Comparison of Long‐Term Clinical Outcomes Between Spontaneous and Therapy‐Induced HBsAg Seroclearance

Background and Aims HBsAg seroclearance is considered a realistic goal in patients with chronic hepatitis B (CHB), known as “functional cure.” However, it remains elusive whether nucleos(t)ide analogue (NUC)‐induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, differs in its association with favorable long‐term clinical outcomes. Approach and Results A total of 1,972 CHB patients with confirmed HBsAg seroclearance at least two consecutive times, 6 months apart, were retrospectively analyzed. Risks of HCC development and composite clinical events, including HCC, liver‐related death, and liver transplantation, were compared between spontaneous and NUC‐induced HBsAg seroclearance. Of 1,972 patients, mean patient age was 53.7 years, and 64.4% were men. Cirrhosis was present in 297 (15.1%) patients. HBsAg seroclearance was achieved spontaneously in 1,624 (82.4%) patients and by NUC treatment in 348 (17.6%). HCC developed in 49 patients, with an annual incidence of 0.38 of 100 person‐years (PY) during a median follow‐up of 5.6 years. With 336 propensity‐score–matched pairs, risks of HCC ( P = 0.52) and clinical events ( P = 0.14) were not significantly different between NUC‐induced and spontaneous HBsAg seroclearance. By multivariable analysis, NUC‐induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, was not associated with the significantly higher risk of HCC (adjusted HR [AHR], 1.49; P = 0.26) and clinical events (AHR, 1.78; P = 0.06). Conclusions Risks of HCC and clinical events were not significantly different between spontaneous and NUC‐induced HBsAg seroclearance. Nonetheless, annual risk of HCC exceeds the recommended cutoff for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required.