1.  Design  Objective –Difference in SVR ≥ 40% between the 2 groups, 99% power SOF + RBV Placebo Randomisation 3 : 1* Double blind HCV infection Genotype 2 or 3 Intolerant to prior IFN-treatment, ineligible, or unwilling IFN-based regimen HCV RNA ≥ 10,000 IU/ml Compensated cirrhosis allowed * Randomisation was stratified on cirrhosis (presence or absence) POSITRON Study: SOF + RBV for HCV genotypes 2 and 3 W12 SVR 12 W24 –SOF : 400 mg qd –RBV (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N = 71 N = 207 POSITRON Jacobson IM. NEJM 2013; 368:1867-77

2. POSITRON Study: SOF + RBV for HCV genotypes 2 and 3 Placebo N = 71 SOF + RBV N = 207 Mean age, years52 Female52%43% Race : white/black93% / 6%91% / 4% Body mass index, mean2829 HCV genotype 2 / 348% / 52%53% / 47% IL28B CC genotype41 %47% HCV RNA log 10 IU/ml, mean (SD) 6.3 ± 0.766.3 ± 0.77 Cirrhosis18%15% Reason for not using IFN treatment Contra-indication46%43% Unacceptable side effects11%8% Patient’s decision42%49% Discontinued treatment, N3 (AE)6 (4 AE) Returned for post-treatment W4 visit71204 Returned for post-treatment W12 visit-171 Baseline characteristics and patient disposition POSITRON Jacobson IM. NEJM 2013; 368:1867-77

3. HCV RNA < 25 IU/ml SOF + RBV Placebo SVR 12 by genotype and cirrhosis POSITRON Study: SOF + RBV for HCV genotypes 2 and 3 POSITRON 25 50 100 75 99 % 100 0 During treatment W4 83 78 92 21 94 No cirrhosis N 204 202 71 207 92 17 84 W12 Post-treatment (SVR) W4W12Cirrhosis Genotype 2Genotype 3 68 14 No cirrhosisCirrhosis 0 Jacobson IM. NEJM 2013; 368:1867-77

4. OR (95% CI)p Female vs male2.67 (1.2 - 5.94)0.016 Genotype 2 vs 38.66 (3.62 - 20.73)< 0.0001 Duration on prior IFN-based therapy ≤ 12 weeks vs no > 12 weeks vs no 0.57 (0.18 - 1.8) 0.13 (0.038 - 0.45) ns 0.0013 POSITRON Study: SOF + RBV for HCV genotypes 2 and 3  Virologic breakthrough during treatment : none  Relapse in patients with HCV RNA < 25 IU/ml at end of completed treatment –40/201 (20%) in patients who completed treatment –2/4 (50%) in patients who did not complete treatment  Multivariate analysis of factors associated with SVR 12  Resistance testing (sequencing) –Done in 39/42 relapses No SOF-associated mutation (S282T) 5 NS5B substitutions in > 2 subjects (no change in susceptibility to SOF) POSITRON Jacobson IM. NEJM 2013; 368:1867-77

5. POSITRON Study: SOF + RBV for HCV genotypes 2 and 3 Placebo N = 71 SOF + RBV N = 207 AE leading to treatment discontinuation34 Serious adverse event2 (3%)11 (5%) AE occurring in > 10% in either group Fatigue24%44% Nausea18%22% Headache20%21% Insomnia4%19% Pruritus8%11% Anemia013% Irritability1%9% Cough3%5% Diarrhea6%9% Rash8%9% Arthralgia1%8% Adverse events, n (%) POSITRON Jacobson IM. NEJM 2013; 368:1867-77

6. POSITRON Study: SOF + RBV for HCV genotypes 2 and 3  Summary –In this phase III study, 12 weeks of treatment with SOF and RBV resulted in a SVR 12 in 78% of patients for whom interferon treatment was not an option In genotype 2 infection, high response rates (SVR 12 > 92%) were observed in all patient subgroups In genotype 3 infection, response rates were lower than in genotype 2 infection, especially in the subgroup of patients with cirrhosis –No virologic resistance was detected in patients who did not have a sustained virologic response –The rate of premature discontinuation of treatment with SOF and RBV due to adverse events was low (2%) –In conclusion, 12 weeks of treatment with SOF and RBV can be an effective option for patients with HCV genotype 2 infection Jacobson IM. NEJM 2013; 368:1867-77 POSITRON