No Resistance Detected in four Phase 3 Clinical Studies in HCV Genotype 1 -6 of Sofosbuvir + Ribavirin with or without Peginterferon
Evguenia S. Svarovskaia1, Hadas S. Dvory1, Christy Hebner1, Brian Doehle1, Viktoria Gontcharova1, Ross Martin1, Edward J. Gane2, Ira M. Jacobson3, David R. Nelson4, Eric Lawitz5, B. Nebiyou Bekele1, Diana M. Brainard1, William T. Symonds1, John G. McHutchison1, Michael D. Miller1, Hongmei Mo1;
1Gilead Sciences Inc, Foster City, CA; 2University of Auckland, Auckland City Hospital, Auckland, New Zealand; 3Weill Cornell Medical College, New York, NY; 4University of Florida, Gainesville, FL; 5Texas Liver Institute, San Antonio, TX
Introduction: SOF combination therapy was demonstrated to be well tolerated and effective in the treatment of HCV genotype (GT) 1-6 in four Phase 3 studies: NEUTRINO, FISSION, POSITRON, and FUSION. We performed resistance testing of the patients that did not achieve SVR thru follow-up week 12 after treatment with SOF-containing regimens from these 4 studies. Methods: Subjects who did not achieve SVR 12 due to virologic failure or early discontinuation were included in the resistance analysis. The HCV NS5B gene was amplified from patient plasma samples at baseline and post-BL time points. PCR products were analyzed using standard population sequencing and deep sequencing with an assay cut-off of 1%. PCR products from patient samples were also cloned into a replicon vector and tested for susceptibility to SOF and RBV. Results: Baseline NS5B population sequences were successfully obtained for 1292/1305 patients. None of the 1292 patients had the SOF-associated NS5B substitution S282T detectable at baseline. There were no statistically significant correlations between the presence of any NS5B variant at baseline and treatment outcome. Among all SOF-treated patients in the Phase 3 studies, 226/991 subjects qualified for resistance testing. All but one of these had post-treatment relapse, with the remaining patient experiencing viral breakthrough associated with nonadherence. Full length NS5B was successfully amplified and deep sequencing results obtained from 208/226 patients at post-treatment Week 4, 12, or 16. In addition, a short NS5B fragment flanking amino acid position 282 was successfully deep and/or population sequenced for an additional 17 patients. Notably, the S282T substitution was not detected by deep sequencing in any the 225 patients analyzed. There were a number of NS5B substitutions observed in more than 2 patients across the 4 Phase 3 studies. All of the substitutions were at residues considered to be polymorphic. Phenotypic analyses demonstrated no reduction in susceptibility to SOF or RBV with these substitutions. Altogether, phenotypic data were obtained for 110 patients. No reduction in SOF susceptibility was observed compared to baseline samples or replicon control references. Conclusions: SOF has an exceptionally high resistance barrier. Natural variation of HCV sequence within NS5B did not appear to affect treatment outcome to the SOF-containing regimens studied. By deep sequencing and phenotypic analyses, no resistance was detected in any patient not achieving SVR12 following SOF+RBV or SOF+PEG/RBV treatment in 4 Phase 3 studies.
Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc; Stock Shareholder: Gilead Sciences Inc
Christy Hebner- Employment: Gilead Sciences, Inc. Brian Doehle - Employment: Gilead Sciences Ross Martin - Employment: Gilead Sciences
Edward J. Gane - Advisory Committees or Review Panels: Roche, AbbVie, Novar-tis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche
Ira M. Jacobson - Consulting: Vertex, Abbott, Achillion, Boehringer Ingelheim, Bristol Myers Squibb, Enanta, Gilead, Glaxo Smithkline, Idenix, Kadmon, Novar-tis, Presidio, Roche / Genentech, Merck, Janssen; Grant/Research Support: Abbott, Achillion, Vertex, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Novartis, Pfizer, Roche / Genentech, Schering / Merck, Tibotec / Janssen; Speaking and Teaching: Vertex, Bristol Myers Squibb, Gilead, Roche / Genentech, Schering / Merck
David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex
B. Nebiyou Bekele - Employment: Gilead Sciences Diana M. Brainard - Employment: Gilead Sciences, Inc. William T. Symonds - Employment: Gilead
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences
Michael D. Miller- Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc.
Hongmei Mo - Employment: Gilead Science Inc
The following people have nothing to disclose: Hadas S. Dvory, Viktoria Gontcharova