Bulevirtide with or without Peg-IFNα-2a for chronic hepatitis D: a systematic review and meta-analysis of randomized controlled trials

Abstract Objective To compare the efficacy and safety of bulevirtide (BLV) monotherapy versus BLV plus pegylated interferon alfa-2a (Peg-IFNα-2a) in adults with chronic hepatitis D. Methods We conducted a systematic review and meta-analysis in accordance with PRISMA 2020 (PROSPERO: CRD420251137112). Randomized controlled trials (RCTs) directly comparing BLV plus Peg-IFNα-2a with BLV monotherapy were identified through PubMed/MEDLINE, Embase, Scopus, the Cochrane Library, Google Scholar, and ClinicalTrials.gov. The original searches were completed in August 2025. All information sources were searched again on September 21, 2026, to identify any newly published eligible trials. Trial-defined virological, biochemical, and combined responses and changes in HDV RNA and ALT were synthesized using random-effects models. The primary analyses used restricted maximum likelihood estimation with the Hartung–Knapp–Sidik–Jonkman (REML-HKSJ) adjustment. DerSimonian–Laird (DL) random-effects analyses with conventional normal-approximation confidence intervals were performed as sensitivity analyses. Results Three RCTs comprising 225 patients were included. At week 24, virological response was numerically higher with BLV plus Peg-IFNα-2a, although the difference was not statistically significant (RR 2.07, 95% CI 0.38–11.40), while no difference was observed in combined response (RR 1.01, 95% CI 0.12–8.48). Combination therapy produced a greater reduction in HDV RNA (Hedges’ g − 0.96, 95% CI − 1.75 to − 0.18). In contrast, biochemical response favored BLV monotherapy (RR 0.36, 95% CI 0.17–0.78), as did ALT change (MD 45.58 U/L, 95% CI 33.51–57.65). At week 48, virological response favored combination therapy (RR 5.33, 95% CI 1.57–18.12), whereas biochemical and combined responses did not differ significantly between groups. At 24 weeks post-EOT, combined response favored combination therapy (RR 4.15, 95% CI 1.05–16.40), while the virological and biochemical response estimates remained imprecise. Peg-IFNα-2a containing combination regimens were associated with higher rates of neutropenia and thrombocytopenia. DL sensitivity analyses yielded narrower confidence intervals for several outcomes and changed the statistical significance of some longer-term estimates. Conclusions BLV plus Peg-IFNα-2a was associated with greater virological suppression, whereas BLV monotherapy showed more favorable on-treatment biochemical responses. Follow-up estimates were based on only two randomized trials, with wide confidence intervals for several outcomes under the primary REML-HKSJ analysis. The available randomized evidence should therefore be interpreted cautiously, particularly for longer-term and post-treatment outcomes. Clinical trial number Not applicable.