Cookson, Shannon Lauriski Background: Over 2500 HCV genotype (GT) 1-infected patients have been treated with ombitasvir/ABT-450/r and dasabuvir (3D) ± ribavirin (RBV) in 2 Phase 2 (M13-386 and AVIATOR) and 6 Phase 3 (SAPPHIRE-I, SAPPHIRE-II, PEARL-II, PEARL-III, PEARL-IV, and TURQUOISE-II) clinical trials. Seventy-four patients experienced virologic failure (VF) in these studies, and were evaluated for the presence

of resistance-associated variants (RAVs) at baseline and at the Ponatinib mouse time of VF. Methods: Baseline polymorphisms and treatment-emergent variants in HCV NS3, NS5A and NS5B from patients who experienced VF were analyzed by population sequencing. The number and percentage of subjects with baseline RAVs was compared between subjects experiencing VF and subjects who achieved sustained virologic response (SVR) by chi-square test. Results: Baseline sequencing was conducted on a subset

of samples comprising over 700 GT1a and 1b-infected patients. Baseline RAVs in either GT1a or 1b in NS3 were rare (<1%); baseline RAVs in NS5A were observed in 12.5% of GT1a and 7.5% of the GT1b samples; baseline RAVs in NS5B were observed in 5.2% of GT1a and 28.6% of the GT1b samples; no subject had baseline Alvelestat RAVs in all 3 targets. The presence of baseline RAVs had no impact on treatment outcome. Among patients receiving the 3D ± RBV regimens in the Phase 2/3 clinical trials, 67 GT1a-infected patients experienced

VF including 18 patients who experienced on-treatment breakthrough and 49 who relapsed; and 7 GT1b-infected patients experienced VF including 2 patients who experienced on-treatment breakthrough and 5 who relapsed. At the time of VF, the predominant RAVs in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The predominant RAVs in GT1b were Y56H+D168V in NS3, Y93H in NS5A, and S556G in NS5B. Among patients see more who experienced VF, 39 GT1a- and 4 GT1b-infected patients had RAVs in all 3 targets; 15 GT1a- and 1 GT1b-infected patient had RAVs in any 2 targets; 4 GT1a-infected patients had RAVs in only 1 target; while 9 GT1a- and 2 GT1b-infected patients had no RAVs in any target. Long-term studies to monitor persistence of these variants are ongoing. Conclusions: In the 3D ± RBV regimens, the virologic failure rate was very low (3.0%). Of the 74 patients who experienced VF, 43 had RAVs in all 3 targets, while 11 had no RAVs in any target.