400100 mg qd N 500 N 100 W12 Placebo gt 18 years Chronic HCV infection Genotype 1 2 4 5 or 6 Naïve or pretreatment with IFNbased regimen Compensated cirrhosis allowed No HBV or HIV coinfection ID: 463533
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Slide1
SOF/VEL400/100 mg qd
N = 500
N = 100
W12
Placebo
>
18 years
Chronic HCV infectionGenotype 1, 2, 4, 5 or 6Naïve or pre-treatment with IFN-based regimenCompensated cirrhosis allowed**No HBV or HIV co-infection
Randomisation*5 : 1Double blind
*
Randomisation
was stratified on genotype
(1, 2, 4, 6 or indeterminate) and cirrhosis (yes or no)Genotype 5 were all included in the active arm
SVR
12
** Metavir F4 or Ishak 5-6 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 and APRI > 2
ASTRAL-1
Design
ObjectiveSVR12 (HCV RNA < 15 UI/ml), with 95% CI, by ITT: superiority > 5% to a prespecified rate of 85% (2-sided significance level of 5%, 90% power)
ASTRAL-1 Study: SOF/VEL in genotype 1, 2, 4, 5 or 6
Feld JJ. N
Engl
J Med. 2015;373:2599-607Slide2
SOF/VELN = 624
Placebo
N = 116
Age, years, mean
54
53
Female
40%
41%
White
79%
78%
Genotype
1a
1b
2
45
6
34%19%17%19%6%7%
40%
16%
18%19%07%HCV RNA, log10 IU/ml, mean6.3 + 0.666.3 + 0.58IL28B CC30%31%Cirrhosis19%18%Treatment experienced PI + PEG-IFN + RBVPEG-IFN + RBVIFN + RBV9%20%4%5%21%3%Discontinuation, NAdverse event / lost to follow-up / investigator decision21 / 1 / 032 / 0 / 1
Baseline characteristics and patient disposition
ASTRAL-1
ASTRAL-1 Study: SOF/VEL in genotype 1, 2, 4, 5 or 6
Feld JJ. N
Engl
J Med. 2015;373:2599-607Slide3
* Superiority to 85% (p < 0.001)SVR12 overall and by genotype, % (95 % CI)
SVR
12 according to baseline NS5A RAVsAbsent, N = 359, SVR
12 = 100% ; Present, N = 257, SVR12 = 99.2%
0
20
40
60
80
100
99 *
(97.9- 99.6)
624
Total
210
98.1
(95.2-99.5)
1a
118
99.2
(95.4-100)
1b
104
100
(96.5-100)
2
116
100
(96.9-100)
4
41
100
(91.4-100)
6
Genotype
35
5
97.1
(85.1-99.9)
1 relapse
2 lost to follow-up
1 withdrew consent
1 relapse
1 death
%
ASTRAL-1
ASTRAL-1
Study
: SOF/VEL in
genotype
1, 2, 4, 5 or 6
Feld JJ. N
Engl
J Med. 2015;373:2599-607Slide4
SVR12 by cirrhosis or prior treatment, % (95% CI)618624
496
501
120
121
418
423
200201
0
20
40
60
80
100
99
99
(97.7-99.7)
99.5
(97.3-100)
99.2
(95.5-100)
98.8
(97.3-99.6)
No
Yes
Naïve
Experienced
Total
Cirrhosis
Treatment History
1 relapse
1 death
1 withdrew consent
2 lost to follow-up
1 relapse
1 death
1 withdrew consent
2 lost to follow-up
1 relapse
1 relapse
624
501
121
423
201
%
ASTRAL-1
ASTRAL-1
Study
: SOF/VEL in
genotype
1, 2, 4, 5 or 6
Feld JJ. N
Engl
J Med. 2015;373:2599-607Slide5
Characteristics of patients with virologic relapse
Age
Sex
Race
GT
Cirrhosis
IL28B
HCVRNA
Timing of virologicfailure
HCVtreatment
history
Resistance-associated variants
NS5A
NS5B
BL
FU
BL
FU
56
M
White
1a
No
CT
6.5
FU W4
Naïve
Q30R (2.6%)
Y93N (> 99%)
None
None
58
M
Black
1b
Yes
TT
6.8
FU W4
PEG-IFN
+
RBV
Q30L (1.1%)
Q30R (98.7%)
L31M (> 99%)
Q30R (> 99%)
L31I (2.8%)
L31M (88.4%)
L31V (8.6%)
Y93H (72.3%)
None
None
HCV RNA in log
10
IU/ml; BL, baseline; FU, follow-up
ASTRAL-1
ASTRAL-1
Study
: SOF/VEL in
genotype
1, 2, 4, 5 or 6
Feld JJ. N
Engl
J Med. 2015;373:2599-607Slide6
SOF/VELN = 624
PlaceboN = 116
At least one adverse
event
78%
77%
Serious adverse
events15 (2%)
0
Grade 3-4 adverse events
18 (3%)
1 (< 1%)
Discontinuation due to adverse
event
1 (< 1%)
Anxiety attack
2 (2%)
Death
1 (<1%)
0 (0%)
Adverse
events in > 10% of patientsHeadache29%28%Fatigue20%20%Nasopharyngitis13%10%Nausea12%11%Hematologic abnormalities7%12%Hemoglobin < 10 g/dl2 (< 1%)0
Lymphocyte count 350-500/mm
3
3 (< 1%)
0
Neutrophil count 500-750/mm
3
4 (1%)
0
Platelet count 25 000-50 000/mm
3
1 (< 1%)
0
Adverse events and hematologic abnormalities, N (%)
ASTRAL-1
ASTRAL-1
Study
: SOF/VEL in
genotype
1, 2, 4, 5 or 6
Feld JJ. N
Engl
J Med. 2015;373:2599-607Slide7
48
0
4
8
12
16
20
24
28
32
36
49
50
51
52
53
54
VEL/SOF
placebo
Week
End
of treatment750481216202428323677798183VEL/SOFplaceboWeekEnd of treatment
0
4
8
12
16
20
24
28
32
36
5,4
5,6
5,8
6
VEL/SOF
placebo
Week
End
of
treatment
0
4
8
12
16
20
24
28
32
36
0
0.05
0.1
0.15
0.2
VEL/SOF
placebo
Week
End
of
treatment
ASTRAL-1
ASTRAL-1
Study
: SOF/VEL in
genotype
1, 2, 4, 5 or 6
Younossi ZM, J. Hepatology 2016;65:33-9Patient-reported outcomesPhysical component (SF-36)Mental component (SF-36)Fatigue scaleFunctional
Assessment of Chronic Illness Therapy-Fatigue Activity/energy scoreWork productivity impairmentActivity impairmentChronic Liver Disease Questionnaire-HCVSlide8
-10
-5
0
5
10
SF-36:
physical
SF-36: mental
FACIT-F: fatigue
FACIT-F: total
CLDQ-HCV
Work
productivity
WPAI:SHP:
activity
-3
0
3
6
9
12
SF-36:
physical
SF-36: mental
FACIT-F: fatigue
FACIT-F: total
CLDQ-HCV
Work
productivity
WPAI:SHP:
activity
ASTRAL-1
ASTRAL-1
Study
: SOF/VEL in
genotype
1, 2, 4, 5 or 6
Younossi
ZM, J.
Hepatology
2016;65:33-9
Independent association with summary patient-reported outcomes
in a mixed longitudinal model of the use of SOF/VEL
(the reference treatment: placebo)
while receiving treatment
After the end of treatmentSlide9
SummaryIn this international, randomized, double-blind, placebo-controlled phase III study, treatment with sofosbuvir–velpatasvir for 12 weeks resulted in high rates of SVR12 (99%) in patients with HCV genotype 1, 2, 4, 5, or 6, including those with cirrhosis and those who had received previous treatment and those who had not been treatedVirologic failure was rare in patients infected with HCV genotype 1, and there were no virologic failures among those with HCV genotype 2, 4, 5Presence of baseline NS5A RAVs did not impact SVR12Although the 2 patients who had a relapse had RAVs at baseline and at the time of virologic failure, 99% of the patients with baseline NS5A RAVs had a SVR12, which suggests that pretreatment testing for RAVs is probably of little clinical value with SOF/VELTreatment with SOF/VEL for 12 weeks was well tolerated, with a safety profile similar to that of placebo treatment SOF/VEL for 12 weeks provides a simple, safe, and highly effective treatment for patients with HCV GT 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis
ASTRAL-1
ASTRAL-1 Study: SOF/VEL in genotype 1, 2, 4, 5 or 6
Feld JJ. N Engl J Med. 2015;373:2599-607