Hepatitis A

MICROBIOLOGY

Piconarvirus, non-enveloped single-stranded RNA virus.
More heat stable than most RNA viruses; for complete inactivation, heat food to > 85° C for at least 1 minute.

CLINICAL

Highly contagious virus acquired by fecal-oral route either by direct contact, sexual contact, or ingestion of contaminated food/water.
- Exposure to high-risk source: travel to endemic areas, undercooked shellfish, infected food handlers, institutionalized patients, daycare, MSM/infected sex partner, floods/water disasters, IDU, clotting factor disorders. Often spread among family members, child care settings or similar.
  - In developed countries with universal HAV immunization, international travel to endemic regions now the biggest risk factor.
  - In low-resource settings with poor hygiene, infection is widespread.
  - In U.S. (2016): 4,000 reported cases
    - Historically 20,000-35,000/year in pre-vaccine era.
    - Epidemics among homeless and drug-using populations [2016-2018] and food outbreaks [2016] increased annual reported cases in U.S. from 1500/yr range [2012-2103].
- Incubation period typically 15-50d, average 28d.
Children less symptomatic with infection (~30%) compared to adults (80%).
- Illness with usually abrupt onset of acute hepatitis: dark urine, jaundice, fever, malaise, nausea, vomiting, abdominal pain, arthralgia, acolic stools.
- Clinical signs: may range from asymptomatic to hepatomegaly, splenomegaly, bradycardia, elevated ALT/AST, elevated bilirubin, lymphocytosis, atypical mononuclear cells.
- Duration of illness:
  - ALT returns to normal in about 7 wks.
  - Usually self-limited, ~3 weeks.
- Unusual to be fulminant, mortality 0.3-0.6% but increases to ~2% for ages >50yrs and patients with chronic liver disease.
Ddx: clinical symptoms of HAV nonspecific, cannot distinguish from other common causes of hepatitis (HBV, HCV, EBV, enteroviruses, HME/HGA, lepospirosis, etc).
Dx:
- Serology: HAV IgM antibody diagnostic, may be positive 5-10d prior to onset of sx.
  - IgM anti-HAV remains elevated for 3-12 months.
    - Note: testing of asymptomatic people discouraged due to false-positive rates of the IgM assay and consequent demands on immunization or immunoglobulin needs when not necessary[15].
    - Reports of persisting anti-HAV IgM positivity >1yr correlate with likely false-positive result.
- Total anti-HAV test detects both IgM and IgG, so if positive, may reflect prior exposure.
- HAV IgG remains lifelong following infection; positive in 20-80% of asymptomatic U.S. adults.
Complications (uncommon): prolonged cholestasis, relapsing disease, fulminant hepatitis, chronic active autoimmune hepatitis, autoimmune extrahepatic disease, depression.

SITES OF INFECTION

Liver
- Virus excreted in bile, with high concentrations in feces.
Will grow in epithelial cells, in vitro.
Extrahepatic manifestations: rare (often immune-related) but reported including hemolytic anemia, aplastic anemia, red cell aplasia, pleural or pericardial effusion, acute reactive arthritis, acute pancreatitis, acalculous cholecystitis, mononeuritis, and Guillain-Barré syndrome.

TREATMENT

Acute Infection

Usually self-limiting infection.

Supportive care: bed rest, fluids.
Approximately 10-15% of symptomatic cases of HAV infection require hospitalization.
Acute HAV may be severe in persons with underlying liver disease (e.g., hepatitis C).

Pre-Exposure Prophylaxis: routine and international travel

Per 2018 recommendations, routine vaccination now recommended for all children > 6 months and adults without contraindications.
- See Hepatitis A vaccine module for additional details on vaccine types and dosings.
- Two-dose schedule for routine indications (0, 6-12 months).
For adults (recommended): at-risk international travelers, high-risk geographic populations or individuals at risk during outbreaks/close personal contacts, MSM, frequent blood/plasma recipients, chronic liver disease (including hepatitis B and hepatitis C), high-risk employment, IDUs, homeless populations.
All household contacts of an international adoptee from a country of high or intermediate HAV endemicity during first 60 days following arrival to U.S. should receive two-dose schedule with first dose asap when adoption is planned, ideally 2 or more weeks before the arrival of the adoptee.
Prevaccine testing: not routinely suggested, optional if considering cost and whether candidate has habit (e.g., IDU) or is from region with high prevalence of HAV.

International travel:
- Give hepatitis A vaccine, one dose adequate anytime prior to departure:
  - Usual adult strategy:
    - VAQTA or HAVRIX, one dose
    - Need for booster dose > 6 months to help engender long-term immunity.
- Immune globulin: use based on risk assessment if special risk factors for severe HAV disease or complications (e.g., older adults, immunocompromised pts, chronic liver dz pts, other chronic conditions.
  - If used, administer simultaneously with vaccine, but at separate anatomical sites. .
  - If pt elects not to receive vaccine (or cannot, e.g., age < 6 mos, etc), single 0.2 mL/kg immunoglobulin dose provides protection for 2 months.

Recommendations for Pre-Exposure Prophylaxis
Indication/Age group	Risk category/Health status	Hepatitis A vaccine	Immune globulin
< 6 mos	Healthy	No	0.1-0.2 mL/kg¶
6-11 mos	Healthy	1 dose∇	None
12 mos - 40 yrs	Healthy	1 dose∇	None
> 40 yrs	Healthy	1 dose∇	0.1-0.2 mL/kg¶ §
All ages	Immunocompromised or chronic liver disease	1 dose∇	0.1-0.2 mL/kg¶ §
> 6 mos	Vaccine contraindicated (life-threatening allergy)	No	0.1-0.2 mL/kg¶

∇Second dose not required for pre-exposure prophylaxis; however, for long-term immunity administer second dose 6-12 months.

¶0.1 ml/kg for travel up to 1 month, 0.2 mL/kg for travel up to 2 months, 0.2 mL/kg every 2 months if travel > 2 months duration.

§Based on provider risk assessment, if both vaccine and Ig warranted, administer simultaneously but at different anatomical sites.

Post-Exposure Prophylaxis

Risk categories to consider for PEP:
- Increased risk of acquisition
  - Household contacts
  - Caretakers
  - Sexual contacts
  - Persons working with non-human primates
  - Lab workers working with HAV
- Increased risk of complications of HAV
  - Immunodeficiency
  - HIV
  - Chronic renal failure or ESRD
  - Solid organ, bone marrow or HSC transplantation
  - Use of immunosuppresive drugs
  - Chronic liver disease
Recommendations: hepatitis A vaccine adequate along for most healthy people.
- Hepatitis A vaccine:
  - Recommended for all ages ≥ 12 months.
  - ACIP recommends hepatitis vaccine alone for healthy individuals age as equivalent efficacy for protection vs. IVIG demonstrated.
Immunoglobulin:
- Only administer to infants or adults ≥ 40 years (based on risk assessment), see table for other circumstances.
- Risk assessment guidance: find here.

Should be administered within 2 wks of exposure.

Recommendations for Post-Exposure Prophylaxis
Indication/Age group	Risk category/Health status	Hepatitis A vaccine	Immune globulin
< 12 mos	Healthy	No	0.1 mL/kg
12 mos-40 yrs	Healthy	1 dose∇	None
> 40 yrs	Healthy	1 dose∇	0.1 mL/kg§
≥ 12 mos	Immunocompromised or chronic liver disease	1 dose∇	0.1 mL/kg¶
≥ 12 mos	Vaccine contraindicated (life-threatening allergy)	No	0.1 ml/kg

∇Second dose not required for PEP; however, for long-term immunity administer second dose > 6 months.

§Based on provider risk assessment, if both vaccine and Ig warranted, administer simultaneously but at different anatomical sites.

¶administer vaccine and Ig simultaneously but at different anatomical sites.

FOLLOW UP

If fulminant hepatitis develops due to HAV, mortality up to 80%.
- Compared to HBV, HAV infection usually milder with less cases of acute liver failure.
- Estimated 100 cases of fulminant HAV in U.S. annually.
Viral shedding in stool highest in 2 wks prior to onset of jaundice. Children shed > adults, up to 10 wks.
Most symptoms resolve within 8 weeks, although 10-15% have problems for up to 6 months.
Once recovered, durable long-long immunity.
Chronic HAV does not exist.
Prolonged or relapsing symptoms described in 10-15% that may last up to 6 months.

OTHER INFORMATION

Hepatitis A rates declining in the U.S. since 1996 introduction of hepatitis A vaccine.
Hepatitis A does not become chronic, unlike potentially HBV or HCV.
Once HAV antibodies are generated, there is lifelong protection against reinfection.
Other vaccines may be administered but at separate sites during immunization with hepatitis A vaccine.

Basis for recommendation

Nelson NP, Link-Gelles R, Hofmeister MG, et al. Update: Recommendations of the Advisory Committee on Immunization Practices for Use of Hepatitis A Vaccine for Postexposure Prophylaxis and for Preexposure Prophylaxis for International Travel. MMWR Morb Mortal Wkly Rep. 2018;67(43):1216-1220. [PMID:30383742]
Comment: Post-exposure and travel related recommendations update 2007 guidance on these populations. Key points are that HepA vaccine recommended for all ≥ 12 months for post-exposure prophylaxis. Adults > 40 years can also receive IgG. For infants 6-12 months heading for international travel, both HAV vaccine and MMR are recommended.
Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (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 Morb Mortal Wkly Rep. 2007;56(41):1080-4. [PMID:17947967]
Comment: Update regarding post-exposure prophylaxis and international travel. Key update: vaccine suggest for post-exposure prophylaxis in group age 1-40.
Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, et al. 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. [PMID:16708058]
Comment: Useful recommendations from ACIP and CDC for active or passive prophylaxis of Hepatitis A infection. These are the ACIP immunization practices that initiated routine HAV vaccination of children in the United States.

References

Foster M, Ramachandran S, Myatt K, et al. Hepatitis A Virus Outbreaks Associated with Drug Use and Homelessness - California, Kentucky, Michigan, and Utah, 2017. MMWR Morb Mortal Wkly Rep. 2018;67(43):1208-1210. [PMID:30383739]
Comment: Report of cases among people who were using drugs or homeless in these states, with outbreaks implicating person-person spread which is different than prior large outbreaks due to contaminated foods. HAV immunization is important for this population, but a group hard to find or to convince.
Bakker M, Bunge EM, Marano C, et al. Immunogenicity, effectiveness and safety of combined hepatitis A and B vaccine: a systematic literature review. Expert Rev Vaccines. 2016. [PMID:26840060]
Comment: Rates of HAV antibodies post immunization have ranged from 96.2-100.0% with a durability of at least 15 yers. Use of either Twinrix™ or monovalent vaccines had similar safety performance.
Ott JJ, Irving G, Wiersma ST. Long-term protective effects of hepatitis A vaccines. A systematic review. Vaccine. 2012;31(1):3-11. [PMID:22609026]
Comment: Cumulative data now suggests that HAV vaccines provide at least 15 years of durable protection without need for booster.
Irving GJ, Holden J, Yang R, et al. Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev. 2012;7:CD009051. [PMID:22786522]
Comment: Review of 11 studies suggested that HAV immunization is sufficient for pre-exposure prophylaxis. Nine randomised trials (including both inactivated and live vaccines), clinically apparent hepatitis A occurred in 31/375,726 (0.01%) versus 505/356,654 (0.18%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.05 to 0.17).
Klevens RM, Miller JT, Iqbal K, et al. The evolving epidemiology of hepatitis a in the United States: incidence and molecular epidemiology from population-based surveillance, 2005-2007. Arch Intern Med. 2010;170(20):1811-8. [PMID:21059974]
Comment: In the post-HAV vaccine era, international travel is now the predominant risk factor for acquisition of infection.
Rating: Important
Adamson R, Reddy V, Jones L, et al. Epidemiology and burden of hepatitis A, malaria, and typhoid in New York City associated with travel: implications for public health policy. Am J Public Health. 2010;100(7):1249-52. [PMID:20466959]
Comment: Study from New York with implications for public health found that 61% of hepatitis A infections were related to travel. Highest risk group were Hispanics.
Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices. Updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of hepatitis A vaccine in close contacts of newly arriving international adoptees. MMWR Morb Mortal Wkly Rep. 2009;58(36):1006-7. [PMID:19763077]
Comment: Update to standard 2006 immunization and 2007 travel-related recommendations, this guidance suggests HAV vaccination for all previously unvaccinated persons who anticipate close personal contact (e.g., household contact or regular babysitting) with an international adoptee from a country of high or intermediate endemicity during the first 60 days following arrival of the adoptee 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 or more weeks before the arrival of the adoptee.
Vogt TM, Wise ME, Bell BP, et al. Declining hepatitis A mortality in the United States during the era of hepatitis A vaccination. J Infect Dis. 2008;197(9):1282-8. [PMID:18422440]
Comment: Since introduction of the hepatitis A vaccine in the U.S., mortality rates of declined 32% (high of 142/yr 1995 to 54 in 2003). Study used death certificate data.
Hammitt LL, Bulkow L, Hennessy TW, et al. Persistence of antibody to hepatitis A virus 10 years after vaccination among children and adults. J Infect Dis. 2008;198(12):1776-82. [PMID:18976095]
Comment: Follow-up study found demonstrable specific anti-HAV antibodies in both children (100%) and adults (96%) who received vaccine. No current information suggests the need for boosting.
Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med. 2007;357(17):1685-94. [PMID:17947390]
Comment: Study examined post-exposure prophylaxis for HAV comparing immunization to immune globulin: rates of HAV were 4.4% for vaccine group and 3.3% for immunization group. Overall, authors conclude that these low rates mean that the vaccine may be a good alternative and have the secondary benefit of long-term protection, although there was a slightly higher rate in the vaccine recipients.
Rating: Important
Martin A, Lemon SM. Hepatitis A virus: from discovery to vaccines. Hepatology. 2006;43(2 Suppl 1):S164-72. [PMID:16447259]
Comment: Covers history of virus and clinical essentials.
Centers for Disease Control and Prevention (CDC). Positive test results for acute hepatitis A virus infection among persons with no recent history of acute hepatitis--United States, 2002-2004. MMWR Morb Mortal Wkly Rep. 2005;54(18):453-6. [PMID:15889006]
Comment: Report builds on earlier case descriptions of likely false positive HAV IgM tests. Recommendation not to use as screen in asymptomatic adults, since positives are likely to be false. Testing should be limited to those with clinical suspicion of HAV. The concern is the false-positives trigger investigations by public health departments and perhaps unnecessary courses of passive and active immunizations.
Rating: Important
Fiore AE. Hepatitis A transmitted by food. Clin Infect Dis. 2004;38(5):705-15. [PMID:14986256]
Comment: Hepatitis A is caused by hepatitis A virus (HAV). Transmission occurs by the fecal-oral route, either by direct contact with an HAV-infected person or by ingestion of HAV-contaminated food or water. Foodborne or waterborne hepatitis A outbreaks are relatively uncommon in the United States. However, food handlers with hepatitis A are frequently identified, and evaluation of the need for immunoprophylaxis and implementation of control measures are a considerable burden on public health resources.
Van Damme P, Banatvala J, Fay O, et al. Hepatitis A booster vaccination: is there a need? Lancet. 2003;362(9389):1065-71. [PMID:14522539]
Comment: Mathematical modelling of antibody response decay kinetics suggests adults may have protective levels of anti-HAV antibodies for > 25 years.
Rating: Important

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