Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure
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- Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure
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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.
Originalsprog | Engelsk |
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Artikelnummer | 6105 |
Tidsskrift | Nature Communications |
Vol/bind | 12 |
Udgave nummer | 1 |
Antal sider | 11 |
ISSN | 2041-1723 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This work was funded by a grant from the Medical Research Council (MR/K01532X/ 1–STOP-HCV Consortium). The work was supported by Core funding to the Wellcome Centre for Human Genetics provided by the Wellcome Trust (203141/Z/16/Z). E.B. is supported by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. M.A.A. is supported by a Sir Henry Dale Fellowship jointly funded by the Royal Society and the Wellcome Trust (220171/Z/20/Z). Further, work performed at CO-HEP was funded by the Novo Nordisk Foundation and the Independent Research Fund Denmark. The views expressed in this article are those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health. This research was funded in whole, or in part, by the Wellcome Trust (220171/Z/20/Z, 203141/Z/16/Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2021, The Author(s).
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