Functional cure for chronic hepatitis B on hepatocellular carcinoma prevention: Evidence and clinical implications

Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). The functional cure for chronic hepatitis B (CHB), defined as sustained hepatitis B surface antigen (HBsAg) seroclearance for at least 24 weeks, undetectable hepatitis B e antigen and HBV DNA, and normalized liver functions, has emerged as a pivotal therapeutic goal due to its association with a significant reduction in long-term complications, particularly HCC. This review comprehensively summarizes the epidemiological burden of HBV-related HCC, elucidates the mechanisms underlying HBV-induced hepatocarcinogenesis, and identifies the key risk factors for HCC development in CHB patients, e.g., advanced age, cirrhosis, family history of HCC, and high HBV DNA levels. A critical focus of the review is the efficacy of first-line antiviral therapies in achieving functional cure and preventing HCC. Nucleos(t)ide analogs effectively inhibit HBV replication and reduce HCC risk by approximately 50%, but they rarely achieve HBsAg seroclearance, leaving a persistent HCC risk with 5-year cumulative incidence ≥7%. Pegylated interferon-α not only achieves higher HBsAg seroclearance rate but also reduces HCC risk by nearly 90%, with a 5-year cumulative incidence < 3%. Long-term follow-up studies confirm that HBsAg seroclearance sustains low HCC risk with 5-year cumulative incidence < 2% even in high-risk CHB patients. Additionally, this review discusses clinical strategies to optimize CHB management for HCC prevention, emphasizing the priority of pursuing functional cure and the necessity of long-term HCC surveillance. Collectively, this review synthesizes evidence demonstrating that achieving functional cure, particularly through pegylated interferon-α-based strategies, should be a primary treatment goal to maximally reduce the long-term risk of HCC in CHB patients.