Immune Control, HBsAg Loss or Flare Requiring Liver Transplant-Diverse Outcomes After Stopping NUC Therapy

Hepatitis B surface antigen (HBsAg) loss is rarely achieved during long-term nucleos(t)ide analogue (NUC) therapy of chronic hepatitis B. Treatment discontinuation may lead to immune activation and HBsAg loss. In a prospective study, HBeAg-negative patients without liver cirrhosis stopped NUC therapy after a duration of at least 3 years. Follow-up for 2 years comprised monthly monitoring for the first six months. Twenty-five patients who discontinued therapy and six randomized controls who continued were included. After stopping NUC therapy, five patients (20%) developed an HBsAg seroclearance pattern, including four who lost HBsAg and one who achieved HBsAg below 1 IU/mL. Seven patients (28%) developed a state of immune control with persistently low HBV DNA and normal ALT. Six patients (24%) experienced severe flares requiring NUC re-initiation; all of them, including one with fulminant hepatitis necessitating liver transplantation, had detectable hepatitis B core-related antigen (HBcrAg) in serum at NUC discontinuation. The peak serum HBV DNA level strongly correlated with and preceded peak ALT. Thus, although half of the patients had favorable outcomes, there was a substantial risk of severe flares preceded by HBV DNA levels above 6 log₁₀ IU/mL. Close monitoring, including frequent HBV DNA testing with rapid turnaround time, is therefore essential.