Evidence to Recommendations for Use of Hepatitis A Vaccine for Persons With HIV

Question: Should routine two-dose* vaccination to prevent hepatitis A virus infection be given to HIV-positive persons?

Population: Adult HIV-positive persons

Intervention: Routine two-dose* hepatitis A vaccination

Comparison(s): No routine two-dose* hepatitis A vaccination

Outcomes:

  • Hepatitis A infection
  • Mild adverse events
  • Serious adverse events
*Or three-dose vaccination when a combination vaccine is used.

Background:

In 2015, there were an estimated 1.12 million persons with HIV (PWHIV) in the United States (1). When PWHIV are co-infected with hepatitis A virus (HAV), they experience higher peak HAV viral loads and a prolonged duration of hepatitis A viremia compared to persons without HIV infection, and are therefore more likely to transmit HAV. HAV co-infection may increase HIV viral load, potentially also increasing HIV transmission. PWHIV respond to hepatitis A (HepA) vaccine with seroconversion rates of 48.5%–94.0% (2,3,4) following a 2-dose monovalent vaccination schedule; factors associated with a protective antibody response in PWHIV include a CD4+ cell count above 200/µl and a low HIV RNA viral load.

The Advisory Committee on Immunization Practices (ACIP) currently recommends HepA vaccine for groups at increased risk of HAV or severe HAV infection, but does not specify PWHIV as a risk group. The groups currently indicated for HepA vaccine include persons traveling to or working in countries that have high or intermediate endemicity of infection, men who have sex with men (MSM), persons who use injection or non-injection drugs, persons with clotting-factor disorders, persons who have occupational risk for infection, persons who anticipate close personal contact with an international adoptee, persons with chronic liver disease, and persons experiencing homelessness. The Medical Monitoring Project (5), which samples PWHIV in the United States and collects clinical and behavioral information, estimates that 59.9% (95% CI: 57.3–62.4) of PWHIV had one of the following indicators: male-to-male sexual contact in the past 12 months, injection or non-injection drug use in the past 12 months, experiencing homelessness in the past 12 months, chronic liver disease, or a clotting factor disorder. Data were not available for proportions of PWHIV who have occupational risk for infection, who travel, or who have close contact with an international adoptee; excluding these groups, 40.1% (95% CI: 37.6–42.7%) of PWHIV in the United States do not have a known ACIP-recommended indication for HepA vaccine.

From January 2017 to February 2019, more than 12,500 cases of HAV infection in the United States were associated with person-to-person transmission in multiple states. HIV co-infection data are available for these cases from a limited number of states. Among 249 reported HAV cases in Tennessee, 11 (4%) patients were PWHIV (6). Six (55%) of these 11 HAV/HIV co-infected patients received partial or complete HepA vaccination prior to acute hepatitis A infection. There were no identified cases of breakthrough acute hepatitis A infection in previously vaccinated persons not infected with HIV. The data from Tennessee and reports from other HAV outbreak–associated states indicate a need to include PWHIV as an indication for HepA routine vaccination, and potentially for additional prophylaxis after a potential exposure to HAV.

Additional background information supporting the ACIP recommendations on the use of hepatitis A vaccines can be found in the relevant publication of the recommendations referenced on the ACIP website.

Problem

 

Resource use model, base, range
Criteria Work Group Judgments Evidence Additional Information
Is the problem of public health importance? Yes
  • PWHIV are at increased risk of HAV infection.
    • HIV infection can lead to an immunocompromised state
    • PWHIV are frequently less likely to be vaccinated for a variety of reasons (missed opportunities for vaccination, lack of access to health care, etc.).
  • Outbreaks that include PWHIV can have prolonged HAV transmission.
    • HAV viremia in PWHIV tends to be higher and more durable.
  • In 2015, there were an estimated 1.12 million PWHIV in the United States (1).
  • HIV co-infection outbreak data are available for a limited number of states.
    • Among 249 reported cases of hepatitis A in Tennessee, 11 (4%) patients were PWHIV (6).
    • Among 359 reported cases of hepatitis A in Massachusetts, 4% were PWHIV (as of June 5, 2019) (7).
    • Among 85 reported cases of hepatitis A in Illinois, 7 (8.2%) were PWHIV (as of June 5, 2019) (8).
  • Infectious Diseases Society of America recommends vaccinating all PWHIV against HAV infection as part of their guidelines (9). Eleven other manuscripts described routinely vaccinating PWHIV as part of clinical practice (10–20).
  • Spain, Italy, and Australia report routinely vaccinating all PWHIV against HAV infection.

Benefits and Harms

Benefits and Harms
Criteria Work Group Judgments Research Evidence Additional Information
How substantial are the desirable anticipated effects? Large
  • HAV infection may increase HIV replication, potentially increasing potential for HIV transmission.
  • HAV viremia in PWHIV tends to be higher, more durable, and can lead to a longer transmission period.
  • HepA vaccine is a highly effective vaccine in the general population.
    • Seroconversion rates in PWHIV are 48.5%–94% (2–4). Higher rates of response among PWHIV to vaccination were associated with higher baseline median CD4+ count at vaccination and/or lower HIV viral load.
How substantial are the undesirable anticipated effects? Minimal
  • Over 20 years of safety monitoring have shown no safety concerns (CDC, unpublished).
  • Similar rates of serious adverse events have been observed in PWHIV vs. HIV-negative persons.
    • No unexpected vaccine adverse events were reported among PWHIV from 1990 to 2016.
  • HepA vaccine does not increase HIV viral load, affect CD4 cell count, or accelerate progression to acquired immunodeficiency syndrome (AIDS).
Do the desirable effects outweigh the undesirable effects? Favors intervention
  • Although seroconversion rates among PWHIV are lower following vaccination compared to the HIV-negative population, seroprotection against HAV infection in PWHIV can be achieved.
  • Out of 130 PWHIV, 89% maintained seropositivity 6–10 years after a two-dose vaccine series (21).
    • Vaccination at higher CD4+ counts is associated with better vaccine-induced immune response.
What is the overall certainty of this evidence for the critical outcomes? Effectiveness of the intervention is Level 2 (Moderate)

Safety of the intervention is Level 3 (Low)

Please refer to GRADE (safety and effectiveness) tables for detailed assessment of the certainty of the evidence. For more information, please see the ACIP Handbook for Developing Evidence-Based Recommendations.pdf icon
  • The benefit outcome, reduction in hepatitis A infection, among randomized controlled trials (RCTs) was graded as EVIDENCE TYPE 2.
    • We downgraded for indirectness due to variability of hepatitis A antibody seroconversion thresholds used.
  • The benefit outcome, reduction in hepatitis A infection, among observational studies was graded as EVIDENCE TYPE 4.
    • We downgraded for indirectness due to variability of hepatitis A antibody seroconversion thresholds used and for risk of bias due to limited studies comparing a 2-dose standard intervention to no vaccine.
  • The harm outcome, mild adverse events, among RCTs was graded as EVIDENCE TYPE 1.
  • The harm outcome, mild adverse events, among observational studies was graded as EVIDENCE TYPE 3.
  • The harm outcome, serious adverse events, among RCTs was graded as EVIDENCE TYPE 3.
    • We downgraded for very serious imprecision due to small study population size.
  • The harm outcome, serious adverse events, among observational studies was graded as EVIDENCE TYPE 4.
    • We downgraded indirectness for use of multiple non-hepatitis A vaccines and for imprecision due to small study population size.
Due to these vaccines’ long-term safety record, and lack of any significant adverse safety signal in the Vaccine Adverse Event Reporting System or in the literature, the workgroup was confident in the safety of this vaccine in this population.

Values

Values
Criteria Work Group Judgments Research Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Probably yes
  • Few studies have been conducted to investigate PWHIV preferences regarding HAV infection.
  • Reasons for non-vaccination (22):
    • Not recommended by providers
    • Lack of expected effectiveness
    • Fear of vaccine adverse effects
Is there important uncertainty about or variability in how much people value the main outcomes? Probably no important uncertainty or variability
  • Few studies have been conducted specifically to determine the value PWHIV assign to protection against HAV.
  • Among people who use injection drugs from five U.S. cities (24.2% of whom were PWHIV) (23), convenience was the important determining factor for initiating HepA/hepatitis B (HepB) vaccination.

Acceptability

Acceptability
Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention acceptable to key stakeholders? Yes
  • The proposed recommendation parallels ACIP recommendations for HepB vaccination in PWHIV.
    • Similarly lower seroresponses have been observed after HepB vaccine administration among PWHIV with low CD4+ counts.
  • ACIP currently recommends that all HIV patients receive their first dose of HepB vaccine during their first HIV care visit after having their hepatitis B virus serologies drawn.
    • This option is safe and effective for PWHIV and less confusing for providers.

Resource Use

Resource Use
Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Uncertain
  • Adult HepA vaccines are licensed only for certain high-risk groups, and cost effectiveness data on vaccine use for these indications are limited.
  • Outbreaks and subsequent response efforts incur medical costs, productivity losses, disruption of other public health services, and diversion of public health resources and extensive human resources.
    • Cost of an outbreak among people who use injection drugs (n = 590, Washington): $3.3 million (24).
    • Cost of an outbreak among MSM (n = 136, Ohio): $520,039 (24).
    • The cost of routine immunization through HIV and primary care clinics may be lower per capita than the cost of large, rapid vaccination campaigns for outbreak response.
A true cost-effectiveness analysis has not been performed.

Feasibility

Feasibility
Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention feasible to implement? Probably yes
  • Vaccine response improves if individuals are vaccinated earlier in the course of HIV infection, when they tend to have higher initial CD4+ counts and lower HIV RNA viral loads.
  • Despite existing recommendations to vaccinate based on specific risk factors, there is inadequate screening and vaccination for HAV among PWHIV, even in HIV clinics.
    • In a US study, 23.3% of eligible outpatient PWHIV received 1 dose of HepA vaccine (25).
    • In a British study, HepA vaccine was indicated in 75% of PWHIV, but had been delivered to only 36% of eligible individuals (26).
Simplifying provider guidance may improve protection of at-risk PWHIV.

Balance of Consequences

Desirable consequences probably outweigh undesirable consequences in most settings

Is there sufficient information to move forward with a recommendation? Yes

Policy Option for ACIP Consideration

ACIP recommends the intervention

Recommendation (text)

All persons with HIV aged 1 year and older should be routinely vaccinated against hepatitis A.

Final deliberation and decision by the ACIP

Final ACIP recommendation

ACIP recommends the intervention

ACIP Considerations

All persons with HIV aged 1 year and older should be routinely vaccinated against hepatitis A.

i This Evidence to Recommendation table is based on the GRADE Evidence to Decision framework developed through the DECIDE project. See further informationexternal icon.

References

  1. Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States, 2010–2015pdf icon. HIV Surveillance Supplemental Report 2018;23(No. 1). Published March 2018. Accessed January 16, 2020.
  2. Weissman S, Feucht C, Moore BA. Response to hepatitis A vaccine in HIV-positive patients. J Viral Hepat. 2006 Feb;13(2):81–6.
  3. 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 Oct 15;39(8):1207-13. Epub 2004 Sep 24.
  4. 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 Aug 12;31(36):3668–74. doi: 10.1016/j.vaccine.2013.06.012. Epub 2013 Jun 15. Erratum in: Vaccine. 2015 Mar 3;33(10):1297.
  5. Centers for Disease Control and Prevention. Medical Monitoring Project (MMP). https://www.cdc.gov/hiv/statistics/systems/mmp/index.html. Accessed January 16, 2020.
  6. Brennan J, Moore K, Sizemore L, et al. Notes from the Field: Acute Hepatitis A virus infection among previously vaccinated persons with HIV infection — Tennessee, 2018. MMWR Morb Mortal Wkly Rep. 2019;68:328–9. doi: http://dx.doi.org/10.15585/mmwr.mm6814a3external icon
  7. https://www.mass.gov/info-details/current-hepatitis-a-outbreak#outbreak-epidemiology-external icon. Accessed June 5, 2019.
  8. Illinois Department of Health. Hepatitis A. http://www.dph.illinois.gov/hepatitisA#Am%20I%20at%20risk%20for%20getting%20hepatitis%20Aexternal icon. Accessed January 16, 2020.
  9. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2013 Nov 13;58(1):e1–34.
  10. Crum-Cianflone NF, Wallace MR. Vaccination in HIV-infected adults. AIDS Patient Care STDS. 2014;28(8):397–410. doi:10.1089/apc.2014.0121
  11. Pham H, Geraci SA, Burton MJ; CDC Advisory Committee on Immunization Practices. Adult immunizations: update on recommendations. Am J Med. 2011;124(8):698–701. doi:10.1016/j.amjmed.2010.07.032
  12. Crane HM, Dhanireddy S, Kim HN, et al. Optimal timing of routine vaccination in HIV-infected persons. Curr HIV/AIDS Rep. 2009;6(2):93–9. doi:10.1007/s11904-009-0014-z
  13. Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med. 2007;356(14):1445–54. doi:10.1056/NEJMra065142
  14. Kresina TF, Hoffman K, Lubran R, Clark HW. Integrating hepatitis services into substance abuse treatment programs: new initiatives from SAMHSA. Public Health Rep. 2007;122 Suppl 2(Suppl 2):96–8. doi:10.1177/00333549071220S219
  15. Schiff ER, Connor BA, Hershey JH, Mahoney MC, Schaffner W. Recommendations from a national conference on universal vaccination against hepatitis B and hepatitis A in adults. J Appl Res. 2007;7(1):3–16.
  16. Brook G. Prevention of viral hepatitis in HIV co-infection. J Hepatol. 2006;44(1 Suppl):S104–7. doi:10.1016/j.jhep.2005.11.022
  17. Gleeson TD, Wallace MR, Tasker SA. Vaccination in patients with HIV infection. Curr Infect Dis Rep. 2006;8(2):151–61. doi:10.1007/s11908-006-0011-y
  18. Sidiq H, Ankoma-Sey V. HIV-related liver disease: infections versus drugs. Gastroenterol Clin North Am. 2006;35(2):487–505. doi:10.1016/j.gtc.2006.05.001
  19. Laurence JC. Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus. Am J Med. 2005;118 Suppl 10A:75S–83S. doi:10.1016/j.amjmed.2005.07.024
  20. Kwong JJ. Hepatitis A and HIV: a clinical review of disease and strategies for prevention. J Assoc Nurses AIDS Care. 1999;10(2):31–6. doi:10.1016/S1055-3290(06)60297-5
  21. Crum-Cianflone NF, Wilkins K, Lee AW, et al. Long-term durability of immune responses after hepatitis A vaccination among HIV-infected adults. J Infect Dis. 2011 Jun 15;203(12):1815–23. doi: 10.1093/infdis/jir180.
  22. Mohseni-Zadeh M, Rey D, Batard ML, et al. Insuffisance de couverture vaccinale d’une cohorte française de patients séropositifs VIH [Inadequate vaccination coverage in a French cohort of HIV positive patients]. Med Mal Infect. 2010;40(12):683–90. doi:10.1016/j.medmal.2010.06.005
  23. Campbell JV, Garfein RS, Thiede H, et al. Convenience is the key to hepatitis A and B vaccination uptake among young adult injection drug users. Drug Alcohol Depend. 2007;91 Suppl 1:S64–72. doi:10.1016/j.drugalcdep.2006.09.022
  24. Luyten J, Beutels P. Costing infectious disease outbreaks for economic evaluation: a review for hepatitis A. Pharmacoeconomics. 2009;27(5):379–89. doi:10.2165/00019053-200927050-00003
  25. Tedaldi EM, Baker RK, Moorman AC, et al. Hepatitis A and B vaccination practices for ambulatory patients infected with HIV. Clin Infect Dis. 2004;38(10):1478–84. doi:10.1086/420740
  26. Quinn KJ, McCarty EJ, Quah SP, Emerson CR, Donnelly CM. Managing vaccines: defining the remit of primary care and specialist HIV clinics in the delivery of immunization to individuals with HIV infection. Int J STD AIDS. 2012;23(2):136–7. doi:10.1258/ijsa.2011.011231
Page last reviewed: June 2, 2020