Amino acid substitutions in genotype 3a hepatitis C virus polymerase protein affect responses to sofosbuvir

Wing, P. A.C. et al. (2019) Amino acid substitutions in genotype 3a hepatitis C virus polymerase protein affect responses to sofosbuvir. Gastroenterology, 157(3), 692-704.e9. (doi: 10.1053/j.gastro.2019.05.007) (PMID:31078622)

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Background and Aims: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England’s National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure. Methods: We collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. Results: We identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system. Conclusions: A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.

Item Type:Articles
Additional Information:HCV Research UK was supported by the Medical Research Foundation (Award number C0365). JM, CB, E-AC and ADSF were supported by the UK Medical Research Council (MC_UU_12014/1) (MC_UU_12014/1). PW was funded by HCV Research UK through the Medical Research Foundation (Award number C0365). EB is funded by the Medical Research Council UK, the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. 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. We also acknowledge the Medical Research Council funded STOP-HCV consortium who supported AA and the sequencing analysis in the Boson study.
Glasgow Author(s) Enlighten ID:Aranday-Cortes, Dr Elihu and Da Silva Filipe, Dr Ana and Bamford, Dr Connor and McLauchlan, Professor John
Authors: Wing, P. A.C., Jones, M., Cheung, M., DaSilva, S., Bamford, C., Lee, W.-Y. J., Aranday-Cortes, E., Da Silva Filipe, A., McLauchlan, J., Smith, D., Irving, W., Cunningham, M., Ansari, A., Barnes, E., and Foster, G. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Gastroenterology
ISSN (Online):1528-0012
Published Online:10 May 2019
Copyright Holders:Copyright © 2019 by the AGA Institute
First Published:First published in Gastroenterology 157(3):692-704.e9
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
644641Establishment of a Resource for Long-Term Study of Hepatitis C Virus Infection in the UKJohn McLauchlanMedical Research Foundation (MEDRESFO)C0365MVLS III - CENTRE FOR VIRUS RESEARCH
656341Virus-host interactions in hepatitis C virus infectionJohn McLauchlanMedical Research Council (MRC)MC_UU_12014/1MVLS III - CENTRE FOR VIRUS RESEARCH