TY - JOUR T1 - Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure JF - bioRxiv DO - 10.1101/2020.05.05.077230 SP - 2020.05.05.077230 AU - David A Smith AU - Andrea Magri AU - Rory Bowden AU - Nimisha Chaturvedi AU - Jacques Fellay AU - John McLauchlan AU - Graham R. Foster AU - William L Irving AU - STOP-HCV Consortium AU - Peter Simmonds AU - Vincent Pedergnana AU - Eleanor Barnes AU - M. Azim Ansari Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/05/05/2020.05.05.077230.abstract N2 - Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. With the recent development of direct acting antivirals (DAA), treatment of chronically infected patients has become highly effective although a subset of patients do not respond to therapy. Sofosbuvir is a common component of current de novo or salvage combination therapies. We used pre-treatment whole genome sequencing 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 found that three common polymorphisms present in HCV NS2 and NS3 proteins (not direct targets of sofosbuvir) were associated with reduced treatment response. These polymorphisms were enriched in post-treatment HCV sequences of patients unresponsive to treatment; they were also associated with lower reductions in viral load in the first week of therapy. The finding of polymorphisms in NS2 and NS3 proteins associated with poor treatment outcomes emphasises the value of more systematic genome-wide analyses of HCV in uncovering indirect but clinically relevant mechanisms of antiviral resistance.Competing Interest StatementGRF: Grants Consulting and Speaker/Advisory Board: AbbVie, Alcura, Bristol-Myers Squibb, Gilead, Janssen, GlaxoSmithKline, Merck, Roche, Springbank, Idenix, Tekmira, Novartis. WLI: Grants, Consulting and Advisory/ Speaker Board: Roche, Janssen Cilag, Gilead Sciences, Novartis, GlaxoSmithKline, Pfizer, Abbvie and Bristol-Myers Squibb. All other authors have no conflicts of interest to declare.HCVHepatitis C VirusDAA(s)Direct Acting AntiviralsSVRSustained Virologic ResponseRAS(s)Resistance Associated SubstitutionsTOP(s)Treatment Outcome associated PolymorphismsNSNon-structuralgtGenotypeGWASGenome Wide Association StudyFDRFalse Discovery RateIFNInterferonIFNL4Interferon Lambda 4SNPSingle nucleotide polymorphism ER -