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

TY - JOUR

T1 - Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

AU - Smith, David A

AU - Fernandez-Antunez, Carlota

AU - Magri, Andrea

AU - Bowden, Rory

AU - Chaturvedi, Nimisha

AU - Fellay, Jacques

AU - McLauchlan, John

AU - Foster, Graham R.

AU - Irving, William L

AU - STOP-HCV Consortium

AU - Dillon, John

AU - Simmonds, Peter

AU - Pedergnana, Vincent

AU - Ramirez, Santseharay

AU - Bukh, Jens

AU - Barnes, Eleanor

AU - Ansari, M Azim

N1 - 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. © 2021. The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

KW - Antiviral Agents/therapeutic use

KW - Genome, Viral/genetics

KW - Genotype

KW - Hepacivirus/drug effects

KW - Hepatitis C, Chronic/drug therapy

KW - Humans

KW - Polymorphism, Genetic

KW - Sofosbuvir/therapeutic use

KW - Treatment Failure

KW - Viral Load/drug effects

KW - Viral Nonstructural Proteins/genetics

UR - https://www.scopus.com/pages/publications/85119368220

U2 - 10.1038/s41467-021-25649-6

DO - 10.1038/s41467-021-25649-6

M3 - Article

C2 - 34671027

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

M1 - 6105

ER -