T1653 Mutation in the Box a Increases the Riskof Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Genotype C Infection

Most patients with chronic hepatitis B virus infection become carriers of inactive virus after hepatitis B e antigen seroconversion; however, a subgroup of patients have persistent abnormal transaminase levels and develop hepatocellular carcinoma after seroconversion. In an age-matched case-control study, 40 carriers of inactive virus (mean age ± standard deviation [SD], 50.9 ± 11.1 years), 40 patients with chronic hepatitis (mean age ± SD, 50.2 ± 8.9 years), and 40 patients with hepatocellular carcinoma (mean age ± SD, 50.7 ± 9.4 years) who were infected with hepatitis B virus genotype C and had test results positive for antibody to hepatitis B e antigen were analyzed. The prevalence of T1653 in the box α was significantly higher among patients with hepatocellular carcinoma than among carriers of inactive virus who did not have hepatocellular carcinoma (70% vs. 25%; P <.0001) or chronic hepatitis (70% vs. 35%; P =.003). Mutations in the basic core promoter region (T1762/A1764) were frequently found in all groups, regardless of clinical status (in 77.5% of carriers of inactive virus, 77.5% of patients with chronic hepatitis, and 90% of patients with hepatocellular carcinoma). In the multivariate analysis, the presence of T1653, an alanine aminotransferase level of ⩾ 37 U/L, and a platelet count of <18 × 104 platelets/mm3 were independent predictive values for hepatocellular carcinoma (odds ratio [95% confidence interval], 5.05 [1.56–16.35], 12.56 [3.05–51.77], and 11.5 [3.47–38.21], respectively). High α -fetoprotein level was the only independent predictive value for T1653 in patients with hepatocellular carcinoma (odds ratio, 12.67; 95% confidence interval, 1.19–134.17]). Among patients with test results positive for antibody to hepatitis B e antigen who had hepatocellular carcinoma and were infected with different genotypes of hepatitis B virus, the prevalence of T1653 was 40%, 15%, 25%, 25%, 67%, and 23% in patients infected with hepatitis B virus genotypes Aa, Ae, Ba, Bj, C, and D, respectively (P <.05 for genotype C vs. genotypes Ae, Ba, Bj, or D). Our data indicate that the addition of T1653 mutation in the box α to the basic core promoter mutation increases the risk of hepatocellular carcinoma in patients with hepatitis B virus genotype C.