1. C-EDGE CO-STAR: grazoprevir/elbasvir for HCV infected drug users on opiod replacement therapy
Design
Randomisation *
2 : 1
Double blind
W12
W16
W24
W28
> 18 years
HCV infection
Genotype 1, 4, 6
HCV RNA ≥ IU/mL
Treatment-naïve
≥ 3 months opioid replacement
Compensated cirrhosis allowed
HIV co-infection allowed
N = 201
GZR/EBR
100/50 mg qd
Placebo
GZR/EBR
(N = 95)
N = 100
* Randomisation was stratified on genotype and cirrhosis (yes or no)
Objective
SVR12 (HCV RNA < 15 IU/mL) with 2 – sided 95% CI
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
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

2. Baseline characteristics and patient disposition
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
Black / White / Asian, %
15 / 78 / 5
7 / 84 / 7
Genotype, %
1a 1b 4 6
IL28B CC, %
28.4
29.0
HCV RNA > 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
Discontinuation before W12 of follow-up (active phase), N
Lost to follow-up
For adverse event
Administrative reason 5 3 1
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

3. Primary endpoint: SVR12 (HCV RNA < 15 IU/mL), % (95% CI), ITT mFAS*
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
100 75 50 25
94.0
( )
95.5
( )
93.3
( )
91.7
( ) 60
( )
All patients
Genotype 1a
Genotype 1b
Genotype 4
Genotype 6
201
154 30 12 5 % N=
SVR12 , ITT, Full analysis set
91.5%
93.5%
93.3%
91.7%
20%
Non-virologic failure 5 3 1
Relapse 7 4 2
Reinfection
* ITT, mFAS: reinfection = success, unrelated discontinuation = excluded
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

4. Primary endpoint: SVR12 (HCV RNA < 15 IU/mL), % (95% CI), ITT mFAS*
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
100 75 50 25
89.5
( )
90.1
( )
92.9
( )
( )
( )
All patients
Genotype 1a
Genotype 1b
Genotype 4
Genotype 6 95 71 14 6 4 % N=
SVR12 , ITT, Full analysis set
89.5%
90.1%
92.9%
100%
50%
Non-virologic failure 7 6 1
Relapse
Breakthrough 2
Reinfection
* ITT, mFAS: reinfection = success, unrelated discontinuation = excluded
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

5. 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 *
Male
Positive
Negative No
Yes
Female
100 75 50 25
92.8
( )
90.4
( )
93.8
( )
91.3
( )
92.5
( )
153
136 65
161 40 % 48 88
87.5
( )
92.0
( )
91.2
( )
113
Sex
Drug screen
Cirrhosis
HCV RNA
> IU/mL
* Reinfection = failure
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

6. SVR12 and SVR24 (HCV RNA < 15 IU/mL), %, per protocol
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
Deferred treatment
100 75 50 25
95.5
94.1
96.6
SVR12
198 88 85
186
SVR24
96.5 N=
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

7. 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
GZR/EBR
Deferred GZR/EBR
Placebo phase
Active phase
Adherence > 95% during the 12 weeks
96.5%
100%
95.8%
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

8. 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)
Subgroup
SVR12
n/N
% (95% CI)
Opiod agonist therapy at D1
Buprenorphine
Methadone
37/39
147/162
94.9 ( )
90.7 ( )
Drug screen during the treatment period
Positive (at least 2 time points)
Negative
123/136 61/65
90.4 ( )
93.8 ( )
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

9. C-EDGE CO-STAR: grazoprevir/elbasvir for HCV infected drug users on opiod replacement therapy
Reinfection
3.0
1.0
0.0
2.0
Reinfections
Virologic failures
TW10 or 12
FW4
FW8
FW12
FW24 %
Reinfection, N (%)
0 (0.0)
5 (1.7)
1 (0.3)
Virologic failure, N (%)
2 (0.7)
3 (1.0)
Incidence of reinfection
4.6 reinfections (CI, 1.7 to 10.0) per 100 person-years
6 reinfections: different genotype, subtype or viral strain
Dore G. EASL 2016, Abs. SAT-163, J Hepatol 2016;64:S771 ;
Dore GJ. Ann Intern Med 2016;165:
C-EDGE CO-STAR

10. 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
Negative
Relapse follow-up W4
56-y, male, no cirrhosis
1.2 million IU/mL
Relapse follow-up W8
63-y, white female, no cirrhosis
3.5 million IU/mL
63-y, black female, no cirrhosis
1.7 million IU/mL 1b
29-y, asian male, no cirhhosis
33.2 million IU/mL 6a
34-y, asian male, no cirrhosis
25.5 million IU/mL
29-y, white female, no cirrhosis
IU/mL
Not done
Relapse follow-up W24
50-y, black female, cirrhosis
9.5 million IU/mL
58-y, black male, cirrhosis
2.8 million IU/mL
Breakthrough W12
59-y, asian male, no cirrhosis
1.9 million IU/mL 6b
43-y, asian male, no cirrhosis
6.8 million IU/mL
48-y, asian male, no cirrhosis
IU/mL
Reinfection (GT 6a) FU W8
33-y, white female, no cirrhosis
IU/mL
Reinfection (GT 1a) FU W8
55-y, white female, cirrhosis
3.2 million IU/mL
Reinfection (GT 3a) FU W8
45-y, asian male, no cirrhosis
4.8 million IU/mL
Reinfection (GT 1b) FU W8
37-y, asian female, no cirrhosis
18.6 million IU/mL
33-y, white male, no cirrhosis
1.5 million IU/mL
Reinfection (GT 3a) FU W24
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

11. per 100 person-years (95% CI)
C-EDGE CO-STAR: grazoprevir/elbasvir for HCV infected drug users on opiod replacement therapy
Reinfection during post-treatment and follow-up (3 years post-treatment)
Reinfections N
Follow-up
person-years
Reinfection rate
per 100 person-years (95% CI)
All persons 10
565
1.8 (0.8 – 3.3)
Post-treatment to 3 years-follow-up
Persons who reported IDU
Persons who did not report IDU 6 1
212
316
2.8 (1.0 – 6.2)
0.3 (0.0 – 1.8)
IDU = intravenous drug use
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165: ; Grebely J. AASLD 2018 ; Abs. 52

12. C-EDGE CO-STAR: grazoprevir/elbasvir for HCV infected drug users on opiod replacement therapy
Reinfection
3.0
1.0
0.0
2.0
Reinfections
Virologic failures
TW10 or 12
FW4
FW8
FW12
FW24 %
Reinfection, N (%)
0 (0.0)
5 (1.7)
1 (0.3)
Virologic failure, N (%)
2 (0.7)
3 (1.0)
Incidence of reinfection
4.6 reinfections (CI, 1.7 to 10.0) per 100 person-years
6 reinfections: different genotype, subtype or viral strain
Dore G. EASL 2016, Abs. SAT-163, J Hepatol 2016;64:S771 ;
Dore GJ. Ann Intern Med 2016;165:
C-EDGE CO-STAR

13. 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
Adverse event leading to discontinuation
Most frequent adverse events
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 2
Total bilirubin > 2.6 x ULN
Hemoglobin < 8.5 g/dL 1
1.1
Creatinine > 2.5 times baseline level
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

14. 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 interferon-free HCV treatment for patients receiving opiate agonist therapy
C-EDGE CO-STAR
Dore GJ. Ann Intern Med 2016;165:

15. 3-year Follow-up on Risk Factors and Rate of Reinfection
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: )
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 person-years (N = 8) [ 95% CI : ]
Including only those patients with persistence of viremia (N = 5), the effective reinfection rate is 2.5/100 person-years [95% CI : ]
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