Steven T. Wiersma

Infectious Agent

Hepatitis A virus (HAV), a 27-nm RNA virus classified as a picornavirus.

Mode of Transmission

• Transmission can occur through direct person-to-person contact; through exposure to contaminated water, ice, or shellfish harvested from sewage-contaminated water; or from fruits, vegetables, or other foods that are eaten uncooked and that were contaminated during harvesting or subsequent handling.
• HAV is shed in the feces of persons with HAV infection. The virus reaches peak levels the week or two before onset of symptoms and diminishes rapidly after liver dysfunction or symptoms appear, which is concurrent with the appearance of circulating antibodies to HAV. Infants and children, however, may shed virus for up to 6 months following infection.

Occurrence

• Worldwide, geographic areas can be characterized by high, intermediate, or low levels of endemicity (Map 2-1). Levels of endemicity are related to hygienic and sanitary conditions in the geographic areas.
• HAV infection is common (high or intermediate endemicity) throughout the developing world, where infections most frequently are acquired during early childhood and usually are asymptomatic or mild.
• In areas of high endemicity, adults are usually immune and epidemics of hepatitis A are uncommon.
• In developed countries, HAV infection is less common (low endemicity), but community-wide outbreaks may occur.
• Map 2-1 indicates the seroprevalence of antibody to HAV (total anti-HAV) as measured in selected cross-sectional studies among each country’s residents. The seroprevalence of anti-HAV provides an estimate of the endemicity of HAV infections, including asymptomatic infections, within a population.

Risk for Travelers

• Hepatitis A is one of the most common vaccine-preventable infections acquired during travel.
• In 2006 in the United States, among cases for which information regarding exposures during the incubation period was collected, the most frequently identified risk factor for hepatitis A was international travel (reported by 15% of case-patients overall).
• As in previous years, most travel-related cases (72%) were associated with travel to Mexico and Central/South America. As HAV transmission in the United States has decreased, cases among travelers to countries in which hepatitis is endemic have accounted for an increased proportion of all cases.
• The risk of acquiring HAV infection for U.S. residents traveling abroad varies with living conditions, length of stay, and the incidence of HAV infection in the area visited. For travelers to other countries, risk for infection increases with duration of travel and is highest for those who live in or visit rural areas, trek in back-country areas, or frequently eat or drink in settings of poor sanitation.
• Nevertheless, many cases of travel-related hepatitis A occur in travelers to developing countries with “standard” tourist itineraries, accommodations, and food consumption behaviors.

Clinical Presentation

• HAV infection may be asymptomatic, or its clinical manifestations may range in severity from a mild illness lasting 1–2 weeks to a severely disabling disease lasting several months.
• Clinical manifestations of hepatitis A often include the abrupt onset of fever, malaise, anorexia, nausea, and abdominal discomfort, followed within a few days by jaundice.
• The incubation period for hepatitis A averages 28 days (range: 15–50 days).
• The likelihood of having symptoms with HAV infection is related to the infected person’s age. In children <6 years of age, most (70%) infections are asymptomatic; if illness does occur, its duration is usually less than 2 months.
• No chronic or long-term infection is associated with hepatitis A, but 10% of infected persons will have prolonged or relapsing symptoms over a 6- to 9-month period.
• The overall case-fatality rate among cases reported to CDC is 0.3%; however, the rate is 1.8% among adults >50 years of age.

Diagnosis

• Demonstration of IgM antibodies against hepatitis A virus (IgM anti-HAV) in the serum of acutely or recently ill patients establishes the diagnosis.
• IgM anti-HAV becomes detectable 5–10 days after exposure. A fourfold or greater rise in specific antibodies in paired sera, detected by commercially available EIA, also establishes the diagnosis.
• If laboratory tests are not available, epidemiologic evidence may provide support for the diagnosis in a clinically compatible case.
• HAV RNA can be detected in blood and stools of most persons during the acute phase of infection through nucleic acid amplification methods, but these are not generally used for diagnostic purposes.

Treatment

No specific treatment is available for persons with hepatitis A. Treatment is supportive.

Preventive Measures for Travelers

Vaccine and Immune Globulin

Monovalent Vaccines

• Two monovalent hepatitis A vaccines are currently licensed in the United States for persons at least 12 months of age:
  • HAVRIX, manufactured by GlaxoSmithKline (Table 2-4), and
  • VAQTA manufactured by Merck & Co., Inc. (Table 2-5).
• Both vaccines are made of inactivated HAV adsorbed to aluminum hydroxide as an adjuvant. HAVRIX is prepared with 2-phenoxyethanol as a preservative, while VAQTA is formulated without a preservative.
• All hepatitis A vaccines should be administered intramuscularly in the deltoid muscle.

Combination Vaccine

• TWINRIX, manufactured by GlaxoSmithKline, is a combined hepatitis A and hepatitis B vaccine licensed for persons ≥18 years of age, containing 720 EL.U. of hepatitis A antigen (50% of the HAVRIX adult dose) and 20 μg of recombinant hepatitis B surface antigen protein (the same as the ENGERIX-B adult dose) (Table 2-6).
• Primary immunization consists of three doses, given on a 0-, 1-, and 6-month schedule, the same schedule as that commonly used for monovalent hepatitis B vaccine.
• TWINRIX contains aluminum phosphate and aluminum hydroxide as adjuvants and 2-phenoxyethanol as a preservative.
• An accelerated schedule of TWINRIX (i.e., doses at days 0, 7, and 21) for travelers has been approved by the FDA. A booster dose should be given at 1 year.
• The immunogenicity of TWINRIX is equivalent to that of the monovalent hepatitis vaccines when tested after completion of the licensed schedule.

Vaccination of Travelers

• All susceptible persons traveling to or working in countries that have high or intermediate hepatitis A endemicity should be vaccinated or receive IG before departure. Hepatitis A vaccine at the age-appropriate dose is preferred to IG. The first dose of hepatitis A vaccine should be administered as soon as travel to countries with high or intermediate endemicity is considered.
• One dose of monovalent hepatitis A vaccine administered at any time before departure can provide adequate protection for most healthy persons <40 years of age.
• Completion of the vaccine series according to the licensed schedule is necessary for long-term protection.
• Many persons will have detectable anti-HAV in response to the monovalent vaccine by 2 weeks after the first vaccine dose. The proportion of persons who develop a detectable antibody response at 2 weeks may be lower when smaller vaccine dosages are used, such as with the use of TWINRIX.
• For optimal protection, older adults, immunocompromised persons, and persons with chronic liver disease or other chronic medical conditions planning to depart to an area in <2 weeks should receive the initial dose of vaccine along with IG (0.02 mL/kg) at a separate anatomic injection site.
• Travelers who receive hepatitis A vaccine less than 2 weeks before traveling to an endemic area and who do not receive IG (either by choice or because of lack of availability) will be at lower risk for infection than those who do not receive hepatitis A vaccine or IG.
• Although vaccination of an immune traveler is not contraindicated and does not increase the risk for adverse effects, screening for total anti-HAV before travel can be useful in some circumstances to determine susceptibility and eliminate unnecessary vaccination or IG prophylaxis of immune travelers. Such serologic screening for susceptibility might be indicated for adult travelers who are >40 years of age and those born in areas of the world with intermediate or high endemicity who are likely to have had prior HAV infection, if the cost of screening (laboratory and office visit) is less than the cost of vaccination or IG prophylaxis and if testing will not delay vaccination and interfere with timely receipt of vaccine or IG before travel. Postvaccination testing for serologic response is not indicated.
• Travelers who are<12 months of age, are allergic to a vaccine component, or who otherwise elect not to receive vaccine should receive a single dose of IG (0.02 mL/kg), which provides effective protection against HAV infection for up to 3 months (Table 2-7).
• Those who do not receive vaccination and plan to travel for >3 months should receive an IG dose of 0.06 mL/kg, which must be repeated if the duration of travel is >5 months.
• In addition, health-care providers should be alert to opportunities to provide vaccination for all travelers whose plans might include travel at some time in the future to an area of high or intermediate endemicity, including those whose current medical evaluation is for travel to an area where hepatitis A vaccination is not currently recommended.
• Those who refuse vaccine and IG should be advised to closely adhere to prevention tips listed below.

Other Vaccine Considerations

• Using the vaccines according to the licensed schedules is preferable. However, an interrupted series does not need to be restarted.
• Given their similar immunogenicity, a series that has been started with one brand of monovalent vaccine (i.e., HAVRIX or VAQTA) may be completed with the other brand.
• Hepatitis A vaccine may be administered at the same time as IG or other commonly used vaccines for travelers, at different injection sites.
• In adults and children who have completed the vaccine series, anti-HAV has been shown to persist for at least 5–12 years after vaccination. Results of mathematical models indicate that, after completion of the vaccination series, anti-HAV will likely persist for 20 years or more. For children and adults who complete the primary series, booster doses of vaccine are not recommended.

Vaccine Safety and Adverse Reactions

• Among adults, the most frequently reported side effects occurring 3–5 days after a vaccine dose are tenderness or pain at the injection site (53%–56%) or headache (14%–16%).
• Among children, the most common side effects reported are pain or tenderness at the injection site (15%–19%), feeding problems (8% in one study), or headache (4% in one study).
• No serious adverse events in children or adults that could be definitively attributed to the vaccine or to increases in serious adverse events among vaccinated persons compared with baseline rates have been identified.
• IG for intramuscular administration prepared in the United States has few side effects (primarily soreness at the injection site) and has never been shown to transmit infectious agents (hepatitis B virus, hepatitis C virus [HCV], or HIV).
• Since December 1994, all IG products commercially available in the United States have had to undergo a viral inactivation procedure or be negative for HCV RNA before release.

Precautions and Contraindications

• These vaccines should not be administered to travelers with a history of hypersensitivity to any vaccine component.
• HAVRIX or TWINRIX should not be administered to travelers with a history of hypersensitivity reactions to the preservative 2-phenoxyethanol.
• TWINRIX should not be administered to persons with a history of hypersensitivity to yeast.
• Because hepatitis A vaccine consists of inactivated virus and hepatitis B vaccine consists of a recombinant protein, no special precautions need to be taken for vaccination of immunocompromised travelers.

Pregnancy

• The safety of hepatitis A vaccine for pregnant women has not been determined.
• However, because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to either the pregnant woman or the developing fetus is thought to be very low.
• The risk of vaccination should be weighed against the risk of hepatitis A in female travelers who might be at high risk for exposure to HAV.
• Pregnancy is not a contraindication to using IG.

Other Prevention Tips

• Boiling or cooking food and beverage items for at least 1 minute to 185° F (85° C) inactivates HAV. Foods and beverages heated to this temperature and for this length of time cannot serve as vehicles for HAV infection unless they become contaminated after heating.
• Adequate chlorination of water as recommended in the United States will inactivate HAV.
• Travelers should be advised that, to minimize their risk of hepatitis A and other enteric diseases in developing countries, they should avoid potentially contaminated water or food.
• Travelers should also be advised to avoid drinking beverages (with or without ice) of unknown purity, eating uncooked shellfish, and eating uncooked fruits or vegetables that are not peeled or prepared by the traveler personally.

References

1. CDC. Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR07):1–23.
2. CDC. Update: Prevention of hepatitis A after exposure to hepatitis A virus and    in international travelers. Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep. 2007;56(41):1080–4.
3. Bell BP, Feinstone SM. Hepatitis A vaccine. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia: W.B. Saunders, 2004. p. 269–97.
4. Mutsch M, Spicher VM, Gut C, Steffen R. Hepatitis A virus infections in travelers, 1988–2004. Clin Infect Dis. 2006;42(4):490–7.
5. Bacaner N, Stauffer B, Boulware DR, et.al. Travel medicine considerations for North American immigrants visiting friends and relatives. JAMA. 2004;291(23):2856–64.
6. CDC. Surveillance for acute viral hepatitis – United States, 2006. MMWR Surv Summ. 2008;57(SS02):1–24.
7. Van Damme P, Banatvala J, Fay O, et al. Hepatitis A booster vaccination: is there a need? Lancet. 2003;362(9389):1065–71.
8. Winokur PL, Stapleton JT. Immunoglobulin prophylaxis for hepatitis A. Clin Infect Dis. 1992;14(2):580–6.
9. Fiore AE. Hepatitis A transmitted by food. Clin Infect Dis. 2004;38(5):705–15.