1. LDV/SOF Open-label Chronic HCV infection Genotype 1 Failure to achieve SVR 12 on a short-course of 1 st line LDV/SOF-containing regimen No cirrhosis N = 34 SVR 12 Co-formulated ledipasvir-sofosbuvir (LDV 90 mg/SOF 400 mg) : 1 pill qd SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF  Design  Objective –Primary endpoint : SVR 12 (HCV RNA < 12 IU/ml) by intention to treat SYNERGY-D W12 Wilson EM. Clin Infect Dis 2016; 62:230-8

2. SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF N = 34 Mean age, years59 Female18% Race : white / black82% / 18% Genotype 1a / 1b, N26 / 8 Fibrosis stage F0-F2 / F3, N33 / 1 HCV RNA log 10 IU/ml, median6.1 Prior relapse to LDV/SOF + GS-9669 x 6 weeks LDV/SOF + GS-9451 x 4 weeks LDV/SOF + GS-9451 + GS-9669 x 4 weeks 1 14 19 Weeks to retreatment, mean25.1 RAVs > 25-fold resistance : NS5A / NS5B85.3% / 2.9% Baseline characteristics SYNERGY-D Wilson EM. Clin Infect Dis 2016; 62:230-8

3. SVR 12 (HCV RNA < 43 IU/ml) ITT Per protocol : 31/32 (96.9%) 2 patients withdrew consent 1 relapse at W8 post-treatment LDV/SOF N = 34 Serious adverse event 1 (chest pain in a cocaine user, unrelated) Death, grade 3 or 4 adverse event0 Adverse event leading to discontinuation0 Diarrhea2 (5.9%) Fatigue2 (5.9%) Constipation2 (5.9%) Grade 3 laboratory abnormality3 (8.8%) Adverse events, N (%) SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF 0 100 75 50 25 91.2 34 % SYNERGY-D Wilson EM. Clin Infect Dis 2016; 62:230-8

4. SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF  Deep sequencing at baseline (before 1 st LDV/SOF treatment), at relapse, and prior to retreatment  Prior to retreatment –NS5A RAVs : 29/34 : SVR 12 in 26/29 (89.7%) [ITT] ; 96.3% per protocol RAVs with > 100 fold resistance to LDV –L31M/V/I, N = 17 (L31M, N = 16) –Q30R/H/T, N = 13 (Q30R, N = 8) –Y93H/C/N, N = 7 (Y93H, N = 6) –NS5B RAV : 1/34 : 1/1 achieved SVR 12 L159F  Relapse (n=1) –Genotype 1b, 1 st treatment with LDV/SOF + GS-9451 x 6 weeks. RAV at baseline = L31M, at 1 st relapse and prior to retreatment : L31M + Y93H, no NS5B mutant. At failure (relapse of retreatment) : emergence of S282T + V321I (NS5B), no additional NS5A RAVs SYNERGY-D Wilson EM. Clin Infect Dis 2016; 62:230-8

5. SYNERGY-D Study: LDV/SOF retreatment in genotype 1 failing short-course LDV/SOF  Summary –Patients with HCV genotype 1 infection who had accumulated RAVs during previous short-course combination therapy containing LDV/SOF achieved an SVR 12 rate of 91% when retreated with 12 weeks of LDV/SOF –Of the 27 patients with mutations associated with > 25-fold baseline NS5A resistance in vitro who completed 12 weeks of therapy, 26 (96.3%) achieved SVR 12 –The patient who relapsed had HCV with > 1000-fold NS5A RAVs L31M and Y93H prior to retreatment and NS5B RAVs S282T and V321I emerged following retreatment, both of which have been shown to reduce in vitro susceptibility to SOF –Retreatment was safe and extremely well tolerated. No patient discontinued the drugs due to adverse events. Side effects were generally mild SYNERGY-D Wilson EM. Clin Infect Dis 2016; 62:230-8