Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy

Background: The serum gradient of hepatitis B surface antigen (HBsAg) varies over time after cessation of nucleos(t) ide analog (NA) treatment in patients with chronic hepatitis B (CHB). The association between the time-varying HBsAg serum gradient and risk of relapse has not been elucidated. Methods: This multicenter cohort study prospectively enrolled CHB patients who discontinued 3 year-NA treatment. Eligible patients were serologically negative for HBeAg and viral DNA at NA cessation. The participants (n = 140) were followed every 3 months through HBsAg quantification. Virological and clinical relapses were defined as viral DNA levels >2000 IU/mL and alanine aminotransferase (ALT) levels >80 U/mL, respectively. The association of time-varying HBsAg levels with relapses was assessed through a time-dependent Cox analysis. Results: During a median follow-up of 19.9 (interquartile range [IQR], 10.6-253) months, virological and clinical relapses occurred in 94 and 49 patients, with a 2-year cumulative incidence of 79.2% (95% confidence interval [CI], 70.9%-86.4%) and 42.9% (95% CI, 34.1%-52.8%), respectively. The serum level of HBsAg was associated with virological (P < 0.001) and clinical (P = 0.01) relapses in a dose-response manner, with adjusted hazard ratios of 2.10 (95% CI, 1.45-3.04) and 2.32 (95% CI, 1.28-4.21). Among the patients (n = 19) whose HBsAg levels ever dropped below 10 IU/mL, only one and three patients subsequently developed clinical and virological relapses. Conclusion: The serum gradient of HBsAg measured throughout the off-therapy observation is associated with the subsequent occurrence of virological and clinical relapses in CHB patients who discontinue NA treatment.