Chronic Hepatitis B and HIV Coinfection: a Continuing Challenge in the Era of Antiretroviral Therapy

With an estimated 257 million people living with chronic hepatitis B (HBV) infection in 2015, HBV is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality worldwide [1•]. Mortality from chronic viral hepatitis has surpassed deaths from HIV, tuberculosis, and malaria globally, which has prompted the World Health Organization (WHO) to call for the elimination of chronic hepatitis B and C by 2030 [1•]. The true extent of chronic hepatitis B infection among people living with HIV (PLWH) is not known given gaps in HBV screening and surveillance in many parts of the world. One systematic review estimated a global prevalence of 7.6% in PLWH, with substantial regional variation and higher (11.8%) prevalence among people who inject drugs [2•]. HIV-HBV coinfection is more common in areas with ongoing perinatal HBV transmission as seen in parts of Asia and Africa [3].

The prevalence of chronic HBV in PLWH far exceeds that of the general population. In contrast to the prevalence of chronic HBV among US households of 0.3%, the prevalence within HIV cohorts in the United States (US) is as high as 8–11% [4‐6]. Overlapping routes of the transmission of HIV and HBV likely account for the disproportionate burden of HBV in PLWH. Susceptible PLWH may also be more likely than those without HIV infection to progress to chronic HBV infection when exposed [7].

Early studies of the natural history of HIV-HBV coinfection demonstrated that coinfected patients were more likely to have unfavorable features and complications of their liver disease compared with HBV-monoinfected patients: greater probability of positive hepatitis B e antigen, higher HBV viral levels, and greater incidence of cirrhosis and liver-related mortality [7‐9]. However, much of these data originated before the era of highly effective HBV-active antiretroviral therapy (ART), and it remains unclear whether these disparities persist in the current ART era.

In this review of HIV-HBV coinfection, three main topics will be discussed, with an emphasis on recent insights and areas of uncertainty: (1) liver disease progression in HIV-HBV coinfection in the current ART era, (2) key strategies for HBV prevention in this population given the WHO call for HBV elimination, and (3) management questions when caring for HIV-HBV-coinfected patients in current clinical practice.

The broad efficacy of direct-acting antiviral therapy for chronic hepatitis C (HCV) has led the way to HIV-infected individuals no longer being considered a special population with regard to HCV-related liver disease [10, 11]. Whether the same can be said of HIV-HBV-coinfected individuals is debatable. Excess liver-related morbidity and mortality among HIV-HBV-coinfected individuals have continued to be noted in the years following the introduction of HBV-active ART [12‐14]. Moreover, unlike HCV, no therapy exists for HBV that provides a sterilizing cure where one can be assured that the virus will never return. HBV eradication is challenging because of the stability of the HBV genome and its incorporation into the hepatocyte nucleus in the form of covalently closed circular (ccc) DNA [15, 16]. HBV antiviral therapy is therefore not considered curative but rather disease-modifying at this time [17].

HBV polymerase (P protein) shares a high degree of homology to the reverse transcriptase of retroviruses like HIV [18]. Most of the nucleoside/nucleotide inhibitors now approved for hepatitis B treatment were first investigated as antiretroviral therapy for HIV, specifically lamivudine (3TC), adefovir (ADV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) (Table 1). Another antiviral, entecavir (ETV), can exert enough anti-HIV-1 activity to select for HIV drug-resistant mutations [19]. In the early ART era, 3TC was the only available antiretroviral agent that had any activity against HBV. This HBV monotherapy was eventually noted to result in high cumulative rates of 3TC HBV resistance—20-25% after 1 year to greater than 50% after 2 years and greater than 90% after 4 years [20‐22]. The limited durability is why 3TC HBV monotherapy should be avoided in HIV-HBV-coinfected patients [23•] and why 3TC is no longer considered a first-line oral antiviral for HBV infection [24]. Highly effective antiviral therapy for HBV in PLWH was therefore not prevalent until the years following the introduction of tenofovir-based ART in 2001. Tenofovir disoproxil fumarate (TDF) or the newer formulation, tenofovir alafenamide (TAF), is considered first-line HBV therapy for HIV-HBV-coinfected patients due to their high potency and high genetic barrier for resistance (Table 2). For persons with HIV and HBV coinfection, TDF or TAF is preferred over entecavir as the main HBV antiviral, largely due to the dual antiviral activity of these tenofovir preparations against both HBV and HIV.

The inclusion of tenofovir to HBV management has resulted in significant improvements in HBV virologic control among HIV-HBV-coinfected patients on ART [28‐30] as well as in the markers of hepatic function among those with decompensated cirrhosis [31]. Fibrosis regression on antiviral therapy has been well described in HBV monoinfection with most individuals demonstrating histologic improvement and 51% achieving regression of fibrosis after 5 years of sustained HBV suppression [32]. Whether this occurs to same extent in HIV-HBV remains unclear. One series of 167 HIV-HBV-coinfected patients on TDF-containing ART from France with a median follow-up of 60 months suggested that despite control of HBV replication, fibrosis progression was still observed in 17% of patients [33]. This study and others have demonstrated that stability in fibrosis appears more likely than widespread improvement in HIV-HBV coinfection [34].

While the short-term benefits of antiviral therapy have been noted, the long-term clinical benefits on liver-related morbidity and mortality are not yet fully delineated in HIV-HBV coinfection. The evidence base for the beneficial impact of antiviral therapy in reducing the risk of adverse clinical outcomes, mainly hepatic decompensation and HCC, is stronger in HBV monoinfection, particularly in patients with cirrhosis [35, 36]. One of the largest longitudinal cohort studies evaluated 3573 individuals with HIV-HBV coinfection from ten clinical cohorts in the North American AIDS Cohort Collaboration from 1996 to 2010 and examined validated end points of end-stage liver disease (ESLD) and HCC [37•]. During follow-up, 111 (3%) developed liver complication (90 with ESLD, 11 with HCC, and 10 with both) with an incidence rate of 8 events per 1000 person-years that did not significantly differ when stratified by early (1996–2001) versus later (2002–2010) ART eras (Fig. 1). Higher baseline Fibrosis-4 (FIB-4) score, lower CD4 cell count, and diabetes mellitus were associated with greater risk of liver complications during follow-up. Sustained HIV suppression (≥ 6 months) appeared to be protective and associated with a lower risk of ESLD/HCC with an adjusted hazard ratio (aHR) of 0.56 (95% confidence interval, 0.35–0.91). The risk of liver complications was also lower for those on HBV-active ART and particularly for regimens that included tenofovir, but results were not statistically significant (aHR 0.36, 95% CI 0.12 to 1.03). This may have been due to the limited duration of follow-up in this study as well as some gaps in tenofovir coverage in this cohort.

Another large population-based study in the current ART era examined differences in clinical outcomes for chronic hepatitis B among those with and without HIV from a centralized database of hospital billing claims in metropolitan France from 2008 to 2013 [38]. The primary outcome was liver disease progression defined as a composite outcome of ESLD or HCC before liver transplantation or death. Among 48,189 patients with chronic HBV, 5757 (12%) were HIV coinfected. Liver disease progression was documented in 15.5% and associated with older age and male gender. Despite having a higher prevalence of risk factors associated with liver disease (i.e., HCV coinfection, diabetes), HIV-HBV-coinfected patients were less likely to experience liver disease progression (aHR 0.77, 95% CI 0.71 to 0.83) than patients with HBV alone, with a lower risk observed especially in those without an AIDS diagnosis at that time. The authors postulated that the more widespread use of HBV treatment among PLWH on ART likely accounted for this protective effect but antiviral therapy was not captured in this study. A Dutch study however did capture antiviral therapy and found no significant difference in time to ESLD or all-cause death when comparing HIV-HBV-coinfected to HBV monoinfected individuals from 2003 to 2015 [39]. The findings from this study need to be interpreted with caution due to the substantial difference in follow-up between monoinfected and coinfected cohorts (median 3.8 vs 10.3 years with attrition of 40% vs 12% respectively).

In summary, we need further research to explore the long-term impact of first-line HBV antiviral therapy on liver disease progression and liver-related mortality in the context of HIV-HBV coinfection.

HBV vaccination remains the cornerstone of HBV prevention and ultimately the core intervention in the global effort to eliminate HBV by 2030. Universal HBV vaccination is recommended for all infants, as well as all unvaccinated children and adolescents [40•]. For adults, the HBV vaccine should be given to all persons at risk of acquiring HBV including persons living with HIV. The introduction of HBV vaccination in 1980s resulted in a 70% decline in HBV infections in the US but no further reduction in the prevalence of persons with chronic HBV [6, 41]. In the Multicenter AIDS Cohort Study, a longitudinal cohort of men who have sex with men in the US, incident HBV infection was nearly 2-fold higher in HIV-infected MSM compared with HIV-uninfected MSM and ART was not found to be completely protective [42]. Nationally in the US, rates of HBV have risen in regions where opioid use has been prevalent [43]. HBV incidence has also been shown to be moderately high in HBV-endemic settings among PLWH with relatively preserved CD4 cell counts [44]. HBV burden is also higher among marginalized populations such as those who inject drugs or are imprisoned, who are also at greater risk of HIV [2, 45].

Unfortunately, despite recommendations to immunize all susceptible persons with HIV against hepatitis B, one study conducted by the US Centers for Disease Control of over 18,000 patients in HIV care from 2009 to 2012 found that 44.2% had no documentation of HBV vaccination, immunity or infection in the medical record [46•]. Among those who were eligible for vaccination, only 9.6% were immunized and 7.5% were found to have new documentation of HBV immunity or infection during the 1-year surveillance period. The prevalence of vaccination was low regardless of clinical or sociodemographic characteristics and particularly low in clinics not supported by Ryan White funding. Notably, this study also identified gaps in ART coverage active against both HIV and HBV with only 65% receiving tenofovir-based ART. A number of barriers probably contributed to these poor immunization rates, including a history of inconsistent recommendations regarding timing of HBV immunization in PLWH and reports of reduced immunogenicity in PLWH. The lack of robust health systems that enable affordable access to adult immunization also likely posed challenges [47].

The US guidelines for the prevention and treatment of opportunistic infections (OI) in HIV acknowledge that patients with lower CD4 cell counts or ongoing HIV viral replication may not achieve seroprotection as often as those with preserved immune status and effective HIV suppression but emphasize that HBV immunization should not be deferred due to concern for lack of response [23•]. This is particularly so for patients at high risk for HBV acquisition or adverse sequelae from HBV infection, such as men who have sex with men, people who inject drugs, and those with HCV coinfection. HBV-active ART may provide some level of HBV pre-exposure prophylaxis for patients who are susceptible [48], but this is not failsafe [42] or the preferred strategy for preventing HBV. All efforts should be made to initiate and complete immunization in susceptible PLWH and assess for seroprotection with hepatitis B surface antibody 1 month after completion.

A variety of strategies including revaccination with double-dose recombinant HBV vaccine have been studied in HIV-infected non-responders [49], but there is no current consensus on the best revaccination strategy. The essential point is that regardless of how, revaccination should be attempted as 44% or more of non-responders can seroconvert with a second HBV vaccine series [23•].

In November 2017, a novel hepatitis B vaccine, HepB-CpG (Heplisav-B), was approved by the US Food & Drug Administration. Like the alum-adjuvanted vaccines (Recombivax or Engerix-B) that have been the standard of care, HepB-CpG contains the yeast-derived recombinant hepatitis B surface antigen but is adjuvanted instead with a cytidine phosphoguanosine (CpG) oligonucleotide which binds to toll-like receptor 9 and signals an innate immune system pathway response. Three phase 3 registration trials were conducted that together enrolled 9597 adults aged 18–70 years to receive HepB-CpG in two doses, spaced 1 month apart with a saline placebo for the final dose compared with standard 3-dose hepatitis B vaccine (Engerix-B) [50‐52]. The overall seroprotection rate (SPR) induced by HepB-CpG was higher in the range of 90–100% compared with 71–90% for Engerix-B with a difference in SPR ranging from 6% for 18–29-year-olds to 19% for 60–70-year-olds. A significant improvement in SPR was also noted for important subpopulations, namely patients with diabetes, tobacco use, or obesity. Whether this efficacy is also seen in PLWH remains to be shown. HepB-CpG is not currently approved for PLWH. The OI guidelines simply note this as an alternate option with limited evidence if a 2-dose strategy is preferred [23•]. The safety and efficacy of HepB-CpG are currently being studied through the clinical trial, B-Enhancement of HBV Vaccination in Persons Living With HIV (BeE-HIVE).

Despite advances in HBV prevention and care in the past few decades, HIV-HBV coinfection remains a significant contributor to non-AIDS-related death and liver-related complications. There have been missed opportunities around HBV screening, HBV immunization, and the use of tenofovir-based ART in all HIV-HBV-coinfected individuals. Achievements in HCV therapy have renewed scientific interest in a functional HBV cure, but until this is attained, future efforts should be directed at refining risk stratification to identify those most vulnerable to HBV-related complications and should focus on implementation science around how best to bridge gaps in clinical practice.