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Fw: NATAP: WIN-R Study, Effect of Fibrosis/Cirrhosis on SVR

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  • Alley Pat
    NATAP http://natap.org/ ... NATAP Report from AASLD Nov 2005: WIN-R Study: final results of Weight-Based dosing study of ribavirin in treatment-naive patients
    Message 1 of 1 , Jun 3, 2006
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      NATAP Report from AASLD Nov 2005:
      WIN-R Study: final results of Weight-Based dosing study of ribavirin in treatment-naive patients (01/31/06)


      The Effect of Liver Fibrosis and Cirrhosis on SVR in 4913 Patients With Hepatitis C: Results From The WIN-R Trial

      â?oâ?¦.Cirrhosis remains an important predictor for SVR in HCV patientsâ?¦It is important to use weight-based dosing of ribavirin to increase SVR in patients with advanced fibrosis, especially for cirrhosisâ?¦..Cirrhosis (F4) is the major histological determinant of SVR according to F stageâ?¦â?

      Reported by Jules Levin
      DDW, May 2006, Los Angeles

      Authors: N. Afdhal, I. Jacobson, R. Brown, B. Freilich,
      J. Santoro, L. Griffel, C. Brass, and the WIN-R Study Group

      Background from authors
      Results from multiple studies suggest that advanced fibrosis is a negative predictor of SVR in treatment-naive patients who receive PEG-IFN alfa plus RBV

      Most studies are small and do not contain a significant proportion of patients with cirrhosis. Patients with F3 fibrosis and cirrhosis (F4) are often analyzed together rather than separately

      WIN-R Trial background
      o PEG IFN alfa-2b 1.5 _g/kg/week + RBV 800 mg/day was superior to 2 other regimens using RBV 1000 to 1200 mg/day in a pivotal trial1
      o Logistic regression analysis showed a linear relationship between RBV dose in mg/kg and SVR
      o Secondary analysis showed superiority of weight-based dosing of RBV
      o A large prospective trial comparing RBV doses was designed to address fixed-dose RBV 800 mg versus weight-based RBV dosing (Weight-Based Interferon and Ribavirin Trial)

      o Win-R: Investigator-initiated access trial involving academic and community sites in the United States
      o 25 regional investigators, 225 sites
      o Nearly 5000 patients evaluated; 500 with cirrhosis*, *Out of 4913 patients in the primary safety analysis.
      o Central randomization stratified by genotype and fibrosis
      o Participant criteria
      - Compensated liver disease, biopsy results consistent with chronic hepatitis C
      - At least 1 elevated alanine transferase level in 6 months before entry

      Study Design

      All patients were followed-up for 24-weeks after treatment cessation.

      Study Populations and Analyses
      o Intent-to-treat population (n = 4913)
      o All subjects who received at least one dose of study drug
      o Used for safety analysis
      o Primary efficacy population (n = 4223)
      o All subjects who received at least one dose of study drug and weighed >/=65 kg
      o Used for primary efficacy analysis - SVR

      Primary Efficacy Analysis
      End of Treatment and Follow-Up Week 24

      Primary efficacy analysis (n = 4223); patients weighing >/=65 kg.

      SVR Rates Within Genotypes

      Patients in the primary safety analysis population for whom genotype was available (n = 4903); no genotype was available for 10/4913 patients.

      Univariate Logistic Regression Analysis:
      Predictors of SVR

      Patients in primary safety analysis (n = 4913).
      AA = African American.

      Hypothesis:
      Fibrosis Is an Independent Predictor
      of SVR

      Aim:
      To Look at the Effect
      of Individual and Combined
      Fibrosis Stages on SVR Rates

      Methods
      o Classification of fibrosis stage was determined by the principal investigator and local pathologist using METAVIR scoring*
      *F0 = none; F1 = portal fibrosis; F2 = few septa; F3 = many septa; F4 = cirrhosis.
      o Univariate and multivariate logistic regression analyses were conducted for fibrosis and SVR
      o Analysis was based on patients (n = 4913) who received at least one dose of study drug

      WIN-R Population: Demographics

      Patients in primary safety analysis (n = 4913).
      * P < .0001 vs F4.
      â? P < .01 vs F4.

      Baseline Fibrosis Scores

      Patients in primary safety analysis (n = 4913).

      Distribution of Fibrosis Stage
      by Body Weight

      Patients in primary safety analysis (n = 4913).


      SVR Rates Across
      Combined (F0-2 and F3-4) Fibrosis Stages

      Patients in primary safety analysis (n = 4913).
      o From the logistic regression, patients with F0-2 have more responders than patients with F3-4.

      SVR Rates Across
      Individual Fibrosis Stages


      Regression Analyses
      OR = odds ratio; CI = confidence interval.
      * Using the chi-square test.

      o Significant effect of fibrosis on SVR when weight-base RBV dosing is used (P = .0502*)
      o Significant effect of fibrosis on SVR when fixed RBV dosing is used (P = .0007*)

      SVR Rates By Genotype
      Among Cirrhotic Patients (F4)

      Cirrhotic patients for whom genotype was available (n = 499); genotype was missing for 1/500 cirrhotic patients in the primary safety analysis population (n = 4913).

      SVR Rates By G2/3 Genotype
      Among Cirrhotic Patients (F4)

      Cirrhotic patients for whom genotype was available (n = 499); genotype was missing for 1/500 cirrhotic patients in the primary safety analysis population (n = 4913).

      SVR Rates in HCV G2 Subjects >/= 65 kg
      F0-2 vs F3-4

      P = NS for all comparisons.

      SVR in HCV G3 Subjects >/= 65 kg
      F0-2 vs F3-4

      P = NS for all comparisons.

      Multivariate Regression Analysis

      o A significant interaction was found between cirrhosis and viral load (P = .0354) where cirrhosis negatively impacted SVR in LVL patients
      o African Americans were 0.3 times as likely to respond to treatment as non-African Americans (P < .0001)

      Summary
      o It is important to use weight-based dosing of ribavirin to increase SVR in patients with advanced fibrosis, especially for cirrhosis
      o Cirrhosis (F4) is the major histological determinant of SVR according to F stage
      o Treatment for 24 or 48 weeks in genotype 2 and 3 has a similar SVR, independent of the presence of advanced fibrosis F3-F4
      o Genotype 3 patients with cirrhosis have significantly reduced SVR compared to genotype 2

      Conclusion
      o Cirrhosis remains an important predictor for SVR in HCV patients
      o Clinical trials need to continue to determine the % of patients with cirrhosis either by biopsy or non-invasive techniques












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