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( F. Mcphee ),( D. Hernandez ),( N. Zhou ),( F. Yu ),( B. Kienzle ),( Y. Zhao ),( M. Linaberry ),( S. Noviello ),( M. L. Yu ),( S. H. Ahn ),( Y. Karino ),( K. Chayama ),( H. Kumada ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
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.
( L. Wei ),( K. Chayama ),( W. L. Chuang ),( S. H. Bae ),( J. Y. Jang ),( R. Bhore ),( V. Vazquez ),( L. Mo ),( M. Linaberry ),( M. Treitel ),( H. Kumada ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: The combination of daclatasvir (DCV) plus asunaprevir (ASV)has demonstrated high sustained virologic response (SVR) rates andis generally well tolerated in clinical studies. This integrated analysisevaluated the safety profile of DCV (60mg once daily) and ASV (100mgsoftgel capsule or 200mg tablets twice daily in genotype 1b (GT1b)infected patients enrolled in four phase 3 and two phase 2 clinicalstudies conducted globally, including Asia.Methods: Integrated safety data from 1218 treatment-naive or treatment-experienced patients were analyzed for adverse events (AEs),serious AEs, discontinuations due to AEs and grade 3/4 AEs andlaboratory abnormalities reported on-treatment.Results: Patients were 58% female, median age was 58 years and23% had compensated cirrhosis. DCV+ASV was associated with infrequentserious AEs and discontinuations due to AEs (Table). Twelvepatients reported treatment-related serious AEs. The most commonAEs (any grade) were diarrhea, nausea, fatigue, and headache. Onepatient died due to coronary heart disease (not treatment-related).The most common grade 3/4 laboratory abnormalities were aminotransferaseelevations (more frequent among Japanese patients); however,all grade 3/4 laboratory abnormality occurred in <5% of patientsoverall. Grade 3/4 total bilirubin elevations were reported in <1%of patients. The DCV+ASV safety profile was similar in patients withor without cirrhosis.Conclusions: DCV+ASV was generally well tolerated across globalnon-Asian patient populations and in Asian patients from Japan, mainlandChina, Korea, and Taiwan.