SOF/VEL 400/100 mg qd N = 250 W24 SOF + RBV W12 * Randomisation was stratified on prior treatment (naïve or experienced) and cirrhosis (yes or no) ** Metavir.

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Presentation transcript:

SOF/VEL 400/100 mg qd N = 250 W24 SOF + RBV W12 * Randomisation was stratified on prior treatment (naïve or experienced) and cirrhosis (yes or no) ** Metavir F4 or Ishak 5-6 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 and APRI > 2 ASTRAL-3 Foster GR. N Engl J Med 2015; 373:  Design  Objective –SVR 12 (HCV RNA < 15 UI/ml), by ITT : non-inferiority of SOF/VEL with a lower bound of 95% CI for difference of - 10%, 94% power ; if non-inferiority, test for superiority with significance level of 0.05 RBV (in 2 divided doses): 1000 mg if < 75 kg or 1200 mg/day if ≥ 75 kg > 18 years Chronic HCV infection Genotype 3 Naïve or pre-treatment with IFN-based regimen Compensated cirrhosis allowed** No HBV or HIV co-infection SVR 12 Randomisation* 1 : 1 Open-label ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3

SOF/VEL 12 weeks N = 277 SOF + RBV 24 weeks N = 275 Age, years, mean4950 Female39%37% White 90%87% HCV RNA, log 10 IU/ml, mean6.2 ± ± 0.71 IL28B CC38%40% Cirrhosis29%30% Treatment experienced26% Response to previous HCV treatment No response Relapse 28% 72% 34% 66% Discontinuation, N Lack of efficacy Adverse event Lost to follow-up Non adherence Withdrew consent Death Baseline characteristics and patient disposition ASTRAL-3 ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Foster GR. N Engl J Med 2015; 373:

ASTRAL-3 *adjusted absolute difference : 14.8 (95% CI : 9.6 to 20.0) ; p < = superiority  SVR 12 according to baseline NS5A RAVs in SOF/VEL group –Absent, N = 231 : SVR 12 = 97.4% –Present, N = 43, SVR 12 = 88.4% (84% if Y93H) ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 SVR 12, % (95% CI) ( ) 277 SOF/VEL 12 weeks 275 SOF + RBV 24 weeks 80.4 ( ) * % Foster GR. N Engl J Med 2015; 373:

ASTRAL-3 SVR 12 by cirrhosis or treatment history ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype No cirrhosisCirrhosisTreatment-naïveTreatment-experienced SVR 12 in cirrhosis : SOF/VEL group : 93% if treatment-naïve ; 89% if treatment-experienced SOF + RBV group : 73% if treatment-naïve ; 58% if treatment-experienced 7 relapses 22 relapses 6 other 4 relapses 2 other 15 relapses 13 other 7 relapses 1 non-response 23 relapses 2 other SOF/VELSOF + RBV (82-92) ) 66 (55-76) 91 (83-96) 86 (81-91) 97 (94-99) 63 (51-75) 90 (81-96) 4 relapses 2 other 16 relapses 8 other Foster GR. N Engl J Med 2015; 373:

ASTRAL-3 Characteristics of patients receiving SOF/VEL who relapsed ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Age, sex, raceGTCirrhosisIL28B HCV RNA (log 10 IU/ml) Timing of virologic failure HCV treatment history Resistance-associated variants NS5A NS5B Baseline and follow-up W12 BaselineFU W12BL 56, F, White3aYesCC6.9FU W4NaïveY93H (15.2%)Y93H (> 99%)None 58,M, White3aYesCC6.3FU W12ExperiencedNoneY93H (> 99%)None 61, M, White3aYesCT6.0FU W12NaïveY93H (> 99%) None 61 / M /White3aNoTT5.5FU W4ExperiencedNoneY93H (> 99%)None 50, M, White3aNoCT6.5FU W4NaïveY93H (> 99%) None 56, M, White3aYesTT6.1FU W4ExperiencedNoneY93H (> 99%)None 45, M, White3NoCC6.9FU W4ExperiencedY93H (2.8%)Y93H (> 99%)None 46, M, White3aYesCT6.1FU W4ExperiencedA30K (> 99%) A30K (> 99%) Y93H (> 99%) None 57, M, White3aYesCT6.3FU W4NaïveNoneY93H (> 99%)None 56, M, White3aYesCT6.3FU W4ExperiencedNoneY93H (> 99%)None 39, M, White3aNoCC6.6FU W12ExperiencedNoneGT1a reinfection Foster GR. N Engl J Med 2015; 373:

SOF/VEL 12 weeks N = 277 SOF + RBV 24 weeks N = 275 At least one adverse event88%95% Serious adverse events6 (2%)15 (5%) Grade 3-4 adverse events12 (4%)23 (8%) Discontinuation due to adverse event09 (3%) Death03 (< 1%) Adverse events in > 10% of patients Headache32% Fatigue26%38% Insomnia11%27% Nausea17%21% Nasopharyngitis12% Irritability8%15% Cough5%13% Pruritus3%13% Dyspepsia3%11% Grade 3-4 laboratory abnormalities7%17% Hemoglobin < 10 g/dl04% Lymphocyte count < 500/mm 3 34 Platelet count 25,000-50,000/mm 3 11 Total bilirubin > 2.5 mg/dl03 Adverse events, N (%) ASTRAL-3 ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Foster GR. N Engl J Med 2015; 373:

ASTRAL-3 ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3  Summary –Rates of SVR 12 in every subgroup of patients with HCV genotype 3 were substantially higher among those who had received 12 weeks of SOF/VEL compared to 24 weeks of SOF + RBV, including patients with cirrhosis and previous treatment failure Overall SVR 12 of 95% with SOF/VEL for 12 weeks versus 80% with SOF + RBV for 24 weeks (p < 0.001) 91% SVR 12 rate in patients with cirrhosis Limitation : small number of black patients –However, the rate of SVR 12 was 88% among patients who had NS5A RAVs at baseline and 97% among those who did not, with the lowest rate (84%) observed among patients with the Y93H variant at baseline –SOF/VEL was well tolerated and, compared with SOF + RBV, lacked toxicities commonly associated with RBV –For patients with HCV genotype 3 infection, SOF/VEL for 12 weeks represents an improvement over standard treatment with 24 weeks of SOF + RBV, with a simple and highly effective regimen, together with shorter duration of treatment and fewer side effects, owing to the removal of RBV from the regimen Foster GR. N Engl J Med 2015; 373: