Comparative Efficacy of Treatment Regimens for Chronic Hepatitis D Virus Infection: A Systematic Review and Network Meta-Analysis

Background and Aims: Treatment of chronic hepatitis delta virus (HDV) infection with pegylated interferon-alpha (PEG-IFN-alpha) is associated with variable and often poor treatment responses. Recently, bulevirtide was approved for chronic HDV infection with promising results. Methods: We conducted a pairwise network meta-analysis of five treatment regimens—bulevirtide, bulevirtide plus PEG-IFN-alpha, PEG-IFN-alpha, lonafarnib and lonafarnib plus PEG-IFN-alpha—by reviewing randomised studies in PubMed, EMBASE and Web of Science. A control group receiving no treatment or nucleos(t)ide analogs alone was included. Primary outcomes were virological response (undetectable HDV RNA or ≥ 2 log₁₀ IU/mL decrease from baseline), biochemical response (ALT normalisation) and combined response (defined as fulfilment of both virological and biochemical responses), measured at end of treatment and 24 weeks post-treatment. Odds ratios (ORs) with 95% confidence intervals (CIs) were used for analysis. Results: Data from 934 patients in 6 randomised studies showed that, at the end of treatment, bulevirtide plus PEG-IFN-alpha combination therapy was more likely to achieve virological response compared to PEG-IFN-alpha (OR, 8.39; 95% CI: 3.46, 20.37) and bulevirtide (OR, 6.31; 95% CI: 3.17, 12.59). Bulevirtide 10 mg plus PEG-IFN-alpha combination therapy was more likely to achieve virological response compared to bulevirtide 2 mg plus PEG-IFN-alpha combination therapy at the end of treatment (OR, 2.43; 95% CI: 1.16, 5.09). Bulevirtide 10 mg (OR, 4.43; 95% CI: 1.17, 16.83) and bulevirtide 2 mg (OR, 10.95; 95% CI: 2.51, 47.74) were more likely to achieve biochemical response compared to PEG-IFN-alpha at the end of treatment, but bulevirtide plus PEG-IFN-alpha combination therapy was not (OR, 3.24; 95% CI: 0.84, 12.50). At 24 weeks post-treatment, bulevirtide plus PEG-IFN-alpha combination therapy was more likely to result in virological response compared to PEG-IFN-alpha (OR, 3.69; 95% CI: 1.05, 12.98) and bulevirtide (OR, 2.79; 95% CI: 1.13, 6.92), as well as biochemical response compared to PEG-IFN-alpha (OR, 3.23; 95% CI: 1.38, 7.56). Bulevirtide plus PEG-IFN-alpha combination therapy was more likely to result in combined response compared to PEG-IFN-alpha (OR, 6.06; 95% CI: 2.03, 18.05) and bulevirtide (OR, 4.67; 95% CI: 2.21, 9.85) at the end of treatment. At 24 weeks post-treatment, neither bulevirtide monotherapy nor bulevirtide plus PEG-IFN-alpha combination therapies at various doses were more likely to achieve combined response compared to PEG-IFN-alpha. Conclusions: Bulevirtide plus PEG-IFN-alpha combination therapy was superior in achieving virological response, both in magnitude and duration, compared to bulevirtide or PEG-IFN-alpha monotherapies in patients with chronic HDV infection.