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 =

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Hepatitis web study Hepatitis web study Sofosbuvir + Peginterferon + Ribavirin in Genotype 2 or 3 LONESTAR-2 Phase 2 Treatment Experienced Lawitz E, et.

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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.

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%,

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:

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.

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.

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.

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.

ARV-trial.com C-SWIFT Study: grazoprevir/elbasvir + SOF in genotypes 1 or 3, with or without cirrhosis Randomisation 1 : 1 Open-label Design W4 W6 W8.

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.

W24 ≥ 18 years Chronic HCV infection Genotype 1 Treatment naïve Early fibrosis to compensated cirrhosis No HBV or HIV co-infection N = 10 SOF + weight-based.

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.

Hepatitis web study Hepatitis web study Sofosbuvir + RBV in Treatment-Naïve Genotypes 2,3 FISSION Trial* Phase 3 *Note: Published in NEJM in tandem with.

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 +

SOF/VEL 400/100 mg qd N = 75 W24 SOF/VEL > 18 years Chronic HCV infection Genotype 1 to 6 Naïve or treatment-experienced No prior treatment with NS5A or.

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

Hepatitis web study Hepatitis web study Sofosbuvir + Peginterferon + Ribavirin in Genotype 2 or 3 LONESTAR-2 Phase 2 Treatment Experienced Lawitz E, et.

> 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.

Asselah T. AASLD 2015, Abs OSIRIS  Design SMV + PEG-IFN + RBV Open label Chronic HCV infection Genotype 4 Treatment-naïve Mild to moderate fibrosis.

 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.

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.

C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 Zeuzem S. Ann Intern Med 2015; 163:1-13 GZR/EBR 100/50 mg qd N = 316 N = 105  Design W12W24.

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.

SOF + RBV GT2 Japanese SOF + RBV Open-label Japanese SOF + RBV Study: SOF + RBV in genotype 2  Design W12 Japanese patients ≥ 20 years Chronic HCV infection.

LDV/SOF Randomisation * 1:1 Open-label ≥ 20 years, Japanese Chronic HCV infection Genotype 1 HCV RNA ≥ IU/ml Treatment-naive, or pre-treated Compensated.

Genotype 1 HCV infection Stable immunosuppressive therapy

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

CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1

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

No cirrhosis or compensated cirrhosis** No HBV or HIV co-infection

Design Randomisation* 1 : 1 Open-label W12

Failure to achieve SVR on No HBV or HIV co-infection

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

SOF/VEL + GS-9857 in genotypes 1-6 Phase II

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

No HBV or HIV co-infection

GS-US Study: SOF/VEL + GS-9857 in genotype 1 - Phase II

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.

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients

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

Presentation transcript:

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 = -15%, 95% power) SOF + RBV (weight based) PEG-IFN  -2a + RBV (fixed-dose) Randomisation 1 : 1* Open-label, active-control * Randomisation was stratified on cirrhosis (presence or absence), genotype (2 or 3) and HCV RNA (< or ≥ 6 log 10 IU/ml) FISSION Study: SOF + RBV vs PEG-IFN  -2a + RBV for HCV genotype 2 and 3 W12 SVR 12 W24 SVR 12 W36 N = 243 N = 256 ≥ 18 years Chronic HCV infection Genotype 2, 3 Treatment-naïve HCV RNA ≥ 10,000 IU/ml Compensated cirrhosis allowed –SOF : 400 mg qd –PEG-IFN  -2a : 180  g SC once weekly –RBV weight based (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg –RBV fixed-dose : 400 mg bid Lawitz E. NEJM 2013;368:

SOF + RBV 12 W N = 256 PEG-IFN + RBV 24W N = 243 Mean age, years48 Female33%36% Race : white/black87% / 5%87% / 2% Body mass index, mean28 HCV genotype 1 / 2 / 31%* / 27% / 71%28% / 72% IL28B CC genotype42%44% HCV RNA log 10 IU/ml, mean (SD) 6.0 ± 0.8 HCV RNA ≥ 800,000 IU/ml57%65% Cirrhosis20%21% Discontinued treatment, N For AE / for virologic failure / lost to follow-up 11 3 / 1 / / 17 / 5 Returned for post-treatment W4 visit Returned for post-treatment W12 visit Baseline characteristics and patient disposition * Excluded from efficacy analysis FISSION FISSION Study: SOF + RBV vs PEG-IFN  -2a + RBV for HCV genotype 2 and 3 Lawitz E. NEJM 2013;368:

HCV RNA < 25 IU/ml SOF + RBV PEG-IFN + RBV FISSION FISSION Study: SOF + RBV vs PEG-IFN  -2a + RBV for HCV genotype 2 and 3 Lawitz E. NEJM 2013;368: W4W12W4W12Genotype 2Genotype 3No cirrhosisCirrhosis During treatmentPost treatment (SVR) SVR 12 by genotype and cirrhosis

 Virologic breakthrough during treatment –1 in SOF + RBV group vs 18 (7%) in PEG-IFN + RBV group  Relapse in patients with HCV RNA < 25 IU/ml at end of completed treatment –74/249 (30%) in SOF + RBV group vs 46/217 (21%) in PEG-IFN + RBV group  Resistance testing (sequencing) in SOF + RBV group –74 relapses : –No SOF-associated mutation (S282T) –No change in susceptibility to SOF in patients with NS5B substitutions Multivariate analysis of factors associated with SVR 12 in SOF + RBV group OR (95% CI)p Genotype 2 (vs 3)42.49 (9.54 – 189.2)< Cirrhosis (no vs yes)2.94 (1.38 – 6.26)0.005 Baseline HCV RNA < vs ≥ 6 log 10 IU/ml2.33 (1.24 – 4.37)0.009 RBV exposure, mg/kg/day1.26 (1.09 – 1.46)0.002 FISSION FISSION Study: SOF + RBV vs PEG-IFN  -2a + RBV for HCV genotype 2 and 3 Lawitz E. NEJM 2013;368:

Adverse events, n (%) SOF + RBV 12W N = 256 PEG-IFN  -2a + RBV 24W N = 243 AE leading to treatment discontinuation3 (1%)26 (11%) Serious adverse event7 (3%)3 (1%) AE occurring in > 15% in either group Fatigue Headache Nausea Insomnia Decreased appetite Influenza-like illness Chills Rash Diarrhea Pruritus Myalgia Irritability 36% 25% 18% 12% 7% 3% 9% 7% 8% 10% 55% 44% 29% 18% 17% 16% FISSION FISSION Study: SOF + RBV vs PEG-IFN  -2a + RBV for HCV genotype 2 and 3 Lawitz E. NEJM 2013;368:

 Summary –In this open-label, randomised trial of previously untreated patients with genotype 2 or 3 infection, the rate SVR 12 was the same among patients who were assigned 12 weeks of SOF + RBV or 24 weeks of PEG-IFN + RBV (67% in each group) In genotype 2, SVR 12 was higher with SOF + RBV (97% vs 78%) In genotype 2, SVR 12 was similarly low in both groups (56% vs 63%) –SOF + RBV was associated with fewer adverse events than PEG-IFN + RBV Influenza-like constitutional symptoms and neuropsychiatric events were less common among patients receiving SOF + RBV than among those receiving PEG- IFN + RBV. Although the rates of anemia was similar in both groups, neutropenia and thrombocytopenia were not observed in the SOF + RBV group –No virologic resistance was detected in patients who did not have a sustained virologic response FISSION FISSION Study: SOF + RBV vs PEG-IFN  -2a + RBV for HCV genotype 2 and 3 Lawitz E. NEJM 2013;368: