Wednesday, October 1, 2014

Infrequent Development of Resistance in Geno 1-6 HCV-Infected Subjects Treated with Sofosbuvir in Phase 2 and 3 Clinical Trials.

Clin Infect Dis. 2014 Sep 28. pii: ciu697. [Epub ahead of print]

Infrequent Development of Resistance in Genotype 1 through 6 HCV-Infected Subjects Treated with Sofosbuvir in Phase 2 and 3 Clinical Trials.

Svarovskaia ES1, Dvory-Sobol H1, Parkin N2, Hebner C1, Gontcharova V1, Martin R1, Ouyang W1, Han B1, Xu S1, Ku K1, Chiu S1, Gane E3, Jacobson IM4, Nelson DR5, Lawitz E6, Wyles DL7, Bekele N1, Brainard D1, Symonds WT1, McHutchison JG1, Miller MD1, Mo H8.

Author information

1Gilead Sciences, Foster City, CA 94404.
2Data First Consulting Inc., Belmont, CA 94002.
3University of Auckland, Auckland City Hospital, Auckland, New Zealand.
4Weill Cornell Medical College, New York, NY, United States.
5University of Florida, Gainesville, FL, United States.
6Texas Liver Institute, San Antonio, TX, United States.
7Division of Infectious Diseases, University of California, San Diego, CA, United States.
8Gilead Sciences, Foster City, CA 94404


Sofosbuvir is a chain-terminating nucleotide analog 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 response, no novel sofosbuvir resistance-associated variants were identified and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In one 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 that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.

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