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Invited Commentary
Gastroenterology and Hepatology
August 23, 2021

Hepatitis B Vaccination in People Living With HIV—If at First You Don’t Succeed, Try Again

Author Affiliations
  • 1Medical Practice Evaluation Center, Massachusetts General Hospital, Boston
  • 2Division of Infectious Diseases, Massachusetts General Hospital, Boston
  • 3Department of Medicine, Harvard Medical School, Boston, Massachusetts
JAMA Netw Open. 2021;4(8):e2121281. doi:10.1001/jamanetworkopen.2021.21281

Prevention of hepatitis B virus (HBV) infection has been a priority for people living with HIV since the early days of the epidemic. HIV and HBV share routes of transmission, and coinfection is common. More than 8% of all people with HIV have active HBV infection according to a recent meta-analysis, and this burden is especially high in sub-Saharan Africa.1 In countries where HBV is not endemic, coinfection is most frequently seen in men who have sex with men and people who use intravenous drugs. People with HIV who are exposed to HBV are more likely to progress to chronic infection compared with people without HIV and, without treatment, live with high levels of HBV DNA.2 People with HIV-HBV coinfection experience higher rates of liver-related complications compared with those with either infection alone,2 and they incur a high mortality rate even when prescribed early antiretroviral therapy (ART) with HBV-active antiviral agents.3 Therefore, prevention of HBV infection among people with HIV remains a priority, and vaccination remains one of the most important tools for prevention.

There has been a long-standing observation that people with HIV have a suboptimal immunological response to HBV vaccination.4 People with HIV are less likely to develop a protective immunological response to vaccination, indicated by anti-HBV surface antibody (anti-HBs) levels greater than or equal to 10 IU/mL, if they have low CD4+ cell counts, elevated HIV viral loads, coinfection with hepatitis C virus (HCV), and other comorbidities.4 Even in an era of widespread treatment, achieving a durable protective level of immunity remains a challenge. Current US clinical practice guidelines recommend that all patients with HIV without chronic HBV infection (HBV surface antigen positivity for over 6 months) and without protective immunity be offered vaccination and that anti-HBs titers be obtained following completion of the vaccine series. How to treat the 30% to 80% of patients who do not produce an immunological response following initial vaccination remains an open question. For patients with detectable HIV RNA or low CD4+ cell counts at the time of vaccination, most specialists await HIV viral suppression and immune reconstitution before repeating the vaccine series. For patients with well-controlled HIV who do not respond to HBV vaccination, some specialists revaccinate with a second vaccine series at a standard dose while others use a double dose in a 4-dose series (Engerix-B 40 µg/mL or Recombivax HB 20 µg/mL at 0, 1, 2, and 6 months).

In this article, Vargas and colleagues5 advance the evidence in support of a double-dose vaccine regimen for people with HIV who have not responded to an initial HBV vaccine series. In this double-masked trial, the investigators randomized people with HIV with anti-HBs less than 10 IU/mL following a standard HBV vaccine series to 2 arms: repeat standard dose (20 µg of Engerix-B) or a double dose (40 µg of Engerix-B). Interestingly, all patients received an accelerated 3-dose vaccine schedule of 0, 1, and 2 months. The main outcome measures were the anti-HBs titer at 1 to 2 months and 12 months following vaccination. Study participants in the double-dose arm were more likely to have anti-HBs greater than 10 IU/mL (72% vs 51%, P < .03) and a higher mean anti-HBs titer (398 IU/mL vs 159 IU/mL; P < .02) 1 to 2 months following vaccination. Among participants with available data at 1-year follow-up, those who initially responded to the double-dose regimen were more likely to retain protective levels of serology compared with those who initially responded to the single dose regimen (80% vs 39%; P < .01).

Prior studies investigating the double-dose intervention found benefit when employed in a 4-dose but not 3-dose vaccine series.4,6,7 In contrast, all participants in this study by Vargas and colleagues received the 3-dose series in an accelerated schedule. The high frequency of vaccine response in this study implies that clinicians can use an accelerated 3-dose schedule in select patients. Some caveats are important to note. Importantly, nearly all participants in this study were receiving ART and had undetectable HIV RNA levels, and the mean CD4+ cell count was greater than 400 cells/μL in both study arms. Furthermore, nearly all participants had normal creatinine and aminotransferase levels, and were predominantly men who have sex with men with only 1 participant (randomized to the double-dose arm) having evidence of HCV infection. This is consistent with observations from a prior study evaluating a double-dose regimen in a 3-dose series that found a statistically significant difference in the study population with CD4+ count greater than 350 cells/μL.6 Therefore, clinicians may still need to defer to the 4-dose series or to other HBV vaccination strategies in their patients with more comorbidities or evidence of immunodeficiency.

An additional strategy that may improve immunological response in people living with HIV is in the use of a recombinant HBV vaccine with a novel cytosine-phosphate-guanine oligonucleotide (CpG1018, a toll-like receptor 9 agonist) adjuvant, which is given in a 2-dose series at 0 and 1 month and commercially available in the US since 2017. Clinical trials in people without HIV suggest that immunological response to this recombinant HBV vaccine with a novel adjuvant is superior to the 3-dose series of the conventional recombinant vaccine.4 A non–statistically significant increase in the number of cardiovascular events observed in intervention arms of these trials suggests that further data on safety will be needed. The overall safety, efficacy, and cost-effectiveness of this recombinant HBV vaccine with the novel CpG1018 adjuvant in people living with HIV is not known, although a clinical trial is ongoing investigating its use as an initial and repeat vaccine regimen in people with HIV.

For people living with HIV, the risk of HBV infection remains high, particularly in endemic areas and in key populations. People with HIV who are exposed to HBV have a higher likelihood of progressing to chronic infection, which is associated with progressive liver disease, hepatocellular carcinoma, and liver-related mortality. In concert with safe sex practices, safe needle use, and improved protection from health care–related exposures, HBV vaccination remains an important and effective means of prevention for people with HIV, even though a substantial proportion of patients do not respond to an initial vaccine series. Based on the study by Vargas and colleagues5 and prior randomized clinical trials, people with HIV who do not respond to initial HBV vaccination may benefit from a double dose of recombinant HBV vaccine if they have well-controlled HIV and few comorbidities. Postvaccination monitoring of anti-HBs titers may still be warranted, especially in patients with ongoing risk of HBV acquisition or who may not be receiving treatment with HBV-active ART.

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Article Information

Published: August 23, 2021. doi:10.1001/jamanetworkopen.2021.21281

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Mohareb AM et al. JAMA Network Open.

Corresponding Author: Amir M. Mohareb, MD, Medical Practice Evaluation Center, 100 Cambridge St, 16th Flr, Boston, MA 02114 (amohareb@mgh.harvard.edu).

Conflict of Interest Disclosures: Dr Kim reported personal fees from the Biomarin, Inc scientific advisory board and personal fees from UpToDate outside the submitted work. No other conflicts were reported.

Funding/Support: Dr Mohareb is supported by a grant from the National Institutes of Health (grant No. T32 AI007433). Dr Kim is supported by the National Institutes of Health (grant Nos. AI131314, AI082630, DA046277, AG062393).

Role of the Funder/Sponsor: The National Institutes of Health had no role in the analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

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Mohareb  AM, Kouamé  GM, Gabassi  A,  et al.  Mortality in relation to hepatitis B virus (HBV) infection status among HIV-HBV co-infected patients in sub-Saharan Africa after immediate initiation of antiretroviral therapy.   J Viral Hepat. 2021;28(4):621-629. doi:10.1111/jvh.13461PubMedGoogle ScholarCrossref
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