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Vertex Pharmaceuticals Incorporated Message Board

  • thirdmeinvestor thirdmeinvestor Sep 7, 2008 1:13 PM Flag

    Clinicians discuss Study 107 (1)

    Data are not new, but their interpretations are provocative. This was made available through email from Clinical Care Options.

    Telaprevir Combined With Peginterferon Alfa-2a and Ribavirin in Previous Nonresponders to Peginterferon Plus Ribavirin
    Nezam H. Afdhal, MD, FRCPI:
    An open-label trial conducted by Poordad and colleagues analyzed the response rates of 60 previous nonresponders to peginterferon alfa-2a plus ribavirin from the PROVE studies who received retreatment with triple therapy containing peginterferon alfa-2a 180 µg/week, ribavirin 1000-1200 mg/day, and telaprevir 750 mg 3 times daily for 12 weeks followed by 12 weeks of peginterferon/ribavirin. Since these patients were derived from a pool of treatment-naive patients who failed to clear the virus by Week 12 in clinical trials, their compliance and virologic response to previous peginterferon/ribavirin therapy was extremely well documented. Based on their previous response to known dosages of peginterferon and ribavirin, they were categorized as null responders (< 1 log10 IU/mL decline in HCV RNA at Week 4 or < 2 log10 IU/mL decline in HCV RNA by Week 12), partial responders (≥ 2 log10 IU/mL decline in HCV RNA by Week 24), relapsers, or breakthrough patients.
    The investigators were able to demonstrate a very high RVR rate in these previous nonresponders; specifically, 70% or more of patients in each previous response group achieved HCV RNA < 25 IU/mL at Week 4 of retreatment. The highest RVR rates were seen in patients with previous breakthrough (100%) or relapse (100%), whereas the lowest RVR rates were seen in patients with previous null response (70% to 75%). These data are important because many clinicians believed that peginterferon/ribavirin nonresponders might not respond to triple therapy with peginterferon, ribavirin, and telaprevir because it might essentially equate to telaprevir monotherapy. However, these patients responded extremely well.
    This was an interesting proof of concept study in a well-characterized cohort of patients. These data have heightened the interest in the current nonresponder study that is underway—the PROVE 3 study—which again is studying peginterferon alfa-2a, ribavirin, and telaprevir combination therapy. Furthermore, these results may impact future study designs since nonresponder trials with triple combinations have now been validated by this study.
    Ira M. Jacobson, MD:
    I agree with Dr. Afdhal’s comments and perceive these findings to be potentially revolutionary. Until just a few months ago, many clinicians were convinced that we would need a regimen containing 2 or more STAT-C drugs, in combination with a backbone of peginterferon plus or minus ribavirin, to obtain successful treatment outcomes in previous nonresponders. The results from this study modify that prediction, although they must be confirmed with larger numbers of patients in studies such as PROVE 3.

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    • third, what was the date of the publication?

    • Great Post Third,

      Thank you,


    • Another interesting finding from this study was that patients who had HCV RNA levels between 10 and 25 IU/mL by Week 4 or 12, and then subsequently achieved HCV RNA < 10 IU/mL, did not experience virologic breakthrough. Therefore, fears that any residual viremia during the early months of therapy would lead to high levels of virologic breakthrough were unfounded. In fact, these data suggest the potential for a new definition of slow response with an entirely new set of parameters in the STAT-C era.
      Nezam H. Afdhal, MD, FRCPI:
      The results from this trial also raise the question of whether the differences in HCV RNA of < 25 IU/mL vs < 10 IU/mL are clinically meaningful. It is possible that achieving HCV RNA < 25 IU/mL is actually as good as achieving undetectability. Data to support this come from previous trials that examined the relationship between RVR and SVR rates.[5] In these trials, achieving RVR with HCV RNA < 50 IU/mL or < 110 IU/mL often leads to very high SVR rates. Therefore, just because the tools have become more sensitive and can detect levels as low as 10 IU/mL does not mean that there is a clinically significant difference between HCV RNA < 10 IU/mL and HCV RNA < 25 IU/mL; either result indicates a profound suppression of virus.
      Ira M. Jacobson, MD:
      That observation also means that definitions of when to stop therapy in subsequent trials can be liberalized; perhaps the rule that therapy can only be stopped when HCV RNA < 25 IU/mL may be unnecessarily restrictive. In fact, I believe the stopping rules in subsequent trials are currently being revised.
      Stefan Zeuzem, MD:
      The investigators of the Poordad study did not explain why only a subset of the patients who failed to respond to peginterferon/ribavirin in the PROVE studies were included in the current trial. Depending on how these patients were chosen, there is a possibility of selection bias.
      In addition, the investigators used the FDA standard definition of null response. However, many experts in the field do not consider this definition to be sufficiently stringent and regard null responders as those patients who never achieve > 0.5 log10 IU/mL decline in HCV RNA. It would be interesting to have seen the results among null responders according to this stricter definition, since the triple therapy in this setting might indeed equate to functional monotherapy. In the current analysis, we do not know what proportion of patients achieved HCV RNA declines that were just modestly < 2.0 log10 IU/mL at Week 12 on peginterferon/ribavirin but were considered null responders.
      Finally, data showing that the response at Week 4 can be used to predict SVR have been derived from studies in treatment-naive patients, and it is not clearly proven that this relationship holds true for the nonresponder population. However, there did not seem to be any significant discord between the responses at Week 4 and Week 12 in this study, suggesting that these responses were probably robust and will be sustained. Therefore, there are considerable grounds for optimism that a substantial number of these patients will be able to translate their virologic response on treatment into an SVR.

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