Temporal Association Between COVID ‐19 Vaccination and HBsAg Loss in Chronic Hepatitis B Infection: An Interrupted Time Series Analysis

Background and Aims Hepatitis B surface antigen (HBsAg) loss, a functional cure in chronic hepatitis (CHB), is rare. Temporal changes in HBsAg loss rates were evaluated in relation to COVID‐19 vaccination rollout in South Korea. Methods An interrupted time series (ITS) analysis was performed using electronic health records of 59,946 adults with CHB (2002–2025). Monthly HBsAg loss incidence rates were estimated using a competing risk framework. National COVID‐19 vaccination coverage was used as a surrogate for population‐level exposure. A three‐phase segmental regression model assessed changes before vaccination, during a predefined vaccination effect period (18 months following ≥ 80% of two‐dose coverage), and after this period. Hepatocellular carcinoma (HCC) incidence was analysed as a negative control. Results Over 382,509 person‐years, 2483 HBsAg loss events occurred. Pre‐vaccination rates were stable (0.11–0.80 per 100 person‐years). Following the COVID‐19 vaccination rollout, the incidence increased to 0.96 in 2021, peaking at 1.27 in 2022, before declining to 0.93 in 2024. In the ITS model, no baseline trend was observed ( p = 0.606). At the intervention point (November 2021), HBsAg loss rates increased significantly (incidence rate ratio; 1.56; 95% CI 1.26–1.93; p < 0.001). No significant slope change was observed during the vaccination period, while a negative slope change was observed post‐vaccination (coefficient −0.039 per month; p = 0.003). Findings were consistent across sensitivity and subgroup analyses. HCC incidence showed no significant changes. Conclusion COVID‐19 vaccination was temporally associated with transiently higher HBsAg loss rates in CHB, followed by attenuation, suggesting a potential population‐level immunomodulatory effect on HBV dynamics.