Amino acid substitutions in genotype 3a hepatitis C virus polymerase protein affect responses to sofosbuvir
| Autor: | Eleanor Barnes, Michelle Cheung, John McLauchlan, William L. Irving, Wing-Yiu Jason Lee, David A. Smith, M. Azim Ansari, Connor G. G. Bamford, Meleri Jones, Sampath DaSilva, Peter A.C. Wing, Elihu Aranday-Cortes, Graham R. Foster, Morven Cunningham, Ana da Silva Filipe |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Wt wild-type Time Factors Sofosbuvir Sustained Virologic Response DAC daclatasvir Hepacivirus Viral Nonstructural Proteins medicine.disease_cause chemistry.chemical_compound 0302 clinical medicine Interferon Pegylated interferon Genotype Gastroenterology virus diseases 3. Good health Phenotype Treatment Outcome HCV hepatitis C virus SVR sustained virologic respone 030211 gastroenterology & hepatology Drug Therapy Combination Response to therapy IC50 50% inhibitory concentration medicine.drug RBV ribavirin Daclatasvir Hepatitis C virus Antiviral Agents Virus Article 03 medical and health sciences Cell Line Tumor Drug Resistance Viral medicine Genetics Humans IFN interferon Polymorphism Genetic Hepatology Dose-Response Relationship Drug business.industry Ribavirin Amino acid change Hepatitis C Chronic Virology digestive system diseases CI confidence interval 030104 developmental biology chemistry Amino Acid Substitution SOF sofosbuvir Mutation business |
| Zdroj: | Gastroenterology |
| ISSN: | 0016-5085 1528-0012 |
| Popis: | BACKGROUND & 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 (SVR) 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 SVR, 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 G3 containing this variant reduces odds of SVR. In addition, we identified rare combinations of variants in HCV G3 that reduce response to sofosbuvir. |
| Databáze: | OpenAIRE |
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