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

David A Smith, Carlota Fernandez-Antunez, Andrea Magri, Rory Bowden, Nimisha Chaturvedi, Jacques Fellay, John McLauchlan, Graham R. Foster, William L Irving, STOP-HCV Consortium, John Dillon, Peter Simmonds, Vincent Pedergnana, Santseharay Ramirez, Jens Bukh, Eleanor Barnes, M Azim Ansari

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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.

Original languageEnglish
Article number6105
Number of pages11
JournalNature Communications
Volume12
Early online date20 Oct 2021
DOIs
Publication statusPublished - Dec 2021

Keywords

  • Antiviral Agents/therapeutic use
  • Genome, Viral/genetics
  • Genotype
  • Hepacivirus/drug effects
  • Hepatitis C, Chronic/drug therapy
  • Humans
  • Polymorphism, Genetic
  • Sofosbuvir/therapeutic use
  • Treatment Failure
  • Viral Load/drug effects
  • Viral Nonstructural Proteins/genetics

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