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Fw: NATAP/EASL: Pegasys/RBV Post Transplant for HCV Recurring

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  • Alley Pat
    NATAP http://natap.org/ ... Pegasys/RBV In Post Liver Transplant for Recurrent HCV Reported by Jules Levin EASL, April 26-30, Vienna, Austria Multicentre
    Message 1 of 1 , May 4, 2006
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      Pegasys/RBV In Post Liver Transplant for Recurrent HCV

      Reported by Jules Levin
      EASL, April 26-30, Vienna, Austria

      'Multicentre randomised trial of HCV treatment with peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in liver transplant patients with established recurrent hepatitis C: interim analysis'

      Christophe Duvoux
      Hôpital Henri Mondor-Paris XII University, Créteil
      France
      For a French Multicentre Study Group

      BACKGROUND
      o After liver transplantation (LT), HCV recurrence is almost universal with 10 to 30% of patients developing cirrhosis within 5 years.
      o Treatment of HCV recurrence after LT is difficult and somewhat disappointing:
      -Sustained virological response with combination therapy had been achieved in 21* to 45%** of the cases.
      - The risk of treatment-induced rejection ranges from 2 to 25%**
      - Tolerance is poor: 20 to 50% of treatment discontinuation.
      o The role of a maintenance ribavirin treatment has not been studied.

      *Samuel et al. Gastroenterology 2003;
      **Dumortier et al. J Hepatol 2004

      AUTHOR CONCLUSIONS
      Encouraging antiviral effects were observed following 1 year of combination therapy with peginterferon alfa-2a (40KD) PEGASYS and ribavirin (COPEGUS)

      A virological response (HCV RNA <50 IU/L) was achieved in 62% of patients overall (ITT analysis) and in 75% of pts in per protocol analysis at one year.

      Virological response 6 months after cessation of combination therapy was achieved in 50% of patients (per protocol) in per protocol analysis.

      Virological response was associated with genotype.

      Keeping in mind the frequent use of growth factors, tolerability was good
      -- 7% discontinuation rate for haematological reasons
      -- 2% incidence of reversible rejection.

      Taken together, these results indicate a favourable risk/benefit ratio of this therapy.

      Study Aims
      o To test for the efficacy of a one-year combination therapy with peginterferon alfa-2a (40KD) plus ribavirin in liver transplant patients with established recurrent HCV infection.
      o To investigate whether a 1-year maintenance therapy with ribavirin following a 1-year combination therapy had a positive impact on post LT HCV recurrence.

      Interim results after 1 year of combination therapy will be presented.
      In addition, preliminary long-term results will also be shown.

      Patients
      15 LT centres between 10/2002 and 08/2004

      Inclusion criteria:
      -- Primary liver transplantation for HCV cirrhosis
      -- Post-transplant follow-up: 1 to 5 years
      -- Previously untreated recurrent HCV infection with serum positive HCV RNA
      -- Fibrosis stage >/= 1 (METAVIR scoring system), on a liver biopsy obtained 1 to 5 years after transplantation

      Exclusion criteria:
      -- Contra-indication to IFN or RBV
      -- Active acute or chronic rejection
      -- Living donor liver transplantation
      -- Mycophenolate mofetil-based immunosuppression
      -- Severe concomitant disease (renal failure, cardiac failure, severe sepsis)
      HIV and HBV coinfection

      Methods: Study design
      And pts were followed for an additional period of 6 months after completion of this second phase of the study.


      Modalities of treatment
      o Peginterferon alfa-2a (40KD) was initiated at 90 ug/week for 2 weeks, then increased to 180 ug/week or adjusted as a function of haematological tolerance.
      o Ribavirin was initiated at 600 mg/day, then increased to
      800 mg/day or adjusted as a function of haematological tolerance.
      o Treatment was stopped for safety reasons or laboratory abnormalities (Hb < 8g/dL, PMN <750/uL, platelets <30,000/uL).
      o Use of growth factors was allowed at investigator discretion.

      Endpoints
      Primary
      Virological response:
      -- Non-detectable serum HCV RNA* after 1 year of combination therapy (12 months)
      -- Non-detectable serum HCV RNA* at the end of follow-up (30 months)
      *COBAS AMPLICOR HCV Test v2.0; lower limit of detection 50 IU/mL

      Secondary
      -- Liver function tests
      -- Histological changes from baseline biopsy and biopsies at Months 12 and 30 (reviewed by a single pathologist in a blinded fashion)
      -- Safety parameters

      Baseline characteristics of the patients


      RESULTS



      Peginterferon alfa-2a plus ribavirin:
      virological response at 12 months


      Effect of treatment on
      transaminase activity


      Effect of treatment on histological
      activity and fibrosis scores


      Virological response at M12 by genotype


      The presenter said: 69.3% of the patients who continued on peg-interferon-ribavirin combination achieved a sustained virological response at the end of follow-up, whereas only 53.4% of those who discontinued therapy at week 24 did. The difference was significant.

      Factors associated
      with virological response at M12
      No correlation between virological response and:
      - Time since LT
      - Histological score at baseline
      - Liver function tests at baseline

      A trend toward a better response on CsA


      Serious adverse events
      22 serious adverse events related to antiviral therapy occurred in 18 patients

      2 rejections episodes (2%)
      -- Moderate: steroid pulses; treatment discontinuation
      -- Mild: increase in basal CNI doses
      -- Reversible in both cases

      Treatment was discontinued in 12 patients, due to SAE:
      Haematological reasons (n=7) :
      -- anaemia 6, leucopenia 1
      -- Psychiatric reasons (n=2)
      -- Impairment in renal function (n=2)
      -- Rejection (n=1)

      Other significant SAEs: Ischemic cardiopathy (1), Diabetes (1), Infection (4)

      No serious adverse event-related death

      Effect of treatment on haemoglobin
      37% patients required erythropoietin and 12% G-CSF


      Virological response at 18 months: pooled, â?ostill blindedâ? data in both treatment arms


      Virological response at M18 by genotype
      The impact of HCV genotype was still observed.




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