Fourati Slim, Pawlotsky Jean-Michel
National Reference Center for Viral Hepatitis B, C, and D; Department of Virology, Hôpital Henri Mondor, Université Paris-Est and INSERM U955, Créteil 94010, France.
Viruses. 2015 Dec 4;7(12):6346-59. doi: 10.3390/v7122941.
Recent advances in molecular biology have led to the development of new antiviral drugs that target specific steps of the Hepatitis C Virus (HCV) lifecycle. These drugs, collectively termed direct-acting antivirals (DAAs), include non-structural (NS) HCV protein inhibitors, NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors (nucleotide analogues and non-nucleoside inhibitors), and NS5A inhibitors. Due to the high genetic variability of HCV, the outcome of DAA-based therapies may be altered by the selection of amino-acid substitutions located within the targeted proteins, which affect viral susceptibility to the administered compounds. At the drug developmental stage, preclinical and clinical characterization of HCV resistance to new drugs in development is mandatory. In the clinical setting, accurate diagnostic tools have become available to monitor drug resistance in patients who receive treatment with DAAs. In this review, we describe tools available to investigate drug resistance in preclinical studies, clinical trials and clinical practice.
分子生物学的最新进展已促成了新型抗病毒药物的研发，这些药物靶向丙型肝炎病毒（HCV）生命周期的特定步骤。这些药物统称为直接作用抗病毒药物（DAA），包括非结构（NS）HCV蛋白抑制剂、NS3/4A蛋白酶抑制剂、NS5B RNA依赖性RNA聚合酶抑制剂（核苷酸类似物和非核苷抑制剂）以及NS5A抑制剂。由于HCV的高遗传变异性，基于DAA的治疗结果可能会因靶向蛋白内氨基酸替代的选择而改变，这会影响病毒对所施用化合物的敏感性。在药物研发阶段，对正在研发的新药进行HCV耐药性的临床前和临床特征分析是必不可少的。在临床环境中，已有准确的诊断工具可用于监测接受DAA治疗患者的耐药性。在本综述中，我们描述了可用于在临床前研究、临床试验和临床实践中调查耐药性的工具。
