Hepatitis B virus (HBV) reactivation in people with HIV after treatment with non-HBV-active antiretroviral therapy

HIV and hepatitis B virus (HBV) are chronic viral infections that share many routes of transmission [1]. For people with HIV who acquire HBV, a variable proportion resolve HBV infection and have serological evidence of past exposure to HBV without chronic infection. In fact, the serologic profile of negative HBV surface antigen (HBsAg) and positive HBV core antibody (HBcAb) with or without HBV surface antibody (HBsAb), indicating likely past exposure to HBV, is present in approximately one third of people with HIV in non-HBV-endemic countries and up to two thirds in HBV-endemic countries [1,2]. People with negative HBsAg but positive HBcAb and HBsAb are sometimes referred to as having “resolved” HBV, though this may be a misnomer because many people with this serologic profile have the potential for HBV reactivation (i.e., HBV DNA increase or HBsAg sero-reversion) especially in the context of immunosuppression [1].

HBV reactivation occurs in people with isolated HBcAb positivity or with resolved HBV because of the replication potential of covalently closed circular DNA (cccDNA), which persists in host hepatocytes. When it does occur, HBV reactivation has the potential to result in chronic HBV, acute liver injury, or liver decompensation. Considering further that people with HIV who develop chronic HBV coinfection have accelerated liver damage, a higher risk of hepatocellular carcinoma, and a higher incidence of all-cause mortality [2,3], there is an interest in preventing chronic HBV when reactivation occurs.

Tenofovir disoproxil fumarate and tenofovir alafenamide are the most effective dual active antiviral drugs against HIV and HBV. Clinical practice guidelines recommend that people with HIV-HBV coinfection (i.e., HBsAg positivity) should be treated with tenofovir-based antiretroviral therapy (ART) indefinitely because of the clear benefits for preventing fibrosis progression and HCC [1], though this is sometimes not uniformly done in practice [4]. However, one open question in the literature, and in HIV clinical practice guidelines [1], is whether people with HIV and resolved HBV infection (i.e., HBcAb positivity without HBsAg) or isolated HBcAb positivity can safely transition to ART regimens without tenofovir. This question is becoming more relevant in the context of tenofovir-sparing ART regimens, such as two-drug oral regimens (e.g., dolutegravir-lamivudine or dolutegravir-rilpivirine) and long-acting injectable ART (e.g., cabotegravir-rilpivirine), which are gaining popularity throughout the world.

The study by Denyer, et al, provides a major step forward to answering this research question. The investigators used the Veterans Aging Cohort Study, a longitudinal dataset of people living with HIV in the US Veterans Affairs system, to study 5,986 people with past HBV exposure who switched from HBV-active (defined as tenofovir, emtricitabine, or lamivudine) to non-HBV-active ART. Their primary outcome of HBV reactivation was defined as any elevation in HBV DNA or positive HBsAg (i.e., HBsAg sero-reversion) after switch. They found that only 40 (0.67%) participants met the study definition of HBV reactivation, corresponding to 25.1 events per 10,000 person-years, with most having reactivation within one year of stopping HBV-active ART. Moreover, aminotransferase elevation (ALT > 100 U/mL) was detected in 15 of the 40 participants with HBV reactivation, highlighting the potential for at least short-term liver injury for people with HBV reactivation in the context of non-HBV-active ART.

The study also elucidates important observations regarding the serologic profiles associated with HBV reactivation. Participants with any recorded history of HBsAg positivity without subsequent HBsAb appeared to be more likely to have reactivation whereas people with a profile of HBcAb and HBsAb positivity without a recorded history of HBsAg positivity had the lowest risk of HBV reactivation. These findings suggest some role in anti-HBV immunity that confers protection against HBV reactivation yet would require more involved immunological studies to confirm.

Several considerations are important as we contextualize these findings. First, this large clinical cohort relied on clinician-directed monitoring of HBV reactivation after ART switch, which is inconsistent between providers and settings. This limitation is, of course, shared across almost all cohort studies based on clinical monitoring. Only 62% of participants in this study had any HBV markers checked at any point after ART switch. A recently published study using the OPERA cohort evaluating tenofovir interruptions similarly found low rate of HBV reactivation (2% in people with HIV and resolved HBV) but with low completeness of HBV monitoring after tenofovir cessation [5]. Published studies that include proactive monitoring of HBV biomarkers and aminotransferase levels, either as part of a clinical trial or prospective cohort study, have reported higher incidence rates of HBV reactivation after cessation of tenofovir-containing therapy (up to 10% in one year) [6,7]. However, these studies are smaller and therefore less precise in their point estimates of HBV reactivation. Larger, high quality prospective cohort studies are needed to refine this risk estimate. It will also be important for future studies to elucidate the clinical significance of HBV reactivation, with the incidence of both short-term clinical events such as acute liver injury and decompensation and outcomes such as HBsAg seroreversion, fibrosis progression, and HCC.

Another important consideration is the inclusion of lamivudine and emtricitabine in the study definition of HBV-active ART. While these drugs do have activity against HBV replication, tenofovir is a more potent anti-HBV agent with a higher genetic barrier to resistance. Lamivudine is associated with a high rate of acquired HBV drug resistance [8], and clinically important events of HBV reactivation have been reported in people transitioning to tenofovir-sparing but lamivudine-containing ART [6,9]. Lamivudine treatment is most effective against HBV when HBV viral activity is low in people with HIV-HBV coinfection [10]. It is unclear whether the risk of HBV reactivation is truly lower in people after switch to lamivudine-containing ART compared with ART regimens with no HBV activity at all. Nevertheless, HBV reactivation could appear later on in time with expression of genetic resistance mutations to lamivudine or after lamivudine discontinuation.

Clinicians and patients who are planning to transition from tenofovir-containing to tenofovir-sparing ART regimens can take a number of steps to ensure safe ART switch. First, updated HBV serologic studies (i.e., HBsAg, HBcAb, and HBsAb) should be reviewed prior to switch with appropriate counselling for those at risk of HBV reactivation and vaccination for those who are susceptible to HBV infection. Monitoring for HBV reactivation should occur, ideally with HBsAg and HBV DNA where it is available. In settings where HBV DNA is not available, monitoring with HBsAg and aminotransferase levels may be an acceptable alternative, though more research is needed on the frequency and duration of monitoring. People with HIV and isolated HBcAb positivity should be offered HBV vaccination, consistent with current HIV treatment guidelines [1].

In summary, tenofovir-sparing ART, either in the form of oral or long-acting injectable regimens, is becoming more widely used as further evidence of its efficacy and safety is emerging across the world. However, the safe implementation of tenofovir-sparing ART depends on a more thorough understanding of the risk of, and factors associated with, HBV reactivation and the optimal post-switch monitoring strategies. This newly published study is a major step forward in defining that risk, but high quality, prospective cohort studies are needed to better address this question, ideally in settings with HBV endemicity, such as in sub-Saharan Africa, and in priority populations who are at risk of HBV exposure.