Infrequent development of resistance in genotype 1-6 hepatitis c virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials

Evguenia S. Svarovskaia, Hadas Dvory Sobol, Neil Parkin, Christy Hebner, Viktoria Gontcharova, Ross Martin, Wen Ouyang, Bin Han, Simin Xu, Karin Ku, Sophia Chiu, Edward Gane, Ira M. Jacobson, David R. Nelson, Eric Lawitz, David L. Wyles, Neby Bekele, Diana Brainard, William T. Symonds, John G. McHutchisonMichael D. Miller, Hongmei Mo

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1666-1674
Number of pages9
JournalClinical Infectious Diseases
Volume59
Issue number12
DOIs
StatePublished - Dec 15 2014
Externally publishedYes

Keywords

  • GS-7977
  • HCV
  • NS5B polymerase
  • antiviral resistance
  • sofosbuvir

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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    Svarovskaia, E. S., Dvory Sobol, H., Parkin, N., Hebner, C., Gontcharova, V., Martin, R., Ouyang, W., Han, B., Xu, S., Ku, K., Chiu, S., Gane, E., Jacobson, I. M., Nelson, D. R., Lawitz, E., Wyles, D. L., Bekele, N., Brainard, D., Symonds, W. T., ... Mo, H. (2014). Infrequent development of resistance in genotype 1-6 hepatitis c virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clinical Infectious Diseases, 59(12), 1666-1674. https://doi.org/10.1093/cid/ciu697