Study for mechanism of drug-resistance of hepatitis B virus against anti-viral therapy for patients with chronic hepatitis B virus infection

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Hepatitis B virus (HBV) is one of the major cause of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HBV infection usually continues chronically, in life-time and is not self-limited. Thus, it is important to control and suppress the viral replication and liver damage by anti-viral therapy. Recently, lamivudine, which is one of the nucleotide analogue suppressing viral replication, is widely used for patients with chronic hepatitis B. This drug has very strong anti-viral activity against HBV, however one thirds of patients treated with this drug show viral breakthrough during therapy year by year. So, it is very important to investigate the mechanism of developing drug-resistance during anti-viral therapy.We investigated the background of the patients and their viral DNA sequences in patients who developed viral breakthrough during lamivudine therapy. The factors which are related with favorable response to the therapy were higher ALT levels and negative-HBeAg status. In contrast, the factors which associated with drug-resistance were only HBV genotype. So, we are going to study the relation between the reversetranscriptase mutations and HBV genotypes. In the reversetranscriptase region, there are some heterogeneities of nucleotide sequences among different HBV genotypes. The relation is important between hot spot mutations and heterogeneities of each genotype. Using the replication model which is constructed by vector system in Huh7 cells recombined with full-genomic sequences of HBV of each genotype, the mechanism of drug-resistance will be further investigated. In addition, the other nucleotide analogues, like adefovir or entecavir, should be also investigated in the same method.