Direct-acting antiviral (DAA) agents specifically target viral proteins. Two DAAs have been already been approved for the treatment of HCV infection and many more are in development. DAA treatment of HCV infection, however, leads to the selection of viral variants (produced by the error-prone HCV polymerase) that are resistant to the DAA agent in use. The selection of DAA-resistant HCV variants has been studied extensively in vitro and in vivo. Common amino acid substitution sites in each of the non-structural proteins are associated with DAA-resistance: D168, A155, A156 and V36 in NS3 protease; L31 and Y93 in NS5A; S282, S96, P495, M423, M414 and C316 in NS5B. In this review we cover the basic principles of DAA resistance, summarise the available resistance data for the various classes of DAAs and discuss the potential of DAA combination therapy for overcoming DAA-resistance, resulting in major advances in the treatment of HCV.

译文

直接作用抗病毒 (DAA) 药物专门针对病毒蛋白。已经批准了两种daa用于治疗HCV感染,并且还有更多的daa正在开发中。但是,对HCV感染的DAA治疗导致选择对使用中的DAA试剂具有抗性的病毒变体 (由易错的HCV聚合酶产生)。抗DAA HCV变体的选择已在体外和体内进行了广泛研究。每个非结构蛋白中常见的氨基酸取代位点与DAA抗性相关: NS3蛋白酶中的D168,A155,A156和V36; NS5A中的L31和Y93; NS5B中的S282,S96,P495,M423,M414和C316。在这篇综述中,我们涵盖了DAA耐药的基本原理,总结了各类DAA的可用耐药数据,并讨论了DAA联合疗法克服DAA耐药的潜力,从而在HCV治疗方面取得了重大进展。

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