Temporal Association Between <scp>COVID</scp> ‐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.