Treatment of chronic hepatitis B for the prevention of development of hepatocellular carcinoma and analyses of hepatitis B virus insertional mutagenesis as a first hit during multistep liver carcinogenesis.

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1.Lamivudine, a nucleoside analog, has been licensed for chronic hepatitis B in Japan since 2000. 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 developed a sensitive assay for these mutant viruses and analyzed their dynamics and mechanisms of emergence. We revealed that variant HBV with mutations at YMDD motif already exists as minority in some HBV carriers without previous lamivudine treatment and YMDD mutants appear as early as within 6 months after lamivudine administration. However, these mutants sometimes disappear spontaneously despite continuous lamivudine administration. We also performed sensitive quantitative assay for early detection of YMDD mutants and a threshold of 10^<2.7> copies/ml was suggested for predicting viral breakthrough during lamivudine treatment.2.Growing evidence demonstrates that HBV integration and resulting insertional mutagenesis plays an important role in cell growth or maintenance in hepatocellular carcinoma (HCC). We analyzed HBV integration in chronic hepatitis tissues without HCC to explore early genetic change due to HBV preceding the development of HCC by a few decades. We found that a few groups of liver cells with a same HBV integration expand in chronic hepatitis tissues and identified several genes affected by HBV insertion. These genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. These data provided firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and revealed usefulness of the HBV-related virus tagging approach to identify genes associated with cell growth and maintenance.