慢性丙型肝炎病毒感染者直接抗病毒治疗后耐药相关替代的模式。
Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals.
机构信息
Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany, German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany.
Institute for Medical Virology, University Hospital Frankfurt, Frankfurt, Germany.
出版信息
Gastroenterology. 2018 Mar;154(4):976-988.e4. doi: 10.1053/j.gastro.2017.11.007. Epub 2017 Nov 13.
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.
背景与目的
由于批准研究中治疗失败的患者数量较少，因此对于介导丙型肝炎病毒（HCV）对直接作用抗病毒药物（DAA）耐药的取代情况知之甚少。确定耐药模式以选择有效的挽救治疗方法非常重要。
方法
我们对 DAA 靶向的 HCV 基因（非结构蛋白[NS]3、NS5A 和 NS5B）中的耐药相关取代（RAS）进行了全面分析。我们比较了 626 名欧洲 DAA 治疗失败患者的 NS3、NS5A 和 NS5B 序列与 2322 名未接受 DAA 治疗的 HCV 基因型 1 至 4 感染患者的序列。如果 RAS 与患者的 DAA 失败相关，或者在体外复制子测定中与参考株相比，敏感性变化超过两倍，则认为 RAS 具有相关性。数据收集了预处理状态、DAA 方案、治疗开始日期和持续时间以及病毒学反应。接受至少 4 周抗病毒治疗的患者纳入分析。
结果
与simeprevir 或 paritaprevir 失败相关的 NS3 中的 RAS 包括 R155K 和 D168E/V。此外，几种 RAS 与 simeprevir（基因型 1a 或 4 患者中的 Q80K/R）或 paritaprevir（基因型 1b 患者中与 D168V 联合的 Y56H）的失败具体相关。NS5A 中的 Y93H 是与基因型 1b 感染患者中 daclatasvir、ledipasvir 或 ombitasvir 失败最相关的 RAS，而 L31M 与 daclatasvir 或 ledipasvir 失败相关，但与 ombitasvir 无关。HCV 基因型 1a 或 4 感染患者的 NS5A 中的 RAS 存在异质性。在基因型 3 感染的患者中，Y93H 与 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。在接受 sofosbuvir 治疗方案失败的患者中，L159F 在基因型 1b（与 C316N 一起）或基因型 3 感染患者中富集，而 RAS S282T 很少观察到。
结论
我们比较了 DAA 治疗失败患者的 NS3、NS5A 和 NS5B 中的 RAS。这些 RAS 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挽救治疗方法。
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