresistant gonorrhea in persons whose partners were adequately treated and whose risk for reinfection is low.Suspected treatment failure has been reported among persons receiving oral and injectable cephalosporins (541)(542)(543)(544)(545)(546)(547)(548)(549)(550)(551)(552)(553)(554)(555)(556)(557)578).Treatment failure should be considered in 1) persons whose symptoms do not resolve within 3-5 days after appropriate treatment and report no sexual contact during the post-treatment follow-up period and 2) persons with a positive test-of-cure (i.e., positive culture ≥72 hours or positive NAAT ≥7 days after receiving recommended treatment) when no sexual contact is reported during the post-treatment follow-up period (579).Treatment failure should also be considered in persons who have a positive culture on test-of-cure (if obtained) if there is evidence of decreased susceptibility to cephalosporins on antimicrobial susceptibility testing, regardless of whether sexual contact is reported during the post-treatment follow-up period.
Most suspected treatment failures in the United States are likely to be re-infections rather than actual treatment failures (86,480,481,577).However, in cases where reinfection is unlikely and treatment failure is suspected, before retreatment, relevant clinical specimens should be obtained for culture (preferably with simultaneous NAAT) and antimicrobial susceptibility testing if N. gonorrhoeae is isolated.Phenotypic antimicrobial susceptibility testing should be performed using disk diffusion, Etest (BioMérieux, Durham, NC), or agar dilution.Data are limited on the use of DNA amplification and sequencing for detection of genetic mutations associated with gonococcal antimicrobial resistance.All isolates of suspected treatment failures should be sent to CDC for antimicrobial susceptibility testing by agar dilution; local laboratories should store isolates for possible further testing if needed.Testing and/or storage of specimens or isolates should be facilitated by the state or local health department according to local public health protocol.
For persons with suspected cephalosporin treatment failure, the treating clinician should consult an infectiousdisease specialist, an STD/HIV Prevention Training Center clinical expert (), the local or state health department STD program, or CDC (telephone: 404-639-8659) for advice on obtaining cultures, antimicrobial susceptibility testing, and treatment.Suspected treatment failure should be reported to CDC through the local or state health department within 24 hours of diagnosis.
Suspected treatment failures first should be retreated routinely with the recommended regimen (ceftriaxone 250 mg IM plus azithromycin 1 g orally), because reinfections are more likely than actual treatment failures.However, in situations with a higher likelihood of treatment failure than reinfection, relevant clinical specimens should be obtained for culture (preferably with simultaneous NAAT) and antimicrobial susceptibility testing performed before retreatment.Dual treatment with single doses of oral gemifloxacin 320 mg plus oral azithromycin 2 g or dual treatment with single doses of intramuscular gentamicin 240 mg plus oral azithromycin 2 g can be considered, particularly when isolates are found to have elevated cephalosporin MICs (569).Persons with suspected treatment failure after treatment with the alternative regimen (cefixime and azithromycin) should be treated with ceftriaxone 250 mg as a single IM dose and azithromycin 2 g orally as a single dose.A test-of-cure at relevant clinical sites should be obtained 7-14 days after retreatment; culture is the recommended test, preferably with simultaneous NAAT and antimicrobial susceptibility testing of N. gonorrhoeae if isolated.Clinicians should ensure that the patient's sex partners from the preceding 60 days are evaluated promptly with culture and presumptively treated using the same regimen used for the patient. |
# Gonococcal Conjunctivitis
In the only published study (conducted in 1989) of the treatment of gonococcal conjunctivitis among adults, all 12 study participants responded to a single 1 g IM injection of ceftriaxone (580).On the basis of experience with other microbes that have developed antimicrobial resistance rapidly, a theoretical basis exists for combination therapy using two antimicrobials with different mechanisms of action (e.g., a cephalosporin plus azithromycin) to improve treatment efficacy and potentially slow the emergence and spread of resistance to cephalosporins.Because gonococcal conjunctivitis is uncommon and data on treatment of gonococcal conjunctivitis in adults are limited, consultation with an infectious-disease specialist should be considered.
# Recommended Regimen
Ceftriaxone 1 g IM in a single dose PLUS Azithromycin 1 g orally in a single dose Consider one-time lavage of the infected eye with saline solution.
# Management of Sex Partners
Patients should be instructed to refer their sex partners for evaluation and treatment.For more information, see Gonococcal Infections, Management of Sex Partners.
# Disseminated Gonococcal Infection
Disseminated gonococcal infection (DGI) frequently results in petechial or pustular acral skin lesions, asymmetric polyarthralgia, tenosynovitis, or oligoarticular septic arthritis (581).The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis.Some strains of N. gonorrhoeae that cause DGI can cause minimal genital inflammation.If DGI is suspected, NAAT or culture specimens from urogenital and extragenital sites, as applicable, should be collected and processed in addition to specimens from disseminated sites of infection (e.g., skin, synovial fluid, blood, and the CNS).All N. gonorrhoeae isolates should be tested for antimicrobial susceptibility.
Hospitalization and consultation with an infectious-disease specialist are recommended for initial therapy, especially for persons who might not comply with treatment, have an uncertain diagnosis, or have purulent synovial effusions or other complications.Examination for clinical evidence of endocarditis and meningitis should be performed.When treating for the arthritis-dermatitis syndrome, the provider can switch to an oral agent guided by antimicrobial susceptibility testing 24-48 hours after substantial clinical improvement, for a total treatment course of at least 7 days.
# Treatment of Arthritis and Arthritis-Dermatitis Syndrome
Recommended Regimen
# Treatment of Gonococcal Meningitis and Endocarditis
Recommended Regimen Ceftriaxone 1-2 g IV every 12-24 hours PLUS Azithromycin 1 g orally in a single dose No recent studies have been published on the treatment of DGI.The duration of treatment of DGI has not been systematically studied and should be determined in consultation with an infectious-disease specialist.Treatment for DGI should be guided by the results of antimicrobial susceptibility testing.Pending antimicrobial susceptibility results, treatment decisions should be made on the basis of clinical presentation.Therapy for meningitis should be continued with recommended parenteral therapy for 10-14 days.Parenteral antimicrobial therapy for endocarditis should be administered for at least 4 weeks.
# Management of Sex Partners
Gonococcal infection frequently is asymptomatic in sex partners of persons who have DGI.Providers should instruct patients to refer partners with whom they have had sexual contact in the past 60 days for evaluation, testing, and presumptive treatment (see Gonococcal Infection, Management of Sex Partners).
# Gonococcal Infections Among Neonates
Prenatal screening and treatment of pregnant women is the best method for preventing GC infection among neonates.Gonococcal infection among neonates results from perinatal exposure to the mother's infected cervix.It is usually an acute illness that manifests 2-5 days after birth.The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened and treated for gonorrhea, and whether newborns receive ophthalmia prophylaxis.The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis.Less severe manifestations include rhinitis, vaginitis, urethritis, and infection at sites of fetal monitoring.
# Ophthalmia Neonatorum Prophylaxis
To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into both eyes of all newborn infants; this procedure is required by law in most states.Ocular prophylaxis is warranted because it can prevent sight-threatening gonococcal ophthalmia, has an excellent safety record, is easy to administer, and is inexpensive.The recommended prophylactic regimen prevents gonococcal ophthalmia; however, its efficacy for prevention of chlamydial ophthalmia is less clear, and it does not eliminate nasopharyngeal colonization by C. trachomatis.
# Recommended Regimen
Erythromycin (0.5%) ophthalmic ointment in each eye in a single application at birth This preparation should be instilled into both eyes of all neonates as soon as possible after delivery, regardless of whether they are delivered vaginally or by cesarean section.Ideally, ointment should be applied using single-use tubes or ampules rather than multiple-use tubes.If prophylaxis is delayed (i.e., not administered in the delivery room), a monitoring system should be established to ensure that all infants receive prophylaxis.
Erythromycin is the only antibiotic ointment recommended for use in neonates.Silver nitrate and tetracycline ophthalmic ointment is no longer manufactured in the United States, bacitracin is not effective, and povidone iodine has not been studied adequately (582,583).Gentamicin ophthalmic ointment has been associated with severe ocular reactions in neonates and should not be used for ocular prophylaxis (584,585).If erythromycin ointment is not available, infants at risk for exposure to N. gonorrhoeae (especially those born to a mother at risk for gonococcal infection or with no prenatal care) can be administered ceftriaxone 25-50 mg/kg IV or IM, not to exceed 125 mg in a single dose (586).
N. gonorrhoeae causes ophthalmia neonatorum relatively infrequently in the United States (587).However, identifying and treating this infection is especially important, because ophthalmia neonatorum can result in perforation of the globe of the eye and blindness (588).
# Diagnostic Considerations
Infants at increased risk for gonococcal ophthalmia include those who did not receive ophthalmia prophylaxis and whose mothers had no prenatal care or have a history of STDs or substance abuse.Gonococcal ophthalmia is strongly suspected when intracellular gram-negative diplococci are identified on Gram stain of conjunctival exudate, justifying presumptive treatment for gonorrhea after appropriate cultures and antimicrobial susceptibility testing for N. gonorrhoeae are performed.Presumptive treatment for N. gonorrhoeae might be indicated for newborns at increased risk for gonococcal ophthalmia who have increased WBCs (but not intracellular gram negative diplococci) in a Gram-stained smear of conjunctival exudate.Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species, organisms that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory.
# Treatment Recommended Regimen
Ceftriaxone 25-50 mg/kg IV or IM in a single dose, not to exceed 125 mg One dose of ceftriaxone is adequate therapy for gonococcal conjunctivitis.Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely.No data exist on the use of dual therapy for the treatment of gonococcal ophthalmia.Topical antibiotic therapy alone is inadequate and unnecessary if systemic treatment is administered.
# Other Management Considerations
Appropriate chlamydial testing should be done simultaneously from the inverted eyelid specimen (see Ophthalmia Neonatorum Caused by C. trachomatis).Infants who have gonococcal ophthalmia should be evaluated for signs of disseminated infection (e.g., sepsis, arthritis, and meningitis).Infants who have gonococcal ophthalmia should be managed in consultation with an infectious-disease specialist.
# Follow-up
Infants who have ophthalmia neonatorum should be managed in consultation with an infectious-disease specialist.
# Management of Mothers and Their Sex Partners
Mothers of infants with ophthalmia neonatorum caused by N. gonorrhoeae should be evaluated, tested, and presumptively treated for gonorrhea, along with their sex partner(s).For more information, see Gonococcal Infections in Adolescents and Adults.
# DGI and Gonococcal Scalp Abscesses in Neonates
DGI might present as sepsis, arthritis, or meningitis and is a rare complication of neonatal gonococcal infection.Localized gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes.Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate.Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum are useful for identifying the primary site(s) of infection.Antimicrobial susceptibility testing of all isolates should be performed.Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae.
# Recommended Regimens
Ceftriaxone 25-50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10-14 days if meningitis is documented OR Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration of 10-14 days if meningitis is documented Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely.No data exist on the use of dual therapy for the treatment of DGI or gonococcal scalp abscesses.
# Other Management Considerations
Appropriate chlamydial testing should be done simultaneously in neonates with gonococcal infection.For more information, see Chlamydia Infection in Neonates.Infants who have DGI should be managed in consultation with an infectious-disease specialist.
# Management of Mothers and Their Sex Partners
Mothers of infants who have DGI or scalp abscesses caused by N. gonorrhoeae should be evaluated, tested, and presumptively treated for gonorrhea, along with their sex partner(s).For more information, see Gonococcal Infections in Adolescents and Adults.
# Neonates Born to Mothers Who Have Gonococcal Infection
Neonates born to mothers who have untreated gonorrhea are at high risk for infection.Neonates should be tested for gonorrhea at exposed sites and treated presumptively for gonorrhea as recommended in these guidelines.No data exist on the use of dual therapy to treat neonates born to mothers who have gonococcal infection.
# Recommended Regimen in the Absence of Signs of Gonococcal Infection
Ceftriaxone 25-50 mg/kg IV or IM in a single dose, not to exceed 125 mg
# Other Management Considerations
Appropriate chlamydial testing should be done simultaneously in neonates with gonococcal infection.For more information, see Chlamydia Infection in Neonates.Follow-up examination is not required.
# Management of Mothers and Their Sex Partners
Mothers who have gonorrhea and their sex partners should be evaluated, tested, and presumptively treated for gonorrhea.For more information, see Gonococcal Infections.
# Gonococcal Infections Among Infants and Children
Sexual abuse is the most frequent cause of gonococcal infection in infants and children (see Sexual Assault or Abuse of Children).For preadolescent girls, vaginitis is the most common manifestation of this infection; gonococcalassociated PID after vaginal infection can be less common in preadolescents than adults.Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are frequently asymptomatic.
# Diagnostic Considerations
NAAT can be used to test vaginal and urine specimens from girls (see Sexual Assault or Abuse of Children), although data are insufficient to recommend the use of these tests in boys and from extragenital sites (rectum and pharynx) in boys and girls (394).Culture remains the preferred method for diagnosing boys and for detecting infection in specimens obtained from extragenital sites regardless of gender (394).Gram stains are inadequate for evaluating prepubertal children for gonorrhea and should not be used to diagnose or exclude gonorrhea.If evidence of disseminated gonococcal infection exists, gonorrhea culture and antimicrobial susceptibility testing should be obtained from relevant clinical sites (see DGI).
# Recommended Regimen for Infants and Children Who
# Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Bacteremia or Arthritis
Ceftriaxone 50 mg/kg (maximum dose: 1 g) IM or IV in a single dose daily for 7 days
# Recommended Regimen for Children Who Weigh >45 kg and Who Have Bacteremia or Arthritis
Ceftriaxone 1 g IM or IV in a single dose daily every 24 hours for 7 days
No data exist regarding the use of dual therapy for treating children with gonococcal infection.
# Other Management Considerations
# Diseases Characterized by Vaginal Discharge
Most women will have a vaginal infection, characterized by discharge, itching, or odor, during their lifetime.With the availability of complementary and alternative therapies and over-the-counter medications for candidiasis, many symptomatic women seek these products before or in addition to an evaluation by a medical provider.
Obtaining a medical history alone has been shown to be insufficient for accurate diagnosis of vaginitis and can lead to the inappropriate administration of medication.Therefore, a careful history, examination, and laboratory testing to determine the etiology of vaginal symptoms are warranted.Information on sexual behaviors and practices, gender of sex partners, menses, vaginal hygiene practices (e.g., douching), and self-treatment with medications should be elicited.The three diseases most frequently associated with vaginal discharge are BV (replacement of the vaginal flora by an overgrowth of anaerobic bacteria including Prevotella sp.,Mobiluncus sp.,G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes), T. vaginalis, and candidiasis.Cervicitis can also cause an abnormal discharge.Although vulvovaginal candidiasis (VVC) is usually not transmitted sexually, it is included in this section because it is frequently diagnosed in women who have vaginal symptoms or are being evaluated for STDs.
Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge.Clinical laboratory testing can identify the cause of vaginitis in most women and is discussed in detail in the sections of this report dedicated to each condition.In the clinician's office, the cause of vaginal symptoms might be determined by pH, a potassium hydroxide (KOH) test, and microscopic examination of fresh samples of the discharge.The pH of the vaginal secretions can be determined by narrow-range pH paper; an elevated pH (i.e., ≥4.5) is common with BV or trichomoniasis.Because pH testing is not highly specific, discharge should be further examined microscopically by first diluting one sample in one or two drops of 0.9% normal saline solution on one slide and a second sample in 10% KOH solution (samples that emit an amine odor immediately upon application of KOH suggest BV or trichomoniasis).Coverslips are then placed on the slides, and they are examined under a microscope at low and high power.
The saline-solution specimen might show motile trichomonads or "clue cells" (i.e., epithelial cells with borders obscured by small bacteria), which are characteristic of BV.The KOH specimen typically is used to identify hyphae or blastospores seen with candidiasis.However, the absence of trichomonads in saline or fungal elements in KOH samples does not rule out these infections, because the sensitivity of microscopy is approximately 50% compared with NAAT (trichomoniasis) or culture (yeast) (475).The presence of WBCs without evidence of trichomonads or yeast may also suggest cervicitis (see Cervicitis).
In settings where pH paper, KOH, and microscopy are not available, alternative commercially available point-of-care tests or clinical laboratory testing can be used to diagnose vaginitis.The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens after laboratory testing suggests the possibility of mechanical, chemical, allergic, or other noninfectious causes of vulvovaginal signs or symptoms.In patients with persistent symptoms and no clear etiology, referral to a specialist may be helpful.
# Bacterial Vaginosis
BV is a polymicrobial clinical syndrome resulting from replacement of the normal hydrogen peroxide producing Lactobacillus sp.in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp.and Mobiluncus sp.),G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes.Some women experience transient vaginal microbial changes, whereas others experience them for longer intervals of time.Among women presenting for care, BV is the most prevalent cause of vaginal discharge or malodor; however, in a nationally representative survey, most women with BV were asymptomatic (203).
BV is associated with having multiple male or female partners, a new sex partner, douching, lack of condom use, and lack of vaginal lactobacilli; women who have never been sexually active are rarely affected (589).The cause of the microbial alteration that precipitates BV is not fully understood, and whether BV results from acquisition of a single sexually transmitted pathogen is not known.Nonetheless, women with BV are at increased risk for the acquisition of some STDs (e.g., HIV, N. gonorrhoeae, C. trachomatis, and HSV-2), complications after gynecologic surgery, complications of pregnancy, and recurrence of BV (590)(591)(592)(593).BV also increases the risk for HIV transmission to male sex partners (594).Although BV-associated bacteria can be found in the male genitalia, treatment of male sex partners has not been beneficial in preventing the recurrence of BV (595).
# Diagnostic Considerations
BV can be diagnosed by the use of clinical criteria (i.e., Amsel's Diagnostic Criteria) (596) or Gram stain.A Gram stain (considered the gold standard laboratory method for diagnosing BV) is used to determine the relative concentration of lactobacilli (i.e., long Gram-positive rods), Gram-negative and Gram-variable rods and cocci (i.e., G. vaginalis, Prevotella, Porphyromonas, and peptostreptococci), and curved Gramnegative rods (i.e., Mobiluncus) characteristic of BV.Clinical criteria require three of the following symptoms or signs:
- homogeneous, thin, white discharge that smoothly coats the vaginal walls; - clue cells (e.g., vaginal epithelial cells studded with adherent coccoobacilli) on microscopic examination; - pH of vaginal fluid >4.5; or - a fishy odor of vaginal discharge before or after addition of 10% KOH (i.e., the whiff test).Detection of three of these criteria has been correlated with results by Gram stain (597).Other tests, including Affirm VP III (Becton Dickinson, Sparks, MD), a DNA hybridization probe test for high concentrations of G. vaginalis, and the OSOM BV Blue test (Sekisui Diagnostics, Framingham, MA), which detects vaginal fluid sialidase activity, have acceptable performance characteristics compared with Gram stain.Although a prolineaminopeptidase card test is available for the detection of elevated pH and trimethylamine, it has low sensitivity and specificity and therefore is not recommended.PCR has been used in research settings for the detection of a variety of organisms associated with BV, but evaluation of its clinical utility is still underway.Detection of specific organisms might be predictive of BV by PCR (598,599).Additional validation is needed before these tests can be recommended to diagnose BV.Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific.Cervical Pap tests have no clinical utility for the diagnosis of BV because of their low sensitivity and specificity.
# Treatment
Treatment is recommended for women with symptoms. |
The established benefits of therapy in nonpregnant women are to relieve vaginal symptoms and signs of infection.Other potential benefits to treatment include reduction in the risk for acquiring C. trachomatis, N. gonorrhoeae, T. vaginalis, HIV, and herpes simplex type 2 (592,593,600).
# Recommended Regimens
Metronidazole 500 mg orally twice a day for 7 days OR Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days Alcohol consumption should be avoided during treatment with nitroimidazoles.To reduce the possibility of a disulfiramlike reaction, abstinence from alcohol use should continue for 24 hours after completion of metronidazole.Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use (refer to clindamycin product labeling for additional information).
Women should be advised to refrain from sexual activity or use condoms consistently and correctly during the treatment regimen.Douching might increase the risk for relapse, and no data support the use of douching for treatment or relief of symptoms.
# Alternative Regimens
Tinidazole 2 g orally once daily for 2 days OR Tinidazole 1 g orally once daily for 5 days OR Clindamycin 300 mg orally twice daily for 7 days OR Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days- - Clindamycin ovules use an oleaginous base that might weaken latex or rubber products (e.g., condoms and vaginal contraceptive diaphragms).Use of such products within 72 hours following treatment with clindamycin ovules is not recommended.
Alcohol consumption should be avoided during treatment with nitroimidazoles.To reduce the possibility of a disulfiramlike reaction, abstinence from alcohol use should continue for 72 hours after completion of tinidazole.
Alternative regimens include several tinidazole regimens (601) or clindamycin (oral or intravaginal) (602).An additional regimen includes metronidazole (750-mg extended release tablets orally once daily for 7 days); however, data on the performance of this alternative regimen are limited.
Certain studies have evaluated the clinical and microbiologic efficacy of using intravaginal lactobacillus formulations to treat BV and restore normal flora (603)(604)(605)(606)(607).Overall, no studies support the addition of any available lactobacillus formulations or probiotic as an adjunctive or replacement therapy in women with BV.Further research efforts to determine the role of these regimens in BV treatment and prevention are ongoing.
# Other Management Considerations
All women with BV should be tested for HIV and other STDs.
# Follow-Up
Follow-up visits are unnecessary if symptoms resolve.Because persistent or recurrent BV is common, women should be advised to return for evaluation if symptoms recur.Detection of certain BV-associated organisms has been associated with antimicrobial resistance and might be predictive of risk for subsequent treatment failure (608)(609)(610)(611)(612)(613).Limited data are available regarding optimal management strategies for women with persistent or recurrent BV.Using a different recommended treatment regimen can be considered in women who have a recurrence; however, retreatment with the same recommended regimen is an acceptable approach for treating persistent or recurrent BV after the first occurrence (614).For women with multiple recurrences after completion of a recommended regimen, 0.75% metronidazole gel twice weekly for 4-6 months has been shown to reduce recurrences, although this benefit might not persist when suppressive therapy is discontinued (615).Limited data suggest that an oral nitroimidazole (metronidazole or tinidazole 500 mg twice daily for 7 days) followed by intravaginal boric acid 600 mg daily for 21 days and then suppressive 0.75% metronidazole gel twice weekly for 4-6 months for those women in remission might be an option for women with recurrent BV (616).Monthly oral metronidazole 2 g administered with fluconazole 150 mg has also been evaluated as suppressive therapy; this regimen reduced the incidence of BV and promoted colonization with normal vaginal flora (617).
# Management of Sex Partners
Data from clinical trials indicate that a woman's response to therapy and the likelihood of relapse or recurrence are not affected by treatment of her sex partner(s) (595).Therefore, routine treatment of sex partners is not recommended.
# Special Considerations Allergy, Intolerance, or Adverse Reactions
Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole or tinidazole.Intravaginal metronidazole gel can be considered for women who are not allergic to metronidazole but do not tolerate oral metronidazole.It is advised to avoid consuming alcohol during treatment with nitroimidazoles.To reduce the possibility of a disulfiram-like reaction, abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole.
# Pregnancy
Treatment is recommended for all symptomatic pregnant women.Studies have been undertaken to determine the efficacy of BV treatment among this population, including two trials demonstrating that metronidazole was efficacious during pregnancy using the 250-mg regimen (618,619); however, metronidazole administered at 500 mg twice daily can be used.One trial involving a limited number of participants revealed treatment with oral metronidazole 500 mg twice daily to be equally effective as metronidazole gel, with cure rates of 70% using Amsel criteria to define cure (620).Another trial demonstrated a cure rate of 85% using Gram-stain criteria after treatment with oral clindamycin (621).Multiple studies and meta-analyses have failed to demonstrate an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns (622,623).Although older studies indicated a possible link between use of vaginal clindamycin during pregnancy and adverse outcomes for the newborn, newer data demonstrate that this treatment approach is safe for pregnant women (624).Because oral therapy has not been shown to be superior to topical therapy for treating symptomatic BV in effecting cure or preventing adverse outcomes of pregnancy, symptomatic pregnant women can be treated with either of the oral or vaginal regimens recommended for nonpregnant women.Although adverse pregnancy outcomes, including premature rupture of membranes, preterm labor, preterm birth, intra-amniotic infection, and postpartum endometritis have been associated with symptomatic BV in some observational studies, treatment of BV in pregnant women can reduce the signs and symptoms of vaginal infection.A meta-analysis has concluded that no antibiotic regimen prevented preterm birth (early or late) in women with BV (symptomatic or asymptomatic).However, in one study, oral BV therapy reduced the risk for late miscarriage, and in two additional studies, such therapy decreased adverse outcomes in the neonate (625).
Treatment of asymptomatic BV among pregnant women who are at high risk for preterm delivery (i.e., those with a previous preterm birth) has been evaluated by several studies, which have yielded mixed results.Seven trials have evaluated treatment of pregnant women with asymptomatic BV at high risk for preterm delivery: one showed harm (626), two showed no benefit (627,628), and four demonstrated benefit (618,619,629,630).
Similarly, data are inconsistent regarding whether treatment of asymptomatic BV among pregnant women who are at low risk for preterm delivery reduces adverse outcomes of pregnancy.One trial demonstrated a 40% reduction in spontaneous preterm birth among women using oral clindamycin during weeks 13-22 of gestation (630).Several additional trials have shown that intravaginal clindamycin given at an average gestation of >20 weeks did not reduce likelihood of preterm birth (628,(631)(632)(633).Therefore, evidence is insufficient to recommend routine screening for BV in asymptomatic pregnant women at high or low risk for preterm delivery for the prevention of preterm birth (111).
Although metronidazole crosses the placenta, no evidence of teratogenicity or mutagenic effects in infants has been found in multiple cross-sectional and cohort studies of pregnant women (634).Data suggest that metronidazole therapy poses low risk in pregnancy (317).
Metronidazole is secreted in breast milk.With maternal oral therapy, breastfed infants receive metronidazole in doses that are less than those used to treat infections in infants, although the active metabolite adds to the total infant exposure.Plasma levels of the drug and metabolite are measurable, but remain less than maternal plasma levels (.gov/cgi-bin/sis/htmlgen?LACT).Although several reported case series found no evidence of metronidazole-associated adverse effects in breastfed infants, some clinicians advise deferring breastfeeding for 12-24 hours following maternal treatment with a single 2 g dose of metronidazole (635).Lower doses produce a lower concentration in breast milk and are considered compatible with breastfeeding (636,637).Data from studies of human subjects are limited regarding the use of tinidazole in pregnancy; however, animal data suggest that such therapy poses moderate risk.Thus tinidazole should be avoided during pregnancy (317).
# HIV Infection
BV appears to recur with higher frequency in women who have HIV infection (638).Women with HIV who have BV should receive the same treatment regimen as those who do not have HIV infection.
# Trichomoniasis
Trichomoniasis is the most prevalent nonviral sexually transmitted infection in the United States, affecting an estimated 3.7 million persons (533).Health disparities persist in the epidemiology of T. vaginalis infection in the United States: 13% of black women are affected compared with 1.8% of non-Hispanic white women (639).T. vaginalis infection affects >11% of women aged ≥40 years (640), and particularly high prevalence has been detected among STD clinic patients (641) (26% of symptomatic women and 6.5% asymptomatic women tested) and incarcerated persons (9%-32% of incarcerated women and 2%-9% of incarcerated men) (136,137,644,645).The prevalence of trichomoniasis in MSM is low (646,647).Some infected men have symptoms of urethritis, epididymitis, or prostatitis, and some infected women have vaginal discharge that might be diffuse, malodorous, or yellow-green with or without vulvar irritation.However, most infected persons (70%-85%) have minimal or no symptoms, and untreated infections might last for months to years (86,639,648,649).Although partners might be unaware of their infection, it is readily passed between sex partners during penile-vaginal sex (650).Among persons who are sexually active, the best way to prevent trichomoniasis is through consistent and correct use of condoms during all penile-vaginal sexual encounters (22).Partners of men who have been circumcised might have a somewhat reduced risk of T. vaginalis infection (56,651).Douching is not recommended because it might increase the risk for vaginal infections, including trichomoniasis (652).
T. vaginalis infection is associated with two-to threefold increased risk for HIV acquisition (653)(654)(655)(656), preterm birth, and other adverse pregnancy outcomes among pregnant women.Among women with HIV infection, T. vaginalis infection is associated with increased risk for PID (657)(658)(659).Routine screening of asymptomatic women with HIV infection for T. vaginalis is recommended because of the adverse events associated with asymptomatic trichomoniasis and HIV infection.
Diagnostic testing for T. vaginalis should be performed in women seeking care for vaginal discharge.Screening might be considered for persons receiving care in high-prevalence settings (e.g., STD clinics and correctional facilities) and for asymptomatic persons at high risk for infection (e.g., persons with multiple sex partners, exchanging sex for payment, illicit drug use, or a history of STD).However, data are lacking on whether screening and treatment for asymptomatic trichomoniasis in high prevalence settings or persons at high risk can reduce any adverse health events and health disparities or reduce community burden of infection.Decisions about screening might be informed by local epidemiology of T. vaginalis infection.
Whether the rectum can be a reservoir for T. vaginalis infection is unclear; data are needed to clarify whether this occasional finding might reflect recent depositing contamination in up to 5% of persons reporting recent receptive anal sex (660,661).Further, the efficacy, benefit, and cost-effectiveness of rectal screening are unknown; therefore, rectal testing for T. vaginalis is not recommended.Similarly, oral testing for T. vaginalis is not recommended because of a lack of evidence for oral infections.T. vaginalis infection is not a nationally notifiable condition in the United States (118,662).
# Diagnostic Considerations
The use of highly sensitive and specific tests is recommended for detecting T. vaginalis.Among women, NAAT is highly sensitive, often detecting three to five times more T. vaginalis infections than wet-mount microscopy, a method with poor sensitivity (51%-65%) (663,664).The APTIMA T. vaginalis assay (Hologic Gen-Probe, San Diego, CA) is FDA-cleared for detection of T. vaginalis from vaginal, endocervical, or urine specimens from women.This assay detects RNA by transcription-mediated amplification with a clinical sensitivity of 95.3%-100% and specificity of 95.2%-100% (665,666).Among women, vaginal swab and urine have up to 100% concordance (663).As analyte-specific reagents, this assay can be used with urine or urethral swabs from men if validated per CLIA regulations.The sale, distribution, and use of analytespecific reagents are allowed under 21 C.F.R. 809.30 pertaining to in vitro diagnostic products for human use.For T. vaginalis diagnosis in men, the sensitivity of self-collected penile-meatal swabs was higher than that of urine in one study (80% and 39%, respectively) (667).The BD Probe Tec TV Q x Amplified DNA Assay (Becton Dickinson, Franklin Lakes, New Jersey) is FDA-cleared for detection of T. vaginalis from endocervical, vaginal, or urine specimens from women.Although it might be feasible to perform these tests on the same specimen used for chlamydia and gonorrhea screening, the epidemiology of trichomoniasis is distinct and should not be overlooked in older adults.
Other FDA-cleared tests to detect T. vaginalis in vaginal secretions include the OSOM Trichomonas Rapid Test (Sekisui Diagnostics, Framingham, MA), an antigen-detection test using immunochromatographic capillary flow dipstick technology that can be performed at the point of care, and the Affirm VP III (Becton Dickinson, Sparks, MD), a DNA hybridization probe test that evaluates for T. vaginalis, G. vaginalis, and Candida albicans.The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, with sensitivity 82%-95% and specificity 97%-100% (666,668).Self-testing might become an option, as a study of 209 young women aged 14-22 years found that >99% could correctly perform and interpret her own self-test using the OSOM assay, with a high correlation with clinician interpretation (96% agreement, κ = 0.87) (669).The results of the Affirm VP III are available within 45 minutes.Sensitivity and specificity are 63% and 99.9%, respectively, compared with culture and TMA; sensitivity might be higher among women who are symptomatic (670,671).Neither the OSOM nor the Affirm VP III test is FDA-cleared for use with specimens obtained from men.
Culture was considered the gold standard method for diagnosing T. vaginalis infection before molecular detection methods became available.Culture has a sensitivity of 75%-96% and a specificity of up to 100% (475).In women, vaginal secretions are the preferred specimen type for culture, as urine culture is less sensitive (475,672,673).In men, culture specimens require a urethral swab, urine sediment, and/or semen.To improve yield, multiple specimens from men can be used to inoculate a single culture.
The most common method for T. vaginalis diagnosis might be microscopic evaluation of wet preparations of genital secretions because of convenience and relatively low cost.Unfortunately, the sensitivity of wet mount is low (51%-65%) in vaginal specimens (475,666) and lower in specimens from men (e.g., urethral specimens, urine sediment, and semen).
Clinicians using wet mounts should attempt to evaluate slides immediately because sensitivity declines as evaluation is delayed, decreasing by up to 20% within 1 hour after collection (674,675).When highly sensitive (e.g., NAAT) testing on specimens is not feasible, a testing algorithm (e.g., wet mount first, followed by NAAT if negative) can improve diagnostic sensitivity in persons with an initial negative result by wet mount (475).Although T. vaginalis may be an incidental finding on a Pap test, neither conventional nor liquid-based Pap tests are considered diagnostic tests for trichomoniasis, because false negatives and false positives can occur.
# Treatment
Treatment reduces symptoms and signs of T. vaginalis infection and might reduce transmission.Likelihood of adverse outcomes in women with HIV also is reduced with T. vaginalis therapy.
# Recommended Regimen
Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose
# Alternative Regimen
Metronidazole 500 mg orally twice a day for 7 days Alcohol consumption should be avoided during treatment with nitroimidazoles.To reduce the possibility of a disulfiramlike reaction, abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole.
The nitroimidazoles are the only class of antimicrobial medications known to be effective against T. vaginalis infections.Of these drugs, metronidazole and tinidazole have been cleared by FDA for the oral or parenteral treatment of trichomoniasis.Tinidazole is generally more expensive, reaches higher levels in serum and the genitourinary tract, has a longer half-life than metronidazole (12.5 hours versus 7.3 hours), and has fewer gastrointestinal side effects (676)(677)(678).In randomized clinical trials, recommended metronidazole regimens have resulted in cure rates of approximately 84%-98% (679-681), and the recommended tinidazole regimen has resulted in cure rates of approximately 92%-100% (680,(682)(683)(684)(685).Randomized controlled trials comparing single 2 g doses of metronidazole and tinidazole suggest that tinidazole is equivalent or superior to metronidazole in achieving parasitologic cure and resolution of symptoms (686).
Metronidazole gel does not reach therapeutic levels in the urethra and perivaginal glands.Because it is less efficacious than oral metronidazole, it is not recommended.
# Other Management Considerations
Providers should advise persons infected with T. vaginalis to abstain from sex until they and their sex partners are treated (i.e., when therapy has been completed and any symptoms have resolved).Testing for other STDs including HIV should be performed in persons infected with T. vaginalis.
# Follow-up
Because of the high rate of reinfection among women treated for trichomoniasis (17% within 3 months in one study) (86), retesting for T. vaginalis is recommended for all sexually active women within 3 months following initial treatment regardless of whether they believe their sex partners were treated (see Diagnostic Considerations).Testing by nucleic acid amplification can be conducted as soon as 2 weeks after treatment (687,688).Data are insufficient to support retesting men.
# Management of Sex Partners
Concurrent treatment of all sex partners is critical for symptomatic relief, microbiologic cure, and prevention of transmission and reinfections.Current partners should be referred for presumptive therapy to avoid reinfection.Partners should be advised to abstain from intercourse until they and their sex partners have been adequately treated and any symptoms have resolved. |