Author(s): Noele Nelson, Mark Weng

Infectious Agent

Hepatitis A virus (HAV) is a nonenveloped RNA virus classified as a picornavirus.

Transmission

HAV is transmitted through direct person-to-person contact (fecal–oral transmission) or through ingestion of contaminated food or water. HAV can survive in the environment for prolonged periods at low pH. Freezing does not inactivate the virus, and HAV can be transmitted through ice and frozen foods. Heat inactivation must occur at temperatures >185°F (>85°C) for 1 minute. HAV can be transmitted from raw or inadequately cooked foods contaminated during growing, processing, or distribution, and through contamination by an infected food handler. Recent large-scale outbreaks have been caused by common-source food exposures (e.g., frozen berries, fresh fruit and vegetables, seafood) and through person-to-person spread among people experiencing homelessness and people who use injection and non-injection drugs.

Infected people shed HAV in their feces. People are most infectious 1–2 weeks before the onset of clinical signs and symptoms of jaundice or elevation of liver enzymes, when virus concentration is greatest in the stool and blood. Viral excretion and the risk for transmission diminish rapidly after liver dysfunction or symptoms appear, which is concurrent with the appearance of circulating antibodies to HAV. Infants and children can shed virus for up to 6 months after infection.

Epidemiology

Hepatitis A is among the most common vaccine-preventable infections acquired during travel. Cases of travel-related hepatitis A can occur in travelers to developed and developing countries and who have standard tourist accommodations, eating behaviors, and itineraries. Risk is greatest for those who live in or visit rural areas, trek in backcountry areas, or frequently eat or drink in settings with poor sanitation. Common-source food exposures are increasingly recognized as a risk for hepatitis A, and sporadic outbreaks have been reported in Australia, Europe, North America, and other regions with low levels of endemic transmission. Multinational hepatitis A outbreaks among men who have sex with men (MSM) have been described, including, since 2016, among MSM who travel to areas in European Union countries with ongoing HAV transmission among MSM.

Hepatitis A is common in areas with inadequate sanitation and limited access to clean water. In highly endemic areas (e.g., parts of Africa and Asia), a large proportion of adults in the population are infected as children, are immune to HAV, and epidemics are uncommon. In areas of intermediate endemicity (e.g., Central and South America, eastern Europe, parts of Asia), childhood transmission is less frequent, more adolescents and adults are susceptible to infection, and outbreaks are more likely. In areas of low endemicity (e.g., western Europe, the United States), infection is less common, but disease occurs among people in high-risk groups and as communitywide outbreaks. Determining HAV endemicity globally is complex, however, and limited data are available on subpopulation variation of HAV antibody seroprevalence within regions (Map 5-06).

In the United States, the most frequently identified risk factors for HAV infection vary from year to year. The Advisory Committee on Immunization Practices (ACIP) recommends routine hepatitis A vaccination for all children, and vaccination for adults at increased risk for HAV infection or at increased risk for severe disease from HAV infection.

Clinical Presentation

The incubation period averages 28 days (range 15–50 days). Infection can range from mild illness lasting 1–2 weeks to severely disabling disease lasting several months. Clinical manifestations include abrupt onset of fever, malaise, anorexia, nausea, and abdominal discomfort, followed by jaundice within a few days. The likelihood of having symptoms with HAV infection is related to the age of the infected person. In children aged <6 years, most (70%) infections are asymptomatic; jaundice is uncommon in symptomatic young children. Among older children and adults, the illness usually lasts <2 months, but ≈10%–15% of infected people have prolonged or relapsing symptoms over 6–9 months.

Severe hepatic and extrahepatic complications, including fulminant hepatitis and liver failure, are rare but more common in older adults and people with underlying liver disease. Chronic infection does not occur. The overall case-fatality ratio varies according to the population affected.

Diagnosis

Hepatitis A cannot be differentiated from other types of viral hepatitis based on clinical or epidemiologic features. Diagnosis requires a positive test for HAV IgM in serum, which is detectable 2 weeks before the onset of symptoms to ≈6 months after symptom onset.

Serologic total HAV IgG and IgM tests are available commercially. The combination of a positive total HAV result and a negative HAV IgM result indicates past infection or vaccination, and hence immunity. Presence of serum HAV IgM usually indicates current or recent infection and does not distinguish between immunity derived from infection versus vaccination. Hepatitis A is a nationally notifiable disease.

Information on how to obtain HAV diagnostic support from the Centers for Disease Control and Prevention (CDC), including contact information, which samples to send, and how to send them is available at CDC's Test Directory webpage. For research use and for outbreak investigations, select “Hepatitis A NAT and Genotyping.” For testing regulated by Clinical Laboratory Improvement Amendments, select “Hepatitis A Serology.”

Treatment

Provide supportive care.

Prevention

Travelers can prevent HAV through vaccination or immune globulin (IG), practicing food and water precautions, and maintaining standards of hygiene and sanitation.

Vaccine

Two single-antigen hepatitis A vaccines, Havrix (GlaxoSmithKline) and Vaqta (Merck), are approved for people ≥12 months of age in a 2-dose series. A combined hepatitis A and hepatitis B vaccine (Twinrix, GlaxoSmithKline) is approved for people ≥18 years of age in the United States (Table 5-10). The immunogenicity of the combination vaccine is equivalent to that of the single-antigen hepatitis A and hepatitis B vaccines when tested after completion of the recommended schedule. Postvaccination testing for serologic response is not indicated for healthy people, but is recommended for people whose subsequent clinical management depends on knowledge of their immune status and people for whom revaccination might be indicated (e.g., people with HIV and other immunocompromised people).

Indications for Use

All susceptible people traveling for any purpose, frequency, or duration to countries with high or intermediate hepatitis A endemicity should be vaccinated or receive IG before departure. Furthermore, prevalence patterns of HAV infection vary among regions within a country; in some areas, limited data result in uncertainty in endemicity maps, especially in low- and middle- income countries. Countries with decreasing prevalence of HAV infection have growing numbers of susceptible people and are at risk for hepatitis A outbreaks. In recent years, large hepatitis A outbreaks have been reported in high-income countries among people exposed to imported HAV-contaminated food, among MSM, among people who use drugs, and among people experiencing homelessness. Considering the complexity of interpreting hepatitis A risk maps and potential risk for foodborne hepatitis A in low-endemicity countries, some experts advise people traveling outside the United States to consider hepatitis A vaccination regardless of destination.

Vaccination is also recommended for unvaccinated household members and other people (e.g., regular babysitters) who anticipate close personal contact with an international adoptee from a high- or intermediate-endemicity country ≤60 days after the child’s arrival in the United States. The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally ≥2 weeks before the arrival of the child (see Sec. 7, Ch. 5, International Adoption).

Administration

All susceptible people (i.e., those unvaccinated or never infected) traveling to or working in countries with high or intermediate hepatitis A endemicity are at risk for HAV infection. Before departure, these travelers should be vaccinated, or receive IG if they are too young or have contraindications for hepatitis A vaccination. For travelers already partially vaccinated (i.e., did not receive a full series of hepatitis A-containing vaccine), administer a dose prior to travel according to the routine immunization schedule.

Infants Younger than 6 Months Old

Infants aged <6 months and travelers allergic to a vaccine component, or who elect not to receive vaccine, should receive IG, which provides effective temporary protection against HAV infection. For travel duration ≤1 month, the manufacturer recommends 1 dose of IG at 0.1 mL/kg; for travel >1 month but ≤2 months, 1 dose of IG at 0.2 mL/kg is recommended. A 0.2 mL/kg dose of IG should be repeated every 2 months for the duration of travel if the traveler remains in a high-risk setting; but encourage hepatitis A vaccination if not contraindicated.

Infants 6–11 Months Old

Administer hepatitis A vaccine to infants aged 6–11 months traveling outside the United States when protection against hepatitis A is recommended. Although hepatitis A vaccine is considered safe and immunogenic in infants, hepatitis A vaccine doses administered before 12 months of age could result in a suboptimal immune response, particularly in infants with passively acquired maternal antibody. Therefore, hepatitis A vaccine doses administered at <12 months of age are not considered to provide long-term protection, and the 2-dose hepatitis A vaccine series should be initiated at age 12 months according to the routine immunization schedule.

Adults Over 40 Years Old

Adults aged >40 years, immunocompromised people, and people with chronic liver disease should receive a single dose of hepatitis A vaccine as soon as travel is considered. People planning travel in <2 weeks can receive IG (0.1 mL/kg) in addition to vaccine at a separate injection site (i.e., separate limbs) based on provider risk assessment, including considerations of the traveler’s age, immune status, underlying conditions, risk for exposure, and availability of IG. The hepatitis A vaccine series should be completed according to the routine immunization schedule.

Twinrix

An alternative accelerated 4-dose schedule is available for Twinrix; doses can be administered at 0, 7, and 21–30 days, then a dose at 12 months. For more details, refer to NP Nelson et al. in the bibliography of this chapter. Although vaccinating an immune traveler is not contraindicated and does not increase the risk for adverse effects, screening for total HAV antibodies before travel can be useful in some circumstances to determine susceptibility and avoid unnecessary vaccination.

Safety & Adverse Reactions

Based on passive surveillance, the most frequently reported adverse events after single-antigen hepatitis A vaccination were fever, injection site reactions, and rash. The most frequently reported adverse events after Twinrix vaccination were dizziness, fever, headache, and injection site reactions. These findings are similar to those for other inactivated vaccines routinely administered among similar age groups.

Precautions & Contraindications

Hepatitis A vaccines should not be administered to travelers with a history of hypersensitivity to any vaccine component, including neomycin. Twinrix should not be administered to people with a history of hypersensitivity to yeast. The tip caps of prefilled syringes of Havrix and Twinrix and the vial stopper, syringe plunger stopper, and tip caps of Vaqta might contain dry natural rubber, which can cause allergic reactions in latex-sensitive people. Because hepatitis A vaccine consists of inactivated virus, and hepatitis B vaccine consists of a recombinant protein, no special precautions are needed for vaccination of immunocompromised travelers with single-antigen vaccines or Twinrix. Check precautions and contraindications before administering IG.

Pregnancy

The ACIP recommends vaccinating selected groups of pregnant people if they have not been vaccinated previously. These include people (e.g., travelers) at increased risk for HAV infection during pregnancy as well as those at risk for having a severe outcome from HAV infection (e.g., those with chronic liver disease or HIV).

Other Considerations

The best approach is to administer hepatitis A vaccine according to the routine immunization schedule; however, an interrupted series does not need to be restarted. Over 90% of vaccinated people develop levels of antibodies to HAV that correlate with protection 1 month after the first dose of hepatitis A vaccines. Given their similar immunogenicity, a series that has been started with one brand of hepatitis A single-antigen vaccine can be completed with another brand of single-antigen vaccine. For children and adults who complete a primary series of hepatitis A-containing vaccine, booster doses of vaccine are not recommended. Measles-mumps-rubella and varicella vaccines should not be administered <6 months after IG administration.

Postexposure Prophylaxis

Travelers exposed to HAV who are asymptomatic and who have not received hepatitis A vaccine should receive 1 dose of single-antigen hepatitis A vaccine or IG (0.1 mL/kg) as soon as possible, ideally ≤2 weeks following exposure. The efficacy of IG or vaccine when administered >2 weeks after exposure has not been established.

Hepatitis A vaccines should be administered as postexposure prophylaxis (PEP) for all people aged ≥12 months who have been exposed to HAV ≤2 weeks and have not previously completed the hepatitis A vaccine series. In addition to hepatitis A vaccine, administer IG (0.1 mL/kg) to people who are immunocompromised or who have chronic liver disease, and to people aged >40 years, depending on the risk assessment, which should include consideration of the exposed person’s age, immune status, underlying conditions, exposure type (risk of transmission), and availability of IG.

Administer PEP as soon as possible. If giving both hepatitis A vaccine and IG (0.1 mL/kg), administer both simultaneously in different anatomic sites (i.e., separate limbs). If only 1 product is available, administer it as soon as possible and have the exposed person return for the other product if it becomes available ≤2 weeks following exposure. When the dose of hepatitis A vaccine given postexposure is the first dose the exposed person has ever received, administer a second dose 6 months after the first for long-term immunity; however, the second dose is not necessary for PEP.

Infants <12 months of age and people who are allergic to a vaccine component or who elect not to receive vaccine should receive a single dose of IG (0.1 mL/kg) as soon as possible ≤2 weeks of exposure.

Do not use Twinrix for PEP. Twinrix contains half of the single-antigen hepatitis A adult dose, and no data are available on the efficacy of combination vaccine for prophylaxis after exposure to HAV.

CDC website: Hepatitis A