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Abstract Details
Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure
Nat Commun. 2021 Oct 20;12(1):6105. doi: 10.1038/s41467-021-25649-6.
David A Smith1, Carlota Fernandez-Antunez2, Andrea Magri1, Rory Bowden3, Nimisha Chaturvedi4, Jacques Fellay456, John McLauchlan7, Graham R Foster8, William L Irving9, STOP-HCV Consortium; Peter Simmonds1, Vincent Pedergnana10, Santseharay Ramirez2, Jens Bukh2, Eleanor Barnes1, M Azim Ansari1112
1Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 1SY, UK.
2Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
4School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
5Precision Medicine Unit, University Hospital and University of Lausanne, Lausanne, Switzerland.
6Swiss Institute of Bioinformatics, Lausanne, Switzerland.
7MRC-University of Glasgow Centre for Virus Research, Glasgow, G61 1QH, UK.
8Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, UK.
9NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
10MIVEGEC, Université de Montpellier, CNRS, 34000, Montpellier, France.
11Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 1SY, UK. azim.ansari@ndm.ox.ac.uk.
12Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. azim.ansari@ndm.ox.ac.uk.
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.