Despite the high virological response rates achieved with current directly acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. The identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultradeep sequencing (UDS) methods, for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV, which are not bona fide resistance-associated substitutions (RAS), from 220 patients who failed therapy. They were present frequently in basal and posttreatment virus of patients who failed different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. They also have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value for treatment response, are discussed.

中文翻译：

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与丙型肝炎病毒感染治疗失败相关的氨基酸替代

尽管目前的直接作用抗丙型肝炎病毒（HCV）的抗病毒药物（DAA）达到了很高的病毒学应答率，但约2％至5％的接受治疗的患者仍未实现持续的病毒应答。与治疗失败相关的氨基酸取代的鉴定需要进行分析设计，例如亚型特异性超深测序（UDS）方法，以进行HCV表征和患者管理。使用该程序，我们从220例治疗失败的患者中鉴定出HCV的NS5A和NS5B中的6个高度代表的氨基酸取代（HRS），它们不是真正的耐药性相关取代（RAS）。它们经常出现在不同基于DAA的疗法失败的患者的基础和治疗后病毒中。与几个RAS相反，根据PAM250替换矩阵，HRS属于可接受的替换子集。在大多数情况下，它们的突变频率由HCV准种内编码相关取代的深测序读数的数量来衡量，范围在90％至100％之间。它们还对包含它们的蛋白质的三维结构具有有限的预测破坏作用。讨论了HRS起源和优势的可能机制，以及它们对治疗反应的潜在预测价值。它们还对包含它们的蛋白质的三维结构具有有限的预测破坏作用。讨论了HRS起源和优势的可能机制，以及它们对治疗反应的潜在预测价值。它们还对包含它们的蛋白质的三维结构具有有限的预测破坏作用。讨论了HRS起源和优势的可能机制，以及它们对治疗反应的潜在预测价值。