Incidence and Characteristics of HBV Reactivation‐Related Events Following HBsAg Seroclearance: Long‐Term Follow‐up of a Population‐Based Cohort in Japan

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) seroclearance is widely regarded as a functional remission of chronic hepatitis B virus (HBV) infection. However, HBV covalently closed circular DNA (cccDNA) may persist in hepatocytes, posing a risk of reactivation even years after seroclearance. We aimed to determine the incidence, clinical context, and virological features of HBV reactivation in a large, population-based cohort from a geographically isolated island region of Japan with a high HBV prevalence. METHODS: Between 1978 and 2008, 34,517 residents of the northern Goto Islands underwent community-based HBsAg screening, identifying 1045 individuals with chronic HBV infection (3.0% prevalence). Among them, 177 achieved spontaneous HBsAg seroclearance and were followed for a median of 6.3 years (1500 person-years). Age- and sex-matched controls were selected from HBsAg-negative residents (3043 person-years). Reactivation-related events were defined as reappearance of HBsAg after confirmed seroclearance. RESULTS: HBV reactivation-related events occurred in 4 of 177 patients (2.3%), corresponding to 27 per 10,000 person-years, whereas none occurred among 354 matched controls. All HBsAg reappearance cases had cirrhosis or hepatocellular carcinoma at baseline. One patient developed a hepatitis flare with high-level viremia and HBeAg reappearance. Viral sequencing demonstrated 99.1% similarity between baseline and reactivated strains, confirming reactivation rather than reinfection. CONCLUSIONS: Reactivation-related events after HBsAg seroclearance were rare in this population-based cohort. These findings suggest that HBsAg seroclearance may not necessarily indicate complete viral eradication and that careful long-term monitoring may be warranted, particularly in patients with advanced liver disease.