Forns X. J Hepatology 2015; 63: 564-72 C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen –NS3 and NS5A RAVs.

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Presentation transcript:

Forns X. J Hepatology 2015; 63: C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen –NS3 and NS5A RAVs identified by population sequencing at baseline and VF  Design N = 79 GZR 100 mg + EBR 50 mg + weight-based RBV (BID dosing ( mg/day) Open-label C-SALVAGE W12W24 > 18 years Chronic HCV infection Genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to ≥ 4 weeks of treatment with PEG-IFN + RBV + (BOC, TVR, or SMV) Compensated cirrhosis* allowed No HBV or HIV co-infection * Metavir F4 or Fibroscan > 12.5 kPa or FibroTest > APRI > 2  Objective –SVR 12 (HCV RNA < 15 IU/ml) with 95% CI, no formal statistical hypothesis : Primary endpoint : per-protocol ; secondary : efficacy and safety on full set

All patients N = 79 Evaluable patients (with baseline sequencing data) Baseline NS3 RAVs N = 34* No baseline NS3 RAVs N = 44 Mean age, years Female42%32%45% Genotype 1a / 1b38% / 62%68% / 32%16% / 84% HCV RNA, log 10 IU/ml, mean Metavir F443%44%43% Prior DAA experience, n (%) Boceprevir Telaprevir Simeprevir 28 (35.4) 43 (54.4) 8 (10.1) 10 (29.4) 19 (55.9) 5 (14.7) 17 (38.6) 24 (54.5) 3 (6.8) Past history of virologic failure83.5%94.1%75% Baseline NS5A polymorphisms8** (10.1%)6 (17.6%)1 (4.5%) Discontinued therapy1 (for AE) C-SALVAGE * Variants with > 5 fold decrease susceptibility to grazoprevir : 4 (11.8%) ** NS5A variants with > 5 fold decrease susceptibility to elbasvir : 5/8 (62.5% ) Baseline characteristics and disposition C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen Forns X. J Hepatology 2015; 63:

C-SALVAGE SVR 12 (HCV RNA < 15 IU/ml), % (95% CI), full analysis set Per protocol : 97.1% ( ) * 3 virologic failures + 3 relapses C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen 96.2 ( ) 66 All patients Prior virologic failure 95.5 * ( ) ( ) Prior non-virologic failure 93.3 (78-99) Genotype 94.1 (80-99) Cirrhosis (89-100) 49 1a1bYesNo 97.8 (88-100) % 0 45 N 34 Forns X. J Hepatology 2015; 63: (77-99) Baseline HCV RNA (IU/ml) < 800,000> 800, (89-100) 50 29

RAV at baseline % (n/N) SVR 12 all patients % (N/n) SVR 12 RAVs with ≤ 5-fold  susceptibility SVR 12 RAVs with > 5-fold  susceptibility NS3 RAVs All patients Present GT 1a Q80K+ GT1b Absent 44% (34/78) 76.7% (23/30) 36.7% (11/30) 22.9% (11/48) 56% (44/78) 91.2% (31/34) 91.3% (21/23) 90.9% (10/11) 100% (44/44) 93.3% (28/30) - 75% (3/4) - NS5A RAVs All patients Present Absent 10% (8/81) 90% (73/81) 75% (6/8) 98.6% (72/73) 100% (3/3) - 60% (3/5) -  In the 3 virologic failures : emergence of resistance variants to grazoprevir (NS3 A156T in 3 cases + other variants in 2 cases) and to elbasvir (NS5A Y93H in 2 cases, Q30R in 1 case) SVR 12 according to baseline NS3 and NS5A RAVs C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen C-SALVAGE Forns X. J Hepatology 2015; 63:

GZR + EBR + RBV, N = 79 Any drug-related adverse event45 ( 57.0) Serious adverse event4 (5.1)* Discontinuations due to an adverse event1 (1.3) Specific adverse event in >10% of patients Fatigue Headache Asthenia Nausea 22 (27.8) 15 (19.0) 12 (15.2) 9 (11.4) Grade 3-4 laboratory abnormalities Total bilirubin > 2.5 x ULN Lipase > 3 x ULN INR > 1 ULN Hemoglobin < 9 g/dl 5 (6.3) 4 (5.1) 1 (1.3) 2 (2.5) C-SALVAGE Adverse events and laboratory abnormalities, N (%) * None related to study medication  RBV dose was reduced in 11 (14%) patients ; all achieved SVR 12 C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen Forns X. J Hepatology 2015; 63:

 Summary –GZR + EBR + RBV for 12 weeks resulted in SVR 12 in 76/79 patients (96.2%) who had failed previous PEG-IFN + RBV plus an earlier-generation PI SVR 12 was attained in 63/66 (95.5%) patients with a history of VF SVR 12 was attained in 31/34 (91.2%) patients harboring baseline NS3 RAVs conferring decreased susceptibility to 1 st -generation PIs –GZR + EBR + RBV was generally well tolerated O nly 1 patient stopped study treatment (adverse event unrelated to study treatment) No serious drug-related adverse event C-SALVAGE C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen Forns X. J Hepatology 2015; 63: