title: Antiviral response and resistance analysis of treatment-naïve HCV infected patients receiving multiple doses of the NS3 protease inhibitor GS-9256.
abstract: The NS3 protease inhibitor (PI) GS-9256 has demonstrated antiviral activity in a monotherapy study and in combination with other DAAs for treatment of chronic hepatitis C virus (HCV) infection. The resistance profile of GS-9256 was investigated in a phase 1 monotherapy study of patients with HCV genotype (GT) 1 infection. No PI resistance associated substitutions (RASs) at positions 36, 155, 156, 168 and 170 were observed at baseline by population sequencing (15% cutoff) in the 54 patients enrolled in the study, however the PI RAS Q80K were detected in 41% of patients at baseline. In patients who received 75 mg of the investigational protease inhibitor (PI) GS-9256 BID, 300 mg of GS-9256 QD and 200 mg of GS-9256 BID for three days, NS3 RASs (A156V, R155K, D168G/E/N/V) were observed in 9/21, 3/7 and 8/8 post-treatment, respectively. Q80K was not selected in any patients post-treatment. The mean maximal viral load response was -3.0 ± 0.42 log10IU/mL HCV RNA in the 200 mg BID cohort. In more than 50% of the patients with RASs detected at Day 4, mutations were no longer detectable by population sequencing at Day 14. One patient had the R155K mutation persist to Week 24. Phenotypic analyses showed that substitutions at R155, A156 and D168 significantly reduced susceptibility to GS-9256. In conclusion, NS3 PI RASs were rapidly selected in the majority of patients receiving GS-9256 as monotherapy, despite undetectable levels at baseline. The R155, A156 and D168 substitutions identified in patients confer reduced susceptibility to GS-9256 and other PIs in vitro.
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA. Electronic address: Hongmei.Mo@gilead.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hedskog
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yang
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Delaney
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Worth
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D010456:Peptides, Cyclic; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C571665:GS-9256; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: Drug resistance profile; Genotype 1; Phase 1 monotherapy study; Sequencing