Prevention and Management of Hepatitis A Virus Infection in Adults With HIV

Purpose of This Guideline

Reviewed and updated: Hector I. Ojeda-Martinez, MD; May 21, 2021
Writing Group: Joseph P. McGowan, MD, FACP, FIDSA; Steven M. Fine, MD, PhD; Rona Vail, MD; Samuel T. Merrick, MD; Asa Radix, MD, MPH, PhD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee: Medical Care Criteria Committee
Date of original publication: August 2018

This guideline on hepatitis A virus (HAV) and HIV coinfection was developed by the New York State Department of Health AIDS Institute (NYSDOH AI). The purpose of this guideline is to inform New York State clinicians about HAV/HIV coinfection, including screening, vaccination, and post-exposure prophylaxis, to accomplish the following:

Increase the number of individuals in New York State with HIV who are screened and vaccinated against HAV.
Provide evidence-based recommendations for post-exposure prophylaxis in adults with HIV who experience an HAV exposure.
Integrate current evidence-based clinical recommendations into the healthcare-related implementation strategies of the Ending the Epidemic initiative, which seeks to end the AIDS epidemic in New York State.

The NYSDOH AI guideline Immunizations for Adults WIth HIV includes recommendations for HAV vaccination.

Burden of HAV

The total annual reported cases of HAV in the United States decreased consistently between 2000 (13,397 cases) and 2014 (1,239 cases), with the decline attributed to the inclusion of HAV vaccination in the recommended pediatric immunization panels for children aged 2 to 18 years [CDC 2018]. Since 2014, however, the number of cases reported in the United States has increased, reaching 12,474 in 2018 [CDC 2020]. In 2017 and 2018, outbreaks among people who use drugs, homeless people, and men who have sex with men (MSM) contributed to substantial increases in the reported cases of HAV. A study using nationally representative data found that from 2007 to 2016, HAV susceptibility among nonvaccinated U.S.-born adults aged 20 years or older was approximately 74.1% [Yin, et al. 2020].

In 2019, the NYSDOH issued an advisory on increases in HAV infection and noted the following:

In New York State (excluding New York City) the annual number of reported HAV cases (2,019) represented a 235% increase between 2016 and 2018 [NYSDOH 2019].
People at high risk for HAV infection are those who use injection or noninjection drugs, have unstable housing or are homeless, are or were recently incarcerated, and who are MSM [NYSDOH 2019].
In New York City, the number of reported HAV cases increased 64% from 2018 to 2019, with the increase largely due to outbreaks among MSM [NYCDOHMH 2020].

References

CDC. Surveillance for Viral Hepatitis – United States, 2016. 2018 Apr 16. https://www.cdc.gov/hepatitis/statistics/2016surveillance/index.htm [accessed 2021 Mar 19]

CDC. Hepatitis A Outbreaks in the United States. 2020 Jul 28. https://www.cdc.gov/hepatitis/outbreaks/hepatitisaoutbreaks.htm [accessed 2021 Mar 19]

NYCDOHMH. New York City Department of Health and Mental Hygiene: Hepatitis A, B, and C in New York City: 2019 Annual Report. 2020 Dec. https://hepfree.nyc/wp-content/uploads/2020/12/Viral-Hep-2019-Annual-Report_Final_Web.pdf [accessed 2021 Mar 24]

NYSDOH. New York State Department of Health. Health Advisory: Outbreak of Hepatitis A Virus. 2019 Dec 12. https://www.health.ny.gov/diseases/communicable/hepatitis/hepatitis_a/docs/2019-12-12_health_advisory.pdf [accessed 2021 Mar 22]

Transmission and Prevention

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Reviewed and updated: Hector I. Ojeda-Martinez, MD, with the Medical Care Criteria Committee; May 21, 2021

Transmission

The modes of HAV transmission are well established: ingestion of contaminated water and food, such as raw clams or oysters; oral-anal contact; person-to-person spread via fomites, such as shared utensils or bath towels; or, very rarely, blood or blood product transfusion. In the last few years, HAV outbreaks have largely been attributed to foodborne transmission and close person-to-person contact with an individual with HAV [CDC 2020].

Men who have sex with men (MSM) and individuals who use drugs are at increased risk for HAV infection, and data from the National Health and Nutrition Examination Survey 2007 to 2016 indicate that, among adults born in the United States aged ≥20 years, the prevalences of HAV susceptibility and nonvaccination, respectively, were 67.5% and 65.2% among MSM and 72.9% and 73.1% among individuals who reported injection drug use [Yin, et al. 2020].

Pre-Exposure Vaccination

All adults with HIV should receive an HAV IgG test, and those who are antibody-negative should be vaccinated against HAV [Nelson, et al. 2020].

Infection with HAV can be prevented by active immunization before exposure with either of the 2 currently licensed vaccines, which are considered equivalent in efficacy. HAV vaccines are highly immunogenic in immunocompetent adults, with >95% seroconversion. However, the seroconversion rates and the geometric mean serum antibodies in individuals with HIV are lower than in those without HIV, with response rates from 50% to 95% [Kemper, et al. 2003; Wallace, et al. 2004; Rimland and Guest 2005; Shire, et al. 2006; Weissman, et al. 2006; Mena, et al. 2013]. HAV vaccine appears to have no effect on the course of HIV infection or on plasma HIV viral load. A combined HAV and hepatitis B virus vaccine is also available and can be used in people susceptible to both hepatitis A and B. It is given in three total doses at 0, 1, and 6 months.

Administration of HAV vaccine is recommended for all adults with HAV regardless of CD4 count. An effective antibody response may not occur in up to 15% of immunocompromised patients [Wallace, et al. 2004; Mena, et al. 2013]. This Committee recommends follow-up HAV antibody testing for patients who are at increased risk for HAV-related morbidity and mortality (see above) to verify vaccine efficacy and to identify those who should be counseled to avoid infection because of continued susceptibility.

Post-Exposure Immune Globulin

Immune serum globulin is the recommended HAV post-exposure prophylaxis for patients with HIV and should be given to individuals who are susceptible to HAV infection within 2 weeks after an exposure to an HAV-infected household contact, sexual partner, or needle-sharing partner [ACIP 2007; CDC 2020]. Consideration should also be given to patients with HIV who are providing other types of ongoing, close personal contact with someone with HAV (e.g., a regular babysitter or caretaker) [ACIP 2007; CDC 2020]. A single dose of 0.1 mL/kg intramuscularly is effective in preventing infection or attenuating HAV infection that might result from such an exposure [Nelson 2017]. Concurrent administration of HAV vaccine with immune serum globulin is indicated for individuals at risk for future infection (see above).

References

ACIP. 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):1080-1084. [PMID: 17947967]

CDC. Hepatitis A Outbreaks in the United States. 2020 Jul 28. https://www.cdc.gov/hepatitis/outbreaks/hepatitisaoutbreaks.htm [accessed 2021 Mar 19]

Kemper CA, Haubrich R, Frank I, et al. Safety and immunogenicity of hepatitis A vaccine in human immunodeficiency virus-infected patients: a double-blind, randomized, placebo-controlled trial. J Infect Dis 2003;187(8):1327-1331. [PMID: 12696015]

Mena G, García-Basteiro AL, Llupià A, et al. Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy. Vaccine 2013;31(36):3668-3674. [PMID: 23777950]

Nelson NP. Updated dosing instructions for immune globulin (human) GamaSTAN S/D for hepatitis A virus prophylaxis. MMWR Morb Mortal Wkly Rep 2017;66(36):959-960. [PMID: 28910270]

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]

Rimland D, Guest JL. Response to hepatitis A vaccine in HIV patients in the HAART era. AIDS 2005;19(15):1702-1704. [PMID: 16184045]

Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-infected patients: a hierarchical bayesian meta-analysis. Vaccine 2006;24(3):272-279. [PMID: 16139398]

Wallace MR, Brandt CJ, Earhart KC, et al. Safety and immunogenicity of an inactivated hepatitis A vaccine among HIV-infected subjects. Clin Infect Dis 2004;39(8):1207-1213. [PMID: 15486846]

Weissman S, Feucht C, Moore BA. Response to hepatitis A vaccine in HIV-positive patients. J Viral Hepat 2006;13(2):81-86. [PMID: 16436125]

Yin S, Barker L, Ly KN, et al. Susceptibility to hepatitis A virus infection in the United States, 2007-2016. Clin Infect Dis 2020;71(10):e571-e579. [PMID: 32193542]

Management of HAV/HIV Coinfection

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Reviewed and updated: Hector I. Ojeda-Martinez, MD, with the Medical Care Criteria Committee; May 21, 2021

Morbidity and mortality: The incubation period of HAV infection averages 28 days (range, 15 to 50 days). Although HAV does not cause chronic hepatitis, it is not a benign disease; the morbidity in adults is substantial. Young children tend to have asymptomatic or minimally symptomatic disease, whereas older children and adults have more severe illness, with jaundice occurring in approximately 70% of cases [Cuthbert 2001]. Approximately 40.8% of patients with reported cases of acute HAV required hospitalization in 2013 [CDC 2015]. Overall case fatality is low, ranging from 0.3% to 0.6% for all ages and up to 1.8% among adults aged >50 years [CDC 2015].

KEY POINT

Currently, no specific treatment is available for HAV, although infection can be prevented by both pre-exposure vaccination and post-exposure serum immune globulin administration.

Coinfection: HAV does not cause more severe clinical illness in people with HIV than in people without. Patients with HIV may have significantly higher HAV viral load levels and significantly prolonged durations of HAV viremia than people who do not have HIV [Gallego, et al. 2011], which may result in a prolonged duration of risk of HAV transmission to others.

Maintain ART: Patients with HIV and acute HAV infection rarely require even temporary interruption of ART. Cessation of ART should be avoided whenever possible because of the potential long-term consequences, such as reduced viral suppression when ART is reinstituted [Lutwick 1999; El-Sadr, et al. 2008]. In the rare instances when interruption of ART is indicated for management of fulminant liver disease, clinicians should consult with a care provider experienced in the treatment of hepatitis and HIV.

References

CDC. Surveillance for Viral Hepatitis – United States, 2013. 2015 May 31. https://www.cdc.gov/hepatitis/statistics/2013surveillance/index.htm [accessed 2021 Mar 19]

Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev 2001;14(1):38-58. [PMID: 11148002]

El-Sadr WM, Grund B, Neuhaus J, et al. Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial. Ann Intern Med 2008;149(5):289-299. [PMID: 18765698]

Gallego M, Robles M, Palacios R, et al. Impact of acute hepatitis A virus (HAV) infection on HIV viral load in HIV-infected patients and influence of HIV infection on acute HAV infection. J Int Assoc Physicians AIDS Care (Chic) 2011;10(1):40-42. [PMID: 21368013]

Lutwick LI. Clinical interactions between human immunodeficiency virus and the human hepatitis viruses. Infect Dis Clin Pract 1999;8(1):9-20. https://journals.lww.com/infectdis/Citation/1999/01000/CLINICAL_INTERACTIONS_BETWEEN_HUMAN.3.aspx

All Recommendations

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Reviewed and updated: Hector I. Ojeda-Martinez, MD, with the Medical Care Criteria Committee; May 21, 2021

ALL RECOMMENDATIONS: PREVENTION AND MANAGEMENT OF HEPATITIS A VIRUS INFECTION IN ADULTS WITH HIV

Pre-Exposure Vaccination

Clinicians should obtain an HAV IgG antibody measurement for all individuals with HIV [a] and should administer the HAV vaccine to those who are HAV antibody-negative, regardless of CD4 count.
- See the NYSDOH AI guideline Immunizations for Adults With HIV > HAV.
Clinicians should administer the 2-dose anti-HAV vaccine series, with the initial dose followed 6 to 12 months later to ensure maximal antibody response [b]. (A1)
- See the NYSDOH AI guideline Immunizations for Adults With HIV > HAV.
Clinicians should obtain a post-vaccination HAV IgG antibody measurement at least 1 month after final dose in patients who are at increased risk for HAV-related morbidity and mortality. (B3)

Post-Exposure Immune Globulin

Clinicians should administer a single dose of immune serum globulin (as a 0.1 mL/kg intramuscular injection) as HAV post-exposure prophylaxis to susceptible patients with HIV within 2 weeks of an exposure to close personal contacts with serologically confirmed HAV infection (i.e., through a blood test), including:
- Household and sexual contacts (A2)
- Individuals who have shared illicit drugs with someone with HAV (A2)
Patients for whom HAV vaccination is also indicated should receive the HAV vaccine concurrently with immune serum globulin to protect against future infection.
Clinicians must report all suspected or confirmed HAV infections to the local health department of the area where the patient resides according to New York State requirements (also see NYSDOH Communicable Disease Reporting Requirements).
- Infections that occur among food handlers or in other settings that pose a high risk of transmission are immediately reportable by telephone to the local health department.

Management of HAV/HIV Coinfection

Whenever possible, ART should not be interrupted in patients with HIV/HAV coinfection; when interruption of ART is indicated for management of severe or fulminant liver disease, clinicians should consult with a care provider experienced in the treatment of hepatitis and HIV. (A3)

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Abbreviations: ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; HAV, hepatitis A virus; IgG, immunoglobulin G.

Notes:

Citing the missed opportunity to vaccinate a patient when available and the possible prolonged risk of exposure to HAV, the Centers for Disease Control and Prevention (CDC) no longer recommends deferring HAV vaccination in patients with a CD4 count <200 cells/mm³[CDC 2020].
The HAV vaccine at the age-appropriate dose is preferred over immune globulin; however, for optimal protection, adults aged >40 years, immunocompromised people, and people with chronic liver disease or other chronic medical conditions planning to depart to an area with a high HAV transmission rate in <2 weeks should receive the initial dose of vaccine along with immune globulin (0.1 mL/kg) at a separate injection site. For additional information regarding HAV vaccination for travelers, see CDC Health Information for International Travel > Travel-Related Infectious Diseases: Hepatitis A.

Guideline Information and Updates

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Guideline Information
Intended users	New York State clinicians in outpatient settings who provide primary and HIV specialty care for adults who have or are at risk of acquiring hepatitis A virus infection
Last reviewed and updated	May 21, 2021
Lead author	Hector I. Ojeda-Martinez, MD
Original publication	August 2018
Writing group	Joseph P. McGowan, MD, FACP, FIDSA; Steven M. Fine, MD, PhD; Rona Vail, MD; Samuel T. Merrick, MD; Asa Radix, MD, MPH, PhD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee	Medical Care Criteria Committee
Developer and funding	New York State Department of Health AIDS Institute (NYSDOH AI)
Development	See Guideline Development and Recommendation Ratings Scheme, below.
Updates
May 21, 2021	Hector I. Ojeda-Martinez, MD, with the MCCC: Updated recommendation in Transmission and Prevention section: Clinicians should obtain an HAV IgG antibody measurement for all individuals with HIV and should administer the HAV vaccine to those who are HAV antibody-negative, regardless of CD4 count. Updated citations and references throughout the guideline. Added new epidemiologic data to Burden of HAV section: A study using nationally representative data found that from 2007 to 2016, HAV susceptibility among nonvaccinated U.S.-born adults aged 20 years or older was approximately 74.1% [Yin, et al. 2020].
August 2018	MCCC: Added new sections: Purpose of This Guideline Transmission and Prevention Updated recommendation in Transmission and Prevention section: The dosing for post-exposure immune globulin was updated to 0.1 mL/kg IM, based on updated CDC recommendation [Nelson 2017].

Guideline Development: New York State Department of Health AIDS Institute Clinical Guidelines Program
Developer	New York State Department of Health AIDS Institute (NYSDOH AI) Clinical Guidelines Program
Funding Source	NYSDOH AI
Program Manager	Clinical Guidelines Program, Johns Hopkins University School of Medicine, Division of Infectious Diseases. See Program Leadership and Staff.
Mission	To produce and disseminate evidence-based, state-of-the-art clinical practice guidelines that establish uniform standards of care for practitioners who provide prevention or treatment of HIV, viral hepatitis, other sexually transmitted infections, and substance use disorders for adults throughout New York State in the wide array of settings in which those services are delivered.
Expert Committees	The NYSDOH AI Medical Director invites and appoints committees of clinical and public health experts from throughout NYS to ensure that the guidelines are practical, immediately applicable, and meet the needs of care providers and stakeholders in all major regions of NYS, all relevant clinical practice settings, key NYS agencies, and community service organizations. See Expert Committees
Committee Structure	Leadership: AI-appointed chair, vice chair(s), chair emeritus, clinical specialist(s), JHU Guidelines Program Director, AI Medical Director, AI Clinical Consultant, AVAC community advisor Contributing members Guideline writing groups: Lead author, coauthors if applicable, and all committee leaders
Conflicts of Interest Disclosure and Management	Annual disclosure of financial relationships with commercial entities for the 12 months prior and upcoming is required of all individuals who work with the guidelines program, and includes disclosure for partners or spouses and primary professional affiliation. The NYSDOH AI assesses all reported financial relationships to determine the potential for undue influence on guideline recommendations and, when indicated, denies participation in the program or formulates a plan to manage potential conflicts. Disclosures are listed for each committee member.
Evidence Collection and Review	Literature search and review strategy is defined by the guideline lead author based on the defined scope of a new guideline or update. A comprehensive literature search and review is conducted for a new guideline or an extensive update using PubMed, other pertinent databases of peer-reviewed literature, and relevant conference abstracts to establish the evidence base for guideline recommendations. A targeted search and review to identify recently published evidence is conducted for guidelines published within the previous 3 years. Title, abstract, and article reviews are performed by the lead author. The JHU editorial team collates evidence and creates and maintains an evidence table for each guideline.
Recommendation Development	The lead author drafts recommendations to address the defined scope of the guideline based on available published data. Writing group members review the draft recommendations and evidence and deliberate to revise, refine, and reach consensus on all recommendations. When published data are not available, support for a recommendation may be based on the committee’s expert opinion. The writing group assigns a 2-part rating to each recommendation to indicate the strength of the recommendation and quality of the supporting evidence. The group reviews the evidence, deliberates, and may revise recommendations when required to reach consensus.
Review and Approval Process	Following writing group approval, draft guidelines are reviewed by all contributors, program liaisons, and a volunteer reviewer from the AI Community Advisory Committee. Recommendations must be approved by two-thirds of the full committee. If necessary to achieve consensus, the full committee is invited to deliberate, review the evidence, and revise recommendations when required. Final approval by the committee chair and the NYSDOH AI Medical Director is required for publication.
External Reviewers	External peer reviewers recognized for their experience and expertise review guidelines for accuracy, balance, clarity, and practicality and provide feedback. Peer reviewers may include nationally known experts from outside of New York State.
Update Process	JHU editorial staff ensure that each guideline is reviewed and determined to be current upon the 3-year anniversary of publication; guidelines that provide clinical recommendations in rapidly changing areas of practice may be reviewed annually. Published literature is surveilled to identify new evidence that may prompt changes to existing recommendations or development of new recommendations. If changes in the standard of care, newly published studies, new drug approval, new drug-related warning, or a public health emergency indicate the need for immediate change to published guidelines, committee leadership will make recommendations and immediate updates. All contributing committee members review and approve substantive changes to, additions to, or deletions of recommendations; JHU editorial staff track, summarize, and publish ongoing guideline changes.

Recommendation Ratings Scheme
Strength		Quality of Evidence
Rating	Definition	Rating	Definition
A	Strong	1	Based on published results of at least 1 randomized clinical trial with clinical outcomes or validated laboratory endpoints.
B	Moderate	*	Based on either a self-evident conclusion; conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.
C	Optional	2	Based on published results of at least 1 well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.
		2†	Extrapolated from published results of well-designed studies (including nonrandomized clinical trials) conducted in populations other than those specifically addressed by a recommendation. The source(s) of the extrapolated evidence and the rationale for the extrapolation are provided in the guideline text. One example would be results of studies conducted predominantly in a subpopulation (e.g., one gender) that the committee determines to be generalizable to the population under consideration in the guideline.
		3	Based on committee expert opinion, with rationale provided in the guideline text.