Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir
Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir
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DOI：
10.1016/j.jhep.2016.11.022
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发表时间：
2017-04-01
影响因子：
25.7
通讯作者：
Gane, Edward J.
中科院分区：
文献类型：
--
作者：
Wyles, David;Dvory-Sobol, Hadas;Gane, Edward J.
背景与目的：在Ⅲ期临床试验中，雷迪帕韦/索非布韦联合治疗使94% - 99%的患者实现了持续的病毒抑制。本研究对治疗失败病例中的耐药性进行了特征分析，这可能有助于为再治疗方案提供依据。
方法：我们对参与雷迪帕韦/索非布韦Ⅱ期和Ⅲ期临床试验的基因1型（GT1）丙型肝炎病毒（HCV）感染患者进行了NS5A和NS5B深度测序。
结果：2144名接受治疗的患者中有51名（2.4%）（42名GT1a型和9名GT1b型）因治疗结束后的病毒学失败符合耐药性分析标准。大多数病毒学失败的患者（51名中的38名；74.5%）在病毒学失败时（深度测序阈值为1%）可检测到雷迪帕韦特异性耐药相关替代突变（RASs）。在治疗6周、8周、12周和24周的患者中，病毒学失败时出现NS5A RASs的患者百分比分别为37.5%、66.7%、94.7%和100%。在失败时检测到的常见替代突变在GT1a型中为Q30R/H和/或Y93H/N，在GT1b型中为Y93H。在失败时，35.3%（18/51）的病毒学失败患者的病毒有两种或更多种NS5A RASs，并且大多数患者携带的NS5A RASs使对雷迪帕韦的敏感性降低100 - 1000倍（n = 10）或>1000倍（n = 23）。在Ⅱ期研究中，1名基线时已知有雷迪帕韦RAS（L31M）的患者在失败时出现了S282T索非布韦（NS5B）RAS。
结论：在接受雷迪帕韦/索非布韦±利巴韦林治疗的基因1型丙型肝炎病毒感染患者中，病毒学失败较为罕见。在大多数病毒学失败的患者中，NS5A中的雷迪帕韦耐药性被选择或增强，其中1名患者还对索非布韦产生了耐药性。
通俗总结：临床研究表明，雷迪帕韦/索非布韦联合治疗可有效治愈大多数基因1型丙型肝炎感染患者。对于少数治疗失败的患者，我们发现大多数患者出现了对雷迪帕韦的耐药性，而对索非布韦的耐药性则不太常见。这对为这些患者选择最佳再治疗策略具有重要意义。（C）2016欧洲肝脏研究协会。由爱思唯尔B.V.出版。保留所有权利。
Background & Aims: Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94-99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options.Methods: We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in ledipasvir/sofosbuvir phase II and III clinical trials.Results: Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24 weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100-1000-fold (n = 10) or >1000-fold (n = 23) reduced susceptibility to ledipasvir. One patient in a phase II study with a known ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure.Conclusions: In GT1 HCV-infected patients treated with ledipasvir/sofosbuvir +/- ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir.Lay summary: Clinical studies have shown that combination treatment with ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.