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

在日本，大约95%的肝细胞癌患者与持续感染的乙肝病毒或丙型肝炎病毒有关，他们的非肿瘤性病变中的大多数组织学表现为晚期慢性肝病。因此，提高慢性肝炎的抗病毒治疗效果，阐明两种慢性肝炎患者的肝癌发生机制具有重要意义。我们建立了一种非常灵敏的检测拉米夫定耐药突变(YMDD基序突变)的方法(PNA介导的聚合酶链式反应夹带RFLP)，在拉米夫定治疗6个月后，约50%的患者检测到YMDD基序突变。在18例肝细胞癌患者中，6例患者显示与细胞增殖相关的基因接近整合。对慢性丙型肝炎患者干扰素治疗后的长期随访研究表明，无论是持续应答者还是暂时性应答者，肝细胞癌的发展都受到显著抑制。在干扰素治疗后维持低血清ALT水平的无应答者，肝癌的发生显著减少。结果表明，干扰素治疗后血清中丙型肝炎病毒核糖核酸的下降呈双相(1、2相)、快速下降和缓慢下降。认为干扰素的抗病毒活性和对感染的肝细胞被细胞凋亡排斥的程度反映了第二阶段。

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.