Several highly effective, interferon‐free, direct‐acting antiviral (DAA)‐based regimens are available for the treatment of chronic hepatitis C virus (HCV) infection. Despite impressive efficacy overall, a small proportion of patients in registrational trials experienced treatment failure, which in some cases was associated with the detection of HCV resistance‐associated substitutions (RASs) at baseline. In this article, we describe methods and key findings from independent regulatory analyses investigating the impact of baseline nonstructural (NS) 3 Q80K and NS5A RASs on the efficacy of current United States Food and Drug Administration (FDA)‐approved regimens for patients with HCV genotype (GT) 1 or GT3 infection. These analyses focused on clinical trials that included patients who were previously naïve to the DAA class(es) in their investigational regimen and characterized the impact of baseline RASs that were enriched in the viral population as natural or transmitted polymorphisms (i.e., not drug‐selected RASs). We used a consistent approach to optimize comparability of results across different DAA regimens and patient populations, including the use of a 15% sensitivity cutoff for next‐generation sequencing results and standardized lists of NS5A RASs. These analyses confirmed that detection of NS3 Q80K or NS5A baseline RASs was associated with reduced treatment efficacy for multiple DAA regimens, but their impact was often minimized with the use of an intensified treatment regimen, such as a longer treatment duration and/or addition of ribavirin. We discuss the drug resistance‐related considerations that contributed to pretreatment resistance testing and treatment recommendations in drug labeling for FDA‐approved DAA regimens. Conclusion: Independent regulatory analyses confirmed that baseline HCV RASs can reduce the efficacy of certain DAA‐based regimens in selected patient groups. However, highly effective treatment options are available for patients with or without baseline RASs. (Hepatology 2018;67:2430‐2448).

中文翻译：

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丙型肝炎病毒多态性对直接作用抗病毒治疗功效的影响：监管分析和前景

几种高效的、无干扰素的、基于直接作用抗病毒 (DAA) 的方案可用于治疗慢性丙型肝炎病毒 (HCV) 感染。尽管总体疗效令人印象深刻，但注册试验中仍有一小部分患者出现治疗失败，这在某些情况下与基线时检测到 HCV 耐药相关替代 (RAS) 相关。在本文中，我们描述了独立监管分析的方法和主要发现，这些分析调查了基线非结构性 (NS) 3 Q80K 和 NS5A RAS 对当前美国食品和药物管理局 (FDA) 批准的 HCV 基因型患者治疗方案的疗效的影响(GT) 1 或 GT3 感染。这些分析侧重于临床试验，这些试验包括以前在其研究方案中未接受 DAA 类的患者，并将在病毒群中富集的基线 RAS 的影响表征为天然或传播的多态性（即，不是药物选择的） RAS）。我们使用一致的方法来优化不同 DAA 方案和患者群体之间结果的可比性，包括对下一代测序结果使用 15% 的灵敏度临界值和 NS5A RAS 的标准化列表。这些分析证实，检测到 NS3 Q80K 或 NS5A 基线 RAS 与多种 DAA 方案的治疗效果降低有关，但使用强化治疗方案（例如更长的治疗持续时间和/或添加利巴韦林）通常会将其影响降至最低. 我们讨论了与 FDA 批准的 DAA 方案的药物标签中的治疗前耐药性测试和治疗建议相关的耐药性相关考虑因素。结论：独立监管分析证实，基线 HCV RAS 可以降低某些基于 DAA 的方案在选定患者组中的疗效。然而，对于有或没有基线 RAS 的患者，都有高效的治疗选择。（肝病学 2018 年；67：2430-2448）。对于有或没有基线 RAS 的患者，都有高效的治疗选择。（肝病学 2018 年；67：2430-2448）。对于有或没有基线 RAS 的患者，都有高效的治疗选择。（肝病学 2018 年；67：2430-2448）。