Why and when could nucleos(t)ide analogues treatment be withdrawn?

Oral antiviral therapy to hepatitis B virus (HBV) with nucleos(t)ide analogues (NUCs) is effective in suppressing the viral load leading to improved clinical outcomes. However, functional cure of HBV, indicated by hepatitis B surface antigen (HBsAg) clearance from the serum, is rare. Although safety and adherence may represent minor issues in long-term treatment with the available NUCs, more efficacious treatments with finite treatment duration for patients with chronic hepatitis B (CHB) are currently undergoing active clinical investigation. Available data suggest that HBsAg loss can be achieved in 10% to 20% of patients after NUC discontinuation, at the cost of about 50% to 80% virological relapse and 40% to 55% retreatment with NUC. With this, NUC treatment in patients with cirrhosis should not be stopped to avoid detrimental risk of hepatic decompensation and death. Viral and immune biomarkers, which may be potentially useful in stratifying the patients at risk of relapse after stopping NUC therapy, are under investigation. In the era of personalized medicine aided by artificial intelligence tools, tight monitoring of viral kinetics and algorithmic modeling appear a promising strategy to assist in individualized decision and conclude the optimal timing of the NUC treatment discontinuation.