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

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. NS5B sequencing and susceptibility testi...

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Published in:Clinical infectious diseases Vol. 59; no. 12; p. 1666
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: United States 15.12.2014
Subjects:
Antiviral Agents - therapeutic use
Drug Resistance, Viral
Female
Hepacivirus - pathogenicity
High-Throughput Nucleotide Sequencing
Humans
Male
Phenotype
Sofosbuvir
Treatment Outcome
Uridine Monophosphate - analogs & derivatives
Uridine Monophosphate - therapeutic use
sofosbuvir
HCV
NS5B polymerase
GS-7977
antiviral resistance
ISSN:1537-6591, 1537-6591
Online Access:Get more information
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Summary: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. 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. 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. 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.
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ISSN:1537-6591
1537-6591
DOI:10.1093/cid/ciu697