A meta-analysis of controlled clinical trials comparing peginterferon-α plus nucleos(t)ide analogs versus peginterferon-α monotherapy for HBsAg clearance or seroconversion in patients with chronic hepatitis B

Background Chronic hepatitis B virus (HBV) infection remains a major global health challenge. Peginterferon-α (PEG-IFN-α) and nucleos(t)ide analogs (NAs) are standard therapies used to suppress HBV replication. Although HBsAg clearance and seroconversion are ideal therapeutic endpoints, whether PEG-IFN-α combined with NAs offers superior efficacy compared with PEG-IFN-α monotherapy remains controversial. Methods Controlled clinical trials published between 2000 and 2025 that compared PEG-IFN-α plus NA combination therapy with PEG-IFN-α monotherapy in patients with chronic hepatitis B, with treatment duration ≥ 48 weeks, were included. The primary outcomes were HBsAg clearance and seroconversion. Results Eleven trials involving 2,439 patients were identified and analyzed. After 48 weeks of treatment, the HBsAg clearance rate was significantly higher in the combination therapy group than in the monotherapy group [odds ratio (OR) = 1.59, 95% confidence interval (CI): 1.01–2.52, P = 0.05]. However, no significant difference in HBsAg clearance rates was observed between the two groups at 24 weeks of post-treatment follow-up (OR = 1.33, 95% CI: 0.76–2.33, P = 0.31). Likewise, no significant differences were found in HBsAg seroconversion rates after 48 weeks of treatment or at 24 weeks post-treatment follow-up (OR = 1.77, 95% CI: 0.94–3.32, P = 0.08; and OR = 1.42, 95% CI: 0.88–2.28, P = 0.15, respectively). Conclusion PEG-IFN-α promotes HBsAg clearance and seroconversion. Combination therapy with PEG-IFN-α plus NAs yields higher short-term clearance than monotherapy; however, sustained benefits appear to require prolonged treatment.