Research
Print page Print page
Switch language
Hvidovre Hospital - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

  1. A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. A non-enzymatic, isothermal strand displacement and amplification assay for rapid detection of SARS-CoV-2 RNA

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Detection and characterization of lung cancer using cell-free DNA fragmentomes

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Inactivated whole hepatitis C virus vaccine employing a licensed adjuvant elicits cross-genotype neutralizing antibodies in mice

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. HCV genome-wide analysis for development of efficient culture systems and unravelling of antiviral resistance in genotype 4

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. High-Titer Hepatitis C Virus Production in a Scalable Single-Use High Cell Density Bioreactor

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Neutralizing Antibodies Against Hepatitis C Virus and Their Role in Vaccine Immunity

    Research output: Contribution to journalEditorialResearchpeer-review

  5. Versatile SARS-CoV-2 Reverse-Genetics Systems for the Study of Antiviral Resistance and Replication

    Research output: Contribution to journalJournal articleResearchpeer-review

  • STOP-HCV Consortium
View graph of relations

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
JournalNature Communications
Volume12
Issue number1
Pages (from-to)1-11
Number of pages11
ISSN2041-1723
DOIs
Publication statusPublished - 20 Oct 2021

Bibliographical note

© 2021. The Author(s).

    Research areas

  • 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

ID: 68558504