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PROVE Combination of Telaprevir With Peginterferon Ribavirin

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					HALT-C: Long-term Maintenance Peginterferon alfa-2a
clinicaloptions.com/hepatitis

   PROVE 1: Combination of Telaprevir With
   Peginterferon/Ribavirin Significantly
   Increases SVR in Treatment-Naive
   Patients With HCV Genotype 1

   Slideset on:
   McHutchison JG, Everson GT, Gordon SC, et al.
   Telaprevir with peginterferon and ribavirin for
   chronic HCV genotype 1 infection. N Engl J Med.
   2009;360:1827-1838.




Jointly sponsored by Postgraduate Institute for
Medicine and Clinical Care Options, LLC

This program is supported by educational grants from
PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin
clinicaloptions.com/hepatitis




 Background and Rationale
     SVR occurs in < 50% of chronic genotype 1 HCV–infected patients receiving
      pegIFN/RBV therapy
        – Response rates even lower in select subpopulations (eg, blacks)

     TPV a novel investigational inhibitor of HCV NS3-4A protease
        – Monotherapy previously demonstrated to lead to viral breakthrough due to
          emergence of resistance mutations[1]

        – Coadministration with pegIFN/RBV hypothesized to reduce risk of emergence of
          resistance mutations while enhancing antiviral potency of standard of care therapy

     Current study assessed efficacy and safety of combining TPV with
      pegIFN/RBV in treatment-naive genotype 1 HCV patients[2]
        – Ability of combination to shorten duration of therapy also assessed


1. Sarrazin C, et al. Gastroenterology. 2007;132:1767-1777.
2. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin
clinicaloptions.com/hepatitis




 Schematic of Study Design
                                           Wk 12                   Wk 24               Wk 48
                                                     24-wk
                             12-Wk Arm             follow-up
                          TPV* + PegIFN/RBV†
                                (n = 17)
                                                                             24-wk
  Treatment-
                              24-Wk Arm                                    follow-up
     naive
    patients              TPV* + PegIFN/RBV†       PegIFN/RBV*
 infected with                  (n = 79)
  genotype 1                                                                                 24-wk
     HCV                     48-Wk Arm                                                     follow-up
                         TPV* + PegIFN/RBV†                    PegIFN/RBV*
   (N = 250)                   (n = 79)
                                                                                                 24-wk
                                                                                               follow-up
                          48-Wk Control Arm
                        PegIFN/RBV† + Placebo                  PegIFN/RBV*
                               (n = 75)
 *1250 mg loading dose of TPV administered on Day 1, then 750 mg 3 times daily.
 †PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day.

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin
clinicaloptions.com/hepatitis




 Main Findings
             100                                                          12-wk TPV + pegIFN/RBV (n = 17)
                                                                          12-wk TPV + 24-wk pegIFN/RBV (n = 79)
                        81* 81*            80                             12-wk TPV + 48-wk pegIFN/RBV (n = 79)
                 80                                                       Control (n = 75)
                                   71 68                        71                          67‡
  Patients (%)




                                                                                    65
                      59*                                                                      61†
                 60                                        57        57

                                                45                                       47
                                                                                                     41
                 40                                                                           35          33

                                                                                                                     23
                 20
                              11
                                                     N/A                  N/A N/A                              2 6
                 0
                       Wk 4         Wk 12      Wk 24                          Wk 48                SVR    Relapse
                                   Undetectable HCV RNA
 N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control.
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin
clinicaloptions.com/hepatitis




 Main Findings
  Rate of ALT normalization similar between TPV arms and control arm
   at end of treatment (76% vs 75%)
  Viral breakthrough occurred in 12 of 175 patients (7%) receiving TPV
        – Most breakthrough events (75%) occurred during Weeks 1-4
        – 10 of 12 patients (83%) experienced breakthrough before HCV RNA
          became undetectable
        – Breakthrough associated with differing pattern of resistance mutations
          according to genotypic subtype

  Treatment discontinuation due to adverse events more frequent in
   TPV arms vs control arm (21% vs 11%, respectively)
        – Rash most common reason for discontinuation
               – Rash typically maculopapular and resolved following treatment discontinuation
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin
clinicaloptions.com/hepatitis




 Main Findings
     Most common adverse events were those typically associated with interferon-based
      treatment
                                12-Wk TPV +
 Adverse Events Occurring                       12-Wk TPV + 24-Wk   12-Wk TPV + 48-Wk   Control
                                PegIFN/RBV
 in ≥ 30% of Patients in Any                     PegIFN/RBV Arm      PegIFN/RBV Arm       Arm
                                    Arm
 Treatment Group, %                                  (n = 79)            (n = 79)       (n = 75)
                                  (n = 17)
 Fatigue                             82                    70              73             76
 Nausea                              65                    56              48             29
 Influenza-like illness              35                    49              38             43
 Pruritus                            24                    48              40             23
 Headache                            53                    47              43             60
 Insomnia                            35                    44              34             39
 Diarrhea                            24                    42              34             28
 Anemia                              35                    37              29             27
 Rash                                53                    60              61             41
 Erythema at injection site          35                    28              32             24

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin
clinicaloptions.com/hepatitis




 Summary of Key Conclusions
  Coadministration of a 12-week course of TPV with 24 or
   48 weeks of pegIFN/RBV significantly increased SVR
   rates in treatment-naive patients infected with genotype 1
   HCV vs 48 weeks of pegIFN/RBV alone
  Coadministration of TPV also resulted in higher rate of
   RVR and lower relapse rate compared with pegIFN/RBV
  TPV coadministration increased rate of treatment
   discontinuation due to adverse effects, predominantly rash
  Small subset of TPV-treated patients experienced virologic
   breakthrough in association with protease resistance
   mutations
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

				
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