Hepatitis B vaccination in people living with HIV: if at first you don’t succeed, try again

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 to people without HIV and, without treatment, live with high levels of HBV DNA.² People with HIV-HBV coinfection suffer higher rates of liver-related complications compared to those with either infection alone,² and they incur a high mortality even when started on early 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) greater than or equal to 10 IU/mL, if they have low CD4+ cell counts, elevated HIV viral loads, coinfection with HCV, and other comorbidities.⁴ Even in an era of widespread treatment, achieving a durable protective level of immunity remains a challenge. Current U.S. clinical practice guidelines recommend that all patients with HIV without chronic HBV infection (HBV surface antigen [HBsAg] positivity for >6 months) and without protective immunity be offered vaccination and anti-HBs titers should be obtained following completion of the vaccine series. How to manage the 30–80% 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 standard dose while others use a double dose in a four-dose series (Engerix-B 40 mcg/mL or Recombivax HB 20 mcg/mL at 0, 1, 2, and 6 months).

In this issue of JAMA Network Open, Vargas and colleagues 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.⁵ In this double-blinded trial, the investigators randomized people with HIV with anti-HBs <10 IU/mL following a standard HBV vaccine series to two arms: repeat standard dose (20mcg of Engerix-B) or a double dose (40mcg of Engerix-B). Interestingly, all patients received an accelerated three-dose vaccine schedule of 0, 1, and 2 months. The main outcome measures were the anti-HBs titer at 1– 2 months and 12 months following vaccination. Study participants in the double dose arm were more likely to have anti-HBs >10 IU/mL (72% versus 51%, p<0.03) and a higher mean anti-HBs titer (398 IU/mL versus 159 IU/mL, p<0.002) 1– 2 months following vaccination. Among participants with available data at one-year follow-up, those who initially responded to the double dose regimen were more likely to retain protective levels of serology compared to those who initially responded to the single dose regimen (80% versus 39%, p<0.01).

Prior studies investigating the double dose intervention found benefit when employed in a four-dose but not three-dose vaccine series.^4,6,7 In contrast, all participants in this study by Vargas and colleagues received the three-dose series in an accelerated schedule. The high frequency of vaccine response in this study implies that clinicians can use an accelerated three-dose schedule in select patients. Some caveats are important to note. Importantly, nearly all participants in this study were on ART with undetectable HIV RNA levels, and the mean CD4+ cell count was >400 cells/uL in both study arms. Further, nearly all participants had normal creatinine and aminotransferase levels, and were predominantly MSM with only one 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 three-dose series which found a statistically significant difference in the study population with CD4+ count >350 cells/uL.⁶ Therefore, clinicians may still need to defer to the four-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 phosphoguanine oligonucleotide (CpG 1018, a toll-like receptor 9 agonist) adjuvant, which is given in a two-dose series at 0 and 1 months and commercially available in the U.S. 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 three-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, though 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 healthcare-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 colleagues, and prior randomized controlled 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. Post-vaccination monitoring of anti-HBs titers may still be warranted, especially in patients with ongoing risk of HBV acquisition or who may not be on treatment with HBV-active ART.