sof/vel 400/100 mg qd n = 250 w24 sof + rbv w12 * randomisation was stratified on prior treatment...

SOF/VEL400/100 mg qd

N = 250

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: 2608-17

Design

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

RBV (in 2 divided doses): 1000 mg if < 75 kg or 1200 mg/day if ≥ 75 kg

> 18 yearsChronic HCV infection

Genotype 3Naïve or pre-treatment

with IFN-based regimenCompensated cirrhosis allowed**

No HBV or HIV co-infection

SVR12

Randomisation*1 : 1

Open-label

ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3

SOF/VEL12 weeksN = 277

SOF + RBV24 weeksN = 275

Age, years, mean 49 50Female 39% 37%White 90% 87%HCV RNA, log10 IU/ml, mean 6.2 ± 0.72 6.3 ± 0.71IL28B CC 38% 40%Cirrhosis 29% 30%Treatment experienced 26% 26%Response to previous HCV treatment

No responseRelapse

28%72%

34%66%

Discontinuation, NLack of efficacyAdverse event Lost to follow-upNon adherenceWithdrew consentDeath

2100100

21194232

Baseline characteristics and patient disposition

ASTRAL-3


Foster GR. N Engl J Med 2015; 373: 2608-17

ASTRAL-3

*adjusted absolute difference : 14.8 (95% CI : 9.6 to 20.0) ; p < 0.001 = superiority

SVR12 according to baseline NS5A RAVs in SOF/VEL group– Absent, N = 231 : SVR12 = 97.4%– Present, N = 43, SVR12 = 88.4% (84% if Y93H)


SVR12, % (95% CI)

0

20

40

60

80

10095.3

(92.1-97.5)

277

SOF/VEL12 weeks

275

SOF + RBV24 weeks

80.4(75.2-84.9)

*

%


ASTRAL-3

SVR12 by cirrhosis or treatment history


197 80 83 206 204 71 71187No cirrhosis Cirrhosis Treatment-naïve Treatment-experienced

SVR12 in cirrhosis : SOF/VEL group : 93% if treatment-naïve ; 89% if treatment-experiencedSOF + RBV group : 73% if treatment-naïve ; 58% if treatment-experienced

7 relapses 22 relapses6 other

4 relapses2 other

15 relapses13 other

7 relapses

1 non-response23 relapses2 other

SOF/VEL SOF + RBV

100

80

60

40

20

0

87(82-92)

9794-99)

66(55-76)

91(83-96) 86

(81-91)

97(94-99)

63(51-75)

90(81-96)

4 relapses2 other

16 relapses8 other


ASTRAL-3

Characteristics of patients receiving SOF/VEL who relapsed


Age, sex, race GT Cirrhosis IL28BHCVRNA (log10 IU/ml)

Timing of virologicfailure

HCVtreatment

history

Resistance-associated variants

NS5ANS5B

Baseline and follow-up W12

Baseline FU W12 BL

56, F, White 3a Yes CC 6.9 FU W4 Naïve 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 Naïve 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 Naïve 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

46, M, White 3a Yes CT 6.1 FU W4 Experienced A30K (> 99%) A30K (> 99%)Y93H (> 99%) None

57, M, White 3a Yes CT 6.3 FU W4 Naïve 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


SOF/VEL12 weeksN = 277

SOF + RBV24 weeksN = 275

At least one adverse event 88% 95%Serious adverse events 6 (2%) 15 (5%)Grade 3-4 adverse events 12 (4%) 23 (8%)Discontinuation due to adverse event 0 9 (3%)Death 0 3 (< 1%)Adverse events in > 10% of patients

Headache 32% 32%Fatigue 26% 38%Insomnia 11% 27%Nausea 17% 21%Nasopharyngitis 12% 12%Irritability 8% 15%Cough 5% 13%Pruritus 3% 13%Dyspepsia 3% 11%

Grade 3-4 laboratory abnormalities 7% 17%Hemoglobin < 10 g/dl 0 4%Lymphocyte count < 500/mm3 3 4Platelet count 25,000-50,000/mm3 1 1Total bilirubin > 2.5 mg/dl 0 3

Adverse events, N (%)

ASTRAL-3



ASTRAL-3

ASTRAL-3 study: SOF/VEL vs SOF + RBV in genotype 3 Summary

– Rates of SVR12 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 SVR12 of 95% with SOF/VEL for 12 weeks versus 80% with SOF + RBV for 24 weeks (p < 0.001)

• 91% SVR12 rate in patients with cirrhosis• Limitation : small number of black patients

– However, the rate of SVR12 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


sof/vel 400/100 mg qd n = 250 w24 sof + rbv w12 * randomisation was stratified on prior treatment...

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