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

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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.

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Acknowledgments

All studies described and the analyses presented were sponsored by Bristol-Myers Squibb. The article processing charges and open access fee for this publication were funded by Bristol-Myers Squibb. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Disclosures

Dennis Hernandez, Fei Yu, Xin Huang, Stefan Kirov, Saumya Pant, and Fiona McPhee are employees and stock holders of Bristol-Myers Squibb.

Compliance with Ethics Guidelines

The AI447026 study was approved by the Institutional Review Board at each participating site and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. All patients provided written informed consent.

Author information

Authors and Affiliations

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

    Dennis Hernandez, Fei Yu & Fiona McPhee

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

    Xin Huang, Stefan Kirov & Saumya Pant

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  1. Dennis Hernandez
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  2. Fei Yu
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Correspondence to Fiona McPhee.

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Hernandez, D., Yu, F., Huang, X. et al. Impact of Pre-existing NS5A-L31 or -Y93H Minor Variants on Response Rates in Patients Infected with HCV Genotype-1b Treated with Daclatasvir/Asunaprevir. Adv Ther 33, 1169–1179 (2016). https://doi.org/10.1007/s12325-016-0354-1

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