Abstract / Summary
Background/Objectives: The clinical implications of HBsAg seroreversion following HBV functional cure therapies remain unclear. In two randomized phase 2 trials, therapeutic vaccine BRII-179 or siRNA elebsiran in combination with PEG-IFNα was evaluated versus PEG-IFNα monotherapy. This pooled analysis characterized the profile of HBsAg seroreversion and explored potential predictors. Methods: Participants achieving HBsAg loss at or shortly after end of treatment (EOT) were included. Binary endpoints were summarized with two-sided 95% CIs using the Clopper–Pearson method. Time-to-event analyses used Kaplan–Meier methods and Cox regression. Longitudinal associations were evaluated using logistic mixed-effects models. Results: Among 55 participants included, 24 (43.6%) experienced HBsAg seroreversion with modest magnitude; all peak levels were <100 IU/mL and most were <10 IU/mL, infrequently accompanied by HBV DNA or ALT elevation after nucleos(t)ide analogue (NA) discontinuation. Anti-HBs > 100 IU/L at EOT was associated with a lower risk of HBsAg seroreversion (HR 0.30, 95% CI 0.10–0.92; p = 0.036). Sustained anti-HBs positivity during post-EOT follow-up was consistently associated with durable HBsAg loss in longitudinal analyses. Exploratory Kaplan–Meier analyses showed numerically higher HBsAg seroreversion rates among HBeAg-positive participants and those with PEG-IFNα treatment duration <12 weeks after HBsAg loss, although these findings were not statistically significant. Conclusions: HBsAg seroreversion after PEG-IFNα with or without BRII-179 or elebsiran was mild and rarely associated with clinically relevant relapse. Higher EOT anti-HBs levels and persistent anti-HBs positivity were associated with greater durability of HBsAg loss and warrant prospective evaluation as a candidate biomarker for risk-adapted off-treatment monitoring.