Download C-EDGE CO-STAR - HCV

C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
 Design
Randomisation *
2:1
Double blind
> 18 years
HCV infection
Genotype 1, 4, 6
HCV RNA ≥ 10 000 IU/mL
Treatment-naïve
≥ 3 months opioid replacement
Compensated cirrhosis allowed
HIV co-infection allowed
W12
W16
W24 W28
N = 201 GZR/EBR
100/50 mg qd
GZR/EBR
(N = 95)
Placebo
N = 100
* Randomisation was stratified on genotype and cirrhosis (yes or no)
 Objective
– SVR12 (HCV RNA < 15 IU/mL) with 2 – sided 95% CI
•
•
•
•
C-EDGE CO-STAR
By intention to treat analysis: includes all patients, reinfection = failure
By modified ITT (primary efficacy endpoint): reinfection = success
Discontinuation without relapse considered as failure
Superiority of immediate GZR/EBR (hypothesis of SVR12 ≥ 85%) vs reference
rate of 67%, 99% power
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
Baseline characteristics and patient disposition
GZR/EBR
N = 201
Placebo
N = 100
Age, years, median
48
47
Female, %
24
23
15 / 78 / 5
7 / 84 / 7
Genotype, %
1a
1b
4
6
76
15
6
2.5
75
15
6
4
IL28B CC, %
28.4
29.0
HCV RNA > 2 000 000 IU/mL, %
56.7
51.0
Fibrosis stage F4, %
19.9
22.0
HIV co-infection, %
8.0
5.0
Urine drug screen positive at D1, %
62.2
53.1
5
3
1
1
7
7
0
0
Black / White / Asian, %
Discontinuation before W12 of follow-up
(active phase), N
Lost to follow-up
For adverse event
Administrative reason
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
Primary endpoint: SVR12 (HCV RNA < 15 IU/mL), % (95% CI), ITT mFAS*
Immediate GZR/EBR
%
94.0
(89.8-96.0)
100
95.5
(90.9-98.2)
93.3
(77.9-99.2)
91.7
(61.5-99.8)
60
(14.7-94.7)
75
50
25
0
N=
201
All patients
SVR12 , ITT, Full analysis set
Non-virologic failure
Relapse
Reinfection
91.5%
5
7
5
154
30
Genotype 1a Genotype 1b
93.5%
3
4
3
93.3%
1
1
0
12
5
Genotype 4
Genotype 6
91.7%
20%
1
0
0
0
2
2
* ITT, mFAS: reinfection = success, unrelated discontinuation = excluded
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
Primary endpoint: SVR12 (HCV RNA < 15 IU/mL), % (95% CI), ITT mFAS*
Deferred GZR/EBR
%
89.5
(81.5-94.8)
100
90.1
(80.7-95.9)
92.9
(66.1-99.8)
100
(54.1-100)
75
50
(6.8-93.2)
50
25
0
N=
95
All patients
SVR12 , ITT, Full analysis set
Non-virologic failure
Relapse
Breakthrough
Reinfection
89.5%
7
1
2
0
71
14
Genotype 1a Genotype 1b
90.1%
6
0
1
0
92.9%
1
0
0
0
6
4
Genotype 4
Genotype 6
100%
50%
0
0
0
0
0
1
1
0
* ITT, mFAS: reinfection = success, unrelated discontinuation = excluded
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
SVR12 (HCV RNA < 15 IU/mL) in the immediate treatment group,
by subgroup, % (95% CI), ITT, Full analysis set *
%
100
92.8
(87.5-96.4)
93.8
(85-98.3)
92.5
91.3
(85.8-95.2) (79.6-98.4)
92.0
(84.3-96.7)
87.5
(74.8-95.3)
90.4
(84.2-94.8)
153
48
136
65
161
40
88
113
Male
Female
Positive
Negative
No
Yes
No
Yes
91.2
(84.3-95.7)
75
50
25
0
Sex
Drug screen
Cirrhosis
HCV RNA
> 2 000 000 IU/mL
* Reinfection = failure
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
SVR12 and SVR24 (HCV RNA < 15 IU/mL), %, per protocol
Immediate treatment
%
100
Deferred treatment
95.5
94.1
96.6
198
186
88
SVR24
SVR12
96.5
75
50
25
N=
0
C-EDGE CO-STAR
SVR12
85
SVR24
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
 Urine drug screen results, from D1 to treatment W12
– At each visit, in both groups
• > 50% of patients with positive urine drug screen of any drug among the
8 following classes: amphetamines, barbiturates, benzodiazepines,
cannabinoids, cocaine, opiates, phencyclidine, propoxyphene
– Positive UDS results at baseline or during treatment (2 or more positive UDS
results) did not affect adherence or efficacy, regardless of which drug class
was positive on UDS
 Adherence to study drugs
Immediate
Adherence > 95% during the 12 weeks
C-EDGE CO-STAR
Deferred GZR/EBR
GZR/EBR
Placebo phase
Active phase
96.5%
100%
95.8%
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
SVR12 and urine drug screen results
in the immediate treatment group (all randomised patients)
SVR12
Subgroup
n/N
% (95% CI)
Opiod agonist therapy at D1
Buprenorphine
Methadone
37/39
147/162
94.9 (82.7-99.4)
90.7 (85.2-94.7)
Drug screen during the treatment period
Positive (at least 2 time points)
Negative
123/136
61/65
90.4 (84.2-94.8)
93.8 (85.0-98.3)
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
 Reinfection
%
Reinfections
3.0
Virologic failures
2.0
1.0
0.0
Reinfection, N (%)
Virologic failure, N (%)
TW10 or 12
FW4
FW8
FW12
FW24
0 (0.0)
2 (0.7)
0 (0.0)
3 (1.0)
5 (1.7)
3 (1.0)
0 (0.0)
2 (0.7)
1 (0.3)
2 (0.7)
 Incidence of reinfection
– 4.6 reinfections (CI, 1.7 to 10.0) per 100 person-years
 6 reinfections: different genotype, subtype or viral strain
C-EDGE CO-STAR
Dore G. EASL 2016, Abs. SAT-163, J Hepatol 2016;64:S771 ;
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
Summary of 18 patients with virological failure or probable reinfection
Age, sex, cirrhotic status
HCV RNA
Genotype
Drug screen
Type/Time of failure
61-y, white male, cirrhosis
5.6 million IU/mL
1a
Positive
Relapse follow-up W12
50-y, black male, cirrhosis
13.6 million IU/mL
1a
Negative
Relapse follow-up W4
56-y, male, no cirrhosis
1.2 million IU/mL
1a
Positive
Relapse follow-up W8
63-y, white female, no cirrhosis
3.5 million IU/mL
1a
Positive
Relapse follow-up W4
63-y, black female, no cirrhosis
1.7 million IU/mL
1b
Negative
Relapse follow-up W12
29-y, asian male, no cirhhosis
33.2 million IU/mL
6a
Positive
Relapse follow-up W4
34-y, asian male, no cirrhosis
25.5 million IU/mL
6a
Positive
Relapse follow-up W8
335 157 IU/mL
1a
Not done
Relapse follow-up W24
50-y, black female, cirrhosis
9.5 million IU/mL
1b
Positive
Relapse follow-up W24
58-y, black male, cirrhosis
2.8 million IU/mL
1a
Positive
Breakthrough W12
59-y, asian male, no cirrhosis
1.9 million IU/mL
6b
Negative
Relapse follow-up W8
43-y, asian male, no cirrhosis
6.8 million IU/mL
6a
Positive
Breakthrough W12
48-y, asian male, no cirrhosis
17 274 IU/mL
1a
Positive
Reinfection (GT 6a) FU W8
33-y, white female, no cirrhosis
535 293 IU/mL
1a
Positive
Reinfection (GT 1a) FU W8
55-y, white female, cirrhosis
3.2 million IU/mL
1a
Positive
Reinfection (GT 3a) FU W8
45-y, asian male, no cirrhosis
4.8 million IU/mL
6a
Positive
Reinfection (GT 1b) FU W8
37-y, asian female, no cirrhosis
18.6 million IU/mL
6a
Positive
Reinfection (GT 6a) FU W8
33-y, white male, no cirrhosis
1.5 million IU/mL
1b
Not done
Reinfection (GT 3a) FU W24
29-y, white female, no cirrhosis
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
 Viral resistance (population sequencing)
– Baseline NS3 RAVs: genotype 1a = 64/149 (43.0%) ; genotype 1b = 3/29
(10.3%)
– Baseline NS5A RAVs: genotype 1a = 3/150 (2.0%) ; genotype 1b = 3/29
(10.3%)
– SVR12 in genotype 1
• 98.2% vs 95.5% if NS3 RAVs absent or present, respectively
• 97.7% vs 83.3% if NS5A RAVs absent or present, respectively
– SVR12 in genotype 4 with baseline NS5A RAVs = 3/3
– Genotype 6
• SVR12 in patients with baseline NS3 RAVs = 3/5
• SVR12 in patients with baseline NS5A RAVs = 3/4
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
Adverse events, %
GZR/EBR
N = 201
Deferred GZR/EBR
Placebo phase
N = 100
Active phase
N = 95
Serious adverse event
3.5
4.0
3.0
Serious drug-related adverse event
0.5
1.0
0
Adverse event leading to discontinuation
0.5
1.0
0
Fatigue
15.9
20.0
13.7
Headache
12.4
13.0
12.6
Nausea
10.9
9.0
7.4
AST/ALT > 3 x ULN
0
2
0
Total bilirubin > 2.6 x ULN
0
0
0
0.5
1
1.1
0
0
0
Most frequent adverse events
Hemoglobin < 8.5 g/dL
Creatinine > 2.5 times baseline level
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
 Summary
– EBR/GZR demonstrated high efficacy in genotype 1
and 4-infected patients receiving opiate agonist therapy
• Limitation: small number of genotype 6-infected patients
– Acceptable safety profile with comparable adverse event rates
between the immediate and deferred treatment arms
– High study medication adherence
– Stable ongoing drug use throughout the initial treatment phase
in both groups
– Reinfection rate is higher in the immediate follow-up period
– These results support the removal of drug use as a barrier to interferonfree HCV treatment for patients receiving opiate agonist therapy
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:625-636
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV
infected drug users on opiod replacement therapy
3-year Follow-up on Risk Factors and Rate of Reinfection
 Observational cohort (6-month follow-up visits)
– Follow-up of 199/296 (67%) patients enrolled in Co-STAR
– Positive urine drug screen (UDS) at enrollment: 56% and 58% of patients in
the 3YFU study and the Phase 3 trial, respectively
– Median time from EOT to the first visit during the 3YFU was 330 days
(range: 206-485)
– 84 (56%) patients reported any drug use (non-injecting or injecting) in the
past 6 months. Injecting drug use in the past 6 months was reported by
25% of patients
– Reinfection rate : higher in the immediate follow-up period through week
(FW)12 (N = 5) than in the period through FW24 (+1) and through the
ongoing observational follow-up
• Overall reinfection rate through the 6-month follow-up period is 4.0/100 personyears (N = 8) [ 95% CI : 1.7-8.0]
• Including only those patients with persistence of viremia (N = 5), the effective
reinfection rate is 2.5/100 person-years [95% CI : 0.8-5.9]
– These data support addressing barriers in the treatment of patients on
opiate agonist therapy and patients with ongoing drug use
C-EDGE CO-STAR
Dore GJ. AASLD 2016, Abs. 871