Symonds – Employment: Gilead John G. McHutchison – Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences The following people have nothing to disclose: Fernando E. Membreno Objective: To evaluate the resistance profile of the NS5A inhibitor LDV in GT 1, chronically infected HCV subjects treated with non-SOF, LDV-containing
regimens for up to 24 weeks. Methods: Six phase 2 studies were analyzed. Studies GS-US-248-0120, GS-US-248-0131, and GS-US-248-0132 evaluated the all oral regimens of either 30 or 90 mg LDV ± the NS3 protease inhibitor vedroprevir (VDV, GS-9451) ± the non-nucleoside NS5B polymerase inhibitor tegobuvir (TGV, GS-9190) Target Selective Inhibitor Library ic50 ± riba- virin (RBV). Studies GS-US-248-0121, GS-US-256-0124, and GS-US-256-0148 evaluated 30 mg LDV ± VDV with pegylated interferon (IFN) + RBV. NS5A population sequencing was attempted for all subjects at baseline and for any subjects who experienced virologic breakthrough, virologic relapse, or early discontinuation Afatinib with HCV RNA >1000 IU/mL. Phenotypic analyses using transient HCV replicon assays were conducted for novel conserved substitutions observed in the first 150 amino acids of NS5A in two or more subjects or >1% of subjects for the remainder of NS5A. LDV resistance-associated variants (RAVs) previously identified include:
K24G/N/E/R, M28T/ A/G, Q30T/L/H/R/G/K/E/D, L31I/M/V, P32L, H58D/L, and Y93C/H/S/L for GT 1a, and L31V/M and Y93H for GT 1b. Results: Overall, 1103 GT 1 subjects (747 GT
1a, 297 GT 1b) were randomized and treated; 1045 (94.7%) had baseline NS5A population sequencing results. Previously identified LDV RAVs were observed in 89 (8.5%) subjects (47 GT 1a [6.3%], 42 GT 1b [14.1%]) at baseline and resulted in numerically lower SVR rates compared to overall SVR rates in most studies. In total, 335 (30.3%) subjects qualified for post-treatment resistance analyses; NS5A sequencing was successful for 329 (287 GT 1a, 42 pheromone GT 1b). Of these, 328 (99.7%) had previously identified LDV RAVs detected, in which 55% GT 1a subjects had 2-5 LDV RAVs whereas only 29% GT 1b subjects had multiple RAVs. In addition, LDV RAVs with >10% prevalence were observed more frequently in GT 1a subjects (M28T, Q30R/E, L31M, H58D, Y93C/N) than GT 1b subjects (Y93H). On-treatment and baseline sequences were compared to determine novel amino acid substitutions that may be associated with LDV resistance. Eleven GT 1a and 1 GT 1b conserved substitutions occurred in multiple subjects and were assessed for LDV susceptibility. Three substitutions (K26E and S38F in GT 1a and L31I in GT 1b) were found to exhibit reduced susceptibility to LDV. Conclusions: Virologic breakthrough and virologic relapse on non-SOF, LDV-containing regimens are associated with the presence of known LDV RAVs at failure. The GT 1a substitutions K26E and S38F and the GT 1b substitution L31I were identified as novel LDV RAVs. Disclosures: Kathryn M.