Abstract:

Chronic hepatitis B (CHB) remains a major global health challenge. Functional cure represents the ideal therapeutic endpoint for CHB. The pathogenesis of CHB is complex, including hepatitis B virus (HBV) DNA integration, persistent covalently closed circular DNA, and impaired specific immune response against HBV, which poses significant challenges to achieving functional cure in CHB. Current therapeutic drugs have limited efficacy in achieving functional cure. After 10 years of nucleos(t)ide analogs (NAs) monotherapy, less than 5% of patients achieve functional cure, while less than 15% of patients achieve functional cure after 48 weeks of pegylated interferon (Peg-IFN) monotherapy. For the favorable population that achieves HBV e antigen (HBeAg) negativity with NAs treatment and has baseline HBV surface antigen (HBsAg) <1 500 IU/mL, the functional cure rate with sequential Peg-IFN therapy is over 20%, with a functional cure rate of over 30% for patients with baseline HBsAg between 500 and 1 500 IU/mL and over 60% for those with baseline HBsAg <100 IU/mL. For non-cirrhotic patients who meet the recommended drug discontinuation criteria in the guidelines, NAs cessation may accelerate HBsAg clearance and facilitate functional cure. However, close monitoring of hepatitis flares and hepatocellular carcinoma is required. To overcome the low functional cure rate of current drugs for CHB, researchers are exploring novel drugs, including direct-acting antivirals targeting different stages of HBV life cycle, and immunomodulatory drugs aimed at restoring immune function against HBV. Based on current research results, no new drug has achieved a functional cure rate of CHB above 30% through monotherapy. Therefore, combination therapy strategies based on new drugs are currently a research focus.

Key words: Chronic hepatitis B, Hepatitis B virus, Functional cure, Clinical cure, Hepatitis B surface antigen