Functional cure of hepatitis B in patients with cancer undergoing immune checkpoint inhibitor therapy

Are checkpoint inhibitors a new treatment option for chronic hepatitis B virus infection?

Despite declining hepatitis B virus (HBV) infection rates, the worldwide prevalence of hepatitis B surface antigen (HBsAg) carriers remains at 3–4%. Current antiviral therapies for chronic hepatitis B virus infection (CHB) only very rarely achieve HBsAg elimination, which is necessary for a functional cure. Exhaustion of HBV-specific CD8 T cells, characterized by overexpression of typical exhaustion markers such as programmed cell death protein 1 (PD1), is a main contributor of HBV chronification. Preclinical studies suggest that checkpoint inhibitors such as anti-PD1 and anti-PD-L1 antibodies could restore antiviral T-cell function. In a retrospective cohort study published in the Journal of Hepatology, Mon et al. investigated the course of HBsAg levels in patients with CHB and cancer undergoing immunotherapy with checkpoint inhibitors. In total, the study population consisted of 3 cohorts: cohort 1 with n = 201 CHB patients with any tumor disease undergoing immunotherapy, cohort 2 with n = 95 CHB patients with hepatocellular carcinoma (HCC) undergoing immunotherapy, and the control cohort 3 with n = 375 CHB patients with HCC undergoing treatment with tyrosine kinase inhibitors (TKIs). The immunotherapeutic agents used were durvalumab, atezolizumab, nivolumab, and pembrolizumab. The majority of patients in all cohorts were receiving antiviral treatment with nucleoside or nucleotide analogues (NUCs) at the time of treatment initiation. In the median follow-up period of 17.5 months, there were no significant differences in the overall incidence of functional cure between the cohorts (cohort 1: 6.8%, cohort 2: 9.1%, cohort 3: 4.7%). However, within the first 24 months, 4.3% of cohort 1 and 16.9% of cohort 2 showed HBsAg loss compared to 0% of the control cohort. The median time to HBsAg loss was significantly shorter in cohorts 1 and 2 (21.1 months and 11.4 months, respectively) compared to 55.1 months in control cohort 3. An HBsAg level of less than 100 IU/ml at the time of treatment initiation was the only independent predictor of HBsAg loss (hazard ratio = 6.274; p = 0.028). In summary, these data suggest that checkpoint inhibitors may accelerate the functional cure of CHB. Given the favorable prognostic implication as well as the potential risks and side effects of long-term therapy with NUCs, these data are of significant clinical relevance. Thus, the beneficial side effects of immunotherapeutics, which are becoming increasingly important in the treatment of HCC, justify regular seroconversion monitoring in CHB patients, especially those with low baseline HBsAg. As immunotherapeutics are further increasingly being tested in curative-intent neoadjuvant and adjuvant treatment settings in clinical trials, differential efficiency of checkpoint inhibitor combinations in HBsAg elimination could also influence future treatment decisions in patients with CHB and HCC. However, there were no differences in the objective tumor response rates in patients with or without HBsAg loss, suggesting that different T-cell subgroups may be responsible for the antiviral and the anti-tumor response.
Since all patients in this study had cancer and were therefore immunocompromised, the data of Mon et al. cannot be directly transferred to the use of checkpoint inhibitors in the primary indication of CHB. Variations in immune compromise could also account for the supposedly higher rate of HBsAg elimination in the cohort of HCC patients (cohort 2) compared to the group with other solid tumors (cohort 1). However, clinical studies have already been conducted to evaluate the efficacy of checkpoint inhibitors for the primary indication of CHB. Interim data from a phase 2b study showed HBsAg loss in 21.1% of patients receiving 24 weeks of therapy with NUCs and the PD-L1 antibody envafolimab compared to 0% with NUCs and a placebo. In view of the potential adverse effects of immunotherapy, however, it remains questionable whether such therapeutic concepts could become established in the future. Given several case reports of HBV reactivation under immunotherapy, checkpoint inhibitors will probably only be able to be used as part of combination therapies with NUCs. As most of the patients in the study by Mon et al. were pre-treated with an NUC, the safety of immunotherapy with regard to HBV reactivation remains unclear also with this novel data.