Background & Aims

Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments.

Methods

We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis.

Results

RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed.

Conclusions

We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

中文翻译：

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慢性 HCV 感染患者直接抗病毒药物治疗后耐药相关替代模式

背景与目标

由于在批准研究中治疗失败的患者数量很少，对介导丙型肝炎病毒 (HCV) 对直接作用抗病毒药物 (DAA) 的耐药性的替代知之甚少。识别抗性模式以选择有效的抢救治疗非常重要。

方法

我们对 DAA 靶向的 HCV 基因（非结构蛋白 [NS]3、NS5A、NS5B）中的耐药性相关取代 (RAS) 进行了全面分析。我们比较了来自欧洲 626 名 DAA 失败患者的 NS3、NS5A 和 NS5B 序列与来自 2322 名未接受 DAA 且感染 HCV 基因型 1 至 4 的患者的序列。我们认为，如果 RAS 与患者的 DAA 失败或与体外复制子测定中的参考菌株相比，赋予了超过两倍的敏感性变化。收集有关预处理状态、DAA 方案、治疗开始日期和持续时间以及病毒学应答的数据。接受至少 4 周抗病毒治疗的患者被纳入分析。

结果

NS3 中与 simeprevir 或 paritaprevir 失败相关的 RAS 包括 R155K 和 D168E/V。此外，一些 RAS 与 simeprevir（基因型 1a 或 4 患者中的 Q80K/R）或 paritaprevir（基因型 1b 患者中的 Y56H 与 D168V 组合）的失败特别相关。NS5A 中的 Y93H 是基因型 1b 感染患者中最常与 daclatasvir、ledipasvir 或 ombitasvir 失败相关的 RAS，L31M 与 daclatasvir 或 ledipasvir 失败相关，但与 ombitasvir 无关。NS5A 中的 RAS 在 HCV 基因型 1a 或基因型 4 感染的患者中存在异质性。在 HCV 基因型 3 患者中，Y93H 与对 daclatasvir 的耐药性相关，但没有 RAS 与 ledipasvir 失败相关，这表明 ledipasvir 在基因型 3 患者中的疗效有限。

结论

我们在 DAA 治疗失败的患者中比较了 NS3、NS5A 和 NS5B 中的 RAS。论文因 HCV 基因型和亚型以及不同的药物类别而异。这些发现可用于选择抢救疗法。