AVIATOR Study: Treatment of Genotype 1 HCV Infection
The AVIATOR study focuses on the treatment of chronic hepatitis C virus (HCV) infection in genotype 1 patients using a combination of paritaprevir/ritonavir, ombitasvir, dasabuvir, and ribavirin. The study design involves randomization and open-label treatment with different drug regimens to assess efficacy and safety in treatment-naïve or null responder patients.
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AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Design 2-steps W8 W12 W24 Randomisation* Open-label PTV150/r + OBV + DSV + RBV N = 80 N = 41 18-70 years Chronic HCV infection Genotype 1 HCV RNA 50,000 IU/ml Treatment-na ve or null responders No cirrhosis No HBV or HIV co-infection PTV150/r + DSV + RBV N = 39 PTV100/r + OBV + RBV N = 40 PTV200/r + OBV + RBV N = 79 Cohort 1 Na ve PTV150/r + OBV + DSV N = 39 PTV100/r + OBV + DSV + RBV N = 40 PTV150/r + OBV + DSV + RBV * Randomisation was stratified on genotype subtype (1a or 1b) and IL28 (CC or non-CC) N = 40 PTV100/r + OBV + DSV + RBV N = 40 PTV150/r + OBV + DSV + RBV Co-formulated paritaprevir/rironavir (PTV/r) : 100/100 or 150/100 or 200/100 mg qd Ombitasvir (OBV) : 25 mg qd Dasabuvir (DSV) : 400 mg bid RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or 75 kg) AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Design Randomisation* 2 : 1 : 1 : 1 : 1 Open-label W12 W24 N = 45 PTV200/r + OBV + RBV 18-70 years Chronic HCV infection Genotype 1 HCV RNA 50,000 IU/ml Treatment-na ve or null responders (NR) No cirrhosis No HBV or HIV co-infection N = 23 PTV100/r + OBV + DSV + RBV N = 22 PTV150/r + OBV + DSV + RBV N = 23 Cohort 2 Prior NR PTV100/r + OBV + DSV + RBV N = 20 PTV150/r + OBV + DSV + RBV * Randomisation was stratified on genotype subtype (1a or 1b) and IL28 (CC or non-CC) Co-formulated paritaprevir/rironavir (PTV/r) : 100/100 or 150/100 or 200/100 mg qd Ombitasvir (OBV) : 25 mg qd ; Dasabuvir (DSV) : 400 mg bid RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or 75 kg) Objective Primary analysis : SVR24with two-sided 95% CI, of na ve patients PTV150/r + OBV + DSV + RBV 8 weeks vs 12 weeks, 80% power to detect a 24% difference between groups (mITT analysis) AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Baseline characteristics and patient disposition Treatment-na ve N = 438 Null responders N = 133 Mean age, years 50.1 51.1 Female 47% 38% Race : black 14% 14% Genotype 1a 68% 61% IL28B genotype CC 28% 3% HCV RNA log10IU/ml, mean HOMA-IR 3 6.53 6.64 25% 30% 29% 50% Fibrosis score F2 Discontinued treatment, N (%) 24 (5.5%) 5 (3.8%) Adverse event Withdrew consent Lost to follow-up Other 1 0 0 4 0 3 8 13 AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 SVR24 (HCV RNA < 25 IU/ml) PTV/r + OBV + DSV + RBV 8W PTV/r + OBV + RBV 12W PTV/r + OBV + RBV 12W PTV/r + OBV + DSV 12W PTV/r + OBV + DSV + RBV 12W PTV/r + OBV + DSV + RBV 24W % 96 95 93 91 100 89 89 89 88 83 75 50 25 N 80 41 79 79 79 80 45 45 43 0 Treatment-na ve Null response to prior treatment SVR24in na ve cohort genotype 1a (76-94%) vs 1b (96-100%); odds ratio : 0.087 [p = 0.0008]) AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Comparison of SVR24 in Treatment-Na ve Patients, according to treatment Regimens Comparator Group vs Group 5 Difference in rate of SVR24 (95 % CI) Comparison SVR24 p Group 1 vs Group 5 8 W vs 12 W 88% vs 96% 0,08 Group 2 vs Group 5 Contribution of OBV 83% vs 96% 0,06 Group 3 vs Group 5 Contribution of DSV 89% vs 96% 0,09 Group 4 vs Group 5 Contribution of RBV 89% vs 96% 0,09 Group 6 vs Group 5 24 W vs 12 W 91% vs 96% 0,24 -30 -20 -10 0 10 Group 5 better Comparator group better AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Resistance emergence No variants at relapse in 7/10 patients in the 8-week groups In the 12-week and 24-week groups, 31/32 samples at breakthrough or relapse showed emergence of resistant variants. Most common : NS3 : position 168 NS5A : positions 28 and 30 NS5B : position 556 AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Adverse events Treatment-Na ve Null responder P/r/O/ D/R-8 P/r/D/ R-12 P/r/O/ R-12 P/r/O/ D-12 P/r/O/D /R-12 P/r/O/D/ R-24 P/r/O/ R-12 P/r/O/D /R-12 P/r/O/D /R-24 Treatment group Discontinuation due to AE 1 0 0 0 2 3 1 0 1 Serious AE 0 0 2 2 1 1 0 0 2 Common AE (> 20%) Fatigue Headache Nausea Insomnia Diarrhea Asthenia Cough 36% 35% 15% 12% 10% 9% 15% 32% 32% 17% 20% 24% 2% 12% 28% 29% 20% 11% 10% 10% 14% 20% 19% 14% 8% 16% 6% 3% 28% 27% 24% 20% 13% 4% 10% 38% 36% 25% 25% 14% 15% 15% 27% 33% 13% 18% 16% 22% 16% 27% 29% 20% 13% 18% 9% 7% 21% 33% 19% 16% 19% 9% 21% P/r : co-formulated paritaprevir/rironavir : 100/100 or 150/100 or 200/100 mg qd O : ombitasvir ; D : dasabuvir ; R : ribavirin; 8 : 8 weeks ; 12 : 12 weeks ; 24 : 24 weeks Grade 3-4 laboratory abnormalities Grade 3 elevation of bilirubin, n = 11 (2%) with no concomitant AST/ALT elevation Grade 3 ALT elevation, n = 5 (1%), Grade 3-4 Triglycerides, n = 7 (1%), Anemia : 5% AVIATOR Kowdley KV. NEJM 2013; 370:222-32
AVIATOR Study: paritepravir/ritonavir + ombitasvir + dasabuvir + ribavirin in genotype 1 Summary In this phase IIb study, all-oral regimens of antiviral agents and RBV were effective both in non-cirrhotic patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy Rates of SVR24ranged from 83% to 100% Among previously untreated patients, the rate of treatment failure was lower among those receiving the triple combination of paritaprevir/ritonavir + ombitasvir + dasabuvir + RBV for 12 weeks than among those who received the same regimen for 8 weeks and among those who received fewer agents; extending the treatment to 24 weeks offered no further benefit Higher number of relapses in 3D + RBV 8 weeks vs 12 weeks Paritaprevir/ritonavir + ombitasvir + dasabuvir + RBV for 12 weeks was associated with SVR24of 93% in null responders to prior therapy For genotype 1b, all regimens led to SVR24of 94%-100% with only 1/24 relapse in the 8-week group AVIATOR Kowdley KV. NEJM 2013; 370:222-32
