Randomized Controlled Open Label Trial of Peg Alpha 2a Interferon and Adjusted-dose of Ribavirin vs. Standard Therapy in the Treatment of Naive Chronic Hepatitis C Patients Infected With Genotype 4

Background: The introduction of Peg interferon and Ribavirin (an oral nucleoside analogue) for chronic Hepatitis C has led to the concept that chronic hepatitis C (HCV) is a curable disease. Improvement of treatment efficacy is still a major challenge. Optimal Ribavirin doses are essential to achieve SVR (sustained virological response). A recent trial showed significantly higher sustained virological response (SVR) in patients receiving 15.2 mg/kg/day of Ribavirin compared with 13.3 mg/kg/day. Ribavirin was given in combination with Peg interferon alpha-2b (1). A small pilot study, in which 10 patients with Chronic Hepatitis C genotype 1 were treated with Ribavirin dosage up to 3600 mg/day- mean of 2540 mg/day- plus Peg-interferon alpha-2a, achieving a target concentration of Ribavirin >15 micromol before W 12, led to 90% of SVR(2). All patients managed to complete the one year treatment period but all needed EPO and two were transfused.

Patient's global exposure to Ribavirin as evaluated by the area under the curve (AUC) seems more pertinent in terms of exposure-effect relationship than measuring Ribavirin level at any single time point. A recent study showed in HCV patients infected with genotype 1 that Ribavirin plasma exposure after the first dose (i.e., interdose AUC0-12h or abbreviated AUC0-4h) was significantly and strongly linked with SVR, whereas AUCs determined at W12 and W24 and trough concentrations at Day 0 and W12 were not (3).

Therefore, we propose a randomized controlled trial to investigate whether adjusted Ribavirin doses based on AUC0-4h obtained at D-7 after 600mg dose of Ribavirin versus fixed standard doses can improve outcome in treatment of chronic hepatitis C naïve patients infected with genotype 4.

Methodology: After AUC0-4h has been determined at D-7 (7 days before randomization) for 190 genotype 4 patients recruited into the trial, the patients are randomized into two groups: Group A: to receive standard dose of Ribavirin 1000-1200 mg/day) and Group B: to receive adjusted-dose of Ribavirin according to AUC0-4h. The individual calculated dose should be administered for each patient beginning on the first day of treatment. Both groups will receive combination treatment with peginterferon alpha 2a 180 mcg/week for a total of 48 weeks.

Both treatment groups will receive Darbepoetin if subsequent Hb is < 11 g/dl for males and females. Our main inclusion criteria will be: patients 18-70 years old with serological evidence of chronic hepatitis C and positive HCV RNA of genotype 4, with a liver biopsy within 3 years prior to recruitment. Our main exclusion criteria will be: decompensated cirrhotic patients, HBV/HIV co-infection, evidence of hepatocellular carcinoma (HCC), significant evolutive cardiovascular, pulmonary, renal or psychiatric disease, pregnancy/breast feeding or patients post liver transplantation and anemia.

Our primary outcome will be: HCV-RNA negativity 24 weeks after the end of treatment (SVR) (input adjusted dose on SVR). Our secondary outcome will be: rapid virological response (RVR), early virological response (EVR), partial early virological response (pEVR), end of treatment response (ETR), relapse after (ETR), biochemical response and safety and tolerability of high doses of Ribavirin.