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OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind 18-70 years Chronic HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to pre-treatment with.

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Presentation on theme: "OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind 18-70 years Chronic HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to pre-treatment with."— Presentation transcript:

1 OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind 18-70 years Chronic HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to pre-treatment with PEG-IFN + RBV No Cirrhosis* No prior failure with PI No HBV or HIV co-infection * Liver biopsy with Metavir ≤ 3 or Ishak ≤ 4, or Fibrotest® ≤ 0.72 + APRI ≤ 2, or Fibroscan kPa < 9.6 N = 97 N = 297 W12W24 ** Randomisation stratified on prior PEG-IFN + RBV therapy response (null, partial, relapse) and on genotype subtype (1a or 1b) OBV/PTV/r + DSV + RBV SVR 12 Open label SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV  Treatment regimens –Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (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)  Design

2 OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind 18-70 years Chronic HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to pre-treatment with PEG-IFN + RBV No Cirrhosis* No prior failure with PI No HBV or HIV co-infection * Liver biopsy with Metavir ≤ 3 or Ishak ≤ 4, or Fibrotest ® ≤ 0.72 + APRI ≤ 2, or Fibroscan kPa < 9.6 W12W24 ** Randomisation stratified on prior PEG-IFN + RBV therapy response (null, partial, relapse) and on genotype subtype (1a or 1b) OBV/PTV/r + DSV + RBV SVR 12 Open label SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV  Objective –Non-inferiority and superiority of SVR 12 assessed vs estimated rate of SVR 12 with a telaprevir-based regimen in prior failure to PEG-IFN + RBV : 65%; 95% CI : 60 to 70). A noninferiority margin of 10.5 % of the 95% CI for the SVR 12 of the new regimen established 60% as the noninferiority threshold; the superiority threshold was 70%. –Analyses by mITT, power > 90%  Design N = 97 N = 297

3 OBV/PTV/r + DSV (3D) + RBV N = 297 Placebo N = 97 Mean age, years51.754.9 Female44%38% Race : white/black90.6% / 7.4%88.7% / 10.3% Body mass index, mean26.3 HCV subgenotype : 1a / 1b58.2% / 41.4%58.8% / 41.2% Fibrosis score F2 or F332%33% IL28B CC genotype11.4 %7.2 % HCV RNA log 10 IU/ml, mean6.556.52 Prior treatment with PEG-IFN + RBV, N (%) Null response146 (49%)47 (49%) Partial response65 (22%)21 (22%) Relapse86 (29%)29 (30%) Discontinued treatment, N51 For adverse event / for virologic failure3 / 00 / 0 SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV Baseline characteristics and patient disposition

4 25 50 100 75 96.3* 96.0 1a1b 96.7 95.3 95.2 100 Relapse Partial response Null response Prior treatment 94.0 95.4 97.2 94.9 1b1a1b1aOverall * 95% CI: 94.2 to 98.4 : noninferior and superior to the historical SVR 12 with TVR + PEG-IFN + RBV SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV SVR 12 (HCV RNA < 25 IU/ml) % 297173123866514650368759N OBV/PTV/r + DSV + RBV Overall HCV subgenotype 0

5 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV Outcomes for patients without SVR 12 on OBV/PTV/r + DSV + RBV SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 Virologic failureTreatment discontinuation N74 On-treatment virologic failure0 Relapse7 (2.4%) Type of prior response to PEG-IFN Relapse Partial response Null response 106106 301301  SVR 12 similar accross subgroups defined by race, age, fibrosis score, and IL28B genotype  Resistance testing (population sequencing) of the 7 relapses –4/5 genotype 1a + 1/2 genotype 1b had ≥ 1 mutant resistant variants Genotype 1a : D168V (N =2) in NS3 ; M28V (N = 3) and Q30R (N = 2) in NS5A ; S556G (N = 2) in NS5B Genotype 1b : Y56H + D168V (NS3), Y93H (NS5A) and C316N + S556G (NS5B)

6 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV OBV/PTV/r + DSV (3D) + RBV N = 297 Placebo N = 97 Any adverse event271 (91.2)80 (82.5) AE leading to treatment discontinuation3 (1.0)0 Serious AE6 (2.0)1 (1.0) AE occurring in > 10% in either group Headache36.4%35.1% Fatigue33.3%22.7% ; p = 0.06 Nausea20.2%17.5% Asthenia15.8%11.3% Insomnia14.1%7.2% Pruritus13.8%5.2% ; p = 0.03 Diarrhea13.1%12.4% Dyspnea12.5%10.3% Cough10.8%5.2% Myalgia7.7%10.3% SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 Adverse events, N (%)

7 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV OBV/PTV/r + DSV (3D) + RBVPlacebo ALT1.7%3.1% AST1.0% Alkaline phosphatase00 Total bilirubin2.4%0 Hemoglobin0.3%0 Creatinine0.7%0 Dose of RBV was modified in 6.4% because of adverse events SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14 Grade 3-4 laboratory abnormalities, N (%)  Other adverse events more frequent in the active-regimen group –Anemia, p = 0.01 –Decrease in hemoglobin level, p = 0.04 –Vomiting, p = 0.006

8 SAPPHIRE-II Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1 with failure to PEG-IFN + RBV  Summary –Rates of response to a 12-week interferon-free combination regimen of ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin, were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. –SVR 12 was non inferior and superior to the historical control rate with telaprevir plus PEG-IFN + RBV in a similar patient population –SVR 12 was similar in patients with HCV genotype 1a or 1b infection, and in various subgroups (age, sex, fibrosis, IL28B) –Tolerability was good, with 1% of patients discontinuing for AE Pruritus, anemia and vomiting more frequent in active group Low incidence of grade 3-4 bilirubin elevation –In conclusion, an all-oral combination regimen of OBV/PTV/r + DSV + RBV resulted in SVR 12 > 95%, regardless of HCV genotype (1a or 1b) and with low rates of treatment discontinuation, in previously treated patients with HCV genotype 1 infection and no cirrhosis,, including those with a prior null response SAPPHIRE-II Zeuzem S. NEJM 2014;370:1604-14

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