Background: Although chronic infection with hepatitis B virus (HBV) has been established as a cause of hepatocellular carcinoma (HCC), the roles of viral load and HBV genotype remain unclear. Methods: From 1988 through 1992, baseline blood samples were collected from 4841 Taiwanese men who were HBV carriers but had not been diagnosed with HCC. We used real-time polymerase chain reaction assays of plasma DNA samples to quantify HBV DNA levels (a measure of viral load) and determine HBV genotypes for 154 case patients who were diagnosed with HCC during 14 years of follow-up and 316 control subjects. Unconditional logistic regression was used to assess odds ratios (ORs) of HCC for HBV-related factors. All statistical tests were two-sided. Results: The risk of HCC increased with increasing HBV viral load (adjusted OR for the highest versus the lowest quintile of HBV DNA copies/mL = 7.26, 95% confidence interval [CI] = 3.54 to 14.89; P-trend < .001). Genotype C HBV was associated with an increased risk of HCC compared with other HBV genotypes (adjusted OR = 5.11, 95% CI = 3.20 to 8.18). Both viral load and genotype were positively associated with HCC within 10-year age categories among subjects aged 30 years old to older than 60 years. Genotype C HBV was associated with increased viral load, and associations of HBV genotype and viral load with HCC risk were additive. The adjusted OR of HCC for those carrying genotype C HBV and with viral load in the highest quintile was 26.49 (95% CI = 10.41 to 67.42) compared with HBV carriers with other HBV genotypes and viral load in the lowest two quintiles. Conclusions: Measurements of HBV viral load and genotype may help to define which male HBV carriers aged 30 years or older are at high risk for HCC.
