NS5A 耐药相关替换与丙型肝炎病毒基因型 1 患者：流行率和对治疗结局的影响。
NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome.
机构信息
Goethe-Universität, Frankfurt am Main, Germany.
National Center for Global Health and Medicine, Chiba, Japan.
出版信息
J Hepatol. 2017 May;66(5):910-918. doi: 10.1016/j.jhep.2017.01.007. Epub 2017 Jan 18.
BACKGROUND & AIMS: The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV.
METHODS
NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir.
RESULTS
Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively.
CONCLUSIONS
Pretreatment ledipasvir-specific RASs that were present in 8-16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV.
LAY SUMMARY
The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8-16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV.
背景与目的
慢性丙型肝炎病毒（HCV）感染患者的 NS5A 抑制剂治疗效果可能受到 NS5A 耐药相关取代（RAS）的影响。我们分析了来自 22 个国家的 35 项 I、II 和 III 期研究的数据，以确定各种 NS5A RAS 在治疗基因 1 型 HCV 患者中使用 ledipasvir-索磷布韦治疗时的预处理流行率及其对治疗结果的影响。
方法
对吉利德临床试验中 5397 名患者的 NS5A 基因进行深度测序分析。在接受包含 ledipasvir-索磷布韦的治疗方案的 1765 名患者中，评估基线 RAS 对持续病毒学应答（SVR）率的影响。
结果
使用 15%的截止值，分别在基因 1a 型患者中检测到 13%和 8%的预处理 NS5A 和 ledipasvir 特异性 RAS，在基因 1b 型患者中检测到 18%和 16%。在基因 1a 型初治患者中，有 ledipasvir 特异性 RAS 的患者 SVR 率为 91%（42/46），无 ledipasvir 特异性 RAS 的患者 SVR 率为 99%（539/546）。在基因 1a 型经治患者中，有 ledipasvir 特异性 RAS 的患者 SVR 率为 76%（22/29），无 ledipasvir 特异性 RAS 的患者 SVR 率为 97%（409/420）。在基因 1b 型初治患者中，有 ledipasvir 特异性 RAS 的患者 SVR 率为 99%（71/72），无 ledipasvir 特异性 RAS 的患者 SVR 率为 99%（331/334）。在基因 1b 型经治患者中，有 ledipasvir 特异性 RAS 的患者 SVR 率为 89%（41/46），无 ledipasvir 特异性 RAS 的患者 SVR 率为 98%（267/272）。
结论
在 8%-16%的患者中存在的预处理 ledipasvir 特异性 RAS 对某些患者群体的治疗结果有影响，特别是基因 1a HCV 感染的经治患者。
要点
慢性丙型肝炎病毒（HCV）感染患者使用 NS5A 抑制剂治疗的效果可能受到 NS5A 耐药相关取代（RAS）的影响。我们回顾了 35 项临床试验的结果，这些试验中基因 1 型 HCV 感染患者接受了包含 ledipasvir-索磷布韦的治疗，以确定 NS5A RAS 在基线时的流行率，并发现 ledipasvir 特异性 RAS 在治疗前存在于 8%-16%的患者中，并且对某些患者群体的治疗结果产生负面影响，特别是基因 1a HCV 感染的经治患者。
Zotero 插件