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

在日本，约95%的肝细胞癌（HCC）患者与B型肝炎病毒（HBV）或丙型肝炎病毒（HCV）的持续感染相关，并且他们的大部分非肿瘤性病变的组织学表现为晚期慢性肝病。因此，提高慢性肝炎抗病毒治疗的效果，阐明慢性肝炎患者肝癌发生的机制具有重要意义。我们建立了一种非常敏感的检测拉米夫定耐药突变体（YMDD基序突变体）的方法（PNA-mediated PCR clamping with RFLP），经拉米夫定治疗6个月后，约50%的患者发现YMDD基序突变体。干扰素（IFN）治疗慢性丙型肝炎患者后的长期随访研究表明，持续和短暂应答者的肝癌发展均受到明显抑制。在IFN治疗后保持低血清ALT水平的无应答者中，肝癌发生率显著降低。结果表明，IFN治疗后血清HCVRNA的下降呈双相性（1<st>相和2相<nd>），即快速下降和缓慢下降。据认为，第2<nd>阶段反映了IFN的抗病毒活性和细胞凋亡对受感染肝细胞的排斥程度。

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.