Association Between Elevation of Serum Alanine Aminotransferase and HBsAg Seroclearance After Nucleos(t)ide Analog Withdrawal

ABSTRACT Background Alanine aminotransferase (ALT) frequently elevates in chronic hepatitis B patients stopping nucleos(t)ide analogs (NAs). Aims To clarify the association between ALT elevation and HBsAg seroclearance after NA withdrawal. Methods This multicenter cohort study reviewed consecutive patients discontinuing NA between 2004/04/01 and 2022/05/24. Treatment initiation and discontinuation generally followed the Asian‐Pacific guidelines. Eligible patients had negative HBeAg and undetectable HBV DNA before treatment cessation, without malignancy, organ transplant or autoimmune disorders. We used competing risk analysis to estimate HBsAg seroclearance incidence and a time‐dependent model to investigate post‐cessation ALT elevation. Results Among 841 patients (74.7% male; median age, 53.2 years; median treatment duration, 34.7 months), 38 patients cleared HBsAg over a median follow‐up of 3.7 years, with a 10‐year cumulative incidence of 12.4%. The median peak ALT level was significantly lower in patients achieving HBsAg seroclearance versus not (93 vs. 127 U/L; p < 0.001). Hepatitis flare after NA cessation (> 5 times upper limit) was inversely associated with HBsAg seroclearance in the univariable analysis (sub‐distribution hazard ratio [SHR], 0.31; 95% confidence interval [CI], 0.13–0.73; p = 0.007), and the association was not significant (adjusted SHR, 0.42; 95% CI, 0.09–2.01; p = 0.28) in the multivariable analysis adjusted for pretreatment HBV DNA. Consistent results were observed in the sensitivity analyses with different ALT cutoffs and subgroup analysis adjusted for HBsAg levels at treatment cessation. Conclusion ALT elevation after NA cessation is not associated with HBsAg seroclearance following NA withdrawal, suggesting cytolytic pathways are not essential for a functional cure.