The review, led by Muhammad Hassan Saeed and colleagues working across institutions in Pakistan and Somalia, was conducted in accordance with the PRISMA 2020 reporting guideline and prospectively registered in PROSPERO (CRD420251137112). The investigators searched PubMed/MEDLINE, Embase, Scopus, the Cochrane Library, Google Scholar, and ClinicalTrials.gov, completing the original searches in August 2025 and re-searching all information sources on September 21, 2026, to capture any newly published eligible trials. Their objective was precise: to compare the efficacy and safety of bulevirtide monotherapy against bulevirtide combined with Peg-IFNα-2a in adults with chronic hepatitis D. Only randomized controlled trials directly comparing the two strategies were eligible, ensuring that the synthesis rested on the highest tier of interventional evidence rather than observational cohorts or single-arm studies.

The methodological rigor of the analysis deserves particular attention because it reflects a broader shift in how meta-analysts handle small trials. The primary analyses used restricted maximum likelihood (REML) estimation with the Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment, a random-effects approach that widens confidence intervals when the number of studies is small and between-trial heterogeneity is uncertain, thereby guarding against the overconfident estimates that conventional methods can produce. As sensitivity analyses, the team also ran DerSimonian–Laird (DL) random-effects models with conventional normal-approximation confidence intervals. Outcomes synthesized included trial-defined virological, biochemical, and combined responses, as well as continuous changes in HDV RNA and alanine aminotransferase (ALT), the liver enzyme that serves as a surrogate marker for inflammatory activity. Standardized mean differences were expressed as Hedges’ g, and binary outcomes as risk ratios (RR).

Three randomized controlled trials comprising 225 patients met the inclusion criteria. At week 24, virological response was numerically higher with the combination regimen, but the difference was not statistically significant under the primary analysis (RR 2.07, 95% CI 0.38–11.40), and combined response showed essentially no difference (RR 1.01, 95% CI 0.12–8.48). Combination therapy did, however, produce a significantly greater reduction in HDV RNA (Hedges’ g −0.96, 95% CI −1.75 to −0.18), indicating deeper viral suppression during the first six months of treatment. In contrast, biochemical response favored bulevirtide monotherapy (RR 0.36, 95% CI 0.17–0.78), as did the ALT change (mean difference 45.58 U/L, 95% CI 33.51–57.65), meaning that patients on the combination were less likely to achieve normalized liver enzymes while on treatment.

The picture changed at week 48. By that point, virological response clearly favored the combination regimen (RR 5.33, 95% CI 1.57–18.12), suggesting that the interferon-containing strategy delivers superior viral control with longer exposure, even though biochemical and combined responses did not differ significantly between the groups at this time point. The divergence between viral and biochemical endpoints is scientifically noteworthy: HDV RNA suppression and ALT normalization do not always move in lockstep, and the mechanisms underlying this dissociation—whether interferon’s immunomodulatory effects, bulevirtide’s entry-blocking pharmacodynamics, or trial-specific response definitions—remain an open question for hepatologists designing future trials.

Post-treatment durability emerged as another key dimension. At 24 weeks after the end of treatment (EOT), combined response favored combination therapy (RR 4.15, 95% CI 1.05–16.40), while the virological and biochemical response estimates remained imprecise, with confidence intervals too wide to support firm conclusions. Sustained off-treatment response is the ultimate goal in chronic hepatitis D, since relapse after stopping therapy is common, and the finding that the combination arm maintained an advantage in combined endpoints at this late stage will inform discussions about treatment duration and discontinuation strategies. Nevertheless, the authors emphasize that these longer-term estimates rested on only two randomized trials, limiting the reliability of the post-treatment synthesis.

Safety signals tracked the known toxicity profile of interferon. Regimens containing Peg-IFNα-2a were associated with higher rates of neutropenia and thrombocytopenia, the hematologic adverse effects that have long constrained interferon use in viral hepatitis. Bulevirtide itself has generally been well tolerated in clinical practice, with the most frequently reported adverse effect being injection-site reactions and, in some studies, transient elevations in bile acids. The meta-analysis thus frames the central clinical trade-off: deeper viral suppression and better sustained combined responses with the combination, at the cost of interferon-related hematologic toxicity and less favorable on-treatment liver enzyme responses.

A technically important caveat concerns the statistical method itself. The DL sensitivity analyses yielded narrower confidence intervals for several outcomes and changed the statistical significance of some longer-term estimates, illustrating how method choice can alter conclusions in meta-analyses built on very few trials. The HKSJ adjustment, which the authors treated as primary, is specifically designed for settings with fewer than five studies, where the conventional DL approach with normal-approximation intervals can be anticonservative. The fact that significance flipped for some endpoints between methods is not a flaw of the review but a faithful reflection of the fragility of the underlying randomized evidence, and it underscores why the authors call for cautious interpretation, particularly for longer-term and post-treatment outcomes.

The authors declare no competing interests and received no funding for the study, and the work is published open access under a Creative Commons Attribution 4.0 license. For clinicians managing chronic hepatitis D, the review provides a technically grounded evidence base: bulevirtide plus Peg-IFNα-2a was associated with greater virological suppression at week 48 and better combined responses 24 weeks after treatment ended, whereas bulevirtide monotherapy showed more favorable on-treatment biochemical responses and avoided interferon-related cytopenias. With only three trials and 225 patients, and wide confidence intervals under the primary REML-HKSJ analysis, the randomized evidence remains limited. Larger, longer randomized trials with standardized endpoint definitions will be needed to determine the optimal position of combination therapy in chronic hepatitis D, particularly as bulevirtide dosing strategies, treatment duration, and off-treatment durability continue to evolve in this rare and devastating disease.

Subject of Research: Virology

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

Article References: Saeed, M. H., Lohana, K. C., Kashish, F. N. U., Nadeem, U., Dadabhoy, S. J., Ahsan, A. E., Zafar, H., Rizvi, S. E. Z., Bux, A., Butt, N., Jama, M. M., & Shaikh, M. A. (2026). Bulevirtide with or without Peg-IFNα-2a for chronic hepatitis D: a systematic review and meta-analysis of randomized controlled trials. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14668-7

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14668-7

Keywords: chronic hepatitis D, bulevirtide, pegylated interferon alfa-2a, HDV RNA suppression, NTCP inhibitor, meta-analysis, randomized controlled trials, viral hepatitis, liver disease, antiviral therapy, without, Peg-IFN