Pegylated-Interferon and Ribavirin Plus Metformin in the Treatment of Chronic HCV Infection and Insulin Resistance

• Combined end-point of non-detectable serum HCV-RNA (<100 copies/mL) and
  
• normal serum ALT activity at the end of the 24 week treatment-free follow up period
  

• End-of-treatment virological and biochemical response
  
• Sustained virological and biochemical response
  
• End-of-treatment improvement of insulin resistance
  
• End-of-treatment improvement of liver histology
  

Chronic hepatitis C virus (HCV) infection is associated with an increased risk for the development of type 2 diabetes and HCV infection itself may promote insulin resistance, irrespective of the severity of liver disease.

• In patients with HCV infection, an increase in fasting insulin levels is associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade. Down-regulation of IRS1 and IRS2 has also been observed in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells.
• High levels of tumor necrosis factor-alpha, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1, may be associated with insulin resistance both in animal models and in HCV patients.

Insulin resistance seems to be genotype specific and may play a role in fibrogenesis in chronic hepatitis C.

• In patients infected with genotype non-3, insulin resistance is associated with the degree of fibrosis, the rate of fibrosis progression and previous failed antiviral treatment.
• Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin. A sustained virological response is achieved in 33% of patients with genotype 1 and insulin resistance compared with 60% of genotype 1 patients without insulin resistance.
• Insulin resistance is associated with a 3-fold risk of failure to antiviral treatment in patients with genotype 1 In an “in vitro” model, increased levels of insulin may promote increased HCV replication.

RATIONALE Decreased insulin resistance and reduced hyperinsulinemia may facilitate the efficacy of anti-viral drugs on HCV replication.

INDICATION Genotype 1 Chronic HCV hepatitis (CHC) associated with insulin resistance (IR).

OBJECTIVES To compare the efficacy and safety of Pegylated-Interferon and Ribavirin plus metformin to Pegylated-Interferon and Ribavirin for treatment of naïve patients with Genotype 1 Chronic HCV infection and insulin resistance.