Treatment of chronic hepatitis and analysis of HBV integration for the purpose of prevention of hepatocellular carcinoma

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Around 95% of hepatocellular carcinoma (HCC) patients in Japan are associated with persistent infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) and most of their histologies in non-tumorous lesions show advanced-staged chronic liver disease. Thus, it is important to improve the effect of antiviral therapy for chronic hepatitis and to clarify the mechanism of hepatocarcinogenesis in both chronic hepatitis patients. We developed a very sensitive assay (PNA-mediated PCR clamping with RFLP) for the detection of lamivudine resistant mutants (YMDD motif mutant) by which YMDD motif mutant was detected in around 50% of patients after 6 months of treatment of lamivudine.Of the 18 cases of HCC patients, 6 patients showed HBV integration close to the genes related to cellular proliferation. Long-term follow-up study after interferon (IFN) therapy for chronic hepatitis C patients demonstrated that the development of HCC was significantly inhibited in both sustained and transient responders. Hepatocarcinogenesis is significantly decreased in the non-responders who preserved low serum ALT level after IFN therapy. We demonstrated that the decrease of serum HCV RNA after IFN administration was biphasic (1^<st> phase and 2^<nd> phase); rapid decrease and slow decrease. it is considered that the 2^<nd> phase is reflected by the antiviral activity of IFN and the grade of exclusion of infected hepatocytes by apoptosis.