Sulkowski M. Lancet 2015;385: C-WORTHY  Design Randomisation* Open-label > 18 years HCV genotype 1, treatment naïve HCV RNA ≥ 10,000 IU/ml No cirrhosis ± HIV infection, on 2 NRTI + RAL > 8 weeks and undetectable HIV RNA > 24 weeks and CD4 ≥ 300/mm 3 C-WORTHY Study: grazoprevir + elbasvir + ribavirin for genotype 1  Dosage of study drugs –Grazoprevir (GZR) 100 mg qd –Elbasvir (EBR) : 20 or 50 mg qd –RBV (bid dosing) : 800mg/day if kg, 1000 mg/day if kg, 1200 mg/day if kg, 1400 mg/day if > 105 kg  Primary efficacy endpoint –SVR 12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI, comparison between groups * Patients and investigators masked to group assignment Part A : HCV mono-infected patients Part B : HCV mono-infected and HCV-HIV coinfected patients

HCV monoinfection genotype 1b GZR + EBR20+ RBV = A1 GZR + EBR50 + RBV = A2 W12 GZR + EBR50 = A3 W8 HCV monoinfection genotype 1a GZR + EBR20 + RBV = A1 GZR + EBR50 + RBV = A2 Part A Part B HCV monoinfection genotype 1a GZR + EBR50 + RBV = B1 GZR + EBR50 + RBV = B2 GZR + EBR50 = B3 HCV monoinfection genotype 1b HCV-HIV co-infection GZR + EBR50 + RBV = B12 GZR + EBR50 = B13 GZR + EBR50 + RBV = B2 Randomisation No randomisation  Treatment groups Sulkowski M. Lancet 2015;385: C-WORTHY C-WORTHY Study: grazoprevir + elbasvir + ribavirin for genotype 1

HCV mono-infectedHIV co-infected GZR + EBR + RBV 8W GZR + EBR + RBV 12W GZR + EBR 12W GZR + EBR + RBV 12W GZR + EBR 12W Treatment armB1A1, A2, B2A3, B3B12B13 Number of patients Mean age, years Female40%53%48%21%20% Metavir F310%5%11%10%7% Genotype 1a / 1b100% / 061% / 37%68% / 32%83% / 17%73% / 27% HCV RNA log 10 IU/ml, mean Discontinued treatment, N All for virologic failure Baseline characteristics and patient disposition Sulkowski M. Lancet 2015;385: C-WORTHY

SVR 12 (HCV RNA < 25 IU/ml), % (95% CI) (61-92) % 93 (85-97) HCV mono-infected 98 (88-100) 97 (82-100) N (69-96) HIV co-infected 30 Early discontinuation13002 Virologic breakthrough01002 Relapse52110 No significant difference for mono and co- infected patients, for regimens with or without RBV 10/12 failures = GT 1a Sulkowski M. Lancet 2015;385: C-WORTHY C-WORTHY Study: grazoprevir + elbasvir + ribavirin for genotype 1 GZR + EBR + RBV 8W GZR + EBR + RBV 12W GZR + EBR 12W GZR + EBR + RBV 12W GZR + EBR 12W 0

SVR 12 (HCV RNA < 25 IU/ml) in patients with 12 weeks of treatment, % (95% CI) Sulkowski M. Lancet 2015;385: C-WORTHY C-WORTHY Study: grazoprevir + elbasvir + ribavirin for genotype 1 GZR + EBR + RBV Genotype 1a GZR + EBR + RBV Genotype 1b GZR + EBR Genotype 1a GZR + EBR Genotype 1b (87-99 % 92 (78-98) 92 (81-98) N (77-100) 76 0

C-WORTHY Study: grazoprevir + elbasvir + ribavirin for genotype 1 HCV mono-infectedHIV co-infected GZR + EBR + RBV 8W GZR + EBR + RBV 12W GZR + EBR 12W GZR + EBR + RBV 12W GZR + EBR 12W Treatment armB1A1, A2, B2A3, B3B12B13 Number of patients Serious adverse events, N01011 Adverse events in ≥ 10% Fatigue47%27%23%7% Headache23%20%35%14%3% Nausea27%19%16%03% Diarrhea17%12% 3%0 Hemoglobin < 10 g/dl3%11%03%0 Elevation of bilirubin > x 5 baseline 3%2%07%0 Adverse events and laboratory abnormalities Sulkowski M. Lancet 2015;385: C-WORTHY

SVR 12 according to detection of resistance-associated variants at baseline NS3 variants at baselineNS5A variants at baseline NOYESNOYES N SVR 12 (HCV RNA < 25 IU/ml) 92%91%95%*68% * Mutations detected Most prevalent NS3 variants at failure : Y56H A156T D168A/N Most prevalent NS5A variants at failure : Q30R/H L31M Y93H/N * p < Sulkowski M. Lancet 2015;385: C-WORTHY C-WORTHY Study: grazoprevir + elbasvir + ribavirin for genotype 1

 Summary –In this phase II study, 12 weeks of oral treatment with grazoprevir and elbasvir, with or without RBV, was well tolerated and led to high rates of SVR 12 (87–98%) in previously untreated patients without cirrhosis with HCV genotype 1 monoinfection or HIV/HCV co-infection The addition of RBV was not associated with increased rates of SVR 12 Similar efficacy was seen in patients with genotype 1a and 1b SVR 12 was similar with 12 weeks of treatment in mono and co-infected patients 8 weeks of GZR + EBR + RBV led to suboptimal SVR 12, mainly because of relapse Patients with NS5A baseline resistance-associated variants had lower SVR 12 Virological relapse was associated with emergence of resistance-associated variants to one or both of the drugs (GZR, EBR) in the regimen Treatment-emergent, clinically significant, adverse events were infrequent No discontinuation for adverse event In HIV co-infected patients, adverse events were less frequently reported, and HIV suppression was maintained Sulkowski M. Lancet 2015;385: C-WORTHY