Hepatitis A

MICROBIOLOGY

Picornavirus, 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 sources: 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 the U.S., cases have risen in recent years due to large outbreak
    - 12,474 cases in 2018, but with underreporting, CDC estimates ~24,900.
      - Historically 20,000-35,000/year in pre-vaccine era.
    - Epidemics among MSM, homeless and drug-using populations and large food outbreaks amplified by person-to-person transmission [since 2016] have increased annual reported cases in the U.S. from 1500/yr range [2012-2103].
      - The recent trend reflects a shift from prior small food-borne outbreaks, daycare centers and unimmunized travelers.
- The incubation period typically 15-50d, average 28d.
Children less symptomatic with infection (~30%) compared to adults (80%). Children under 6 yrs typically asymptomatic.
Symptoms: illness with usually an abrupt onset of acute hepatitis: dark urine, jaundice, fever, malaise, nausea, vomiting, abdominal pain, arthralgia, acholic stools.
- Clinical signs: may range from asymptomatic to hepatomegaly, splenomegaly, bradycardia, elevated ALT/AST, elevated bilirubin, lymphocytosis, atypical mononuclear cells.
- Duration of illness: see CDC graphic for helpful details.
  - 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.
- Relapse has been described within the first six months.
Ddx: clinical symptoms of HAV nonspecific, cannot distinguish from other common causes of hepatitis (HBV, HCV, EBV, enteroviruses, HME/HGA, leptospirosis, etc).
Dx:
- Serology: HAV IgM antibody diagnostic, may be positive 5-10d prior to the onset of sx.
  - IgM anti-HAV remains elevated for up to 12 months after the resolution of infection.
    - 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[12].
    - Reports of persisting anti-HAV IgM positivity >1yr correlate with likely false-positive results.
  - The 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.
- Molecular:
  - Detection of viral RNA by PCR in blood or stool specimens possible, but uncommonly needed to make a diagnosis of acute HAV infection.
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
- GI: acalculous cholecystitis
- Heme: hemolytic anemia, aplastic anemia, red cell aplasia
- Musculoskeletal: acute reactive arthritis
- Neurologic: mononeuritis, Guillain-Barré syndrome
- Pulmonary: pleural or pericardial effusion

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).

General considerations for Prophylaxis/Immunization

Risk categories to consider for prophylaxis/immunization:
- Increased risk of acquisition
  - International travelers
  - Household contacts of index patient or international adoptee
  - Caretakers
  - Sexual contacts, especially men who have sex with men (MSM)
  - People who use injection or non-injection drugs
  - People who are homeless
  - Lab workers working with HAV or those with occupational risk (e.g., persons working with non-human primates)
  - People with developmental disabilities
  - People who are incarcerated
  - People involved in outbreaks
- Increased risk of complications of HAV
  - Immunodeficiency
  - HIV
  - Chronic renal failure or ESRD
  - Solid-organ, bone marrow or HSC transplantation
  - Use of immunosuppressive drugs
  - Chronic liver disease
  - People ≥ 40 yrs
    - Reflects increased likelihood that HAV in this age group may result in hospitalization.
No longer specifically recommended for people with hemophilia or clotting disorders.

Pre- and Post-Exposure Prophylaxis

Per ACIP 2020 recommendations, routine vaccination now recommended for all children > 12 months and adults without contraindications.
- See hepatitis A vaccine module for additional details on vaccine types and dosings.
  - All children should be immunized between ages 12-23 months.
- Two-dose schedule for routine indications (0, 6-12 months).
- Typically immunization alone is sufficient; however, if immediate protection needed or following exposure for most groups except healthy people age 12 mos to 40 years.
  - Decreasing titers of antibodies specific to hepatitis A in the general population have necessitated an increase in the amount of immune globulin dose (since 2017) to provide protection.
  - See the chart below for details.
Pre-exposure prophylaxis: for adults (recommended) at-risk international travelers, high-risk geographic populations or individuals at risk during outbreaks/close personal contacts, MSM, chronic liver disease (including hepatitis B and hepatitis C), high-risk employment, IDUs, homeless populations (see list above).
- All household contacts of an international adoptee from a country of high or intermediate HAV endemicity during the first 60 days following arrival to the U.S. should receive a two-dose schedule with the 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 the candidate has a habit (e.g., IDU) or is from a region with a high prevalence of HAV.
If received one dose in the past, no need to restart series.
No need for a post-immunization check of antibody status as assumed seropositive due to excellent vaccine responses in most people.
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 after 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 the vaccine, but at separate anatomical sites.
  - If the patient elects not to receive the vaccine (or cannot, e.g., age < 6 mos, etc), a single 0.2 mL/kg immunoglobulin dose provides protection for 2 months (while 0.1mL/kg IM provides 1 month of protection).
    - May be repeated every 2 months if necessary.

Post-exposure prophylaxis: should be administered within 2 wks of exposure.

Recommendations: hepatitis A vaccine adequate along for most healthy people.
- Hepatitis A vaccine:
  - Recommended for all ages ≥ 12 months.
  - ACIP recommends the hepatitis A 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.

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

∇The second dose not required for PEP; however, for long-term immunity administer the 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.

Post-Exposure Prophylaxis

Recommendations: hepatitis A vaccine adequate along for most healthy people.
- Hepatitis A vaccine:
  - Recommended for all ages ≥ 12 months.
  - ACIP recommends the hepatitis A 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.

**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 is milder with fewer cases of acute liver failure.
- Estimated 100 cases of fulminant HAV in the U.S. annually.
Viral shedding in stool highest in 2 wks prior to the 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

Now a vaccine-preventable illness, hepatitis A rates declining in the U.S. since the 1996 introduction of the hepatitis A vaccine.
Hepatitis A does not become chronic, unlike potentially HBV or HCV.
Once HAV antibodies are generated appear to have lifelong protection against reinfection (at least > 20 years, to date).
Other vaccines may be administered but at separate sites during immunization with the hepatitis A vaccine (deltoid location as gluteal generates less immune response).

Basis for recommendation

Desai AN, Kim AY. Management of Hepatitis A in 2020-2021. JAMA. 2020. [PMID:32628251]
Comment: Concise but comprehensive review including diagnosis and management.
Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of Hepatitis A Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices, 2020. MMWR Recomm Rep. 2020;69(5):1-38. [PMID:32614811]
Comment: This document incorporates all recent updates and recommendations regarding HAV prevention. New or updated recommendations include a) immunize all children 2-18 yrs if not previously receiving, b) all HIV infected children > 1 yr, c) immunize all with chronic liver disease or if > 2x ULN transaminases, d) pregnant women at risk, e) all involved in Hep A outbreaks if at risk, f) those who provide services to people with risk factors, g) no longer recommended: people who routinely receive blood products.

References

Foster MA, Hofmeister MG, Kupronis BA, et al. Increase in Hepatitis A Virus Infections - United States, 2013-2018. MMWR Morb Mortal Wkly Rep. 2019;68(18):413-415. [PMID:31071072]
Comment: CDC report speaks to the significant increases in Hepatitis A infections that now reflect some person to person spread through MSM, intravenous drug use, homelessness and larger than previous foodborne outbreaks. Targeting high-risk groups for HAV immunization will help but people who are involved are often difficult to engage in organized medical care.
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;15(7):829-51. [PMID:26840060]
Comment: Rates of HAV antibodies post-immunization have ranged from 96.2-100.0% with the durability of at least 15 years. The use of either Twinrix™ or monovalent vaccines had similar safety performance.
Irving GJ, Holden J, Yang R, et al. Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev. 2012. [PMID:22786522]
Comment: A review of 11 studies suggested that HAV immunization is sufficient for pre-exposure prophylaxis. Nine randomized 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).
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: A study from New York with implications for public health found that 61% of hepatitis A infections were related to travel. The highest risk group was Hispanics.
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 the introduction of the hepatitis A vaccine in the U.S., mortality rates of declined 32% (high of 142/yr 1995 to 54 in 2003). The 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: The 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, the 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 the 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

Media

Hepatitis A Clinical and Immunologic Events

Source CDC

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