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Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

Author

Listed:
  • David A. Smith

    (University of Oxford)

  • Carlota Fernandez-Antunez

    (University of Copenhagen)

  • Andrea Magri

    (University of Oxford)

  • Rory Bowden

    (University of Oxford)

  • Nimisha Chaturvedi

    (School of Life Sciences, École Polytechnique Fédérale de Lausanne)

  • Jacques Fellay

    (School of Life Sciences, École Polytechnique Fédérale de Lausanne
    University Hospital and University of Lausanne
    Swiss Institute of Bioinformatics)

  • John McLauchlan

    (MRC-University of Glasgow Centre for Virus Research)

  • Graham R. Foster

    (Queen Mary University of London)

  • William L. Irving

    (Nottingham University Hospitals NHS Trust and the University of Nottingham)

  • Peter Simmonds

    (University of Oxford)

  • Vincent Pedergnana

    (MIVEGEC, Université de Montpellier, CNRS)

  • Santseharay Ramirez

    (University of Copenhagen)

  • Jens Bukh

    (University of Copenhagen)

  • Eleanor Barnes

    (University of Oxford)

  • M. Azim Ansari

    (University of Oxford
    University of Oxford)

Abstract

Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease, worldwide. With the development of direct-acting antivirals, treatment of chronically infected patients has become highly effective, although a subset of patients responds less well to therapy. Sofosbuvir is a common component of current de novo or salvage combination therapies, that targets the HCV NS5B polymerase. We use pre-treatment whole-genome sequences of HCV from 507 patients infected with HCV subtype 3a and treated with sofosbuvir containing regimens to detect viral polymorphisms associated with response to treatment. We find three common polymorphisms in non-targeted HCV NS2 and NS3 proteins are associated with reduced treatment response. These polymorphisms are enriched in post-treatment HCV sequences of patients unresponsive to treatment. They are also associated with lower reductions in viral load in the first week of therapy. Using in vitro short-term dose-response assays, these polymorphisms do not cause any reduction in sofosbuvir potency, suggesting an indirect mechanism of action in decreasing sofosbuvir efficacy. The identification of polymorphisms in NS2 and NS3 proteins associated with poor treatment outcomes emphasises the value of systematic genome-wide analyses of viruses in uncovering clinically relevant polymorphisms that impact treatment.

Suggested Citation

  • David A. Smith & Carlota Fernandez-Antunez & Andrea Magri & Rory Bowden & Nimisha Chaturvedi & Jacques Fellay & John McLauchlan & Graham R. Foster & William L. Irving & Peter Simmonds & Vincent Pederg, 2021. "Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25649-6
    DOI: 10.1038/s41467-021-25649-6
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    References listed on IDEAS

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    1. Ivo C. Lorenz & Joseph Marcotrigiano & Thomas G. Dentzer & Charles M. Rice, 2006. "Structure of the catalytic domain of the hepatitis C virus NS2-3 protease," Nature, Nature, vol. 442(7104), pages 831-835, August.
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