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Study for mechanism of drug-resistance of hepatitis B virus against anti-viral therapy for patients with chronic hepatitis B virus infection

慢性乙型肝炎病毒感染者乙型肝炎病毒抗病毒治疗耐药机制研究

基本信息

批准号：
17590667
负责人：
ORITO Etsuro
金额：
$ 2.18万
依托单位：
NAGOYA CITY UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Hepatitis B virus (HBV) is one of the major cause of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HBV infection usually continues chronically, in life-time and is not self-limited. Thus, it is important to control and suppress the viral replication and liver damage by anti-viral therapy. Recently, lamivudine, which is one of the nucleotide analogue suppressing viral replication, is widely used for patients with chronic hepatitis B. This drug has very strong anti-viral activity against HBV, however one thirds of patients treated with this drug show viral breakthrough during therapy year by year. So, it is very important to investigate the mechanism of developing drug-resistance during anti-viral therapy.We investigated the background of the patients and their viral DNA sequences in patients who developed viral breakthrough during lamivudine therapy. The factors which are related with favorable response to the therapy were higher ALT levels and negative-HBeAg status. In contrast, the factors which associated with drug-resistance were only HBV genotype. So, we are going to study the relation between the reversetranscriptase mutations and HBV genotypes. In the reversetranscriptase region, there are some heterogeneities of nucleotide sequences among different HBV genotypes. The relation is important between hot spot mutations and heterogeneities of each genotype. Using the replication model which is constructed by vector system in Huh7 cells recombined with full-genomic sequences of HBV of each genotype, the mechanism of drug-resistance will be further investigated. In addition, the other nucleotide analogues, like adefovir or entecavir, should be also investigated in the same method.

B型肝炎病毒（Hepatitis B virus，HBV）是慢性肝炎、肝硬化、肝细胞癌等慢性肝病的主要病因之一。HBV感染通常持续慢性，在生命的时间，并不是自限性的。因此，通过抗病毒治疗来控制和抑制病毒的复制和肝损伤是非常重要的。拉米夫定作为一种抑制病毒复制的核苷酸类似物，近年来被广泛应用于慢性B型肝炎的治疗。该药对HBV具有很强的抗病毒活性，但每年有三分之一的患者在治疗期间出现病毒突破。因此，研究拉米夫定耐药的机制具有重要意义。本研究对拉米夫定治疗过程中发生耐药的患者进行了背景和病毒DNA序列分析。治疗效果好的相关因素为ALT升高和HBeAg阴性。与耐药相关的因素仅为HBV基因型。因此，我们将研究逆转录酶突变与HBV基因型之间的关系。不同基因型HBV逆转录酶区核苷酸序列存在一定的异质性。热点突变与各基因型的异质性之间的关系是重要的。利用载体系统在Huh7细胞中构建的HBV全基因组重组复制模型，进一步研究HBV耐药机制。此外，其他核苷酸类似物，如阿德福韦或恩替卡韦，也应在相同的方法进行研究。