A large real‐world cohort study examining the effects of long‐term entecavir on hepatocellular carcinoma and HBsAg seroclearance

Real-world studies examining reduction in risk of hepatocellular carcinoma (HCC) in patients receiving antivirals are limited by the small size of the studies, or by data insufficiency and heterogeneity with short follow-up duration. We aimed to examine the real-world long-term outcome of patients receiving entecavir treatment on HCC incidence and HBsAg seroclearance. The incidence of HCC in 1225 entecavir-treated patients between 2002 and 2015 was compared with the HCC incidence estimated using the REACH-B, GAG-HCC and CU-HCC scores. Standardized incidence ratios (SIR) were calculated. The impact of entecavir treatment on HBsAg seroclearance was also explored. The median follow-up of the cohort was 6.6 years, with 66 cases of HCC development. Using the REACH-B model, the reduction of HCC risk was significant from year 6 onwards with SIR of 0.68 (95% CI 0.535-0.866) at year 10. In subgroup patients without cirrhosis, consistent risk reduction was observed from the fifth year and the SIR reached 0.51 (95% CI 0.271-0.704) by year 10. Benefit in cirrhotic patients was demonstrated when using the GAG-HCC and CU-HCC score, with the SIR at year 10 being 0.38 (95% CI 0.259-0.544) and 0.46 (95% CI 0.314-0.659), respectively. The cumulative rate of HBsAg seroclearance was 5.2%. HBsAg level at third year of treatment and baseline-to-3-year percentage reduction was predictive of subsequent HBsAg seroclearance. In conclusion, long-term entecavir therapy was associated with significant reduction in the risk of HCC in the real world. However, HBsAg seroclearance rate remained low. Additional therapy may be considered in patients with adverse predictive factors for subsequent HBsAg seroclearance.