预先存在的NS5A-L31或-Y93H微小变异对接受达卡他韦/阿舒瑞韦治疗的丙型肝炎病毒1b型感染患者应答率的影响。

Impact of Pre-existing NS5A-L31 or -Y93H Minor Variants on Response Rates in Patients Infected with HCV Genotype-1b Treated with Daclatasvir/Asunaprevir.

作者信息

Hernandez Dennis, Yu Fei, Huang Xin, Kirov Stefan, Pant Saumya, McPhee Fiona

机构信息

Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA.

Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA.

出版信息

Adv Ther. 2016 Jul;33(7):1169-79. doi: 10.1007/s12325-016-0354-1. Epub 2016 Jun 10.

DOI:10.1007/s12325-016-0354-1

PMID:27287851

Abstract

INTRODUCTION

The combination of daclatasvir (DCV, pan-genotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan, Korea and other countries for the treatment of chronic hepatitis C virus (HCV) genotype (GT)-1. A high (~90 to 100%) sustained virologic response (SVR) with DCV/ASV therapy has been achieved by excluding patients infected with HCV GT-1b with baseline NS5A resistance-associated variants (RAVs) at L31 or Y93H detected by direct sequencing (DS). We set out to determine whether patients with minor variants at NS5A-L31 or -Y93H, detected by next-generation sequencing (NGS), impacted SVR rates with DCV/ASV therapy.

METHODS

Baseline samples from 222 interferon (IFN)-ineligible/intolerant (N = 135) and prior non-responder (N = 87) patients infected with GT-1b who were treated with DCV/ASV for 24 weeks in the Phase 3 clinical study AI447026 were prepared for NGS (Ion-Torrent platform). The prevalence of baseline NS5A RAVs and their impact on SVR when observed at ≥1% by NGS in a patient's virus population were examined. NGS and DS (sensitivity ≥20%) data were compared.

RESULTS

The prevalence of baseline NS5A RAVs at L31 or Y93H was 29% (63/219) and 18% (39/214) by NGS and DS, respectively. SVR24 rates were comparable in patients without observed baseline L31 or Y93H polymorphisms whether assessed by NGS (96%; 148/154) or by the less sensitive DS platform (95%; 164/173).

CONCLUSION

Optimal SVR rates (≥95%) to DCV/ASV treatment were achieved using DS to exclude patients infected with GT-1b with NS5A RAVs at L31 or Y93H representing ≥20% of their virus population. Exclusion by NGS of patients with minor variants in NS5A (<20%) did not enhance SVR rates. These results suggest that the presence of minor variants in NS5A does not appear to impact the overall SVR rate in patients with GT-1b treated with DCV/ASV.

FUNDING

This study was sponsored by Bristol-Myers Squibb.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT01497834.

摘要

引言

在日本、韩国和其他国家，达卡他韦（DCV，泛基因型NS5A抑制剂）联合阿舒瑞韦（ASV；NS3蛋白酶抑制剂）被批准用于治疗慢性丙型肝炎病毒（HCV）基因1型（GT-1）。通过排除直接测序（DS）检测到基线时存在NS5A耐药相关变异（RAV）L31或Y93H的HCV GT-1b感染患者，DCV/ASV治疗实现了较高（约90%至100%）的持续病毒学应答（SVR）。我们旨在确定通过下一代测序（NGS）检测到NS5A-L31或-Y93H存在微小变异的患者是否会影响DCV/ASV治疗的SVR率。

方法

在3期临床研究AI447026中，对222例不符合干扰素（IFN）治疗标准/不耐受（N = 135）以及既往治疗无应答（N = 87）的GT-1b感染患者的基线样本进行了准备，用于NGS（Ion-Torrent平台）检测，这些患者接受了24周的DCV/ASV治疗。研究了基线NS5A RAV的流行率及其在患者病毒群体中通过NGS观察到≥1%时对SVR的影响。比较了NGS和DS（灵敏度≥20%）的数据。

结果

通过NGS和DS检测，基线时NS5A在L31或Y93H处RAV的流行率分别为29%（63/219）和18%（39/214）。无论通过NGS（96%；148/154）还是灵敏度较低的DS平台（95%；164/173）评估，未观察到基线L31或Y93H多态性的患者的SVR24率相当。

结论

使用DS排除基线时存在NS5A RAV L31或Y93H且占其病毒群体≥20%的GT-1b感染患者，可实现DCV/ASV治疗的最佳SVR率（≥95%）。通过NGS排除NS5A存在微小变异（<20%）的患者并不能提高SVR率。这些结果表明，NS5A存在微小变异似乎不会影响接受DCV/ASV治疗的GT-1b患者的总体SVR率。