Treatment Failure and Resistance with Direct-Acting Antiviral Drugs Against Hepatitis C Virus
Treatment Failure and Resistance with Direct-Acting Antiviral Drugs Against Hepatitis C Virus
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DOI：
10.1002/hep.24262
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发表时间：
2011-05-01
期刊：
影响因子：
13.5
通讯作者：
Pawlotsky, Jean-Michel
中科院分区：
文献类型：
--
作者：
Pawlotsky, Jean-Michel
目前慢性丙型肝炎病毒（HCV）感染的治疗基于聚乙二醇化干扰素-α和利巴韦林的组合。最近开发的对 HCV 具有活性的直接作用抗病毒 (DAA) 分子，以及体外和体内研究表明，这些药物如果单独给药，可能会导致耐药病毒的选择，引起了人们的担忧，即耐药性可能会破坏基于 DAA 的治疗。一种基于聚乙二醇化干扰素-α、利巴韦林和蛋白酶抑制剂（特拉匹韦或波普瑞韦）三重组合的新标准护理治疗很快将适用于感染基因 1 型 HCV 的初治患者和经历过治疗的患者。通过这种疗法，大多数坚持治疗的患者未能根除感染的原因是在第一代蛋白酶抑制剂耐药性遗传屏障较低的情况下，对聚乙二醇化干扰素-α和利巴韦林的反应不足。本文回顾了正在开发的 HCV DAA 药物的耐药模式、这些药物与聚乙二醇化干扰素 α 和利巴韦林联合治疗失败的机制、治疗失败的后果以及优化未来使用 DAA 疗法的可能方法。 （肝病学 2011；53：1742-1751）
Current treatment of chronic hepatitis C virus (HCV) infection is based on the combination of pegylated interferon-alpha and ribavirin. The recent development of direct-acting antiviral (DAA) molecules that are active on HCV, together with in vitro and in vivo studies showing that these drugs may lead to the selection of resistant viruses if administered alone, has raised concerns that resistance may undermine therapy based on DAAs. A new standard-of-care treatment will soon be available for both treatment-naive and treatment-experienced patients infected with HCV genotype 1, based on a triple combination of pegylated interferon-alpha, ribavirin, and a protease inhibitor (either telaprevir or boceprevir). With this therapy, most failures to eradicate infection in treatment-adherent patients are due to an inadequate response to pegylated interferon-alpha and ribavirin, in the context of a low genetic barrier to resistance of first-generation protease inhibitors. This article reviews patterns of resistance to HCV DAA drugs in development, the mechanisms underlying treatment failure when these drugs are combined with pegylated interferon-alpha and ribavirin, the consequences of treatment failure, and possible means of optimizing future therapies that use DAAs. (HEPATOLOGY 2011;53:1742-1751)