• HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR) [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
  

• HCV-RNA negativity at week 4 (rapid virological response, RVR) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  
• HCV-RNA negativity at week 12 (complete early virological response, cEVR) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  
• HCV-RNA ≥ 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  
• HCV- RNA negativity at week 48 (end of treatment response, ETR) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  
• Relapse rate after ETR [ Time Frame: 48 weeks - end of follow up ] [ Designated as safety issue: No ]
  
• Safety and tolerability of high-dose daily ribavirin (serious adverse events, grade 4 NCI toxicity, percentage of patients completing treatment on full or >80% of total intended dose and reasons for dose adjustments) [ Time Frame: week 0 till end of follow up ] [ Designated as safety issue: Yes ]
  
• Biochemical response (normalization of serum ALT at the end of therapy and at the end of follow-up) [ Time Frame: week 0 - end of follow up ] [ Designated as safety issue: No ]
  
• Health related quality of life and psychopathology before, during and after treatment by SF-36 and SCL-90 questionnaires [ Time Frame: week 0 - week 72 ] [ Designated as safety issue: No ]
  

Optimal ribavirin dosages are essential in achieving SVR. The initial evidence supporting higher doses of ribavirin for peginterferon alfa-2b comes from a secondary analysis of the pivotal multicenter trial of peginterferon alfa-2b and ribavirin. Patients receiving more than 10.6 mg/kg/day ribavirin experienced significantly higher SVR rates (48% vs. 38%). A large multicenter trial designed to test standard dose ribavirin (1000-1200 mg/day) versus low-dose ribavirin (800 mg/day) in combination with peginterferon alfa-2a, showed 52% SVR in the standard dose group versus 41% in the low-dose group for genotype 1 infected patients. In the pooled data from two pivotal studies with peginterferon alfa-2a and ribavirin, the probability of achieving an SVR for genotype 1 patients was influenced by the ribavirin dose per kg body weight. A 40-50% increase in the probability of SVR was found for a 12-16 mg/kg dose increase of ribavirin. For peginterferon alfa-2b it was also shown among genotype 1 patients, that weight-based ribavirin (800-1400 mg/day) leads to higher SVR rates compared to fixed dose ribavirin (800 mg/day) (34% vs. 29%). Moreover, ribavirin dosing up to 1400 mg/day was safe and the rate of treatment discontinuation was the same for both treatment groups. In a small pilot study, 10 genotype 1 patients with a high baseline load were treated with peginterferon alfa-2a and individualized high-dose ribavirin in order to achieve a ribavirin target concentration in serum of 15 μmol/l. The mean ribavirin dose of 2540 mg/day (range 1600-3600 mg/day) was high, but resulted in 90% SVR. All patients experienced severe anemia, which was treated with concomitant epoetin beta and blood transfusion.

As mentioned before, the main concern of high-dose ribavirin will be a dose-dependent hemolytic anemia and the addition of epoetin alfa has shown significant increase of haemoglobin during (peg)interferon/ribavirin therapy. Erythropoietin doses from 9,000 to 60,000 IU/week have been used in order keep the highest possible ribavirin doses. A recent trial showed a significant higher SVR rate in genotype 1 patients treated with peginterferon alfa-2b, increased dose ribavirin (15.2 mg/kg/day) and epoetin alfa than in patients treated with peginterferon alfa-2b and standard dose ribavirin (13.3 mg/kg/day) with or without epoetin alfa. Using the standard ribavirin dose, routine use of erythropoietin significantly decreased the frequency of anemia and the mean ribavirin dose reduction. Moreover, with the addition of erythropoietin, a significant higher mean dose could be given to patients in the increased ribavirin dose arm.