TURQUOISE-I OBV/PTV/r + DSV + RBV Randomisation* 1 : 1 Open-label 18-70 years HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Naïve or pre-treated with PEG-IFN +

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VALENCE SOF + RBV Not randomised Open label* ≥ 18 years Chronic HCV infection Genotype 2 or 3 HCV RNA ≥ 10,000 IU/ml Treatment naïve or prior IFN-based.

Kwo PY. NEJM 2014;371: CORAL-I  Design OBV/PTV/r + DSV + RBV Open label Phase II years Chronic HCV infection, genotype 1 Liver transplantation.

ATOMIC  Design  Objective –SVR 24 by ITT-analysis, detection of a 30% or 25% difference between two treatment groups, 2-sided significance level of 5%,

LDV/SOF 90/400 mg qd Non-randomised Open-label N = 21 W12 SVR 12 NIAID SYNERGY GT4 Kohli A. Lancet Infect Dis 2015; Juky 15, ePub ahead of print ≥ 18 years.

ELECTRON  Design SOF + RBV Randomisation* 1 : 1 : 1 : 1 Open-label ELECTRON Study: SOF-based therapy for genotypes 1, 2 and 3 W8W4W12 ≥ 19 years Chronic.

OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind years Chronic HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to pre-treatment with.

OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV Randomisation* 1 : 1 Open label years Chronic HCV infection Genotype 1b Prior failure to PEG-IFN + RBV HCV.

No prior therapy with PI

CURRY  Design Open-label CURRY Study: SOF + RBV for HCV with liver cancer before transplantation ≥ 18 years Chronic HCV infection Any genotype HCV RNA.

Egyptian Ancestry  Design  Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI SOF 400 mg qd + RBV Randomised 1 : 1 Open-label Egyptian Ancestry Study:

OBV/PTV/r Open label years Chronic HCV infection Genotype 1b Treatment-naïve or failure to PEG-IFN + RBV HCV RNA > 10,000 IU/ml Without or with cirrhosis*

COSMOS SOF + SMV + RBV SOF + SMV Randomisation 2 : 1 : 2 : 1* Open-label * Randomisation was stratified on genotype (1a or 1b) in both cohorts, IL28B in.

SMV + PEG-IFN + RBV Open-label W12 W24* or W48* N = years Chronic HCV infection Genotype 4 Treatment-naïve or experienced with relapse or partial.

Randomisation* 2 : 1 Double blind *Randomisation was stratified on genotype (1a or 1b or other) and IL28B genotype (CC, CT or TT) N = 133 N = 260 W24W48.

FUSION  Design  Objectives –SVR ≥ 20% compared with historical control of 25%, 97% power –Difference of SVR > 20% between the 2 groups, 82% power SOF.

FISSION  Design  Objective –Non inferiority of SOF + RBV : SVR 12 (2-sided significance level of 5%, lower margin of the 95% CI for the difference =

AI Study  Design SOF 1W then DCV + SOF 23W DVC + SOF Randomisation* 1 : 1 : 1 Open-label AI Study: DCV + SOF + RBV for genotypes 1, 2 and.

No HBV or HIV co-infection

SOF + PEG-IFN  -2a + RBV Open-label Single arm ≥ 18 years Chronic HCV infection Genotype 1, 4, 5 or 6 Treatment-naïve HCV RNA ≥ 10,000 IU/ml Compensated.

SMV SOF 400 Open-label OPTIMIST-2 Study: SMV + SOF for genotype 1 and cirrhosis W12  Objective –Superiority of SVR 12 (HCV RNA historical control.

SMV 150 mg QD + SOF 400 mg QD Randomisation 1 : years HCV genotype 1 Naïve or pre-treated with IFN-based regimen No cirrhosis HCV RNA ≥

UNITY-1 DCV/ASV/BCB No randomisation Open-label UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir in genotype 1 without cirrhosis  Design W12 ≥ 18 years.

OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV + placebo Randomisation* Partial blind years Chronic HCV infection Genotype 1 Treatment-naïve HCV RNA > 10,000.

NIAID ERADICATE Open-label W12 ≥ 18 years Chronic HCV infection Genotype 1 Treatment naïve HIV infection on stable ART ≥ 8 weeks and HIV RNA < 50 c/ml.

Reddy KR. Lancet Infect Dis. 2015;15:27-35 ATTAIN SMV + TVR placebo + PEG-IFN + RBV TVR + SMV placebo + PEG-IFN + RBV Randomisation* 1 : 1 Double-blind.

Placebo + PR W48 Placebo + PR Yes Hezode C. Gut 2015;64: COMMAND-1 COMMAND-1 Study: daclatasvir + PEG-IFN + RBV for genotype 1 or 4 DCV60 + PEG-IFN.

SIRIUS Placebo LDV/SOF + placebo Randomisation* 1 : 1 Double-blind SIRIUS Study: LDV/SOF ± RBV for genotype 1 and cirrhosis with non response to prior.

ION-4  Design LDV/SOF Open-label ION-4 Study: LDV/SOF in HIV co-infection W12 ≥ 18 years Chronic HCV infection Genotype 1 or 4 HCV RNA ≥ 10,000 IU/ml.

ION-1  Design LDV/SOF LDV/SOF + RBV Randomisation* 1 : 1 : 1 : 1 Open-label ION-1 Study: LDV/SOF + RBV for genotype 1 W24W12 ≥ 18 years Chronic HCV infection.

OBV/PTV/r Placebo Randomisation** 2 : years Chronic HCV Genotype 1b HCV RNA ≥ 10,000 IU/ml Naïve or pre-treated, no prior failure with DAA Without.

 Treatment regimens –Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg QD = 2 tablets –Dasabuvir (DSV) : 250 mg bid  Objective.

SOLAR-1 LDV/SOF + RBV Randomisation* of the 7 groups 1 : 1 Open-label SOLAR-1 Study: LDV/SOF + RBV in advanced liver disease  Design W12W24 ≥ 18 years.

 Treatment regimens –Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg QD = 2 tablets –Dasabuvir (DSV) : 250 mg BID –RBV.

No randomization N = 59 W12W24 Arm B : compensated cirrhosis N = 31 N = 29 Arm C : compensated cirrhosis Arm A : No cirrhosis AGATE-II Study: OBV/PTV/r.

ALLY-3  Design  Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI DCV 60 mg qd + SOF 400 mg qd Not randomised Open-label ALLY-3 Study: DCV + SOF for.

> 18 years Chronic HCV infection Genotype 1 Failure (relapse) to 4, 6 or 8 weeks of GZR/EBR + SOF in C-SWIFT Part A Compensated cirrhosis assessed by liver.

SOF/VEL 400/100 mg qd N = 250 W24 SOF + RBV W12 * Randomisation was stratified on prior treatment (naïve or experienced) and cirrhosis (yes or no) ** Metavir.

Asselah T. AASLD 2015, Abs. 714 Randomisation 1:1 Open-label years HCV genotype 4 HCV RNA ≥ 1,000 IU/ml Naïve or pre-treated with PEG-IFN + RBV (Part.

Sulkowski M. Lancet 2015;385: C-WORTHY  Design Randomisation* Open-label > 18 years HCV genotype 1, treatment naïve HCV RNA ≥ 10,000 IU/ml No cirrhosis.

OBV/PTV/r + DSV Open label Chronic HCV infection Genotype 1 Treatment-naïve HCV RNA > 1,000 IU/ml Chronic kidney disease with eGFR < 30 ml/min/1.73m 2.

No randomisation Open-label years HCV genotype 1 Naïve or null-response to PEG-IFN + RBV HCV RNA > 10,000 IU/ml No cirrhosis No HBV or HIV co-infection.

 Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI, next observation carried backward DCV + SOF + RBV Randomised* 1:1 Open-label ALLY-3+ study: DCV.

SOF + RBV Randomisation* 1 : 1 : 1 Open-label BOSON Study: SOF + RBV + PEG-IFN for genotypes 2 and 3 ≥ 18 years Chronic HCV infection Genotype 2, treatment-

 Design  Objective –Difference in SVR ≥ 40% between the 2 groups, 99% power SOF + RBV Placebo Randomisation 3 : 1* Double blind HCV infection Genotype.

SAPPHIRE-I Feld JJ. NEJM 2014;370: SAPPHIRE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1  Treatment regimens.

Open-label W24 ≥ 18 years Chronic HCV infection All genotypes HCV RNA ≥ 10,000 IU/ml Liver transplantation months earlier Child Pugh ≤ 7 and MELD.

 Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI, by ITT, descriptive analysis OBV/PTV/r + DSV + RBV No randomisation Open-label CORAL-I Study cohort.

LDV/SOF Failure Open-label W24 Chronic HCV infection Genotype 1 Failure to achieve SVR on LDV/SOF-containing regimen Compensated cirrhosis (liver biopsy.

SOF/VEL 400/100 mg qd N = 120 W12 SOF + RBV > 18 years Chronic HCV infection Genotype 2 Naïve or pre-treatment with IFN-based regimen Compensated cirrhosis.

Placebo + PR W24 DCV + PR Placebo + PR Yes Dore GJ. Gastroenterology 2015;148: COMMAND GT2/3 COMMAND GT2/3 Study: daclatasvir + PEG-IFN + RBV for.

 Objective –SVR 12 (HCV RNA < 25 IU/ml), by ITT OBV/PTV/r + DSV + SOF +RBV Open-label W24 ≥ 18 years Chronic HCV Genotype 1 Prior failure on DAA-regimen.

Dore G. J Hepatol 2016; 64:19-28 MALACHITE TVR + PEG-IFN + RBV Randomisation Open-label years HCV genotype 1 HCV RNA > 10,000 IU/ml Naïve (MALACHITE-I)

 Design Randomisation* 2 : 1 Double blind *Randomisation was stratified on genotype (1a vs 1b) and ILB28 genotype (CC or non-CC) N = 134 N = 257 W24W48.

Poordad F. NEJM 2014;368: D Phase IIa  Design  Treatment regimens – Paritaprevir/rironavir (PTV/r) : PTV 250 or 150 mg qd/ritonavir 100 mg qd (2.

 Design Open-label years Chronic HCV infection Genotype 1 HCV RNA > 10,000 IU/mL HIV co-infection Stable ART* with HIV RNA < 50 c/mL ≥ 24 weeks.

PHOTON-1  Design  Objective –SVR 12 with 2-sided 95% CI, descriptive analysis –Multivariate analyses of predictors of SVR 12 SOF + RBV, N= 114 SOF +

 Objective –SVR 12 (HCV RNA < 25 IU/ml), by ITT OBV/PTV/r + SOF + RBV OBV/PTV/r + SOF Not randomised Open-label QUARTZ-II Study: OBV/PTV/r + SOF for HCV.

ARV-trial.com RUBY-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir for HCV genotype 1a or 4 with severe renal impairment Design Open label W12.

TOPAZ-II Study: OBV/PTV/r + DSV + RBV for genotype 1

PHOTON-2 Study: SOF + RBV in HCV-HIV co-infection

Retreatment study: SOF/VEL + RBV in prior NS5A failure - Phase II

ARV-trial.com RUBY-I Study, cohort 2: ombitasvir/paritaprevir/ritonavir + dasabuvir + RBV for HCV genotype 1 with renal impairment Design Open label W12.

QUARTZ II-III : OBV/PTV/r + SOF RBV in genotype 2 or 3

LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1

No HBV or HIV co-infection

ION-3 Study: LDV/SOF + RBV for naïve genotype 1

ARV-trial.com TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients Randomisation 1 : 1 Open-label.

LDV/SOF ± RBV in genotype 3 or 6 – Phase 2

Presentation transcript:

TURQUOISE-I OBV/PTV/r + DSV + RBV Randomisation* 1 : 1 Open-label years HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Naïve or pre-treated with PEG-IFN + RBV HIV infection, on ATV/r or RAL HIV RNA < 40 c/ml and CD4 ≥ 200/mm 3 Cirrhosis Child-Pugh A allowed No HBV co-infection  Design N = 32 N = 31 W12W24 * Randomisation stratified on prior PEG-IFN + RBV therapy, and cirrhosis ; naïve patients also stratified on IL-28B (CC vs non-CC); experienced patients also stratified on 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)  Primary efficacy endpoint –SVR 12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI, comparison between groups TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients Sulkowski MS, JAMA 2015;315:

Baseline characteristics and patient disposition 12 weeks N = weeks N = 32 Mean age, years50.9 Female6%9% Body mass index, mean Genotype : 1a / 1b87% / 13%91% / 9% IL28B non-CC genotype84 %78 % HCV RNA log 10 IU/ml, mean (SD) 6.54 ± ± 0.78 Fibrosis score F0-F1 / F2 / F3 / F4 (%)52 / 16 / 13 / 1963 / 16 / 3 / 19 Prior treatment with PEG-IFN + RBV, N (%)11 (35%)10 (31%) Null response55 Partial response52 Relapse13 CD4/mm 3, mean ARV regimen : ATV/r / RAL52% / 48%38% / 63% Discontinued treatment, N 1 (withdrew consent) 1 (virologic breakthrough) TURQUOISE-I TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients Sulkowski MS, JAMA 2015;315:

Virologic Outcome 12 weeks N = weeks N = 32 SVR 12 (HCV RNA < 25 IU/ml)94% (95% CI: )91 % (95% CI : ) Failure*, N Reasons 2 1 consent withdrawn 1 relapse 3 1 virologic breakthrough 2 re-infection Mutations detected Relapse NS3 : D168V NS5A : M28T NS5B : S556G Breakthrough NS3 : R155K NS5A : Q30R NS5B : S556G Prior PEG-IFN + RBV therapy in failures Naïve = 1, Null response = 1Naïve = 2, Null response = 1 Fibrosis stage in failuresF3 / F4F4 / F0-F1 / F0-F1 * All 5 = genotype 1a  No HIV RNA failure (3 blips in W12-group and 5 blips in W24-group)  Decrease in absolute but not relative CD4 cell counts TURQUOISE-I TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients Sulkowski MS, JAMA 2015;315:

12 weeks, N = 3124 weeks, N = 32 AE leading to treatment discontinuation00 AE leading to RBV dose reduction56 Serious adverse event00 AE occurring in > 10% in either group Fatigue58%38% Insomnia16%22% Nausea16%19% Headache19%13% Upper respiratory tract infection13%16% Pruritus19%6% Cough7%16% Ocular icterus16%3% Diarrhea3%13% Hyperbilrubinemia13%3% ALT > 5 x ULN / AST > 5 x ULN0 / 00 / 1 Total bilirubin > 3 x ULN35%19% Adverse events, n (%) TURQUOISE-I TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients Sulkowski MS, JAMA 2015;315:

TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients  Summary –In this open-label, randomised uncontrolled study, treatment with the all-oral, IFN-free 3D plus ribavirin regimen resulted in high SVR 12 rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks No discontinuation for AE The 2 failures (1 virologic breakthrough and 1 relapse) were observed in patients with genotype 1a and F4 fibrosis –Limitations Small sample size ARV therapy limited to ATV/r- or RAL-containing regimens Role of RBV not addressed Sulkowski MS, JAMA 2015;315: TURQUOISE-I