Epidemiology and Prevention of Viral Hepatitis A to E: An Overview
                        Hepatitis Branch
           Centers for Disease Control and Prevention
[SLIDE 1] Title Slide
[This slide set presents an overview of the clinical and epidemiologic features for viral hepatitis A,
B, C, D, and E and prevention measures for these infections.  More detailed information regarding
the epidemiologic features and prevention measures for hepatitis B are presented in two previously
published slide sets: 1) "Elimination of hepatitis B virus transmission in the United States: routine
childhood vaccination," and 2) "Prevention of perinatal and early childhood hepatitis B virus
infections in the United States," both of which are available from the National Technical Information
Service (800-CDC-1824).  

[SLIDE 2] Viral Hepatitis: Historical Perspective
Before the discovery of hepatitis A virus (HAV) and hepatitis B virus (HBV) during the 1960s and
1970s, patients with viral hepatitis were classified based on epidemiologic studies as having either
infectious (transmitted person to person by the fecal-oral route) or serum (transmitted by transfusion
of blood products) hepatitis.  When diagnostic tests for hepatitis A virus (HAV) and hepatitis B virus
(HBV) infection were developed, HAV was found to be the major cause of infectious hepatitis and
HBV was found to be the major cause of serum hepatitis.  Hepatitis Delta virus (HDV), discovered
in 1977, is  a defective virus requiring the presence of HBV in order to replicate.  However, some
patients with typical signs and symptoms of viral hepatitis did not have serologic markers of HAV,
HBV or HDV infection and were categorized based on epidemiologic characteristics as having either
parenterally transmitted non-A, non-B hepatitis or enterically transmitted non-A, non-B hepatitis. 
During the past decade, two additional viruses have been discovered: hepatitis C virus (HCV) and
hepatitis E virus (HEV).  HCV is the major cause of parenterally transmitted non-A, non-B hepatitis
and HEV is the major cause of enterically transmitted non-A, non-B hepatitis.  In addition, some
patients with typical signs and symptoms of acute viral hepatitis do not have serologic markers of
any of these types of viral hepatitis and can be classified as having non-ABCDE hepatitis.  Recently, 
new viruses have been discovered in patients with non-ABCDE hepatitis.  Characterization of the
epidemiology and clinical features of these and other possible agents of viral hepatitis will await the
development of diagnostic assays.

[SLIDE 3] Viral Hepatitis: Overview
For HAV and HEV, the primary source of virus is in feces and the fecal-oral route is the
predominant mode of transmission.  HBV, HCV, and HDV are bloodborne viruses and are primarily
transmitted by percutaneous and mucosal exposures. HAV and HEV cause only acute infection,
while HBV, HCV, and HDV can result in chronic infection.  Both immune globulin (IG) and
hepatitis A vaccine are available for prevention of hepatitis A.  Immune globulin can be used as
either pre- or postexposure prophylaxis and hepatitis A vaccine can be used for preexposure
prophylaxis.  The primary measure for prevention of hepatitis B is immunization; hepatitis B can
be prevented using either preexposure prophylaxis with hepatitis B vaccine or postexposure
prophylaxis with hepatitis B immune globulin (HBIG) and hepatitis B vaccine.   No products are
available to prevent hepatitis C, and development of immunoprophylaxis for this disease is proving
to be difficult because an effective protective antibody response has not been demonstrated
following HCV infection.  Thus, the primary strategies for hepatitis C prevention are blood donor
screening and risk behavior modification.  Because HDV infection is dependent on HBV for
replication, immunization to prevent HBV infection, through either pre- or postexposure
prophylaxis, can also prevent HDV infection.  In persons who are chronically infected with HBV,
risk behavior modification is the primary measure to prevent HDV superinfection.  For hepatitis E,
no products are available for prevention; IG prepared from Western blood donor sources does not
prevent infection and it is unclear if IG prepared from serum of donors from high endemic areas will
prevent infection.  In the absence of immunoprohylaxis, the primary measure to prevent hepatitis
E is to ensure the safety of drinking water.  

[SLIDE 4] Acute Viral Hepatitis, by Type, United States, 1982-1993
Of acute hepatitis cases in the United States from 1982 through 1993, 47% were attributable to 
hepatitis A, 34% to hepatitis B, 16% to hepatitis C, and 3% were negative for serologic markers of
HAV, HBV, and HCV infection. An estimated 4% of acute HBV infections are coinfections with
HDV. Hepatitis E has only rarely been reported in the United States, almost always in persons who
had recently traveled to HEV endemic areas.

[SLIDE 5] Estimates of Acute and Chronic Disease Burden for Viral Hepatitis, United States
Viral hepatitis causes substantial morbidity and mortality in the United States. During the past
decade, an estimated 125-200,000 HAV infections, 140-320,000 HBV infections, 35-180,000 HCV
infections, and 6-13,000 HDV infections have occurred each year (based on the estimated annual
incidence for these types of viral hepatitis from 1984-1994).   As a result of acute infection with
these viruses, approximately 285 deaths from fulminant hepatitis occur annually, 100 from hepatitis
A, 150 from hepatitis B, and 35 from HBV-HDV coinfection or superinfection.  In addition, persons
infected with HBV, HCV, and HDV may develop chronic infection.  In the United States,
approximately 1-1.25 million persons are chronically infected with HBV, 3.5 million with HCV, and
70,000 with HDV.  An estimated 15,000 persons with chronic infection die each year as a result of
chronic liver disease (cirrhosis and liver cancer), 5,000 with HBV infection, 8-10,000 with HCV
infection, and 1,000 with HDV infection.  

[SLIDE 6] Hepatitis A Virus
Hepatitis A is caused by infection with HAV, a 27-nm RNA virus that is classified as a picornavirus. 
HAV infection appears to induce lifelong protection against subsequent infection.  Only one
serotype has been observed among HAV isolates collected from various parts of the world.

[SLIDE 7] Hepatitis A: Clinical Features
The average incubation period for hepatitis A is 30 days with a range of 15 to 45 days. The severity
of clinical disease associated with HAV infection increases with increasing age; icteric disease
occurs among <10% of children younger than 6 years of age, 40%-50% of older children, and 70%-80% of adults.   Complications of hepatitis A include fulminant hepatitis in which the case-fatality
rate can be >50% despite modern medical interventions such as liver transplantation, cholestatic
hepatitis with very high bilirubin levels that can persist for months, and relapsing hepatitis in which
exacerbations can occur months after apparent recovery.  Chronic infection has not been reported
to occur following HAV infection.  
 
[SLIDE 8] Age-specific Mortality Due to Hepatitis A
Hepatitis A produces occasional mortality, with an estimated 100 deaths each year in the United
States due to fulminant hepatitis A.  The overall case-fatality rate is approximately 0.4%;  the
highest case-fatality rate is among persons >49 years of age (17.5 per 1000). In this age group,
preexisting chronic liver disease appears to be associated with an increased risk of death from acute
hepatitis A.

[SLIDE 9] Hepatitis A Virus Infection: Typical Serologic Course
The diagnosis of acute HAV infection is confirmed during the acute or early convalescent phase of
infection by the presence of IgM antibodies to HAV (IgM anti-HAV).  IgM anti-HAV is generally
present 5-10 days into the incubation period and remains detectable for up to 6 months after onset
of illness.  IgG anti-HAV, which also appears early in the course of infection, remains detectable
for the lifetime of the individual and confers lifelong protection against disease.   The concentration
of HAV in the stool of infected persons is highest during the 2-week period before onset of jaundice. 
Fecal HAV excretion generally persists for <1 week after onset of jaundice in adults; however, virus
has been detected during disease relapse up to 2 months after illness onset. Children and infants may
shed HAV for longer periods than observed in adults, possibly for several weeks after onset of
clinical illness.  In infants born prematurely, viral RNA has been detected intermittently by
polymerase chain reaction (PCR) in stool specimens for up to 6 months after infection. Chronic
shedding of HAV in feces has not been demonstrated.

[SLIDE 10] Concentration of Hepatitis A Virus in Various Body Fluids 
Feces can contain up to 108 infectious virions per ml and are the primary source of HAV.  Viremia
occurs during the prodromal phase of illness and HAV has been transmitted on rare occasions by
transfusion.  Virus has also been found in saliva during the incubation period in experimentally
infected animals, but transmission by saliva has not been reported to occur. 

[SLIDE 11] Hepatitis A Virus Transmission
Transmission of HAV generally occurs as a result of ingestion by a susceptible person of virus shed
in the feces of an infected person.  Close personal contact is the most common mode of HAV
transmission as demonstrated by high rates of infection among household and sex contacts of
persons with hepatitis A and among children in day care center outbreaks.  Contaminated food and
water can also serve as vehicles of HAV transmission; the vehicles of transmission in foodborne
outbreaks are most often uncooked foods or foods touched by human hands after cooking, but
outbreaks have been reported in association with foods contaminated before wholesale distribution. 
Because HAV can survive for 12 weeks to 10 months in water, infection can occur by ingestion of
a variety of raw shellfish harvested from sewage-contaminated areas.  Waterborne outbreaks have
also been reported both in association with drinking fecally contaminated water and with swimming
in contaminated swimming pools and lakes.  In addition, HAV transmission can occur as a result
of blood exposures such as injecting drug use or blood transfusion because viremia can occur prior
to onset of illness in infected persons; however,  such transmission is rare.  

[SLIDE 12] Incidence of Hepatitis A, United States, 1952-1993
During the past several decades, the incidence of hepatitis A in the United States has been cyclic,
with nationwide epidemics occurring every 10 to 15 years; the latest epidemic occurred in 1989. 
Between epidemics, hepatitis A continues to occur at relatively high levels.  For example, in 1993,
24,238 hepatitis A cases were reported to the National Notifiable Diseases Surveillance System of
the CDC; these cases are estimated to correspond to 75,000 cases of hepatitis A and 125,000 HAV
infections, after correcting for underreporting and asymptomatic infections.  

[SLIDE 13] Age-specific Incidence of Hepatitis A, United States, 1983-1993
Children play an important role in the transmission of HAV in the United States.  In recent years,
peak rates of disease have been among children 5-14 years of age and nearly 30% of all reported
cases are among children younger than 15 years of age.  However, reported disease rates do not
reflect the extent of transmission among young children, because most children who are infected
before age 5 have unrecognized asymptomatic infection. 

[SLIDE 14] Sources of Hepatitis A Virus Infection by Mutually Exclusive Groups, United
States, 1983-1993
The most frequently reported source of infection for reported hepatitis A cases is personal contact
(household or sexual) with an infected person, which is consistently reported by about 25% of
persons with acute hepatitis A.  About 15 percent of cases involve a child or employee at a day care
center or a contact of a day care-related case, and 5-7% involve persons with a history of recent
international travel or of being part of a recognized food or waterborne outbreak.  Injecting drug use
and homosexual activity are generally associated with <5% of cases; however, prolonged outbreaks
in which person-to-person contact has been thought to be the predominant source of infection have
occurred among persons with these risk factors.  A large percentage (approximately 45% in 1993)
of persons with reported hepatitis A do not have a recognized risk factor for acquiring infection; this
is a reflection of the fact that most hepatitis A in the United States occurs in communitywide
outbreaks with extended person-to-person transmission.  Contact with children may be an important
source of infection for persons without identified risk factors because children <5 years of age reside
in approximately 50% of these case-households.   
 
[SLIDE 15, SLIDE 16] Global Patterns of Hepatitis A Virus Transmission, Geographic
Distribution of HAV Infection*
Worldwide, four different patterns of HAV transmission can be defined on the basis of age-specific
seroprevalence data.  In general, these transmission patterns correlate with socioeconomic and
hygienic conditions.  In many developing countries where environmental sanitation generally is
poor, nearly all children <9 years of age have evidence of prior HAV infection.  In these areas,
distinct outbreaks rarely occur and clinical disease related to HAV infection is uncommon.  As
hygienic conditions improve, transmission shifts to older age groups and the incidence of clinically
evident disease increases.  In most industrialized countries, low levels of endemic HAV transmission
occur.  The relatively high prevalence of prior HAV infection among older age groups in these areas
is likely to be related to the presence of lower socioeconomic and hygienic conditions in the past. 
Because most of the population is susceptible to HAV infection, disease outbreaks are relatively
common in most of these countries.  However, in a few industrialized countries hepatitis A
outbreaks are uncommon, and nearly all HAV transmission occurs among drug users and travelers
to high endemic areas.  
*(Note: The map of anti-HAV prevalence generalizes available data and patterns may vary within
countries.)  

[SLIDE 17] Hepatitis A Vaccine Efficacy Studies
The hepatitis A vaccine currently licensed in the United States, HAVRIX * (manufactured by
SmithKline Beecham Pharmaceuticals), is a formalin-inactivated vaccine.  Application has been
made for licensure of another inactivated vaccine, VAQTA  (manufactured by Merck & Co., Inc.). 
Both of these vaccines are highly immunogenic, inducing anti-HAV titers above those observed
following administration of IG in more than 99% of adults.  The efficacy of HAVRIX  was
evaluated in a double-blind, placebo-controlled, randomized clinical trial in Thailand among 38,157
children aged 1-16 years living in an area with high endemic rates of hepatitis A.  Following two
doses of vaccine (360 EL.U. per dose) given 1 month apart, the efficacy of vaccine in protecting
against clinical hepatitis A was 94% (95% confidence interval [CI], 79%-99%). A double-blind,
placebo-controlled, randomized clinical trial using VAQTA  was conducted among 1037 children
aged 2 to 16 years living in a single U.S. community with a high endemic rate of hepatitis A.  After
18 days following one dose (25 units) of vaccine, the efficacy in protecting against clinical disease
was 100% (95% CI, 85%-100%). 
*Use of trade names is for identification only and does not imply endorsement by the Public Health 
Service or the U.S. Department of Health and Human Services. 

[SLIDE 18] Hepatitis A Vaccination Strategies: Epidemiologic Considerations  Epidemiologic
features of HAV infection that need to be considered in developing hepatitis A vaccination strategies
include the following:
        1.     Most hepatitis A in the United States occurs due to extended community-wide
               outbreaks in which a large proportion of cases have no identifiable risk factor.  In
               these outbreaks, the highest rates of disease occur among children 5-14 years of age
               and person-to-person transmission, especially from children to adults, is the primary
               mode of transmission.
        2.     The primary groups with an increased risk of infection include the following:
     Travelers to developing countries. The risk among such travelers who do not
     receive IG is about 3-5/1000 per month of stay. 
     Men who have sex with men. Hepatitis A outbreaks among homosexual men have
     been reported frequently and serosurveys have demonstrated a prevalence of HAV
     infection among homosexual men several-fold higher than among control
     populations.
     Injecting drug users. During the past decade outbreaks were reported in the United
     States among injecting drug users and during the late 1980s 10%-20% of persons
     with hepatitis A reported a history of injecting drug use.  
[SLIDE 19] Routine Childhood Hepatitis A Vaccination
Because of their important role in transmission of HAV, children should be considered the primary
target of immunization strategies to lower disease incidence and the most effective means of
achieving control of hepatitis A is likely to be routine hepatitis A vaccination of infants or young
children.  This strategy has a number of potential benefits: 1) an established vaccine delivery system
is in place, 2) vaccination would occur before the greatest risk for clinical disease, and 3) the
potential exists to interrupt transmission among children, which could result in a significant impact
on the disease burden in other age groups.  However, a number of issues need to be resolved before
routine childhood vaccination can be recommended: 1) determining the appropriate dose and timing
of vaccination in the first or second year of life, and determining the importance of the effect of
maternal antibody on immunogenicity, 2) developing combination vaccines that incorporate hepatitis
A vaccine, 3) determining the duration of protection following vaccination in children, and 4)
determining the cost-effectiveness of such a vaccination strategy.   

[SLIDE 20] ACIP Recommendations - Preexposure Hepatitis A Vaccination 
Until routine vaccination of children against hepatitis A is feasible, the Immunization Practices
Advisory Committee (ACIP) has recommended hepatitis A vaccine for the following persons who
are at increased risk for infection: 
     Persons who plan to travel repeatedly or reside for long periods in countries
     with high or intermediate endemicity of HAV infection.  These persons should
     be vaccinated before departure.  Persons can be assumed to be protected by 4 weeks
     after receiving the initial vaccine dose, although the second dose 6 to 12 months later
     is necessary for long-term protection.  Individuals who will travel to high-risk areas
     <4 weeks after the initial dose of vaccine should also be given IG, but at different
     injection sites.  Travelers to high-risk areas who are allergic to a vaccine component
     or otherwise elect not to receive vaccine should receive IG. 
     Sexually active homosexual and bisexual men. These persons should be
     vaccinated.  
     Injecting drug users or persons who use non-injection street drugs.  These
     persons should be vaccinated if local epidemiologic and surveillance data indicate
     that persons with such risk behaviors are at increased risk for HAV infection.
     Persons with chronic liver disease.  Susceptible persons with chronic liver disease,
     including persons awaiting or having received liver transplants, may be at increased
     risk for complications of hepatitis A and should be vaccinated. 
In addition, the ACIP has recommended that routine childhood vaccination be used as the primary
vaccination strategy in communities with high endemic rates of HAV infection and periodic hepatitis
A outbreaks (e.g., Alaska Natives and American Indians).  In these communities, children should
be routinely vaccinated at or after 2 years of age.  In addition, previously unvaccinated older
children should be vaccinated to prevent epidemics of hepatitis A.  Vaccination of school children
prior to school entry should receive highest priority, followed by vaccination of older children. The
upper age for catch-up vaccination should be determined using age-specific seroprevalence data for
HAV infection, if available.  Vaccination is not warranted in age groups with the lowest rates of
disease because the prevalence of immunity is high (e.g., adults).   

[SLIDE 21] Features of Community-wide Hepatitis A Outbreaks
Most hepatitis A in the United States occurs through person-to-person transmission during
community-wide outbreaks.  As a frame of reference for considering the use of hepatitis A vaccine,
communities that experience hepatitis A outbreaks can be classified into two types: high rate and
intermediate rate, based on epidemiologic characteristics, including age-specific rates of infection
and temporal patterns of disease incidence.  
High-rate communities typically have epidemics every 5-10 years that may last for several years,
have very high rates of disease (as high as 2,000 per 100,000 per year), and have few cases among
persons >15 years of age.  Seroprevalence data show that many children (30%-40%) in these
communities acquire infection before age 5 years and nearly all persons become infected before
reaching young adulthood.  These communities are relatively well defined or isolated, either
geographically or ethnically, and include American Indian, Alaska Native, Pacific Islander, and
certain religious communities.
Compared with epidemics in high-rate communities, those in intermediate-rate communities produce
lower rates of disease.  In these communities, hepatitis A rates of 50-200 per 100,000 per year can
persist for several years; cases occur in children, adolescents, and young adults; and disease rates
are highest in census tracts or neighborhoods with low socioeconomic levels.  In some communities,
injecting drug users or other adult risk groups may account for a relatively large percentage of cases. 
Available surveillance data often indicate that these epidemics occur with regular periodicity;
however, single prolonged outbreaks do occur.  Intermediate-rate communities tend to be less
geographically or ethnically defined than high-rate communities, but cases are often concentrated
in specific census tracts or neighborhoods within a larger community.     

[SLIDE 22] ACIP Recommendations - Control of Community-wide Outbreaks: High-Rate
Communities 
The primary vaccination strategies recommended by ACIP to prevent or control outbreaks in high-rate communities are 1) routine vaccination of young children, and 2) accelerated implementation
of catch-up vaccination of older children.  Several studies have examined the effectiveness of
hepatitis A vaccine in controlling outbreaks in these communities.  In a study conducted in Monroe
County, New York, vaccination of children 2 to 16 years of age with VAQTA  resulted in a
substantial decrease in community hepatitis A rates.  In addition, vaccination of susceptible persons
<30 years of age with one dose of HAVRIX  (720 EL.U.) in several Alaska villages experiencing
hepatitis A outbreaks resulted in a rapid decrease in the number of cases.
 
[SLIDE 23] ACIP Recommendations - Control of Community-wide Outbreaks: Intermediate-Rate Communities 
Hepatitis A vaccination of children and/or adolescents may have the potential to control outbreaks
occurring in communities with intermediate rates of disease.  However, these communities are often
large cities or counties, and therefore widespread vaccination may not be possible. Targeting
vaccination among subpopulations or groups with the highest rates of disease may be more feasible,
but the effectiveness of using vaccine in these settings has not been determined. 
Use of hepatitis A vaccine can be considered to control outbreaks that occur in intermediate-rate
communities.  To determine possible target groups for vaccination, local surveillance and
epidemiologic data should be used to define populations (e.g., age groups, drug users) or areas
within the community (e.g., census tracts) with the highest rates of disease.  Occasionally, when day
care centers play a role in sustaining a communitywide outbreak, consideration should be given to
adding hepatitis A vaccine to the immunoprophylaxis regimen for children and staff in involved
centers.   In addition, persons who work as foodhandlers may develop hepatitis A during
communitywide outbreaks, and the food industry may want to consider vaccination of these
employees. 
In making a decision to attempt vaccination to control outbreaks in communities with intermediate
rates of infection, several factors should be considered including: 1) the feasibility of rapidly
vaccinating the target populations of children, adolescents, and young adults; 2) program cost; and
3) the ability to continue ongoing vaccination of young children to maintain high levels of immunity
and prevent future outbreaks.

[SLIDE 24] ACIP Recommendations - Prevaccination Serologic Testing
Several factors should be considered in deciding whether prevaccination testing may be indicated
in a particular setting including: 1) the cost of vaccination compared with the cost of serologic
testing (including the cost of an additional visit); 2) the expected prevalence of immune individuals;
and 3) the likelihood that prevaccination testing will not interfere with completion of the vaccine
series.  For example, if the cost of screening (including laboratory testing and office visits) is  one-third the cost of the vaccine series, then screening of potential recipients from populations where the
prevalence of infection is >33% should be cost-effective.  
Prevaccination testing is generally not indicated before vaccination of children.  Populations for
whom prevaccination screening will likely be most cost-effective include adults who were born or
lived for extensive periods of time in geographic areas with a high endemicity of HAV infection;
older adolescents and young adults in certain population groups (i.e., American Indians, Alaska
Natives, Pacific Islanders); and adults in certain risk groups with high prevalence of infection (e.g.,
homosexual men, older adults).  Among adults >40 years of age in the United States, the anti-HAV
prevalence is generally >33% (regardless of race/ethnicity or income level).  Therefore,
prevaccination screening for any adult >40 years of age would be likely to be cost-effective
(assuming the cost of screening is one-third the cost of the vaccination series).  Commercially
available tests for total anti-HAV should be used for prevaccination testing.

[SLIDE 25] ACIP Recommendations - Postvaccination Testing
Postvaccination serologic testing is not indicated because of the very high rate of vaccine response
among both children and adults.  In addition, a commercially available test with the sensitivity to
detect the lower anti-HAV concentrations associated with protection is not approved in the United
States. 
[SLIDE 26] Recommended Doses and Schedules of Hepatitis A Vaccine
The dose and schedule of administration for HAVRIX  varies according to age.  For adults (>18
years of age), 1440 ELISA units (EL.U.) per dose are given in a two-dose schedule 6-12 months
apart. For children and adolescents (2 to 18 years of age), 360 EL.U. per dose are given in a three-dose schedule at 0, 1, and 6-12 months.  The vaccine should be given by intramuscular injection into
the deltoid muscle.  

[SLIDE 27] Hepatitis A Prevention - Immune Globulin
Immune globulin is 80%-90% effective in preventing clinical hepatitis A when administered before
exposure or early in the incubation period.  The primary indication for use of IG for preexposure
prophylaxis is for travelers to high HAV endemic regions.  Postexposure prophylaxis with IG is
effective if administered within 14 days of exposure.  The primary routine indication for
postexposure prophylaxis is for household or other intimate contacts of persons with hepatitis A. 
In addition, postexposure prophylaxis may be indicated when hepatitis A cases occur in some
institutional settings (e.g., child day care centers), and for some common-source exposures (e.g.,
eating food prepared by an infected food handler).  Local and/or state health departments should be
consulted regarding the use of IG for postexposure prophylaxis in these settings.    

[SLIDE 28] Hepatitis B Virus
HBV is a 42-nm, double-shelled deoxyribonucleic acid (DNA) virus of the class Hepadnaviridae. 
The outer surface membrane contains hepatitis B surface antigen (HBsAg), which also circulates
in blood as 22-nm spherical and tubular particles.  HBsAg is the primary component of hepatitis B
vaccine; this antigen induces a protective, neutralizing antibody that provides long-term protection
against HBV infection. The inner core of the virus contains hepatitis B core antigen (HBcAg),
hepatitis B e antigen (HBeAg), a single molecule of partially double-stranded DNA, and
DNA-dependent DNA polymerase. 

[SLIDE 29] Hepatitis B - Clinical Features
The incubation period for hepatitis B ranges from 45-180 days (mode, 60-90 days), and the onset
of acute disease is generally insidious.  Clinical illness associated with acute infection is age-dependent with jaundice occurring in <10% of children less than 5 years of age and in 30%-50% of
older children and adults.  The case-fatality rate for reported acute cases in the United States is
approximately 0.5%-1%.  Most acute HBV infections in adults result in complete recovery with
clearance of HBsAg from the blood and the production of anti-HBs designating immunity from
future infection.  However, approximately 30%-90% of young children and 2%-10% of adults who
are infected with HBV develop chronic infection, and most of the serious sequelae associated with
HBV occur in these persons.  Persons with chronic HBV infection are often asymptomatic, but these
persons are at high risk for developing chronic hepatitis, and approximately 15%-25% may die
prematurely from either cirrhosis or liver cancer.  

[SLIDE 30] Acute Hepatitis B Virus Infection with Recovery: Typical Serologic Course
Serologic markers of HBV infection vary depending on whether the infection is acute or chronic.
The first serologic marker to appear following acute infection is HBsAg, which can be detected as
early as 1 or 2 weeks and as late as 11 or 12 weeks (mode, 30-60 days) after exposure to HBV.  In
persons who recover, HBsAg is no longer detectable in serum after an average period of about 3
months.  HBeAg is generally detectable in patients with acute infection; the presence of HBeAg in
serum correlates with higher titers of HBV and greater infectivity.  A diagnosis of acute HBV
infection can be made on the basis of the detection of IgM class antibody to hepatitis B core antigen
(IgM anti-HBc) in serum; IgM anti-HBc is generally detectable at the time of clinical onset and
declines to subdetectable levels within 6 months.  IgG anti-HBc persists indefinitely as a marker of
past infection.  Anti-HBs becomes detectable during convalescence after the disappearance of
HBsAg in patients who do not progress to chronic infection.   The presence of anti-HBs following
acute infection generally indicates recovery and immunity from reinfection.  

[SLIDE 31] Progression to Chronic Hepatitis B Virus Infection: Typical Serologic Course
In patients with chronic HBV infection, both HBsAg and IgG anti-HBc remain persistently
detectable, generally for life.  HBeAg is variably present in these patients.  The presence of HBsAg
for 6 months or more is generally indicative of chronic infection.  In addition, a negative test for IgM
anti-HBc together with a positive test for HBsAg in a single serum specimen usually indicates that
an individual has chronic HBV infection. 

[SLIDE 32] Rate of Reported Hepatitis B by Age Group, United States, 1990
In the United States, hepatitis B is largely a disease of young adults.  The rate of reported cases is
highest for persons 20-39 years of age.  Rates among children <15 years of age are relatively low;
however, the rate of infection in this age group is higher than reflected from reported cases because
infection in children is often asymptomatic and therefore not detected through disease surveillance. 

[SLIDE 33] Age at Acquisition of Acute and Chronic HBV Infection, United States, 1989
Estimates
Although most acute HBV infections in the United States occur among adults, about 24% of 
chronic HBV infections are acquired perinatally and about 12% are acquired during early childhood. 

[SLIDE 34] Outcome of HBV infections by Age at Infection
The outcome of acute HBV infection varies substantially depending on the age at which infection
occurs.  In children less than 5 years of age, <5% of acute HBV infections are symptomatic;
however, chronic infection occurs in about 80%-90% of infants infected during the first year of life
and in about 30%-50% of children infected between 1-4 years of age.  In comparison, 30%-50% of
adults with acute HBV infection are symptomatic, but only 2%-10% develop chronic infection.  

[SLIDE 35, SLIDE 36] Global Patterns of Chronic HBV Infection, Geographic Distribution
of Chronic HBV infection* 
Approximately 45% of the global population live in areas with a high prevalence of chronic HBV
infection (> 8% of the population is HBsAg-positive); 43% in areas with a moderate prevalence
(2%-7% of the population is HBsAg-positive); and 12% in areas with a low prevalence (< 2% of the
population is HBsAg-positive).  In high prevalence areas, the lifetime risk of HBV infection is
>60%, and most infections are acquired at birth or during early childhood when the risk of
developing chronic infection is greatest.  In these areas, because most infections in children are
asymptomatic, very little acute disease related to HBV occurs, but rates of chronic liver disease and
liver cancer in adults are very high.  In moderate prevalence areas, the lifetime risk of being infected
is 20%-60% and infections occur in all age groups.  Acute disease related to HBV is common in
these areas because many infections occur in adolescents and adults; however, the high rates of
chronic infection are maintained mostly by infections occurring in infants and children.  In low
prevalence areas, the lifetime risk of infection is <20%.  Most HBV infections in these areas occur
in adults in relatively well defined risk groups.  
*(Note: The map of HBsAg prevalence generalizes available data and patterns may vary within
countries.)  

[SLIDE 37] Concentration of Hepatitis B Virus in Various Body Fluids
HBV is transmitted by percutaneous or permucosal exposure to infectious  blood or body fluids from
persons who have either acute or chronic HBV infection.  The highest concentrations of virus are
in blood and serous fluids; lower concentrations are found in semen, vaginal fluid, and saliva. 
Therefore, blood exposure and sex contact are relatively efficient modes of transmission.  Saliva can
be a vehicle of transmission through bites; however, transmission has not been documented to occur
as a result of other types of exposure to saliva, including kissing.  HBsAg has also been detected in
low concentrations in other body fluids, including tears, sweat, urine, feces, breast milk,
cerebrospinal fluid, and synovial fluid; however, these fluids have not been associated with
transmission. 

[SLIDE 38] Hepatitis B Virus: Modes of Transmission
In the United States, the most important route of HBV transmission is by sex contact, either
heterosexual or homosexual, with an infected person.  Direct parenteral inoculation of HBV by
needles during injecting drug use is also an important mode of transmission.  Transmission of HBV
may also occur by other percutaneous exposures, including tattooing, ear piercing, and acupuncture,
and by needlesticks or other injuries from sharp instruments sustained by medical personnel;
however, these exposures account for only a small proportion of reported cases in the United States.
In addition, transmission can occur perinatally from a chronically infected mother to her infant, most
commonly by contact of maternal blood to the infant's mucous membranes at the time of delivery. 
 
[SLIDE 39] Risk Factors for Acute Hepatitis B, United States, 1992-1993
Of persons with acute hepatitis B reported in the CDC Sentinel Counties Study of Acute Viral
Hepatitis in 1992-1993, 50% had a sexual risk factor (>1 sex partner during the previous 6 months,
sex contact with a person with hepatitis, or homosexual activity), 15% reported injecting drug use,
and 4% had other risk factors (e.g., household contact with a hepatitis patient, health care
employment). No risk factor could be identified for 31% of reported cases.  

[SLIDE 40] Elimination of Hepatitis B Virus Transmission, United States: Goals and
Objectives
The current hepatitis B vaccination strategy in the United States has an overall goal of eliminating
HBV transmission. Because most of the serious consequences related to HBV occur among persons
with chronic HBV infection, the primary objectives of this strategy are to prevent chronic HBV
infection and its consequences, cirrhosis and liver cancer.  A secondary objective is to prevent
symptomatic illness associated with acute HBV infection.  

[SLIDE 41] Elimination of Hepatitis B Virus Transmission, United States: Strategy
The hepatitis B elimination strategy includes the following components: 1) preventing perinatal
HBV transmission by screening all pregnant women for hepatitis B surface antigen (HBsAg) and
providing hepatitis B immune globulin (HBIG) and hepatitis B vaccine to infants of HBsAg-positive
mothers; 2) providing hepatitis B vaccine to all infants as part of the routine childhood vaccination
schedule; 3) making special efforts to provide catch-up vaccination for children in high risk groups,
including Alaska Natives, Pacific Islanders and infants of immigrants from countries with a high
prevalence of chronic HBV infection;  4) providing hepatitis B vaccine to adolescents, including a)
all previously unvaccinated children at 11-12 years of age and b) adolescents of all ages who are at
high risk for infection (see adult high-risk groups below); and 5) vaccinating adults in high-risk
groups including a) men and women with a history of other sexually transmitted diseases and
persons who have a history of multiple sex partners (>1 partner/6 months), b) household contacts
and sex partners of persons with chronic HBV infection and health care and public safety workers
who have exposure to blood in the workplace, d) clients and staff of institutions for the
developmentally disabled, e) international travelers who plan to spend >6 months in countries with
high rates of HBV infection and who will have close contact with the local population, f) injecting
drug users, g) sexually active homosexual and bisexual men, and h) recipients of clotting-factor
concentrates.

[SLIDE 42] Estimated Incidence of Acute Hepatitis B, United States, 1978-1993
Since hepatitis B vaccine was licensed for use in the United States in 1981, the incidence of acute 
hepatitis B has changed dramatically.  During the 1980s, use of hepatitis B vaccine had little impact
on disease incidence, which actually increased during the early 1980s.   The incidence declined
between 1985 and 1988, and between 1988 and 1991, when fewer cases were reported among
homosexual men and among injecting drug users, respectively.  In both of these groups the decline
in incidence was likely related to behavioral changes in response to the epidemic of acquired
immunodeficiency syndrome (AIDS) rather than to vaccine use.  The incidence has continued to
decline during the first half of the 1990s; a likely contributing factor for this most recent decline is
the widespread use of hepatitis B vaccine in response to regulations issued by the Occupational
Safety and Health Administration. Future declines in incidence are expected to occur as a result of
the implementation of routine infant and routine adolescent vaccination, which have been
recommended in the 1990s.   

[SLIDE 43] Hepatitis C Virus
HCV is an enveloped, single-stranded RNA virus,  approximately 50 nm in diameter, that has been
classified as a separate genus in the Flaviviridae family.   Before HCV was visualized, the virus
genome was cloned and sequenced.  The 5' end of the genome codes for core and envelope proteins,
followed by nonstructural proteins, which extend to the 3' end.  The ability of HCV to undergo rapid
mutation in a hypervariable region(s) of the genome coding for  envelope protein allows it to escape
immune surveillance by the host; thus, most persons infected with HCV develop chronic infection.
[SLIDE 44] Hepatitis C: Clinical Features
The average incubation period for hepatitis C is generally 6-7 weeks with a range of 2 weeks to 26
weeks.  About 30% to 40% of persons with acute infection develop symptomatic illness and 20%
to 30% have jaundice. Chronic liver disease develops in about 70% of persons who become infected
with HCV and nearly all (85%-100%) persons with acute HCV infection become persistently
infected; these persons are at risk for developing cirrhosis and liver cancer.  No protective antibody
response has been identified following HCV infection. 

[SLIDE 45] Primary Etiology of Chronic Liver Disease: Mutually Exclusive Groups, Jefferson
County, Alabama, 1989
The findings of a study conducted in Jefferson County, Alabama, suggest that viral hepatitis may
be responsible for at least 50% of all chronic liver disease in the United States and HCV may be as
important as alcohol as a cause of chronic liver disease.  In this study, 40% of identified patients
with chronic liver disease had evidence of HCV infection, 41% had a history of excessive alcohol
intake, 14% had chronic HBV infection, and 5% had other causes of chronic liver disease; for 17%
no etiology could be determined.  If these proportions are applied to the estimated 32,000 deaths
each year in the United States from chronic liver disease, 8-10,000 deaths may be related to chronic
HCV infection each year -- about twice the number that are attributable to chronic HBV infection. 

[SLIDE 46] Hepatitis C Virus Infection: Typical Serologic Course
HCV RNA is the earliest marker of HCV infection and is detectable by polymerase chain reaction
(PCR) testing as early as 2 weeks after exposure.  However, because PCR testing for HCV RNA is
not licensed for use in the United States, diagnosis of HCV infection is generally made on the basis
of detection of antibody to HCV (anti-HCV).  Anti-HCV is detectable by 5 to 6 weeks after onset
of hepatitis in 80% of patients and by 12 weeks in 90%.  Because the appearance of anti-HCV may
be delayed in patients with acute HCV infection, testing should be repeated if hepatitis C is
suspected in a patient and initial testing is negative for anti-HCV.  No tests are available to
differentiate acute from chronic infection.  Diagnosis of chronic hepatitis C in an anti-HCV positive
individual is generally based on the presence of elevated liver enzymes for >6 months.  

[SLIDE 47] Risk Factors Associated with Transmission of HCV
Percutaneous exposures, including transfusion and transplantation from an infectious donor and
injecting drug use, are the most efficient modes of HCV transmission.  The overall prevalence of
anti-HCV among persons with these exposures generally exceeds 60%.  Other types of percutaneous
exposures, including hemodialysis and needlestick injuries, have also been associated with HCV
transmission.  The risk of HCV transmission following a needlestick exposure to an anti-HCV-positive patient is approximately 5% to 10%.  Other risk factors that have been associated with HCV
transmission include sexual or household exposure to an anti-HCV-positive contact, having multiple
sex partners, and being an infant of an HCV-infected mother.  However, the magnitude of the risk
associated with these exposures has not been well defined.  
[SLIDE 48] Estimated Incidence of Acute Hepatitis C, United States, 1982-1993
Based on data from the CDC Sentinel Counties Study of Acute Viral Hepatitis, the incidence of
acute hepatitis C remained relatively stable through much of the 1980s at 12-18 cases per 100,000
persons per year.  However, between 1989 and 1993,  a decline in incidence of >75% occurred, from
18 cases per 100,000 to <5 cases per 100,000.  Much of the recent decline in incidence can be
accounted for by a decline in cases among injecting drug users that may be related to safer needle
using practices. A substantial decline has also occurred in the number of cases of
transfusion-associated hepatitis C.  The latter decline began in 1985 when changes in donor selection
practices were instituted in response to the AIDS epidemic and continued through the early 1990s
after screening of the blood supply for anti-HCV was initiated.  Trends in other risk factors,
including sexual and household exposure and occupational exposures, have remained relatively
stable over time.

[SLIDE 49] Risk Factors for Acute Hepatitis C, United States, 1990-1993
In the CDC Sentinel Counties Study of Acute Viral Hepatitis, persons with percutaneous exposures,
including blood transfusion (4%),  injecting drug use (38%), occupational exposure to blood (2%),
hemodialysis (1%), and sexual or household exposures (10%), accounted for 55% of cases of  acute
hepatitis C between 1990-1993.  Persons with no specific source for their HCV infection also
account for a substantial amount of disease, and low socioeconomic level is associated with a large
proportion of these patients.   More than 50% of these persons report histories of some type of high-risk behavior or contact, including imprisonment, use of noninjection illegal drugs, one or more
sexually transmitted diseases, contact with a sex partner or household member who used injection
drugs, but not in the 6 months preceding illness.   Low socioeconomic level and other high-risk
attributes identified among these patients have been associated with transmission of a number of
infectious diseases, and probably serve as surrogate indicators for routes of transmission; however,
the nonspecific nature of these factors make disease prevention difficult.

[SLIDE 50] Prevalence of HCV Infection among Blood Donors*
Knowledge of the geographic distribution of HCV infection is based primarily on seroprevalence
studies among blood donors because few population-based seroprevalence studies have been
conducted worldwide.  An extremely low anti-HCV prevalence (<0.1%) has been reported among
blood donors in the United Kingdom and Scandinavia; a slightly higher prevalence (0.2-1%) has
been reported in other Western European countries, Australia, and North America; an intermediate
prevalence (1.1%-5%) has been reported in South America, Eastern Europe, Mediterranean
countries, South Africa and Asia; and the highest prevalence (as high as 20% in Egypt) has been
reported in the Middle East.  
* (Note: The map of anti-HCV prevalence is based on data available for studies in which first- or
second-generation anti-HCV tests and supplemental testing was used.  This map generalizes
available data and patterns may vary within countries.)  
[SLIDE 51] Prevention of Hepatitis C
There are currently no vaccine or immune globulin products available to prevent transmission of
HCV and developing such products is proving to be difficult because no effective protective
antibody response has been demonstrated following infection with HCV. In the absence of
immunoprophylaxis, the primary measures available to prevent hepatitis C are screening of blood,
organ, and tissue donors; modification of high-risk behavior; and use of blood and body fluid
precautions.  Blood donors have been screened for anti-HCV in the United States since May 1990. 
Using first-generation anti-HCV tests, the risk of HCV infection per recipient is estimated to have
declined from about 5% to 1% and using second generation tests, the risk is <0.1% per recipient. 
High-risk behavior modification, such as safer needle using practices, seems to have reduced the
number of hepatitis C cases among injection drug users.  However, there is uncertainty regarding
whether this downward trend will be maintained, and many persons who acquire hepatitis C cannot
be readily identified as belonging to this or other high-risk groups.    

[SLIDE 52] Postexposure Prophylaxis for Hepatitis C: ACIP Revised Recommendation,
February 1994
In February 1994, the ACIP made the following recommendation regarding use of IG for
postexposure prophylaxis for hepatitis C: "Recent studies indicate that IG does not protect against
infection with HCV.  Thus, available data do not support the use of IG for prophylaxis of hepatitis
C.  There are no data on the efficacy of IG for post-exposure prophylaxis of other (non-HCV)
parenterally-transmitted, non-A, non-B hepatitis." 

[SLIDE 53] Postexposure Prophylaxis for Hepatitis C: Issues and Considerations for
Recommendations
Data considered by ACIP in making this recommendation include the following:
        1.     No protective antibody response has been identified following HCV infection.  The
               extraordinarily high rate of persistent infection observed in humans and the lack of
               protection against rechallenge with homologous and heterologous HCV strains
               demonstrated in experimental studies in chimpanzees suggest that HCV fails to
               induce an effective neutralizing antibody response.  
        2.     Prior studies of IG use to prevent posttransfusion non-A, non-B hepatitis may not be
               relevant in making recommendations regarding postexposure prophylaxis for
               hepatitis C.  In some of these studies, IG seemed to reduce the rate of clinical disease
               (although not overall infection rates); and in one, patients were less likely to develop
               chronic hepatitis.  However, the results of these studies are difficult to compare and
               interpret because 1) the first dose of IG was given after exposure in only one of these
               studies, making it difficult to assess the value of IG for postexposure prophylaxis;
               2) uniform diagnostic criteria were not used; 3) mixed sources of donors (volunteer
               and commercial) were used; 4) different study designs (some lacking blinding and
               placebo controls) were used; and 5) none of these data have been reanalyzed since
               anti-HCV testing became available.
        3.     Experimental studies in chimpanzees have demonstrated that neither standard IG nor
               IG with a high titer of anti-HCV prevents infection when used for postexposure
               prophylaxis.   

[SLIDE 54] Public Health Service Recommendations for Counseling Anti-HCV-Positive
Persons
Anti-HCV-positive persons should: 
        1.     Be considered potentially infectious.   
        2.     Keep cuts or skin lesions covered to prevent the spread of infectious secretions or
               blood.
        3.     Be informed of the potential for sexual transmission of HCV.  HCV transmission by
               sex contact appears to occur, but this route of transmission appears to be much less
               efficient than for other bloodborne sexually transmitted diseases (e.g., HBV, HIV). 
               For persons with a steady sex partner, data are insufficient to  recommend changes
               in sex practices.  However, to prevent many sexually transmitted diseases, including
               hepatitis and HIV infection, persons with multiple sex partners should follow safer
               sex practices, including reducing the number of sex partners and using barriers (e.g.,
               latex condoms) to prevent contact with body fluids. 
        4.     Be informed of the potential for perinatal transmission of HCV.  The risk of perinatal
               transmission appears to be low (<10%).  At the present time, there is no evidence to
               support advising against pregnancy or breastfeeding based on anti-HCV status alone,
               or to advise any special treatments or precautions for pregnant women or their
               offspring.  
Anti-HCV-positive persons should not: 
        1.     Donate blood, body organs, other tissue, or semen.
        2.     Share personal articles such as toothbrushes and razors that could be contaminated
               with blood.

[SLIDE 55] Hepatitis D (Delta) Virus  
HDV is a defective single-stranded RNA virus that requires the helper function of HBV to replicate. 
HDV requires HBV for synthesis of envelope protein composed of HBsAg, which is used to
encapsulate the HDV genome.  

[SLIDE 56] Delta Hepatitis: Clinical Features
HDV infection can be acquired either as a coinfection with HBV or as a superinfection of persons
with chronic HBV infection.  Persons with HBV-HDV coinfection may have more severe acute
disease and a higher risk of fulminant hepatitis (2%-20%) compared with those infected with HBV
alone; however, chronic HBV infection appears to occur less frequently in persons with HBV-HDV
coinfection.  Chronic HBV carriers who acquire HDV superinfection usually develop chronic HDV
infection. In long-term studies of chronic HBV carriers with HDV superinfection, 70%-80% have
developed evidence of chronic liver diseases with cirrhosis compared with 15%-30% of patients
with chronic HBV infection alone.

[SLIDE 57] Delta Hepatitis: Modes of Transmission
The modes of HDV transmission are similar to those for HBV, with percutaneous exposures the 
most efficient.  Sexual transmission of HDV is less efficient than for HBV.  Perinatal HDV
transmission is rare.

[SLIDE 58] HBV-HDV Coinfection: Typical Serologic Course
The serologic course of HDV infection varies depending on whether the virus is acquired as a
coinfection with HBV or as a superinfection of a person with chronic HBV infection.   In most
persons with HBV-HDV coinfection, both IgM antibody to HDV (anti-HDV) and IgG anti-HDV
are detectable during the course of infection.  However, in about 15% of patients the only evidence
of HDV infection may be the detection of either IgM anti-HDV alone during the early acute period
of illness or IgG anti-HDV alone during convalescence.  Anti-HDV generally declines to
subdetectable levels after the infection resolves and there is no serologic marker that persists to
indicate that the patient was ever infected with HDV.  Hepatitis Delta antigen (HDAg) can be
detected in serum in only about 25% of patients with HBV-HDV coinfection.  When HDAg is
detectable it generally disappears as HBsAg disappears and most patients do not develop chronic
infection.  Tests for IgG anti-HDV are commercially available in the United States. Tests for IgM
anti-HDV, HDAg and HDV RNA by PCR are only available in research laboratories.

[SLIDE 59] HBV-HDV Superinfection: Typical Serologic Course
In patients with chronic HBV infection who are superinfected with HDV several characteristic
serologic features generally occur, including: 1) the titer of HBsAg declines at the time HDAg
appears in the serum, 2) HDAg and HDV RNA remain detectable in the serum because chronic
HDV
infection generally occurs in most patients with HDV superinfection, unlike the case with
coinfection,  3) high titers of both IgM and IgG anti-HDV are detectable, which persist indefinitely. 
 
[SLIDE 60] Geographic Distribution of HDV Infection*
In general, the global pattern of HDV infection corresponds to the prevalence of chronic HBV
infection; however, several distinct features of the distribution of  HDV infection have been
identified.  In countries with a low prevalence of chronic HBV infection, HDV prevalence is
generally low among both asymptomatic HBV carriers (<10%) and among patients with chronic
HBV-related liver disease (<25%).  HDV infection in these countries occurs most commonly among
injecting drug users and persons with hemophilia.  In countries with moderate and high levels of
chronic HBV prevalence, the prevalence of HDV infection is highly variable.  In southern Italy and
in parts of Russia and Romania, the prevalence of HDV infection is very high among both
asymptomatic HBV carriers (>20%) and among patients with HBV-related chronic liver disease
HBV (>60%).  Other countries, including northern Italy, Spain, Turkey, and Egypt, have a moderate
prevalence of HDV infection among asymptomatic HBV carriers (10%-19%) and among patients
with chronic HBV-related liver disease (30%-50%).  However, in most of Southeast Asia and China,
where the prevalence of chronic HBV infection is very high, HDV infection is uncommon.  In some
South American countries in the Amazon River Basin, periodic epidemics of HDV infection have
occurred among chronic HBV carriers in relatively isolated regions.  Disease related to HDV
infection in these outbreaks has been very severe, with  rapid progression to fulminant hepatitis and
case-fatality rates of 10%-20%.  The cause of the atypical course of HDV infection in these
populations is unknown.
*(Note: The map of anti-HDV prevalence generalizes available data and patterns may vary within
countries.)  
[SLIDE 61] Delta Hepatitis: Prevention
Because HDV is dependent on HBV for replication, HBV-HDV coinfection can be prevented with
either pre- or postexposure prophylaxis for HBV.  However, no products exist to prevent HDV
superinfection of persons with chronic HBV infection.  Thus, prevention of HDV superinfection
depends primarily on education to reduce risk behaviors. 

[SLIDE 62] Hepatitis E Virus
Hepatitis E virus (HEV), the major etiologic agent of enterically transmitted non-A, non-B hepatitis
worldwide, is a spherical, nonenveloped, single stranded RNA virus that is approximately 32 to 34
nm in diameter.  Based on similar physicochemical and biologic properties, HEV has been
provisionally classified in the Caliciviridae family; however, the organization of the HEV genome
is substantially different from that of other caliciviruses and HEV may eventually be classified in
a separate family. 

[SLIDE 63] Hepatitis E: Clinical Features
The incubation period following exposure to HEV ranges from 15 to 60 days (mean, 40 days). 
Typical clinical signs and symptoms of acute hepatitis E are similar to those of other types of viral
hepatitis and include abdominal pain anorexia, dark urine, fever, hepatomegaly, jaundice, malaise,
nausea, and vomiting.  Other less common symptoms include  arthralgia, diarrhea, pruritus, and
urticarial rash.  The period of infectivity following acute infection has not been determined but virus
excretion in stools has been demonstrated up to 14 days after illness onset.  In most hepatitis E
outbreaks, the highest rates of clinically evident disease have been in young to middle-age adults;
lower disease rates in younger age groups may be the result of anicteric and/or subclinical HEV
infection.  No evidence of chronic infection has been detected in long-term follow-up of patients
with hepatitis E.

[SLIDE 64] Hepatitis E Virus Infection: Typical Serologic Course
The typical serologic course following HEV infection has been characterized using experimental
models of infection in nonhuman primates and human volunteer studies.  In two human volunteer
studies, liver enzyme elevations occurred 4-5 weeks after oral ingestion and persisted for 20-90
days.  Virus excretion in stools occurred approximately 4 weeks after oral ingestion and persisted
for about 2 weeks.   Both IgM and IgG antibody to HEV (anti-HEV) are elicited following HEV
infection.  The titer of IgM anti-HEV declines rapidly during early convalescence; IgG anti-HEV
persists and appears to provide at least short-term protection against disease.  No serologic tests to
diagnose HEV infection are commercially available in the United States.  However, several
diagnostic tests are available in research laboratories, including enzyme immunoassays and Western
blot assays to detect IgM and IgG anti-HEV in serum, polymerase chain reaction tests to detect HEV
RNA in serum and stool, and immunofluorescent antibody blocking assays to detect antibody to
HEV antigen in serum and liver. 
[SLIDE 65] Hepatitis E: Epidemiologic Features
HEV is transmitted primarily by the fecal-oral route and fecally contaminated drinking water is the
most commonly documented vehicle of transmission.  Although hepatitis E is most commonly
recognized to occur in large outbreaks, HEV infection accounts for >50% of acute sporadic hepatitis
in both children and adults in some high endemic areas.  Risk factors for infection among persons
with sporadic cases of hepatitis E have not been defined.  Unlike hepatitis A virus, which is also
transmitted by the fecal-oral route, person-to-person transmission of HEV appears to be uncommon. 
However, nosocomial transmission, presumably by person-to-person contact, has been reported to
occur.  Virtually all cases of acute hepatitis E in the United States have been reported among
travelers returning from high HEV-endemic areas.   

[SLIDE 66] Geographic Distribution of Hepatitis E*
Outbreaks of hepatitis E have occurred over a wide geographic area, primarily in developing
countries with inadequate environmental sanitation.  The reservoir of HEV in these areas is
unknown.  The occurrence of sporadic HEV infections in humans may maintain transmission during
interepidemic periods, but a nonhuman reservoir for HEV is also possible.  In the United States and
other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low 
prevalence of anti-HEV (<2%) has been found in healthy populations.  The source of infection for
these persons is unknown.  
* (Note: The map of HEV infection generalizes available data and patterns may vary within
countries.)  

[SLIDE 67] Prevention and Control Measures for Travelers to HEV-Endemic Regions
Prevention of hepatitis E relies primarily on the provision of clean water supplies.  Prudent hygienic
practices that may prevent hepatitis E and other enterically transmitted diseases among travelers to
developing countries include avoiding drinking water (and beverages with ice) of unknown purity,
uncooked shellfish, and uncooked fruits or vegetables that are not peeled or prepared by the traveler. 
No products are available to prevent hepatitis E.  IG prepared from plasma collected in non-HEV-endemic areas is not effective in preventing clinical disease during hepatitis E outbreaks and the
efficacy of IG prepared from plasma collected in HEV-endemic areas is unclear.  In studies
conducted to date with prototype vaccines in animals, vaccine-induced antibody attenuated HEV
infection, but did not prevent virus excretion in stools.  If a vaccine is developed, the epidemiology
of hepatitis E needs to be further defined in order to determine whether vaccination strategies could
be effectively used to prevent this disease.
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