Discussion

Hepatitis A: Burden of Disease

From 1980-1995, approximately 22,000 to 36,000 cases of infection with hepatitis A virus (HAV) were reported annually to the Centers for Disease Control and Prevention (CDC). In that pre-vaccine era, an estimated 270,000 infections occurred annually, with more than half among children[1]. The cost and morbidity associated with hepatitis A is considerable. Each year during 1980-1995, an estimated 100 persons died as a result of acute liver failure due to hepatitis A infection (HAV)[2]. One case series that examined the economic consequences of hepatitis A in 1997 estimated an attributable annual cost of 8.8 billion, which included medical expenses and productivity losses[3].

Impact of Hepatitis A Vaccine

Hepatitis A vaccines, available in the United States since 1995, are highly effective in preventing HAV infection. In 1996, the US Advisory Committee on Immunization Practices (ACIP) recommended the use of HAV vaccine for persons at high risk of acquiring HAV and for children living in communities with the highest rates of HAV infection and disease[2]. In 1999, the ACIP issued guidance to expand the use of hepatitis A vaccines to include children living in states, counties, and communities that had rates of HAV infection consistently higher than the national average[2]. Since the introduction of the hepatitis A vaccine in the mid 1990's, the incidence of reported hepatitis A in the United States has sharply declined (Figure 1 and Figure 2), to a historic low of 1.0 case per 100,000 population in 2009[4].

HAV Vaccine

Currently available hepatitis A vaccines contain inactivated HAV. The single-antigen vaccines, HAVRIX and VAQTA, are each licensed as two formulations whose dosages differ depending on the age of the person being immunized (Figure 3). The combination vaccine TWINRIX contains both HAV and HBV antigens and is licensed only for persons aged 18 years or older.

All of the hepatitis A vaccines are highly immunogenic and efficacious. Approximately 97 to 100% of children, adolescents, and adults develop protective antibody levels within 1 month of the first dose of vaccine. Essentially 100% of vaccinees develop high antibody titers after completing the 2-dose series, with long-term persistence of protective antibody levels 10 years out from vaccination[5]. In randomized double-blind placebo-controlled trials, 94-100% children were protected against clinical hepatitis A after receiving the equivalent of a single dose[6,7].

Reduced vaccine immunogenicity, as measured by final antibody concentrations, has been observed in several groups: persons who have received concurrent administration of hepatitis A immune globulin[8], infants who still retain passively transferred maternal anti-HAV antibody[9], and persons with chronic liver disease[10]. Lower rates of seroconversion after HAV immunization have also been demonstrated in HIV-infected patients; 87% of patients with a CD4 count less than 300 cells/mm3 achieved protective antibody response compared with 100% of those with a CD4 count of 300 cells/mm3 or greater[11].

Indications for Hepatitis A Vaccination

In 2006, the ACIP issued recommendations that specifically addressed the prevention of hepatitis A through active or passive immunization. In this document, the ACIP recommended routine HAV vaccination for all children of at least 1 year of age, persons at increased risk for infection (Figure 4), and anyone who wishes to obtain immunity to HAV[2]. Persons considered at increased risk for HAV compared with the general population include susceptible persons who travel to countries of moderate to high endemnicity for HAV (Figure 5), men who have sex with men, and users of injection or non-injection drugs[2]. Persons with chronic liver disease (which includes patients with compensated disease, chronic hepatitis B or C virus infection, and those with non-viral etiologies, such as autoimmune hepatitis or hemochromatosis) are not necessarily at increased risk for HAV, but are more likely to have severe manifestations of HAV infection[12,13] and therefore should receive HAV vaccination.

Immunizing Travelers with HAV Vaccine

Hepatitis A is one of the most common vaccine-preventable infections among non-immune travelers visiting developing countries, second only to influenza[14]. The incidence ranges from 4 to 30 cases per 100,000 person-months of stay, with the highest rates observed among travelers to Africa, the Indian subcontinent, and Latin America[15]. Children of foreign nationals visiting friends and relatives appear to be at particular risk[15,16]. The ACIP recommends administering HAV vaccine or immune globulin prior to departure for all susceptible persons traveling to countries with intermediate or high endemnicity for HAV (Figure 5)[18]. Most countries have intermediate or high endemnicity, except for the United States, Canada, western Europe, Japan, New Zealand, and Australia.

Previously, the ACIP recommended that persons receiving hepatitis A vaccine within 4 weeks of traveling to a high risk area for hepatitis A should, for optimal protection, also receive immune globulin[2]. Based on comparative data indicating HAV vaccine and immune globulin provide similar protection when given as postexposure prophylaxis among healthy persons aged 1 to 40 years[17], the ACIP concluded that hepatitis A vaccine alone could be recommended for healthy international travelers aged 1 to 40 years of age, regardless of the traveler's departure date[18]. Although one dose of single-antigen hepatitis A vaccine given any time before departure provides adequate protection, the traveler should ideally receive the first hepatitis A vaccine dose as soon as travel is considered[18]. For travelers departing within 2 weeks who are at risk for more severe disease from HAV (adults older than 40 years of age, immunocompromised persons, or persons with chronic liver disease or other chronic medical conditions), passive immunization with immune globulin (0.02 mL/kg) should be administered in addition to HAV vaccine for optimal protection. The traveler can receive immune globulin at the same time as HAV vaccine, but the two should be administered in different anatomic sites. Immune globulin provides protection for up to 3 months.

Other Known Risk Factors

Hepatitis A virus is transmitted person-to-person by the fecal-oral route and has historically occurred in the context of community-wide outbreaks, typically within households or networks of close contacts. Outbreaks have occurred among men who have sex with men in urban settings in North America, Europe and Australia. Some studies have suggested that a greater of number of sex partners and greater frequency of oral-anal contact are associated with HAV infection[19]. Outbreaks have also occurred in the US among both injection and non-injection users of illicit drugs. Cross-sectional studies have shown higher seroprevalence of anti-HAV among injection-drug users than in the general population[20]. Transmission of HAV could occur through both percutaneous and fecal-oral spread, although parenteral transmission is thought to be uncommon because of the short duration of HAV viremia during infection[21]. HAV vaccination is not recommended routinely for those who work in health care, child care, or food service, or for workers who are exposed to sewage. The only occupational group for which HAV vaccination is routinely recommended is research laboratory workers studying hepatitis A[2].

Because HAV infection among children is typically mild or asymptomatic, children play a key role in HAV transmission. Thus, exposure to a child care center is a well-recognized risk factor for HAV[22]. Nevertheless, the ACIP does not recommend routine vaccination of workers at child care centers for two reasons. First, the incidence of outbreaks associated with child care centers has declined as HAV vaccination of very young children has become routine. Second, serologic surveys have not demonstrated an increased prevalence of HAV infection among child care center workers compared with the general population. In February 2009, however, the ACIP recommended household members and other close personal contacts (such as babysitters) of newly adopted children from countries of intermediate or high HAV endemnicity undergo routine hepatitis A vaccination[23]. These guidelines were issued in light of 34 cases of acute hepatitis A reported to the Centers for Disease Control and Prevention since 2006 following exposure to adoptees newly arriving from HAV-endemic countries[24]. These new adoptees, if actively infected, are usually nonjaundiced and asymptomatic and thus pose a risk of transmitting HAV to susceptible contacts[24]. In this setting, the first dose of the HAV series should be administered as soon as adoption is planned, with the second dose given ideally at least 2 weeks prior to the arrival of the international adoptee.

Postexposure Prophylaxis

Hepatitis A vaccine has recently been added to the regimen recommended by the ACIP for postexposure prophylaxis to HAV. A randomized double-blind clinical trial conducted among 1,090 susceptible household and day-care contacts of HAV cases compared the efficacy of HAV vaccine to immune globulin (IG) in preventing hepatitis A infection. When administered within 14 days of exposure, these approaches were found to have comparable efficacy[17]. The primary outcome of laboratory-confirmed symptomatic HAV infection occurred in 25 (4.4%) of 568 vaccine recipients compared with 17 (3.3%) of 522 IG recipients [relative risk 1.35; 95% confidence interval (CI) 0.70-2.67]. Assuming IG is 90% efficacious in prevention HAV, the vaccine was estimated to have 86% efficacy in preventing clinical HAV (95% CI 73-93%). These data prompted the new recommendation that persons who have recently been exposed to hepatitis A and who have not previously received HAV vaccination should be administered a single-dose of HAV single-antigen vaccine or immune globulin as soon as possible.

Deciding which approach to use for post-exposure prophylaxis depends on several factors. From the public health perspective, the vaccine has a number of advantages compared with IG: induction of active immunity and longer protection, greater ease of administration, higher acceptability, and widespread availability. For the individual patient, the ACIP recommends post-exposure prophylaxis with HAV vaccine in healthy persons aged 12 months to 40 years, but continues to recommend IG in exposed persons older than 40 years and in those who have chronic liver disease[18]. These recommendations reflect the relative lack of data on HAV vaccine performance and greater risk of severe consequences of HAV infection in these latter groups. IG should also be used for exposed children younger than 1 year, immunocompromised persons and persons for whom vaccine is otherwise contraindicated (discussed below). For more discussion, see the case on Postexposure Prophylaxis After Exposure to Hepatitis A virus.

Serologic Testing Before or after Vaccination

According to ACIP recommendations, prevaccination testing for the presence of anti-HAV antibodies may be considered among populations expected to have high rates of previous HAV infection and natural immunity in order to reduce costs by not vaccinating persons already immune to HAV [2]. Serologic screening is most likely to be cost-effective with the following three groups:

(1) Adults aged greater than 40 years since the seroprevalence of anti-HAV was estimated to be greater than 33% in this group[25], particularly among American Indian, Alaska Native, and Hispanic populations;

(2) Adolescents or adults who were born in or have resided for an extended length of time in regions of high or intermediate HAV endemnicity; and

(3) Risk groups with high HAV seroprevalence, such as injection-drug users, men who have sex with men (MSM), or HIV-infected patients.

Post-vaccination confirmation of anti-HAV antibody is not recommended because of the high rates of protective response to vaccination in both children and adults[2].

Contraindications to HAV Vaccination

Hepatitis A vaccines should not be given to anyone with a history of hypersensitivity to any vaccine component, such as alum or aluminum (which is contained both HAVRIX and VAQTA), or 2-phenoxyethanol which is a preservative in trace amounts in HAVRIX. The vaccines, like other inactivated viral vaccines, are most likely safe in pregnancy and lactation. However because the safety of hepatitis A vaccine in pregnancy has not been clearly established, there should be a clear indication for use before administering the vaccine[2].

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  • The following link will open in a new window.
    Figure 1 - Rate (per 1000,000 population) of Reported Hepatitis A, by Age Group and Year—United States, 1990-2004

    This figure is reproduced from Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1-23.


    Figure 1
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    Figure 2 - Rate (per 100,000 population) of Hepatitis A, by county in United States, 1987-1997 and 2004

    Source: National Notifiable Disease Surveillance System

    This figure shows rates of HAV infection (per 100,000 population) in the United States during the years 1987-1997 (before widespread use of hepatitis A vaccine) compared with rates in 2004 (after widespread use of hepatitis A vaccine). As shown, the rates of HAV infection have dramatically declined in 2004 when compared with 1987-1997.


    Figure 2
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    Figure 3 - Licensed Doses of Hepatitis A Vaccines

    *TWINRIX is a combination hepatitis A and B vaccine and each dose consists of 720 ELISA units of hepatitis A and 20 ug of hepatitis B.
    ELISA = Enzyme-linked immunosorbent assay
    0 months represents timing of initial dose; subsequent numbers represent months after the initial dose.


    Figure 3
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    Figure 4 - Recommendations for Preexposure Use of Hepatitis A Vaccine

    These recommendations are from the Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1-23.


    Figure 4
  • The following link will open in a new window.
    Figure 5 - Prevalence of Antibody to Hepatitis A Virus, by Country, 2006

    This figure is reproduced from: Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1-23.


    Figure 5