Pharmacogenomics of Interferon and Ribavirin Treatment in Patients With Chronic Hepatitis C Virus Infection

Background and Research Plan:

Chronic HCV infection often follows a progressive course over many years, and can ultimately result in cirrhosis and the need for liver transplantation or hepatocellular carcinoma. The decision to treat patients with chronic hepatitis C infection is based upon several factors including the natural history and stage of the disease and the efficacy and adverse effects related to therapy. As a general rule patients who are considered for treatment should have histologic and virologic evidence of chronic infection (i.e., HCV RNA detectable in serum) and an elevated serum ALT (1). Combination treatment with Interferon and Ribavirin is currently the best available treatment for chronic HCV infection. However, response to therapy is suboptimal and there are several side effects.

Side effects seen during therapy of patients with Interferon and Ribavirin include flu-like symptoms mostly due to interferon, cytopenias and haemolysis induced by Ribavirin. Psychiatric changes due to interferon, occur in up to 50% and thyroid abnormalities requiring therapy occur in about 1 to 5% treated with interferon. Autoimmune disease and retinal haemorrhages have also been reported. In addition, combination therapy is associated with significant risks in patients with renal dysfunction, cardiac disease and haemolytic anaemias as treatment may be associated with anaemia. Patients who are depressed or suicidal should also be excluded (2).

To this point little DNA microarray work done has been done with HCV. However, what work has been done is interesting and shows promise. In studies comparing Hepatitis B (HBV) with Hepatitis C, HBV infection was found to express genes predominantly involved in inflammation. In contrast, with HCV infection anti-inflammatory genes were found to be expressed (3). In another study HCV associated cirrhosis has been shown to be characterized by proinflammatory, pro-fibrotic and proapoptotic gene expression profiles (4).

The progression of HCV infection by gene expression analysis of liver biopsies in acutely infected chimpanzees that develop persistent infection, transient viral clearance, or sustained clearance has been examined. Transient and sustained viral clearance were uniquely associated with induction of IFN-gamma-induced genes and other genes involved in antigen processing and presentation and the adaptive immune response. The study revealed genome-wide transcriptional changes that reflect the establishment, spread, and control of infection, and they reveal potentially unique antiviral programs associated with clearance of HCV infection (5).