W24 SOFVEL gt 18 years Chronic HCV infection Genotype 1 to 6 Naïve or treatmentexperienced No prior treatment with NS5A or NS5B inhibitor ChildPugh B cirrhosis No hepatocellular ID: 760339
Download Presentation The PPT/PDF document "SOF/VEL 400/100 mg qd N = 75" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
SOF/VEL400/100 mg qd
N = 75
W24
SOF/VEL
>
18 years
Chronic HCV infectionGenotype 1 to 6Naïve or treatment-experiencedNo prior treatment with NS5A or NS5B inhibitorChild-Pugh B cirrhosis **No hepatocellular carcinomaNo liver transplantationCreatinine clearance > 50 ml/minPlatelets > 30,000/mm3
Randomisation*1 : 1 : 1Open-label
* Randomisation was stratified on HCV ge
notype
*
* Metavir F4 or Ishak 5-6 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 and APRI > 2
ObjectivesSVR12 (HCV RNA < 15 UI/ml) with 2-sided 95% CI, by ITT, 99% power to detect a SVR12 ≥ 41% ;not powered to detect significant differences in SVR among the treatment groupsChanges in MELD and CPT scores
SVR
12
W12
SOF/VEL + RBV
SVR
12
RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)
ASTRAL-4
Curry MP. N
Engl
J Med 2015; 373: 2618-28
N = 75
N = 75
Design
ASTRAL-4 Study: SOF/VEL in patients
with decompensated liver disease
Slide2SOF/VEL , 12WN = 90SOF/VEL + RBV, 12WN = 87SOF/VEL , 24WN = 90Age, years, mean585858Female37%24%30%White88%91%90%Genotype 1a1b32 / 4 / 656%20%16%4% / 4% / 052%16%15%5% / 2% / 061%18%13%4% / 2% / 1%HCV RNA, log10 IU/ml, mean6.05.95.9IL28B CC22%25%24%Treatment-experienced64%54%47%MELD score : median / ≥ 1510 / 4%10 / 5%11 / 16%Ascites82%75%83%Encephalopathy58%62%66%Albumin, g/dl, median3.23.13.1Platelets/mm3758680Discontinuation, NLack of efficacyAdverse eventNon adherence101051406141
Baseline characteristics and patient disposition
Charlton MR, AASLD 2015, Abs. LB13 ; Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients
with decompensated liver disease
Slide3Charlton MR, AASLD 2015, Abs. LB13 ; Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients with decompensated liver disease
SVR12, % (95% CI)
SOF/VEL 12W
SOF/VEL + RBV 12W
SOF/VEL 24W
0
20
40
60
80
100
Overall
Genotype 1a
Genotype 3
Genotype 2, 4, 6
83
(
74-90)
94
(87-98)
86
(77-92)
50
(23-77)
85
(55-98)
50
(21-79)
100
100
86
90
87
90
14
13
12
4
4
4
G2
2
2
G4
1
G6
89
(65-99)
100
(77-100)
88
(62-98)
18
14
16
88
(76-96)
94
(85-99)
93
(82-98)
5
0
54
55
Genotype 1b
Breakthrough, N
Relapse, N
LTFU, N
Death, N
-
11
1
3
-
2
-
2
1
7
3
2
-
-
-
-
-
---
----
----
----
---1
----
----
----
-6-1
1*1--
14-1
*Patient with non-detectable drug levels at time of virological failure, LTFU, lost to follow-up
4
%
Slide4Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients with decompensated liver disease
GroupType ofvirologic failureAge, sex, raceGTIL28BHCVRNATime of virologic failureNS5A RAVsNS5B RAVsPre-treatmentPost-treatmentPost-treatmentSOF/VEL12WRelapse55, F, white3aCT5.9PT W12Y93H (> 99%)Y93H (> 99%)L320I (1%)58, M, white1aCT5.1PT W12M28V (6%)NoneNone57, M, white3aCT6.2PT W4Y93H (5%)Y93H (> 99%)None56, M, white3aCC6.5PT W12NoneY93H (> 99%)None62, M, white1aCT6.2PT W4NoneNoneNone60, M, black1bCT6.4PT W4Y93H (80%)L31M (50%), L31V (50%),Y93H (> 99%)None57, M, white3aTT5.6PT W4NoneY93H (> 99%)None48, M, white3aCT6.3PT4NoneY93H (> 99%)None57, M, white1aCT6.5PT12NoneY93N (> 99%)None57, M, white3aCT6.0PT4NoneY93H (> 99%)None59, M, black1bTT6.1PT12L31I (8%), L31M (3%), Y93H (60%)L31M (90%), L31V (10%), Y93H (> 99%)L159F (14%)S282T (4%)SOF/VEL+ RBV12WRelapse59, M, white1aCT6.4PT12NoneNoneNone48, M, white3CT5.9PT4NoneY93H (> 99%)NoneBreakthrough56, M, white3aTT5.9W8Y93H (3%)Y93H (> 99%)N142T (3%)E237G (2%)SOF/VEL24WRelapse61, M, black3aCT6.3PT4NoneY93H (> 99%)None58, M, white3aCT6.2PT4NoneY93H (99%)None57, M, white3aCT6.3PT4NoneY93H (> 99%)None60, M, white1a-6.9PT4Q30H (65%), Y93H (57%), Y93N (1%)Q30H (> 99%),Y93H (> 99%)L159F (96%)S282T (3%)51, M, white1bTT5.4PT12L31M (> 99%)L31M (98%), L31V (2%),Y93H (> 99%)None62, M, white1aCT5.5PT12NoneQ30R (95%), H58D (95%),Y93N (4%)None53, F, white3aCC6.0PT4NoneM28T (2%), Y93H (> 99%)NoneBreakthrough52, M, white3aCT5.3W12NoneY93H (98%)E237G (2%)
Characteristics of patients with
virologic
failure
Slide5Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients with decompensated liver disease
CPT score change : baseline to follow-up W12 (% of patients)
11%
11% Worsened
47% Improved
0
10
20
40
50
60
30
< 1
< 1
2
12
32
42
8
2
< 1
< 1
1
1
5
31
79
106
21
4
1
1
-5
-4
-3
-2
-1
0
1
2
4
5
Change in
CPT score
N =
17/267patients had no follow-up W12 assessment
%
Slide6ASTRAL-4 Study: SOF/VEL in patients with decompensated liver disease
MELD change: baseline to follow-up W12 (% of patients)
0
10
20
40
50
30
Baseline
MELD < 15
N = 223
27% Worsened
51% Improved
0
0
3
9
22
4
1
-11
-8
-7
-5
0
2
4
7
Change in MELD
N =
0
0
2
-6
4
-4
18
-3
34
-2
44
-1
49
30
1
2
3
1
11
< 1
< 1
2
1
10
13
20
15
8
2
4
1
2
22
Baseline
MELD
>
15
N = 27
0
10
20
40
50
30
8% Worsened
84% Improved
0
11
0
0
7
0
0
4
0
1
3
4
0
2
0
1
1
4
0
3
11
1
1
0
2
-11
-8
-7
-5
Change in MELD
N=
1
-6
4
-4
5
-3
1
-2
7
-1
0
4
4
4
4
7
15
19
26
Curry MP. N
Engl
J Med 2015; 373: 2618-28
ASTRAL-4
17/267patients had no follow-up W12 assessment
%
%
Slide7SOF/VEL12 weeksN = 90SOF/VEL + RBV12 weeksN = 87SOF/VEL24 weeksN = 90At least one adverse event81%91%81%Serious adverse events19%16%18%Grade 3-4 adverse events18%13%19%Discontinuation due to adverse event1 (1%)4 (5%)4 (4%)Death3 (3%)3 (3%)3 (3%Adverse events in > 10% of patientsFatigue26%39%23%Nausea24%25%20%Headache26%21%19%Anemia4%31%3%Diarrhea7%21%8%Insomnia10%14%10%Pruritus11%5%4%Muscle spasm3%11%4%Dyspnea4%10%2%Cough2%10%0Hemoglobin < 10 g/dl / < 8.5 g/dl8% / 1%23% / 7% *9% / 1%
Adverse events, N (%)
* RBV discontinuation : 17%, dose reduction : 37%
Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients
with decompensated liver disease
Slide8SOF/VEL12 weeksN = 90SOF/VEL + RBV12 weeksN = 87SOF/VEL24 weeksN = 90Hemoglobin < 10 g/dl / < 8.5 g/dl8% / 1%23% / 7% *9% / 1%White cell count 1000-1500/mm3 < 1000/mm31 (1%)1 (1%)1 (1%)1 (1%)4 (4%)0Lymphocyte count350-500/mm3< 350/mm310 (11%)3 (3%)12 (14%)12 (14%)8 (9%)6 (7%)Neutrophil count500-750/mm3< 500/mm32 (2%)01 (1%)1 (1%)1 (2%)1 (1%)Platelet count25,000-50,000/mm3< 25,000/mm315 (17%)1 (1%)10 (11%)018 (20%)0
Hematologic abnormalities, N (%)
* RBV discontinuation : 17%, dose reduction : 37%
Charlton MR, AASLD 2015, Abs. LB13 ; Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients
with decompensated liver disease
Slide9SummaryTreatment with SOF/VEL for 12 or 24 weeks or SOF/VEL + RBV for 12 weeks resulted in high SVR12 rates in HCV patients with decompensated cirrhosis caused by HCV of all genotypesSOF/VEL + RBV resulted in the highest overall SVR12 rates, with the lowest rates of virologic failure in HCV genotype 3 patientsTreatment was associated with improved MELD and CPT scores largely due to decreased bilirubin and improvement in synthetic function (albumin)SOF/VEL for 12 or 24 weeks or SOF/VEL + RBV for 12 weeks was safe and well tolerated, with adverse events consistent with clinical sequelae of advanced liver disease and RBV toxicityLimitationsStudy not powered to detect significant differences among the 3 treatment groupsOnly patients with moderate hepatic decompensation were enrolledThe numbers of patients with HCV genotype 2, 4, or 6 were smallLimited number of black patients
Curry MP. N Engl J Med 2015; 373: 2618-28
ASTRAL-4
ASTRAL-4 Study: SOF/VEL in patients
with decompensated liver disease