부산대학교 도서관

Aims: A pooled analysis of emergent RAS was performed in HCV genotype (GT-)1b-infected patients receiving daclatasvir and asunaprevir (DCV+ASV) and the persistence of DCV- and ASV-resistant substitutions through ≥post-treatment Week (PTWK)192 was assessed to understand the RAS profile and help guide potential retreatment options. Methods: HCV GT-1b-infected patients without a sustained virologic response (SVR) and with HCV RNA ≥1000 IU/mL on or after DCV+ASV treatment were included from 5 Phase 2 and 3 studies. Baseline and post-baseline plasma samples were sequenced at a sensitivity cut-off ł20%. To determine the persistence of emergent RAS, samples at the end of study (up to PTWK48) and/or from a 3-year long-term follow-up rollover study were sequenced (sensitivity cut-off ≥20%, and ≥1% for select samples). Results: 152 DCV+ASV-treated patients without SVR met the resistance testing criteria: 89% (136/152) had NS5A and 95% (145/152) had NS3 sequences at both baseline and virologic failure (VF). NS5A and NS3 RAS emerged in 99% (134/136) and 89% (129/145), respectively, at VF (Table). Overall, 93% (142/152) of patients with VF had both NS5A and NS3 sequence data at failure, of which 77% (109/142) had RAS at L31, Y93 and D168. Emergent NS5A RAS persisted at PTWK96 (92%;24/26) and ≥PTWK192 (100;7/7compared with 22% (6/27) and 14% (1/7), respectively, for emergent NS3 RAS. Replacement of emergent NS5A and NS3 RAS observed at VF occurred in 8% (2/26) of NS5A and 74% (17/23) of NS3 sequences at PTWK96 and in 0% (0/7) of NS5A and 86% (6/7) of NS3 sequences at ≥PTWK192. Conclusions: NS5A and NS3 RAS emerged in most patients treated with DCV+ASV who experienced VF, and NS5A RAS persisted post-treatment. Therapy options for DCV+ASV treatment failures may depend on the timing of retreatment: an NS3 inhibitor-containing regimen may be possible if NS3 RAS are no longer observed, while regimens not impacted by the NS5A-L31+Y93 and NS3-D168 RAS combination would offer an immediate alternative.