1.慢性乙型肝炎诊疗规范.ppt

HBV侵入人体后，与肝细胞膜上的受体结合，脱去包膜，穿入肝细胞质内，然后脱去衣壳，部分双链环状HBV DNA进入肝细胞核内，在宿主酶的作用下，以负链DNA为模板延长正链，修补正链中的裂隙区，形成共价闭合环状DNA (cccDNA)，然后以cccDNA为模板，在宿主RNA聚合酶II的作用下，转录成几种不同长短的mRNA，其中3.5kb的mRNA含有HBV DNA序列上全部遗传信息，称为前基因组RNA。后者进入肝细胞质作为模板，在HBV 逆转录酶作用下，合成负链DNA；再以负链DNA为模板，在HBV DNA聚合酶作用下，合成正链DNA，形成子代的部分双链环状DNA，它与在内质网内生成的含有s抗原的囊膜成分最后装配成完整的HBV，释放至肝细胞外。胞质中的子代部分双链环状DNA也可进入肝细胞核内，再形成cccDNA并继续复制。 Many factors may contribute to the development of antiviral drug resistance. These can be broadly classified into virus, patient, and drug factors. Virus factors Active viral replication is required for the development of drug resistance [1]. The number of mutations needed to overcome drug suppression and the impact of mutations on fitness impact the development of resistance [1]. Patient factors The patient’s profile in turn influences the response to antiviral therapy. Patient factors that compromise the delivery and maintenance of optimal drug concentrations at its site of action include poor adherence to drug therapy, poor drug uptake and activation, and high drug metabolism [2]. Prior antiviral drug exposure may compromise the efficacy of current antiviral drug therapy if it has already selected for mutants with resistance [3]. Patient factors also influence the extent to which the virus replicates. Since the immune response of the host clears HBV-infected hepatocytes, patient immunodeficiency, caused for example by coinfection with HIV or immunosuppressive treatments, may be associated with increased viral load [2]. The emergence of drug-resistant mutants requires sufficient numbers of uninfected hepatocytes as targets. This so-called ‘replication space’ is generated by liver growth and hepatocyte turnover, and so the scope for mutant outgrowth depends on immune-mediated clearance of infected hepatocytes and the ability of the liver to replace them [2]. Drug factors In addition to the intrinsic antiviral activity of the HBV polymerase inhibitor [2, 3], the pharmacokinetics of the drug may determine