Gene expression profiling of liver biopsies from 21 chronic hepatitis C patients undergoing antiviral therapy

Pegylated interferon-α (pegIFN-α) has replaced un-modified recombinant IFN-α for the treatment of chronic viral hepatitis because of its superior anti-viral efficacy that is generally attributed to improved pharmacokinetic properties. However, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. We analyzed pegIFN-α induced signaling and gene regulation in paired liver biopsies obtained before treatment and during the first week after injection of pegIFN-α in 18 patients. Despite sustained high serum concentrations of pegIFN-α over the entire one-week dosing interval, IFN-α signaling through the Jak-STAT pathway occurs only during the first day. PegIFN-α induces hundreds of genes that can be classified into 4 clusters based on different temporal expression profiles. In all clusters, gene transcription is mainly driven by IFN stimulated gene factor 3 (ISGF3). IFN induced secondary transcription factors do not cause additional waves of gene expression. We could not confirm a role of un-phosphorylated STAT1 in prolonging IFN-α induced gene transcription. Collectively, our results reveal that the major effects of pegIFN-α in the liver are caused by an early and transient activation of ISGF3. Prolonging the serum half-life of IFN-α does not necessarily improve its pharmacodynamic properties. Paired liver biopsy samples were collected before and during the first week of pegylated interferon alpha treatment of 21 chronic hepatitis C patients. Total: 21 patients and 42 samples.