Treatment of hepatitis B virus without inducing antiviral resistant viruses and analyses of HBV integration at an early stage of infection before development of hepatocellular carcinoma.

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1.Lamivudine, a nucleoside analog, is recently used for treatment of HBV infection. However, it is reported that prolonged administration of this drug results in emergence of resistant viruses with point mutations at tyrosine-methionine-aspartate-aspartate (YMDD) motif of viral DNA polymerase and exacerbation of clinical course. We have developed a sensitive assay for these mutant viruses and analyzed emergence of variant viruses before and during lamivudine treatment to clarify mechanisms involved in outbreak of YMDD-mutant viruses. We have demonstrated that variant HBV with mutations at YMDD motif already exists as minority in some HBV carriers without lamivudine treatment. However, existence of these mutant viruses did not always lead to their outbreak during lamivudine treatment. These results imply that outbreak of YMDD mutants needs other selection forces or factors, possibly, mutations in other regions than YMDD motif, impaired host immunity to HBV, and such.2.Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). We previously reported that HBV integration occurs early during HBV infection, even after acute self-limiting hepatitis. Insertional mutagenesis may, therefore, represent the first drastic genetic change preceding the development of HCC by a few decades. Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and related to liver tumorigenesis. In contrast to the previous consensus, we demonstrated a preferred chromosome for HBV integration which implies a selection mechanism for some integrants.