Factors associated with the development of hepatocellular carcinoma after HBeAg seroclearance

Abstract

BACKGROUND: The role of core promoter mutation, precore mutation, and genotype in the development of hepatocellular carcinoma (HCC) in patients after HBeAg seroclearance is unclear. METHODS: The CHB E-Seroclearance Study (C.H.E.S.S.) cohort follows up a large population of patients with documented HBeAg seroclearance. Surveillance for HCC was performed at regular intervals with alpha-fetoprotein and ultrasonography. This substudy includes patients who had precore and core promoter mutation and genotype determined at 3 to 24 months after the time of HBeAg seroclearance. RESULTS: A total of 293 CHB subjects were included with a median follow up of 124 months (range, 15 to 254) after HBeAg seroclearance, totaling 3,200 patient-years. The median age of HBeAg seroclearance was 34 years, of which 164 (56%) were male. The presence of core promoter and precore mutation was observed in 181 (61.8%) and 249 (85.0%) patients respectively. The majority of patients were of genotype C (88.1%). The cumulative rates of HCC at 5, 10 and 20 years after HBeAg seroclearance were 3.5%, 6.9%, and 8.8% respectively. There were a total of 19 cases of HCC, with a median time to HCC development (from the time of HBeAg seroclearance) of 57 months (range, 17 to 192). The median age of HCC development was 50 years (range, 33 to 72). Males had a significantly higher rate of HCC compared to females (12.5% vs 3.8% at 20 years respectively, p=0.037). The median age of HBeAg seroclearance was significantly higher for those who subsequently developed HCC compared to those without HCC (43 vs 34 years respectively, p<0.001). The presence of core promoter mutation was associated with significantly higher rate of HCC (18.5% vs 2.3% respectively, p<0.001). There was no significant difference in HCC development with respect to the presence of precore mutation or with viral genotype (p=0.55 and p=0.69 respectively). There was no significant difference between those with spontaneous versus those who received antiviral therapy at the time of HBeAg seroclearance (p=0.17). A higher median HBV DNA was observed for those with HCC compared to those without (6.79 vs 4.76 log copies/mL respectively, P=0.041). CONCLUSION: In patients undergoing HBeAg seroclearance, male sex, older age at the time of HBeAg seroclearance, higher HBV DNA and the presence of core promoter mutation after HBeAg seroclearance was associated with higher rates of HCC development.