Declining but persistent hepatocellular cancer risk beyond 10 years of entecavir or tenofovir in chronic hepatitis B: Results from the PAGE-B cohort

BACKGROUND & AIMS: Long-term outcome data in patients with chronic hepatitis B (CHB) treated with high-genetic-barrier nucleos(t)ide analogues (NAs) beyond year 10 are scarce. We assessed the incidence and predictors of hepatocellular carcinoma (HCC), liver transplantation (LT), all-cause and liver-related death, and HBsAg loss among patients treated with NAs for >10 years. METHODS: The long-term PAGE-B cohort included 1,644 Caucasian patients with CHB treated with entecavir or tenofovir. Cumulative incidence was estimated using Kaplan-Meier methods or cumulative incidence functions accounting for competing events. Incidence rates (IRs) per 100 person-years (/100 PYs) were calculated. RESULTS: Of 1,644 patients, 903 were followed beyond year 10 (mean:14 ± 2 years). The 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%, respectively. The HCC IR was 1.25 before year 10 and 0.55/100 PYs after year 10 (p 10 years of NA therapy, patients with CHB remain at risk of HCC, although the incidence rate declines significantly. HCC remains the main determinant of mortality. The rate of HBsAg loss increases after year 10 but remains low, occurring more frequently in older patients and those who were initially HBeAg positive. IMPACT AND IMPLICATIONS: Despite more than 10 years of effective nucleos(t)ide analogue therapy, patients with chronic hepatitis B remain at risk of hepatocellular carcinoma, highlighting the need for continued long-term surveillance. Although the incidence of hepatocellular carcinoma declined after year 10, it remained the main determinant of long-term outcomes. These findings reinforce the importance of sustained risk stratification, particularly among patients with lower baseline platelet counts or other risk factors. The gradual increase in hepatitis B surface antigen loss beyond 10 years provides further evidence that prolonged antiviral therapy may offer ongoing benefits, although functional cure remains uncommon and is more likely among older patients and those who were initially HBeAg-positive.