1. No prior therapy with PI
ARV-trial.com
TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Randomisation**
1 : 1
Open-label
Design
W12
W24
18-70 years
HCV genotype 1
Naïve or pre-treated
Cirrhosis*
Child-Pugh A < 7
HCV RNA ≥ 10,000 IU/ml
No prior therapy with PI
N = 208
OBV/PTV/r + DSV + RBV
OBV/PTV/r + DSV + RBV
N = 172
* Liver biopsy with Metavir > 3 or Ishak > 4, or Fibroscan kPa > 14.6
** Randomisation stratified on prior Peg-IFN + RBV therapy ;
Naïve patients, stratified on genotype (1a vs 1b) and IL-28B (CC vs non-CC)
Experienced patients stratified on genotype subtype, prior response (null, partial, relapse)
Treatment regimens
Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg qd = 2 tablets
Dasabuvir (DSV) : 250 mg bid
RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)
TURQUOISE-II
Poordad F, NEJM 2014;370: 1

2. No prior therapy with PI
TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Randomisation
1 : 1
Open-label
Design
W12
W24
18-70 years
HCV genotype 1
Naïve or pre-treated
Cirrhosis*
Child-Pugh A < 7
HCV RNA ≥ 10,000 IU/ml
No prior therapy with PI
N = 208
OBV/PTV/r + DSV + RBV
OBV/PTV/r + DSV + RBV
N = 172
* Liver biopsy with Metavir > 3 or Ishak > 4, or Fibroscan kPa > 14.6
Primary efficacy endpoint
Sustained virologic response (HCV RNA < 25 IU/ml) 12 weeks after end of treatment, with two-sided 97.5% CI
Non-inferiority of SVR12 assessed vs estimated rate of SVR24 with a telaprevir-based regimen (47%; 95% CI : 41 to 54). A noninferiority margin of 10.5 % established 43% as the noninferiority threshold; the superiority threshold was 54%
Analyses by mITT
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3. TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
HCV RNA : COBAS TaqMan real-time RT–PCR assay, v 2.0 (Roche)
Virologic failure
2 consecutive HCV RNA > 1 log10 IU/ml above the nadir at any time during treatment,
HCV RNA ≥ 25 IU/ml at all assessments during treatment among patients who received at least 6 weeks of treatment,
confirmed HCV RNA ≥ 25 IU/ml after a level < 25 IU/ml during treatment
Virologic relapse : confirmed HCV RNA ≥ 25 IU/ml between the end of treatment and 12 weeks after the last dose of study drug among patients who completed treatment and had an HCV RNA < 25 IU/ml at the final visit during the treatment period
Exploratory analysis : stepwise logistic-regression model to assess the association between the rate of SVR12 and continuous and categorical subgroup variables
TURQUOISE-II
Poordad F, NEJM 2014;370:

4. Baseline characteristics and patient disposition
ARV-trial.com
TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Baseline characteristics and patient disposition
12 weeks
N = 208
24 weeks
N = 172
Mean age, years
57.1
56.5
Female
30%
Race : white/black
95.7% / 2.9%
93.6% / 3.5%
Body mass index
27.9 ± 4.1
27.9 ± 4.3
Genotype : 1a / 1b
67.3% / 32.7%
70.3% / 29.7%
IL28B non-CC genotype
83.2 %
80.2%
HCV RNA log10 IU/ml
6.41 ± 0.62
6.53 ± 0.52
Prior treatment with PEG-IFN + RBV, N
122 98
Null response 75 62
Partial response 18 13
Relapse 29 23
Platelet count x 10-9/l, median (IQR)
140 ( )
142.5 ( )
Serum albumin, g/l, median (IQR)
40 (37-42)
39 (37-42)
Discontinued treatment, N 4 9
For adverse event / for virologic failure
4 / 0
4 / 3
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5. SVR12 (HCV RNA < 25 IU/ml)
ARV-trial.com
TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
SVR12 (HCV RNA < 25 IU/ml)
12 weeks
24 weeks 25 50
100 75
91.8
95.9 %
p = 0.09
88.6
94.2
HCV subgenotype
Overall 1a
No prior
treatment 1b
98.5
94.6
96.6
86.7
95.2
94.4
Relapse
Partial
response
Null
Prior treatment N
208
172
140
121 68 51 86 74 29 23 18 13 62
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6. Outcomes for patients without SVR12
TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Outcomes for patients without SVR12
12 weeks
N = 208
24 weeks
N = 172
N (%)
17 (8.2%)
7 (4.1%)
On-treatment virologic failure 1 3
Relapse
12 (5.9%) *
1 (0.6%)
Other 4
* 7/12 had genotype 1a and prior null response to PEG-IFN + RBV
Resistance testing (population sequencing) of the 17 virologic failures (on-treatment or relapse)
No resistance, N = 2
Resistance, N = 15
D168V (NS3) and Q30R (NS5A) most frequent in genotype 1a
D168V (NS3), Y93H (NS5A) and C316Y + M414I (NS5B) in the single genotype 1b case
TURQUOISE-II
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7. TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
SVR12 (HCV RNA < 25 IU/ml), according to genotype and prior treatment
12 weeks
N = 208
24 weeks
N = 172
N/ total N (%)
Genotype 1a
No prior treatment
59/64 (92.2)
52/56 (92.9)
Prior treatment
Null response
40/50 (80)
39/42 (92.9)
Partial response
11/11 (100)
10/10 (100)
Relapse
14/15 (93.3)
13/13 (100)
Genotype 1b
22/22 (100)
18/18 (100)
25/25 (100)
20/20 (100)
6/7 (85.7)
3/3 (100)
14/14 (100)
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8. TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Multivariate Analysis of Association of Variables with a SVR12
Estimated odds ratio (95% CI) p
Model including former injection-drug use *
Previous PEG-IFN + RBV treatment (null response vs partial response, relapse or no prior treatment)
0.39 ( )
0.04
Genotype (1a vs 1b)
0.12 ( )
Former injection-drug use (yes vs no)
0.35 ( )
0.02
Model excluding former injection-drug use **
0.33 ( )
0.10 ( )
0.03
* Also adjusted for baseline Child–Pugh score and ethnic group; ** also adjusted for geographic region and treatment duration
Continuous variables : age, BMI, platelet, albumin, alpha-foetoprotein, HCV RNA level
Categorical variables : treatment duration, genotype, IL28B genotype, previous PEG-IFN + RBV, sex, race, ethnicity, geographic region, Child–Pugh score, diabetes, history of depression or bipolar disorder , former injection-drug use
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9. TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Adverse events, N (%)
12 weeks, N = 208
24 weeks, N = 172
Any adverse event
191 (91.8)
156 (90.7)
AE leading to treatment discontinuation
4 (1.9)
4 (2.3)
Serious adverse event
13 (6.2)
8 (4.7)
AE occurring in > 10% in either group
Fatigue
32.7%
46.5% (p < 0.01)
Headache
27.9%
30.8%
Nausea
17.8%
20.3%
Pruritus
18.3%
19.2%
Insomnia
15.4%
18.0%
Diarrhea
14.4%
16.9%
Asthenia
13.9%
12.8%
Rash
11.1%
14.5%
Irritability
7.2%
12.2%
Anemia
7.7%
10.5%
Dyspnea
5.8%
12.2% (p<0.05)
Death
1 (0.5)
TURQUOISE-II
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10. TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
AE leading to discontinuation
12 weeks, N = 208
24 weeks, N = 172
N = 4
Acute hepatitis,
Mental status change
Extradural hematoma
Lactic acidosis
Anemia,
COPD,
Suicidal ideation,
CNS symptoms + asthenia + dehydration
Laboratory abnormalities, N (%)
12 weeks, N = 208
24 weeks, N = 172
ALT, grade 3-4
6 (2.9%)
0 (p < 0.05)
AST, grade 3-4
1 (0.5%)
Alkaline phosphatase, grade 3-4
Total bilirubin, grade 3-4
28 (13.5%)
9 (5.2%) (p < 0.01)
Hemoglobin
Grade 1
49.5%
56.4%
Grade 2
5.8%
10.5%
Grade 3
1.0%
0.6%
Grade 4
0.5%
TURQUOISE-II
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11. ARV-trial.com
TURQUOISE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV with cirrhosis
Summary
In both treatment groups of 3D + RBV, the primary efficacy end points met the prespecified criteria for noninferiority and superiority to the historical rate with telaprevir plus PEG-IFN + RBV among patients with HCV genotype 1 infection and cirrhosis
12 or 24 weeks of treatment with coformulated ombitasvir/paritaprevir/ritonavir and dasabuvir, administered with RBV, resulted in high rates of SVR12 (91.8% and 95.9%, respectively)
Patients with cirrhosis and a prior null response had SVR12 of 86.7% and 95.2% in the 12-W and 24-W groups, respectively.
Patients with genotype 1a and a prior null response had a SVR12 of 80% with 12 weeks of treatment and 92.9% with 24 weeks of treatment.
All other subgroups with genotype 1a, including previously naïve patients, those with a prior partial response, with a prior relapse, had rates of SVR12 of 92 to 100% with 12 weeks or 24 weeks of treatment
Patients with genotype 1b and a prior null response had a SVR12 of 100% with either treatment duration
Drug discontinuations due to adverse events were infrequent
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