Hepatitis B functional cure: Current and future perspective

Chronic hepatitis B (CHB) remains a significant global health challenge, affecting more than 250 million individuals worldwide. A functional cure, defined as the loss of hepatitis B surface antigen (HBsAg) and suppression of hepatitis B virus (HBV) DNA to undetectable levels, represents the optimal therapeutic endpoint for managing CHB. However, the complex pathogenesis of CHB, which includes HBV DNA integration, persistence of covalently closed circular DNA, and impaired immune responses, presents substantial barriers to HBsAg clearance. Current therapies offer limited success in achieving a functional cure, with HBsAg seroclearance occurring in only 3%-5% of patients after 10 years of nucleos(t)ide analogs (NAs) therapy and 8%-14% within 3-5 years of pegylated interferon treatment. To overcome these limitations, novel direct-acting antivirals targeting different stages of the HBV life cycle are being investigated. Additionally, immunomodulatory approaches, including therapeutic vaccines and immune checkpoint inhibitors, are being explored to enhance HBV-specific immune responses. The concept of NAs cessation in carefully selected non-cirrhotic patients may accelerate HBsAg loss, although the risks of hepatic flare and hepatocellular carcinoma necessitate rigorous monitoring. This review provides a comprehensive overview of the current understanding of HBsAg seroclearance in CHB, discussing its clinical significance, therapeutic challenges, and evolving treatment landscape in the pursuit of a functional cure.