Comparative Efficacy of Bulevirtide, Interferons, and Nucleos(t)ide Analogs for Chronic Hepatitis Delta: A Systematic Review and Network Meta‐Analysis

Background Chronic hepatitis D virus (HDV) continues to be a global health concern, and the infection remains challenging to treat. Over the past few decades, pegylated interferons, typically in combination with therapy for hepatitis B, have become the standard of care, with considerable side effects and frequently unsatisfactory results. Several new therapies are emerging, including bulevirtide and lonafarnib. We conducted a systematic review and network meta‐analysis (NMA) to compare the efficacy of bulevirtide, interferons, and nucleos(t)ide analogs, alone or in combination, for the treatment of chronic hepatitis D. Methods PubMed, Embase, and Cochrane databases were searched for randomized controlled trials and nonrandomized interventional studies assessing HDV RNA suppression, biochemical response, combined response, and histological improvement with various therapies. NMA was performed using a frequentist random‐effects model. Odds ratios (OR) with 95% confidence intervals (CI) were calculated and forest plots were generated. Results Thirteen studies ( n = 922) were included, studying nine possible treatment arms. At the end of treatment, 31.8% achieved a virological response. Bulevirtide monotherapy (OR 38.63, p < 0.05) and combinations with NA (OR 69.36, p < 0.05) and peginterferon alpha (OR 260.08, p < 0.05) significantly suppressed HDV RNA, with the bulevirtide–peginterferon alpha combination having the highest HDV RNA suppression. At ≥ 24‐week follow‐up, no regimen maintained significant HDV RNA suppression. Biochemical response was achieved in 42.7% at the end of treatment; however, no group reached statistical significance versus control, though bulevirtide and its combination with peginterferon alpha outperformed peginterferon alpha alone. Combined response was highest with bulevirtide–peginterferon alpha (OR 112.69, p < 0.05), followed by bulevirtide monotherapy. Histological response (five studies, n = 183) was not statistically significant with any intervention compared with control. Conclusion Bulevirtide and peginterferon alpha combination therapy may offer the most promising treatment for chronic hepatitis D. More studies are needed to assess the efficacy of this regimen and establish the optimum dose and duration of treatment.