High Dose Ribavirin in the Treatment of Chronic Hepatitis C

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