Finite nucleos(t)ide-analogue therapy for functional cure in HBeAg-negative chronic hepatitis B: recent development in the paradigm shift

Long-term nucleos(t)ide analogue (Nuc) therapy in chronic hepatitis B (CHB) may lead to hepatitis B virus (HBV) suppression, alanine aminotransferase (ALT) normalization, improvement of histological lesions, and prevention of liver disease progression, but rarely achieve HBsAg loss, the hallmark of functional cure. HBeAg-negative CHB patients have often been recommended to continue Nuc therapy until HBsAg loss, which usually means indefinitely. However, long-term/life-long Nuc therapy is associated with increasing costs and concerns of adverse outcomes subsequent to poor adherence and/or self-cessation/loss-to-follow-up. Hence, 2012 Asian-Pacific guidelines recommended that HBeAg-negative CHB patients can stop Nuc therapy after ≥12 months of HBV DNA undetectability. Subsequent Asian and few European studies have found the strategy of finite Nuc therapy to be feasible and reasonably safe. In 2016-2017, stopping Nuc was also included as a conditional strategy for HBeAg-negative CHB patients in the American and European guidelines. Furthermore, progressively increasing HBsAg loss rates with prolongation of off-Nuc follow-up were documented, being higher in Caucasians and more apparent beyond years 4-5 in Asian patients. Recently, a large study in patients with HBV cirrhosis showed not only higher 10-year HBsAg loss rate (15.3 vs. 1.6%) but also ~50% lower 10-year hepatocellular carcinoma incidence (16.5 vs. 29.5%) and 60% lower liver-related mortality/transplantation rate (6.1 vs. 15.1%) after Nuc cessation, as compared with well-matched patients continuing Nuc therapy. Since novel drug development aiming for functional cure has not been satisfactory, the strategy of finite Nuc therapy in HBeAg-negative CHB seems to be the best realistic option for functional cure today.