ASTRAL-3 Study: SOF/VEL vs. SOF+RBV in Genotype 3 Randomisation
This study compares SOF/VEL versus SOF+RBV treatment in patients with genotype 3 chronic HCV infection. The objective is to achieve SVR12 with non-inferiority of SOF/VEL with a lower bound of 95% CI for difference of -10% and 94% power. Baseline characteristics, patient disposition, SVR12 rates, and outcomes by cirrhosis or treatment history are discussed.
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ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Design Randomisation* 1 : 1 Open-label W12 W24 SOF/VEL 400/100 mg qd > 18 years N = 250 Chronic HCV infection Genotype 3 Na ve or pre-treatment with IFN-based regimen Compensated cirrhosis allowed** No HBV or HIV co-infection SVR12 SOF + RBV N = 250 * Randomisation was stratified on prior treatment (na ve 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 RBV (in 2 divided doses): 1000 mg if < 75 kg or 1200 mg/day if 75 kg Objective SVR12 (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 ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Baseline characteristics and patient disposition SOF/VEL 12 weeks N = 277 49 39% 90% 6.2 0.72 38% 29% 26% SOF + RBV 24 weeks N = 275 50 37% 87% 6.3 0.71 40% 30% 26% Age, years, mean Female White HCV RNA, log10IU/ml, mean IL28B CC Cirrhosis Treatment experienced Response to previous HCV treatment No response Relapse Discontinuation, N Lack of efficacy Adverse event Lost to follow-up Non adherence Withdrew consent Death 28% 72% 2 1 0 0 1 0 0 34% 66% 21 1 9 4 2 3 2 ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 SVR12, % (95% CI) * 95.3 % (92.1-97.5) 100 80.4 (75.2-84.9) 80 60 40 20 277 275 0 SOF/VEL 12 weeks SOF + RBV 24 weeks *adjusted absolute difference : 14.8 (95% CI : 9.6 to 20.0) ; p < 0.001 = superiority SVR12according to baseline NS5A RAVs in SOF/VEL group Absent, N = 231 : SVR12= 97.4% Present, N = 43, SVR12= 88.4% (84% if Y93H) ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 SVR12by cirrhosis or treatment history SOF/VEL SOF + RBV 97 (94-99) 97 100 91 90 94-99) 87 86 (83-96) (81-96) (82-92) (81-91) 80 66 63 (55-76) (51-75) 60 22 relapses 6 other 7 relapses 7 relapses 40 4 relapses 2 other 16 relapses 8 other 1 non-response 23 relapses 2 other 15 relapses 13 other 4 relapses 2 other 20 197 187 80 83 206 204 71 71 0 No cirrhosis Cirrhosis Treatment-na ve Treatment-experienced SVR12in cirrhosis : SOF/VEL group : 93% if treatment-na ve ; 89% if treatment-experienced SOF + RBV group : 73% if treatment-na ve ; 58% if treatment-experienced ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Characteristics of patients receiving SOF/VEL who relapsed Resistance-associated variants HCV RNA (log10 IU/ml) Timing of virologic failure HCV NS5B Age, sex, race GT Cirrhosis IL28B treatment history NS5A Baseline and follow-up W12 Baseline FU W12 BL 56, F, White 3a Yes CC 6.9 FU W4 Na ve Y93H (15.2%) Y93H (> 99%) None 58,M, White 3a Yes CC 6.3 FU W12 Experienced None Y93H (> 99%) None 61, M, White 3a Yes CT 6.0 FU W12 Na ve Y93H (> 99%) Y93H (> 99%) None 61 / M /White 3a No TT 5.5 FU W4 Experienced None Y93H (> 99%) None 50, M, White 3a No CT 6.5 FU W4 Na ve Y93H (> 99%) Y93H (> 99%) None 56, M, White 3a Yes TT 6.1 FU W4 Experienced None Y93H (> 99%) None 45, M, White 3 No CC 6.9 FU W4 Experienced Y93H (2.8%) Y93H (> 99%) None A30K (> 99%) Y93H (> 99%) 46, M, White 3a Yes CT 6.1 FU W4 Experienced A30K (> 99%) None 57, M, White 3a Yes CT 6.3 FU W4 Na ve None Y93H (> 99%) None 56, M, White 3a Yes CT 6.3 FU W4 Experienced None Y93H (> 99%) None 39, M, White 3a No CC 6.6 FU W12 Experienced None GT1a reinfection ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Adverse events, N (%) SOF/VEL 12 weeks N = 277 88% 6 (2%) 12 (4%) 0 0 SOF + RBV 24 weeks N = 275 95% 15 (5%) 23 (8%) 9 (3%) 3 (< 1%) At least one adverse event Serious adverse events Grade 3-4 adverse events Discontinuation due to adverse event Death Adverse events in > 10% of patients Headache Fatigue Insomnia Nausea Nasopharyngitis Irritability Cough Pruritus Dyspepsia Grade 3-4 laboratory abnormalities Hemoglobin < 10 g/dl Lymphocyte count < 500/mm3 Platelet count 25,000-50,000/mm3 Total bilirubin > 2.5 mg/dl 32% 26% 11% 17% 12% 8% 5% 3% 3% 7% 0 3 1 0 32% 38% 27% 21% 12% 15% 13% 13% 11% 17% 4% 4 1 3 ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Summary Rates of SVR12in 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 SVR12of 95% with SOF/VEL for 12 weeks versus 80% with SOF + RBV for 24 weeks (p < 0.001) 91% SVR12rate in patients with cirrhosis Limitation : small number of black patients However, the rate of SVR12was 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 ASTRAL-3 Foster GR. N Engl J Med 2015; 373: 2608-17
