Insulin Resistance Associated With Chronic Hepatitis C (CHC) and the Effect of Antiviral Therapy

The first phase will include patients with hepatitis C who are candidates for anti-viral treatment, and patients with chronic hepatitis B who have undergone a recent liver biopsy showing hepatitis without cirrhosis, with equal numbers in each group (100/ group).

Phase 2 (40 patients)- Patients with hepatitis C found in phase 1 by the HOMA test to have increased insulin resistance will be recruited to phase 2 (interventional phase). Patients with HBV infection will not be studied further.

The study will be conducted at a single center using an open-label design. All patients will be treatment naïve. Up to 40 patients will be treated per current standard of care with combination pegylated interferon alfa and ribavirin (Phase 2). Patients with genotype 2 or 3 will be treated with combination weekly Pegasys with a daily Copegus dose of 800 mg given for 24 weeks (Group A). Patients with genotype non-2 or 3 will be treated with combination weekly Pegasys with a daily Copegus dose of 1000-1200 mg given for 48 weeks (Group B). Both groups will have an untreated follow-up period of 24 weeks. Pegasys will be administered sc once weekly (180 microg in 0.5 or 1 mL solution) and Copegus will be taken po daily in split doses of 400 mg in the morning and 400 mg in the evening (i.e., 2 tablets of 200 mg bid). For doses of 1000 mg (genotype non- 2 or 3 patients whose body weight < 75 kg) Copegus will be administered po daily: 400 mg (i.e. 2 tablets of 200 mg) in the morning and 600 mg (i.e. 3 tablets of 200 mg) in the evening. For genotype non-2 or 3 patients whose body weight is 75 kg, 600 mg (i.e. 3 tablets of 200 mg) in the morning and 600 mg (i.e. 3 tablets of 200 mg) in the evening is recommended. All patients in this study will receive Copegus treatment with food. By definition, Copegus "with food" means taking their doses within 1 hour before or 2 hours after a meal. The meal should be considered "regular" as opposed to "fat-restricted".

All 40 patients who meet inclusion criteria will also have indices of body fat assessed through calculation of their BMI, DEXA scanning, and waist-to-hip circumference measurements. Prior to therapy all patients will undergo the OGTT , which is a dynamic test for insulin resistance providing accurate information on the relationship between insulin and glucose.

At week 12 of treatment patients will have a quantitative assessment of HCV viral load and a second OGTT . The current standard of therapy is to discontinue anti-viral therapy in patients with genotype 1 or 4 without a ≥ 2-log fall in HCV RNA. Those who have a ≥ 2-log fall in HCV RNA are expected to have a SVR. Patients to be continued on anti-viral therapy will then be followed to SVR.

Twenty-four weeks after completion of anti-viral therapy, a OGTT will be repeated (SVR OGTT). The effect of viral clearance on insulin resistance will be assessed by comparing the OGTT at SVR (SVR OGTT) to pre-treatment OGTT.

Patients who are Non-Responders should also be assessed for safety 4-8 weeks after their last dose of test medication following premature discontinuation from the study. Non-Responders are defined as patients without a 2-log drop in PCR between baseline and week 12 or a positive PCR at their last visit. Responders should be followed for until Week 48 (Group A patients) or Week 72 (Group B patients). Responders are defined as patients who have a 2-log drop in PCR between baseline and week 12 and a negative PCR at their last visit. Female patients receiving Copegus should continue to do the home-based pregnancy test every 4 weeks for the 6-month period after the last dose of study drug.

Efficacy assessments consist of serum HCV-RNA via PCR. Quantitative viral titers (AMPLICOR HCV MONITOR Test, v2.0) will be obtained at Weeks 0 and 12 from all patients. Qualitative HCV-RNA results (AMPLICORÒ HCV Test, v2.0) will be obtained at treatment period Week 24 for all patients and Week 48 for group B; in addition during follow-up at week 24 for all patients.

Insulin resistance as determined by the OGTT method will be assessed prior to initiation of therapy, at 12 weeks of therapy, and during follow-up at week 24 for all patients.

Study Outcome:

Phase 1 - To evaluate the prevalence of insulin resistance in patients with hepatitis C without cirrhosis and compare it to that observed in patients with hepatitis B also without cirrhosis.

Phase 2 - Interventional phase - To evaluate the effect of anti-viral therapy on insulin resistance, determined by the OGTT method, in patients with hepatitis C found to have insulin resistance pre-treatment.

• To evaluate the safety, efficacy and tolerability of Pegasys (peginterferon alfa-2a) given in combination with Copegus (ribavirin) given for 24 weeks or 48 weeks in treatment naïve patients with chronic hepatitis C (CHC).