University of California San Diego, CA, USA.
Gilead Sciences, Foster City, CA, USA.
J Hepatol. 2017 Apr;66(4):703-710. doi: 10.1016/j.jhep.2016.11.022. Epub 2016 Dec 5.
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.
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.
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 24weeks, 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.
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.
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.
在 III 期临床试验中，利迪帕韦/索磷布韦联合治疗使 94%-99%的患者持续病毒抑制。本研究对治疗失败患者的耐药性进行了特征描述，这可能有助于为重新治疗提供信息。
我们对接受利迪帕韦/索磷布韦 II 期和 III 期临床试验治疗的基因型 (GT) 1 感染患者的 HCV 进行 NS5A 和 NS5B 深度测序。
由于治疗结束后病毒学失败，2144 名 (2.4%) (42 名 GT1a 和 9 名 GT1b) 治疗患者中的 51 名符合耐药性分析标准。大多数病毒学失败患者 (38/51;74.5%) 在病毒学失败时具有可检测到的利迪帕韦特异性耐药相关取代 (RAS) (1%深度测序临界值)。在治疗 6、8、12 和 24 周的患者中，病毒学失败时 NS5A RAS 的患者比例分别为 37.5%、66.7%、94.7%和 100%。在 GT1a 中检测到的常见取代是 Q30R/H 和/或 Y93H/N，而在 GT1b 中则是 Y93H。在失败时，35.3% (18/51) 的病毒学失败患者的病毒有两个或更多的 NS5A RAS，大多数患者携带 NS5A RAS，导致对利迪帕韦的敏感性降低 100-1000 倍 (n=10) 或 >1000 倍 (n=23)。在一项 II 期研究中，一名基线时已知存在利迪帕韦 RAS (L31M) 的患者在失败时出现了索磷布韦 (NS5B) RAS 的 S282T。
在接受利迪帕韦/索磷布韦±利巴韦林治疗的 GT1 HCV 感染患者中，病毒学失败很少见。在大多数病毒学失败的患者中，NS5A 中的利迪帕韦耐药性被选择或增强，其中一名患者还对索磷布韦产生了耐药性。
临床研究表明，利迪帕韦/索磷布韦联合治疗可有效治愈大多数基因型 1 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利迪帕韦的耐药性，而对索磷布韦的耐药性则较少见。这对这些患者的最佳重新治疗策略的选择具有重要意义。
