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Induction IFN therapy may be crucial for genotype 1 and high HCV viral load

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  • claudine intexas
    NATAP - www.natap.org ... AASLD Nov 9-13, Dallas reported by Jules Levin Abstract 694. CLINICAL IMPLICATIONS OF A NEW TRI-PHASIC MODEL FOR HEPATITIS C VIRAL
    Message 1 of 1 , Dec 1, 2001
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      NATAP - www.natap.org

      Nov 9-13, Dallas
      reported by Jules Levin


      The authors of this study suggest that induction IFN
      therapy may be crucial for genotype 1 and high HCV
      viral load. Future studies should consider exploring
      high induction dosing with daily interferon followed
      by pegylated interferon, or perhaps higher dosing of
      pegylated interferon.

      Claudia C Bergmann, Bar-Ilan Univ, Ramat-Gan Israel;
      Jennifer E Layden, Univ of Illinois, Chicago, IL;
      Rachel S Levy-Drummer, Bar-Ilan Univ, Ramat Gan
      Israel; Thomas J Layden, Univ of Illinois, Chicago,
      IL; Bart L Haagmans, Erasmus Univ Rotterdam, Rotterdam
      Netherlands; Avidan U Neumann, Bar-Ilan Univ,
      Ramat-Gan Israel

      Background: A bi-phasic model currently describes HCV
      dynamics during IFN-a therapy and its 2nd phase slope
      is the best predictor for sustained viral response
      (SVR). According to this model the 2nd slope is mainly
      determined by the strength of the immune response in
      killing infected cells, and to a lesser degree by the
      dose of IFN. However, viral decline in a large
      fraction (30-40%) of patients appears to be
      tri-phasic, with a first rapid decline followed by a
      flat intermediate plateau region (shoulder phase) that
      turns into a slow decline later. Moreover, new results
      show that 1st phase parameters can predict the 2nd
      phase slope and consecutively SVR, although this
      cannot be explained by the bi-phasic model.

      Methods: We re-analyzed previous studies of HCV
      kinetics in patients (N=200) with frequent sampling
      during the period of 3-28 days. We use a new
      tri-phasic model that allows the loss rate of infected
      cells to be accelerated during therapy as function of
      decreasing viral load. We assume an initial
      hypo-responsiveness of cellular immune response in
      presence of high virus titers that is restored when
      viral load decreases below a suppression threshold.

      Results: Our model predicts that if viral load does
      not decline during the 1st phase below the suppression
      threshold then the 2nd phase slope is flat, while if
      it is considerably below the threshold then a rapid
      2nd slope is achieved. A tri-phasic decline will occur
      only if the viral load at the end of the 1st phase is
      just about the suppression threshold level. An
      intermediate shoulder phase with a slow decline is
      then observed until the immune response "kick-starts"
      and the 2nd phase slope accelerates. Indeed, the viral
      decline patterns in all studies agree with these
      predictions. The estimated viral load suppression
      threshold is 100,000 IU/ml (� 60,000) and the length
      of the plateau-phase (3-21 days) is significantly
      correlated with the viral load at the end of the 1st
      phase. The model predicts that following a dose
      reduction, which gives rise to lower blocking of
      virion production, there will occur a rebound in viral
      load and the 2nd phase slope will be slowed. However,
      if the dose reduction occurs after viral load declined
      considerably below the suppression threshold these
      effects will be diminished and the 2nd slope will
      still be rapid. We found that SVR rate among patients
      with a rapid slope (larger than 0.1/day) after the
      shoulder phase is equivalent to that of patients with
      a rapid slope immediately after the first phase.

      Conclusions: The new tri-phasic model, which better
      describes the HCV kinetics during IFN therapy,
      predicts that it is necessary to considerably lower
      viral load already during the 1st phase in order to
      allow the patient to have a rapid viral response in
      the 2nd phase and consecutively SVR. Therefore in
      patients with HCV genotype 1, who have low IFN
      effectiveness in blocking production, and high
      baseline viral load it will be important to treat with
      high dose of IFN. High dose induction should continue
      until the immune response overcomes its
      hyporesponsiveness (i.e., at the end of the shoulder
      phase) and then switched to lower dose given daily or
      in pegylated form. In patients with a shoulder phase
      it is important to correctly define the 2nd phase
      slope after the end of the shoulder in order to
      evaluate the probability to achieve SVR. Nevertheless,
      this model allows to construct a framework to predict
      SVR already from the 1st phase parameters, 24 hours
      after beginning of treatment.

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