Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response†

Despite great advances in the treatment of chronic hepatitis C infection, the current therapy with peginterferon and ribavirin is effective in only about 50% of patients.1,2 The reasons for treatment failure are not well understood but likely are related to both viral and host factors.3 The viral genotype has the greatest impact on the treatment outcome. A sustained virological response (SVR) is achieved in 42%-46% of genotype 1 infections after a year of therapy, in contrast to rates of 80% in genotype 2 and 3 infections after just 6 months of treatment.1,2 In addition to the genotype, the baseline viral load is also an important factor, particularly in genotype 1 infection.2 Although numerous viral strategies for interfering with host viral defense mechanisms have been identified, none has been clearly shown to be responsible for the genotypic differences in the treatment response. From large treatment trials, a number of host factors have been found to be associated with the treatment response. Gender and race are the most important factors. Men consistently respond less well to therapy than women, and African Americans have poorer outcomes than Caucasian populations.4 Age, obesity, and the degree of liver fibrosis also affect the treatment outcome.5 Although these factors have been consistently identified in multiple studies, the mechanism by which they affect the treatment outcome remains unknown. To gain a further understanding of the host factors, microarray technology has been used to evaluate hepatic gene expression prior to antiviral therapy. Chen et al.6 found that pretreatment gene expression profiles from liver biopsies were predictive of the ultimate treatment outcome. Patients who did not respond to therapy showed up-regulation of numerous interferon-stimulated genes (ISGs) prior to treatment in comparison with both sustained responders and normal controls. Hepatic gene expression has not been reported in humans undergoing therapy. Several studies have reported gene expression in peripheral blood mononuclear cells (PBMCs) during the course of therapy; however, gene induction in PBMCs may not be entirely reflective of events in the liver.7–9 The addition of ribavirin to interferon (IFN) therapy significantly improves the treatment response rates; however, the mechanism by which this occurs is poorly understood. Numerous mechanisms of action for ribavirin have been proposed, including inosine-5-monophosphate dehydrogenase inhibition (IMPDH), direct viral inhibition, increased mutagenesis leading to error catastrophe, and promotion of a Th1 immune response.10 Although there is some experimental evidence to support all of these mechanisms, none accounts for the magnitude of the benefit seen with the addition of ribavirin. In order to gain further understanding of the genetic factors that may contribute to the treatment response, we evaluated gene expression from liver biopsy samples from patients currently undergoing treatment with peginterferon. Half the patients also received ribavirin prior to liver biopsy, and this allowed us to assess the contribution of this agent to gene expression. Expression profiles from on-treatment patients were compared with those from pretreatment liver biopsy samples of a matched control population.