Objective: Hepatitis B virus (HBV) is a major causative agent of hepatocellular carcinoma (HCC). We aimed to use the Invader assay to measure the intrahepatic total HBV DNA and covalently closed circular (ccc) DNA in the tumorous and non-tumorous tissues of HCC patients. Methods: Paired liver biopsy samples from tumorous and non-tumorous tissues were obtained from 19 patients with HBV-related HCC. Total HBV DNA, cccDNA and human genomic DNA were measured by the Invader assay. Results: There was no significant difference in the median total HBV DNA levels between the tumorous and non-tumorous paired tissues (0.354 vs. 0.220 copies/cell respectively, P = 0.904). The tumorous tissues tended to have a higher median cccDNA level than their non-tumorous counterparts (0.350 vs. 0.160 copies/cell respectively, P = 0.053). The proportion of cccDNA over total HBV DNA in the tumorous tissues was significantly higher than that in the non-tumorous counterparts (median values: 100% vs. 27.6% respectively, P = 0.005). In 15 out of 19 (79%) HCC tissues, HBV DNA were 100% in the form of cccDNA. Conclusions: HBV DNA was present in both the tumor and non-tumor tissues in HCC patients. The proportion of cccDNA/total HBV DNA was significantly higher in the tumor tissue, with 79% of tumors having HBV DNA solely in the form of cccDNA. The role of HBV cccDNA in carcinogenesis remains to be elucidated. Whether the depletion of HBV cccDNA with nucleoside analogues can prevent the formation of HCC remains to be studied.

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