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

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Presentation transcript:

ION-3 Study: LDV/SOF + RBV for naïve genotype 1 ARV-trial.com ION-3 Study: LDV/SOF + RBV for naïve genotype 1 Design Randomisation* 1 : 1 : 1 Open-label W8 W12 ≥ 18 years Chronic HCV infection Genotype 1 HCV RNA ≥ 10,000 IU/ml Treatment-naïve No cirrhosis** No HBV or HIV co-infection N = 215 LDV/SOF SVR12 N = 216 LDV/SOF + RBV SVR12 N = 216 LDV/SOF SVR12 * Randomisation was stratified on genotype (1a or 1b) ** Liver biopsy with Metavir ≤ F3 or Ishak ≤ 4, or Fibrotest® ≤ 0.48 + APRI ≤ 1 Co-formulated ledipasvir-sofosbuvir (LDV 90mg/SOF 400 mg) : 1 pill qd RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg) Objective Primary endpoint : SVR12 > 30% than historical control (adjusted rate of 60%), with a 2-sided significance level of 0.025, 90% power Secondary end-point : non inferiority of LDV/SOF 8W : SVR12 by intention to treat analysis (significance level of 2.5%, lower margin of the 95% CI for the difference = 12%) ION-3 Kowdley KV. NEJM 2014;370:1879-88 1

ION-3 Study: LDV/SOF + RBV for naïve genotype 1 ARV-trial.com ION-3 Study: LDV/SOF + RBV for naïve genotype 1 Baseline characteristics and patient disposition LDV/SOF 8W N = 215 LDV/SOF + RBV 8W N = 216 LDV/SOF 12W Mean age, years 53 51 Female 40% 46% 41% Race : white/black 76% / 21% 81% / 17% 77% / 19% Body mass index, mean 28 HCV genotype : 1a / 1b 80% / 20% If biopsy, fibrosis score : F0-F2 / F3 59% / 13% 50% / 13% 9% / 13% IL28B CC genotype 26% 28% HCV RNA log10 IU/ml, mean 6.5 6.4 Completed study treatment 215 213 211 ION-3 Kowdley KV. NEJM 2014;370:1879-88 2

ION-3 Study: LDV/SOF + RBV for naïve genotype 1 ARV-trial.com ION-3 Study: LDV/SOF + RBV for naïve genotype 1 SVR12 (HCV RNA < 25 IU/ml) LDV/SOF 8W LDV/SOF + RBV 8W LDV/SOF 12W % n All 1a 1b All 1a 1b All 1a 1b All groups had superior SVR12 than the historical control of 60% (p < 0.001 for all comparisons) LDV/SOF 8W non inferior to LDV/SOF + RBV 8W (difference 0.9% (95% CI : - 3.9 to 5.7)) LDV/SOF 8W non inferior to LDV/SOF 12W (difference - 1.4% (95% CI : - 6.4 to 3.6)) ION-3 Kowdley KV. NEJM 2014;370:1879-88 3

ION-3 Study: LDV/SOF + RBV for naïve genotype 1 ARV-trial.com ION-3 Study: LDV/SOF + RBV for naïve genotype 1 Virologic failure Virologic breakthrough: None Post-treatment relapse 11 (5%) in the LDV/SOF 8W group 9 (4%) in the LDF-SOV + RBV 8W group 3 (1%) in the LDV/SOF 12W group NS5A resistant variants (deep sequencing) Baseline resistance in 116 (18%) of 647 patients tested SVR12 in 104 (90%) of the 116 patients with NS5A resistance 15 of the 23 patients (65%) with relapse had NS5A resistance at relapse 9/15 had variants present at baseline No S282T NS5B-resistant variants detected at baseline or after treatment ION-3 Kowdley KV. NEJM 2014;370:1879-88 4

ION-3 Study: LDV/SOF + RBV for naïve genotype 1 Adverse events LDV/SOF 8W N = 215 LDV/SOF + RBV 8W N = 216 LDV/SOF 12W N = 216 Discontinuation of LDV/SOF for adverse event 1 Road accident 2 Arthralgia ; Lung cancer Serious adverse event 4 5 Adverse event in ≥ 7% in either group Fatigue Headache Nausea Insomnia Irritability Diarrhea Arthralgia Rash Pruritus Anemia 21% 14% 7% 5% 1% 4% 35% 25% 18% 12% 13% 6% 9% 8% 23% 15% 11% 2% ION-3 Kowdley KV. NEJM 2014;370:1879-88

ION-3 Study: LDV/SOF + RBV for naïve genotype 1 ARV-trial.com ION-3 Study: LDV/SOF + RBV for naïve genotype 1 Summary In this phase III trial, all 3 groups of previously untreated patients, with HCV genotype 1 infection without cirrhosis, who received treatment with LDV/SOF, had rates of SVR12 that were higher than 90% LDV/SOF 8 weeks was non inferior to LDV/SOF 12 weeks or to LDV/SOF + RBV 8 weeks, suggesting that adding RBV did not improve SVR while worsening treatment burden and increasing toxicity SVR12 was not different in genotype 1a and 1b Relapse occurred in few patients, more commonly in 8-week groups None had evidence of mutations conferring resistance to SOF Mutations associated with resistance to NS5A inhibitors were present in most patients at baseline and at the time of relapse In conclusion, 8 weeks of treatment with a single-tablet regimen of LDV/SOF resulted in a high rate of SVR12 among previously untreated patients with HCV genotype 1 infection without cirrhosis ION-3 Kowdley KV. NEJM 2014;370:1879-88 6