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Design

* Randomisation was stratified on genotype and ILB28 genotype (CC or non-CC)

Treatment regimens

• SMV 150 mg : 1 pill qd ; PEG-IFNα-2a : 180 mg SC once weekly
• RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

Response-guided therapy : in SMV group, patients with HCV RNA < 25 IU/ml at W4 and < 15 IU/ml at W12 stopped treatment at W24, otherwise they continued until W48
Virological stopping rules : SMV or placebo discontinued if HCV RNA >1000 IU/ml at W4, with continuation of PEG-IFN + RBV. PEG-IFN + RBV discontinued if RNA reduction < 2 log 10 IU/ml at W12, or if HCV RNA confirmed = 25 IU/ml at W24 or W36

Objectives

• Difference in SVR₁₂ (HCV RNA < 25 IU/ml) between the 2 groups : estimation of 45% in the control group, power of 90% to detect a difference > 20%, by intention to treat
• Sensitivity analysis : comparison of SVR₁₂ in both groups with a logistic regression model including baseline HCV RNA (log10 IU/ml, included as a continuous variable) and the stratification factors (HCV genotype 1 subtype and IL28B genotype)
• Secondary endpoints : SVR₂₄ , % patients stopping treatment at W24 based on response-guided therapy, failure, safety

Baseline characteristics and patient disposition

SVR₁₂ (HCV RNA < 25 IU /ml)

Response-guided therapy : in SMV group, patients with HCV RNA < 25 IU/ml at W4 (undetectable or detectable) and < 15 IU/ml at W12 (undetectable) stopped treatment after W24

• Of the 224 (85%) patients who met RGT, 91% had SVR₁₂
• Of the 28 who did not, 21% had SVR₁₂

SVR₁₂ (HCV RNA < 25 IU /ml)

SVR₁₂ by baseline HCV RNA :

• ≤ 800,000 IU/ml : 42/46 (91%) in SMV vs 74% in placebo ; p = 0.0003
• > 800,000 IU/ml : 162/218 (77%) in SMV vs 42% in placebo ; p < 0.0001

Virologic failure

• Emergence of resistance among SMV-treated patients who failed to achieve SVR₁₂
  • Emergence of NS3 mutations in 35/38 (92%)
    • Genotype 1a : most common = R155K alone or in combination with mutations 80 and/or 168
    • Genotype 1b : most common = D168V
• No impact of RBV dose reduction (22% of SMV and 23% of placebo) on outcome

Adverse events

Summary

• A significantly higher percentage of treatment-naive patients with chronic HCV genotype 1 infection achieved SVR₁₂ (primary efficacy endpoint) with SMV in combination with PEG-IFN + RBV than with placebo in combination with PEG-IFN + RBV and has lower on-treatment failure and relapse rates.
• 85% of patients in the SMV group met criteria for response-guided therapy and were eligible to shorten treatment and stop at W24, and 91% of these subsequently achieved SVR₁₂
• HCV genotype 1a, IL28B non-CC genotype, cirrhosis, and high baseline HCV RNA were associated with lower SVR rates
• In patients with HCV genotype 1a who had the Q80K polymorphism at baseline, SVR₁₂ was significantly lower, and not different between SMV and placebo
• Most patients treated with SMV who did not achieve SVR₁₂ had emergent mutations at the time of failure
• The reported adverse events in the SMV group were clinically manageable, and most were grade 1 or 2. A lower percentage of patients in the SMV group discontinued treatment than did those in the placebo group