Given that human immunodeficiency virus (HIV) and hepatitis B virus (HBV) share similar routes of transmission, coinfection with the two viruses is common (1). Globally, almost 10% of people living with HIV (PLWH) are infected with HBV (2, 3). HBV-related liver disease affects the life expectancy of PLWH. In individuals infected with HIV, HBV more often becomes a chronic infection, with patients more likely to experience progression to cirrhosis, hepatocellular carcinoma (4, 5), and liver failure (6, 7). While antiretroviral therapy (ART) has led to a decline in AIDS-related mortality, liver disease remains a major cause of morbidity and mortality in PLWH (8–10).

International guidelines highly recommend HBV immunization (11, 12). HBV infection has declined with the popularization of HBV vaccines, especially as current A2 recombinant HBV vaccines show cross-reactivity and cross-protection against the non-A2 HBV genotype (13). U.S. and British guidelines specify that PLWH should also be vaccinated for HBV. HBV vaccine responsiveness is measured by assessing seroconversion after vaccination, with HBV surface antibody [anti-HBs] ≥10 IU/L measured at 4–8 weeks after the last dose defined as a positive response. While the HBV vaccine has been certified by the CDC as an effective way to prevent HBV infection (14), PLWH often have a lower seroresponse after HBV vaccination than HIV-negative individuals. Indeed, immune responses to most vaccines are impaired in PLWH (15, 16). Several studies have worked on improving the response rate by changing the inoculation time and dose of the vaccine. While there is no consensus on an appropriate HBV vaccination schedule for PLWH, high-dose vaccine schedules may induce stronger response rates against HBV (17–20).

Several questions remain about the appropriate HBV vaccine schedule and dose for PLWH. This is in part because the number of PLWH who are susceptible to vaccine-preventable infectious diseases remains unknown and historic data from the pre-ART era may skew findings. Effective ART can increase CD4⁺ T-cell counts in PLWH, which strengthens both humoral and cellular immunity. The meta-analysis presented here summarizes the efficacy of HBV vaccines among PLWH. A subgroup analysis is conducted based on PLWH vaccination and treatment background, clarifying response rates and associated factors of the HBV vaccine among PLWH and providing evidence-based prevention recommendations.

This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42018081009) and is reported fully in line with the Preferred Reporting Items for Systematic Reviews and Meta-analysis.

The aim of this meta-analysis was to pool available data on the response rates of HBV vaccines in PLWH. To provide credible evidence, only RCT and prospective studies were included. The findings indicated that both a double dose of the HBV vaccine and the four-dose schedule were associated with a better immune response than the standard HBV vaccine regimen in PLWH. In addition, higher seroconversion rates were observed in PLWH with CD4⁺ T-cell levels >500 cells/mm³.

By analyzing 17 studies that met the inclusion criteria during 2000 to 2016, the pooled response rate of HBV vaccination for PLWH was 71.5% (95% CI 64.0%–77.9%, p < 0.001, Figure 2 ). Using the “classic schedule” (20 μg of HBsAg at months 0–1–6), PLWH response rates to the vaccine were lower than those of non-HIV-infected people (20%–70% vs. 90%–95%) (22, 35–38). According to a previous study, high plasma viral load, prevaccination total serum IgG, and elevated prevaccination IgG1 among PLWH were associated with poor vaccine response (38).

The double-dose HBV vaccine regimen had a significantly higher response rate than the standard-dose regimen (75.2% and 65.5%, respectively; p < 0.001). Several studies (20, 33, 34, 39) have shown that PLWH who have never received the HBV vaccine had higher response rates after the double-dose vaccination. Moreover, two meta-analyses found that a higher dose vaccination could improve the anti-HB immune reaction in previously unvaccinated patients and could ultimately result in a high response rate (OR 1.96, 95% CI 1.47–2.61) (19, 40). Beginning in 2013, the British HIV Association recommended 40-μg doses of HBV vaccine for primary vaccination and revaccination of PLWH (41). In some studies, double-dose groups had higher and more long-lived anti-HB titers, which warrants additional study. However, other studies indicated that there is no relationship between vaccine dose and level of anti-HB response (17, 18, 21). In an open-label RCT, a total of 178 PLWH were randomized to receive either standard-dose (20 mg, three-dose) or double-dose (40 mg, three-dose) HBV vaccines at months 0, 1, and 6. A similar response was seen between the standard-dose and double-dose groups (67% vs. 74%, p > 0.05) (17). Another RCT by Fonseca et al. reported that seroconversion in response to 20 and 40 mg of the three-dose regimen among PLWH were 34% and 47%, respectively, at week 28. However, this difference was not significant (p > 0.05) (18).

In addition to double dose, several studies have shown that increased HBV vaccine schedules are more effective in PLWH. Launay et al. (20) proved that PLWH vaccinated with a four-double-dose regimen had higher anti-HBV titers and stronger immune responses than those vaccinated with the standard three-dose regimen (82% vs. 65%, p < 0.05). Chaiklang et al. compared the immunogenicity and safety of three-standard dose and four-double dose vs. four-standard dose in an RCT (21). Higher response rates were not observed in the double-dose or four-double-dose groups. This may have been impacted by low CD4⁺ T cell counts, high viral load of the participants, and small sample size. The meta-analysis described here showed a similar result. However, the subgroup analysis did not include the time interval of the three-dose regimen studies because the number of studies including three subgroups varied. Further studies are needed to explore the relationship between immune response and time interval for three- or four-dose HBV vaccination regimens in PLWH.

Several studies have found that the response to HBV vaccination is significantly associated with undetectable virus load (29, 42) and high or even close to normal CD4⁺ T-cell counts (18, 22, 29) in PLWH. Veiga et al. (29) found that vaccine responders had higher CD4⁺ T-cell numbers than non-responders (452 vs. 359 cells/mm³). The results shown in this meta-analysis were similar. PLWH with higher CD4⁺ T-cell counts had a stronger response to HBV vaccination than those with low CD4⁺ T-cell counts, especially those with a baseline CD4⁺ T-cell count >500 cells/mm³ (p < 0.001). It is suggested that vaccination as early as possible after diagnosis with high CD4⁺ T-cell counts is necessary for PLWH. However, according to the CDC, vaccination should not be deferred until CD4⁺ T-cell counts return to a certain level because patients with low CD4⁺ T-cell counts can still mount a response to the HBV vaccine (43). The lack of response to the HBV vaccine is attributed to a variety of immunological mechanisms, including antigen presentation of the peptide-based vaccine to T cells as well as B-cell activity. The functions of T and B cells in HBV vaccine non-responders are complicated. S gene escape mutants created after HBV vaccination may change host susceptibility or lead to vaccine escape from immune attack, as shown previously (44).

Immune responses are lower following HBV vaccination of PLWH than individuals without HIV infection. For PLWH, achieving a durable and protective level of immunity remains a challenge, especially for those with detectable HIV RNA or low CD4⁺ T-cell counts at the time of vaccination. For multiple reasons, completing and maintaining adequate HBV immunity in HIV-infected individuals is complex, and new strategies have emerged to overcome these barriers (45). Some specialists suggest waiting for HIV viral suppression and immune reconstitution before vaccination (30, 33). One study recommended a second vaccine series for PLWH with high CD4⁺ T-cell counts and undetectable HIV RNA who do not respond to HBV vaccination (17). The benefits of double dosage and increased dose frequency remain controversial. In this meta-analysis, results indicated that a higher vaccine dose, higher CD4⁺ T-cell levels, and multiple injections are associated with a better response to HBV vaccination in PLWH. In patients with lower CD4⁺ T-cell counts, higher HBV vaccine doses or increased dose frequency may be warranted to accentuate the immune response, and in patients with higher CD4⁺ T-cell counts, standard HBV vaccination should be performed as soon as possible after diagnosis. Importantly, the role of ART in vaccination is not evaluated in our study and there is only one study conducted in treatment-naive PLWH (28). Data showed that even after a double dose of vaccine, HBsAb titers were much lower in HIV-positive patients than HIV-negative adults.

This study has some limitations. The HIV patients included were from many different regions, including the Americas (USA 2, Brazil 5, Mexico 1, and Chile 1), Europe (France 3 and Italy 1), and East Asia and Southeast Asia (India 1 and Thailand 3). However, studies from the country with the highest HBsAg prevalence, Africa (46), are absent. The heterogeneity of this analysis was significant (I ² > 50%) and the observed differences may be due to differences in sample size, demographics, and CD4⁺ T-cell counts or inadequate statistical power. The results of this study are credible but need to be interpreted with caution.

Besides, the funnel plot showed that some studies are outside the scope of the confidence interval (triangle jurisdiction). The scattered funnel plot also revealed significant heterogeneity in our study. However, the random-effect model and the performed subgroup analysis were adopted to reduce the effect of heterogeneity. The asymmetric funnel plot also suggested that there was possible publication bias; however, we conducted a comprehensive search to make sure no study was omitted.

PLWH have significantly lower initial response rates after HBV vaccination than immunocompetent individuals. Additional vaccine doses and other methods for strengthening immunity should be considered for PLWH. This meta-analysis indicated that there were higher seroprotection rates to HBV vaccine in response to double-dose vaccination, increased dose frequency, and higher baseline CD4⁺ T-cell counts. To obtain the best response to hepatitis B vaccine in PLWH, additional large-scale studies that explore the role of other potential factors should be conducted in the future.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

XH, CG, and HW conceptualized the study and developed the research protocol. YT, WH, and YW identified articles for full-text review and extracted data that matched the inclusion criteria. YT performed the statistical analyses. All authors contributed to the writing of the manuscript. XH, TZ, and WW polished and revised the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the National Science and Technology Major Project of China During the 13th Five-year Plan Period (2017ZX10201101, 2018ZX10715-005-002-002), the Beijing Excellent Talent Plan (2018000021223ZK04), the Beijing Talent Project in the New Millennium (2020A35), and Beijing Hospitals Authority “Peak Climbing” Planning (DFL20191701).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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