Hepatitis B surface antigen level identifies patients with inactive chronic hepatitis B from Asia with HCC risk below surveillance threshold

Background Chronic hepatitis B (CHB) is a major global health concern primarily due to hepatocellular carcinoma (HCC) development. Objective This study aimed to identify patients with inactive CHB with negligible HCC risk using hepatitis B surface antigen (HBsAg) levels, which is the key to define partial HBV cure. Design Data from 2674 patients with inactive CHB (non-cirrhotic, hepatitis B e antigen negative, normal alanine transaminase (ALT), HBV DNA <2000 IU/mL) in the ERADICATE-B and REVEAL-HBV cohorts were analysed. The primary endpoint was HCC development, with HBsAg levels used to identify patients with annual HCC risk <0.2%. Results were validated using the NTUH-iMD cohort. Results Over a median follow-up of 26.3 years, 76 patients developed HCC. Among 989 patients with inactive CHB with HBsAg<100 IU/mL, the annual HCC incidence was 0.08% (95% CI 0.05% to 0.13%), lower than those with HBsAg≥100 IU/mL (adjusted HR 0.35, 95% CI 0.21 to 0.61). Their HCC risk was lower than the recommended threshold for HCC surveillance and was close to the risk of the general population. Even for older patients recommended for HCC surveillance, those with HBsAg levels <100 IU/mL were associated with HCC risk lower than the surveillance threshold. Moreover, patients with inactive CHB with negligible HCC risk could be identified by combining HBsAg <100 IU/mL and normal ALT levels, without the need for HBV DNA testing, as validated in the NTUH-iMD cohort. Conclusion Serum HBsAg levels <100 IU/mL effectively identify patients with inactive CHB with negligible HCC risk and limited viral activity, which is important in optimising surveillance strategies and defining partial HBV cure.