High Dose Ribavirin in the Treatment of Chronic Hepatitis C
Condition: Chronic Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic
Study type: Interventional
Phase: Phase 2

Summary: 
      Treatment of patients with chronic hepatitis C infected with genotype 1 hepatitis C virus
      (HCV) consists of combined peginterferon/ribavirin for 48 weeks. Approximately 50% of
      patients experience sustained virological response which equals cure. All other patients
      either do not respond or experience recurrence of HCV virus and chronic hepatitis. Important
      predictors of successful treatment are sustained dosing of both peginterferon and ribavirin.
      With regard to the latter, clinical evidence indicates that higher ribavirin doses may in
      fact even improve treatment outcome. However, high ribavirin doses cause hemolytic anemia
      which require dose reductions. Recent clinical experience show that erythropoetic growth
      factors, including erythropoetin, can counteract hemolytic anemia caused by antiviral
      treatment in chronic hepatitis C patients. Therefore, the current trial aims to test whether
      higher ribavirin doses adapted to a target plasma concentrations instead of a weight-based
      dosing result in better healing rates, and whether ribavirin-associated hemolytic anemia can
      be compensated by concommitant erythropoetin treatment.

      Using a randomized, controlled, open-label design, the investigators hypothesize that
      patients with high ribavirin doses adapted to plasma levels experience better viral clearance
      than patients treated with standard weight-based ribavirin doses. In addition, the
      investigators hypothesize that erythropoetin treatment will counteract hemolytic anemia
      induced by ribavirin thereby allowing maintenance of target plasma concentrations without
      ribavirin dose reductions.
    

Detailed description: 
      Background

      Prevalence and incidence of chronic hepatitis C (CHC) are rising worldwide. Complications
      include chronic liver failure and hepatocellular carcinoma, and chronic hepatitis C is a
      major indication for liver transplantation. Effective treatment is required to prevent these
      outcomes.

      Current treatment consists of a combination of peginterferon (PegIFN) and ribavirin (RBV)
      given for 24 or 48 weeks depending on the viral genotype. While genotypes 2 and 3 respond
      well to 24 weeks of PegIFN/RBV with approximately 80% viral clearance, genotype 1 infected
      patients only achieve about 40-50% sustained viral response (SVR) with 48 weeks of
      combination therapy.

      RBV is a nucleoside analog with structural similarities to guanosine, which modulates RNA and
      DNA synthesis. RBV reveals antiviral activity against respiratory syncytial (RS)-virus,
      influenza virus, Lassa virus uand others. The exact mode of antiviral activity is yet unknown
      but believed to relate to reducing survival of HCV-infected hepatocytes thereby allowing for
      elimination of infected cells by interferon-stimulated immune mechanisms.

      Generally, RBV is well tolerated. With standard daily doses between 1.000 and 1.200mg,
      irritability, sleeping abnormalities, cough and pruritus. The most prevalent and typical side
      effect of RBV is a dose-dependent hemolytical anemia which responds well to dose reduction or
      interruption of RBV therapy. RBV-associated anemia impairs quality of life and, overall,
      25-36% of patients require dose reductions and/or RBV cessation. However, reduction/cessation
      of RBV is associated with a significant drop of SVR and measures to maintain RBV doses are
      clearly warranted. Several recent studies have shown that erythropoetin can counteract
      RBV-induced hemolytic anemia, and improve quality of life.

      The relevance of RBV dose with regard to therapeutic response to combination therapy is
      well-established and currently, RBV is dosed according to weight: patients with CHC genotype
      1 are treated with 1.000mg if body weight is <65kg, and receive 1.200mg if >65kg.

      Retrospective studies have shown that relapsers and non-responders to antiviral treatment
      with RBV had lower RBV levels than those who had a SVR. In a retrospective analysis of 4
      studies investigating a total of 1105 patients treated with RBV, RBV plasma concentrations
      measured at 4 weeks of treatment correlated with viral clearance: SVR was 31.8% in those with
      RBV levels <1,000ng/ml, and increased to 62.5% with RBV concentrations at >4,000ng/ml.

      A pilot trial from Sweden investigated whether dosing RBV according to a plasma level of
      15mcmol/l (3.7mcg/ml) in 10 patients. Median RBV dose was 2.540mg/day and all patients
      received erythropoetin.SVR was achieved in 9 of 10 patients.

      So far, a randomized, controlled trial comparing weight-based RBV (standard) vs. RBV dosed
      according to kidney function and plasma levels.

      Objective

      Comparison of efficacy and tolerability of treatment with PegIFN-alpha 2a + RBV dosed
      according plasma concentrations vs PegIFN-alpha 2a + weight-based RBV in patients with
      chronic hepatitis C genotype 1

      Methods

      Prospective, controlled, open label randomized human trial
    

Intervention name(s): High ribavirin dose; Standard ribavirin dose
Intervention type(s): Drug; Drug
Intervention description(s): Ribavirin dose started according to kidney function (usually 1,800mg) and adapted according to plasma level during follow-up; Ribavirin dose started at 1,000mg (body weight <65kg) or 1,200mg (body weight equal or >65kg)
Intervention MeSH terms: Ribavirin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic hepatitis C; Antiviral treatment; Ribavirin; Sustained virological response; Hemolytic anemia; Erythropoetin