Infrequent Development of Resistance in Genotype 1–6 Hepatitis C Virus–Infected Subjects Treated With Sofosbuvir in Phase 2 and 3 Clinical Trials

• Published in: Clinical infectious diseases Vol. 59; no. 12; pp. 1666 - 1674
• Main Authors: Svarovskaia, Evguenia S., Dvory-Sobol, Hadas, Parkin, Neil, Hebner, Christy, Gontcharova, Viktoria, Martin, Ross, Ouyang, Wen, Han, Bin, Xu, Simin, Ku, Karin, Chiu, Sophia, Gane, Edward, Jacobson, Ira M., Nelson, David R., Lawitz, Eric, Wyles, David L., Bekele, Neby, Brainard, Diana, Symonds, William T., McHutchison, John G., Miller, Michael D., Mo, Hongmei
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.12.2014
• Subjects: and Commentaries; Antiviral Agents - therapeutic use; Antivirals; ARTICLES AND COMMENTARIES; Biological and medical sciences; Clinical trials; Drug resistance; Drug Resistance, Viral; Female; Genotype & phenotype; Genotypes; Hepacivirus; Hepacivirus - pathogenicity; Hepatitis; Hepatitis C; High throughput nucleotide sequencing; Human viral diseases; Humans; Infections; Infectious diseases; Male; Medical sciences; Phenotype; Prescription drugs; Relapse; Sequencing; Sofosbuvir; Treatment Outcome; Uridine Monophosphate - analogs & derivatives; Uridine Monophosphate - therapeutic use; Viral diseases; Viral hepatitis; Virology; Viruses; Human; Typing; Hepatic disease; Genotype; Infection; Virus; Resistance; Microbiological investigation; Treatment; Viral disease; Digestive diseases; Clinical trial; Flaviviridae; Hepatitis C virus; Hepacivirus; Viral hepatitis C; sofosbuvir; HCV; NS5B polymerase; GS-7977; antiviral resistance
• ISSN: 1058-4838; 1537-6591; 1537-6591
• DOI: 10.1093/cid/ciu697

Background. Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1–6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B. Methods. NS5B sequencing and susceptibility testing of HCV from subjects infected with genotypes 1–6 who participated in phase 2 and 3 sofosbuvir clinical trials was performed. Results. No NS5B variants present at baseline among 1645 sofosbuvir-treated subjects were associated with treatment failure; sofosbuvir susceptibility was within 2-fold of reference. Among 282 subjects who did not achieve sustained virologic response, no novel sofosbuvir resistance–associated variants were identified, and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In 1 subject with S282T observed at relapse 4 weeks after sofosbuvir monotherapy, the resistant variant (13.5-fold reduced sofosbuvir susceptibility, replication capacity <2% of control) became undetectable by deep sequencing 12 weeks after treatment. L159F and V321A were identified as treatment-emergent variants but did not confer resistance to sofosbuvir in the replicon system. Conclusions. These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.