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Design

* Randomisation was stratified on genotype (1a vs 1b) and ILB28 genotype (CC or non-CC)

Treatment regimens

• SMV 150 mg : 1 pill qd ; PEG-IFNα-2a 180 mg SC once weekly or PEG-IFNα-2b 1.5 mg/kg/week
• 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 log10 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

PEG-IFN Therapy

• 63% of patients in each arm were randomized to receive PEG-IFNα-2a or PEG-IFNαlfa-2b; the remainder was assigned PEG-IFNα-2a

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 225 (91%) patients who met RGT, 86% had SVR₁₂
• Of the 16 who did not, 31% had SVR₁₂

SVR₁₂ (HCV RNA < 25 IU /ml)

SVR₁₂ by baseline HCV RNA :

• ≤ 800,000 IU/ml : 454/58 (93%) in SMV vs 81% in placebo ; p < 0.0001
• > 800,000 IU/ml : 155/199 (78%) in SMV vs 39% in placebo ; p < 0.0001

Virologic failure

• Emergence of resistance among SMV-treated patients who failed to achieve SVR₁₂
  • Emergence of NS3 mutations in 41/42 (52%)
    • Genotype 1a (N = 16) : most common = R155K alone (N =13) or in combination (N = 2), or D168V (N = 1) ; 5/16 with Q80K at baseline
    • Genotype 1b (N = 25) : most common = D168V ; Q80R + D168E ; no Q80K at baseline
• No impact of RBV dose reduction (24% of SMV and 31% 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
• This superiority of SMV was seen irrespective of the type of PEG-IFN-alfa used
• 91% of patients in the SMV group met criteria for response-guided therapy and were eligible to shorten treatment and stop at W24, and 86% of these subsequently achieved SVR₁₂
• IL28B non-CC genotype, cirrhosis, and high baseline HCV RNA were associated with lower SVR rates
• In patients with HCV genotype 1a
  • SVR₁₂ was similarly high in patients with or without the Q80K polymorphism at baseline
  • However, SVR₁₂ was significantly lower in placebo group overall vs SMV group with Q80K polymorphism (p < 0.05)
• Most patients treated with SMV who did not achieve SVR₁₂ had emergent mutations at the time of failure
• Adverse events in the SMV group were clinically manageable, and most were grade 1 or 2. Discontinuation for adverse event was rare in both groups