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/L 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
X X X X X Northeast Connecticut X X X X X Maine X X X Massachusetts X X New Hampshire X X X New Jersey X X X X New York X X X X X X Pennsylvania X X X X Rhode Island X X X X X Vermont X X X Midwest Illinois X X X X X X Indiana X X X X X X Iowa X X X X X X Kansas X X X X X X Michigan X X X X Minnesota X X X X X Missouri X X X X X X X Nebraska X X X X X North Dakota X X X X X X Ohio X X X X X South Dakota X X X X X Wisconsin X X X X X
Alabama X X X X X X X X Arkansas X X X X X X X X X Delaware X X X X Florida X X X X X Georgia X X X X Kentucky X X X Louisiana X X X X Maryland X X X X X X Mississippi X X X X X X North Carolina X X X X Oklahoma X X X X X X South Carolina X X X X X X Tennessee X X X X X Texas X X X X X X X Virginia X X X X X West Virginia X West Alaska X X X X Arizona X X X X California X X X X Colorado X X X X X Hawaii X X X Idaho X X X X X X X Montana X X X X Nevada X X X X X X X New Mexico X X Oregon X X Utah X X X X Washington X X X X X X Wyoming X X X

# 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/L (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/L 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/L (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/L results in decreased morbidity and mortality compared with starting therapy for persons with CD4 counts of 350 cells/ L, 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/L, 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/L. 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/L, 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/L. 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/L (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/L, 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/L). - Recommended for all nonimmune persons with CD4 counts 200 cells/L.

# Varicella-Zoster (VZV)
- Live vaccine is contraindicated for use in patients with severe immunosuppression (CD4 count of <200 cells/L). - Consider for HIV-infected, VZV-seronegative persons with CD4 counts 200 cells/L. - 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/L are considered to have limited immune deficits, whereas patients with CD4 counts of >500 cells/L 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/L 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 pate, or heat until steaming hot. Canned or shelf-stable pate 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/L. Measles immune globulin should be considered for those with CD4 counts of <200 cells/L who are traveling in measles-endemic areas. - Varicella vaccine can be considered for VZV-seronegative persons with CD4 counts of 200 cells/L. - 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/L who were prescribed Pneumocystis jiroveci pneumonia prophylaxis
(Group 1 measure)
Percentage of clients with HIV infection and a CD4 count of <50 cells/L 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/L 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/L, the CD4 count should be monitored closely. PCP prophylaxis should be considered for patients with a CD4 count of 200-250 cells/L 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/L 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/L, 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/L 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/L.

# Primary Prophylaxis: Indications
Prophylaxis should be administered to all HIV-infected patients with CD4 counts of <50 cells/L. 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/L 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/L.
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/L on ART. Secondary prophylaxis should be reintroduced if the CD4 count decreases to <100 cells/L.

# 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/L 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/L on ART. Secondary prophylaxis should be reintroduced if CD4 counts drop to <200 cells/L.

# 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/L, 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/L 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/L 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/L 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/L.

# 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/L. 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/L for at least 6 months, but should be restarted if the CD4 count drops to <250 cells/L.
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/L 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-Guerin (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 37C 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/L), 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/L rather than 500 cells/L, 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/L) versus deferred (<350 cells/L) 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/L). 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/L)
- Rapidly declining CD4 counts (e.g., >100 cells/L/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/L. 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/L 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/L, 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/L).
- 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/L 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/L) 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/L to 50-100 cells/L 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/L 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/L. 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/L 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/L 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/L) 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/L), 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/L (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/L. 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/L, obtain blood culture for acidfast bacilli (AFB); if <100 cells/L, 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/ L), 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/L). 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/L) 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/L 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/L. 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/L. 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/L). 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/L), 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/L for at least 6 months during ART). Maintenance therapy should be restarted if the CD4 count declines to <200 cells/L.

# 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/L 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/L.

# 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/L 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/L. 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/L) 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/L. 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/L. 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/L 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/L 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/L, as doing so is associated with higher rates of vaccine response. For patients with CD4 counts of 200 cells/L. 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/L, 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/L), 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/L, 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/L should be educated about precautions for avoiding exposure.
Primary prophylaxis can be discontinued if the CD4 count remains >150 cells/L for 6 months on effective ART; prophylaxis should be restarted if the CD4 count drops to 150 cells/L.

# 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/L), 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/L, 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/L. 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/L).

# 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/L 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/L), 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/L 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 >101F (>38.3C)
- 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/L. 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/L for more than 3 months.
In patients with stable CD4 count of >200 cells/L 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/ L, 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/L 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/L. 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/L 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/L 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/L, 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/L) is suggestive but not specific. Note that mononuclear pleocytosis (up to 5-20 cells/L) 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/L. 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/L 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/L 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/L or men with CD4 counts of >400 cells/L), 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/L, 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/L), 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/L, 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.

# Insomnia | 575
Section 8: Neuropsychiatric

# 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., Sjogren 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/L). 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/L.

# 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/L).

# 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/L.

# 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/L, 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 100.5F 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/L, 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.