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Design

*Randomisation was stratified on genotype (1a or 1b or other) and IL28B genotype (CC, CT or TT)

• SMV 150 mg : 1 pill QD ; PEG-IFNα -2a 180 m g 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

• Primary endpoint : difference in SVR₁₂ (HCV RNA < 25 IU/ml) between the 2 groups : estimation of 20% in the placebo group, power of 90% to detect a significant difference with a 5% 2-sided significance level, by ITT
• Secondary endpoints
  • Virologic response in different patient subgroups (including METAVIR score, HCV 1 subtype , and IL28B genotype )
  • Proportion of SMV-treated patients meeting RGT criteria to complete treatment at W24
  • Incidence of viral breakthrough (HCV-RNA increase of > 1 log 10 IU/ ml from the lowest level observed or HCV RNA > 100 IU/ ml when previously < 25 IU/ ml) , on-treatment failure ( confirmed detectable HCV RNA at end of treatment) , or viral relapse (detectable HCV RNA during follow-up or at the time of SVR assessments after achieving undetectable levels at end of treatment)
  • Incidence of adverse events and laboratory abnormalities
  • Quality -of-life measures

Baseline characteristics and patient disposition

SVR₁₂ (HCV RNA < 25 IU/ml)

• Response guided therapy (RGT) : in SMV group, patients with HCV RNA < 25 IU /ml at W 4 (undetectable or detectable) and < 15 IU /ml at W 12 (undetectable) stopped treatment after W24
  • Of the 241 (93%) patients who met RGT, 83% had SVR₁₂
  • Of the 15 who did not, 40% had SVR₁₂

SVR₁₂ (HCV RNA < 25 IU/ml)

Virologic failure

• Emergence of resistance among SMV-treated patients who failed to achieve SVR₁₂ (sequencing data available in 52/59)
  • Emergence of NS3 mutations in 47/52 (90%)
    • Genotype 1a (N = 30/32) : most common = R155K alone (N =15) or in combination (N = 4), or D168V/A/E/H (N = 10) ; 14/32 with Q80K at baseline
    • Genotype 1b (N = 17/20) : most common = D168V or D168A/E/T

Adverse events

Summary

• Oral, once-daily SMV150 mg for 12 weeks in combination with PEG-IFN + RBV followed by 12 –36 weeks of PEG-IFN + RBV led to a significant improvement in SVR₁₂ compared with that seen in the placebo group, in patients with chronic HCV genotype 1 infection who had relapsed after previous IFN-based therapy
• Overall , 79.2 % of SMV- treated patients achieved SVR₁₂ compared with 36.1% of those who received PEG-IFN + RBV alone
  • This superiority of SMV was seen across the different baseline characteristics (Gender, HCV RNA, Metavir score, IL28B genotype, HCV 1 subtype)
• Almost all SMV- treated patients (92.7%) met RGT criteria and were eligible to stop PEG-IFN + RBV at W 24 . The SVR₁₂ rate in these patients was 83%
• The SVR₁₂ rate with SMV was lower in HCV genotype 1a patients who had the Q80K polymorphism at baseline
• Relapse rate was higher in genotype 1a
• Most patients treated with SMV who did not achieve SVR₁₂ had emergent mutations at the time of failure
• The safety and tolerability profile of SMV + PEG-IFN + RBV was generally similar to that of PEG-IFN + RBV alone, with no additional treatment-related adverse events. Discontinuation for adverse event was rare in both groups