Basic aspects of the treatment for hepatitis C: mechanisms of action of interferon alpha and ribavirin and the bases of individualization

Abstract

The treatment of patients with chronic hepatitis C hasdeveloped considerably in recent years. However, it is stillbased on the use of interferon alpha (IFN-α) as an antiviraland immunomodulatory agent against the hepatitis C virus(HCV).The IFNs are a family of proteins that are naturallyproduced by the cells of the immune system. The IFN-a proteinpresents antiviral, antiproliferative and immunomodulatoryactivity [1-3]. Its mechanism of biological action occursthrough the activation of specific genes, influencing cellgrowth and division, as well as modulating some immunesystem activities. Therefore, IFNs have an indirect antiviraleffect on HCV [2,4].Commercially, IFN- α is produced by means of recombinantDNA techniques and is available in preparations of two distinctsubtypes (IFN-α 2a or IFN-α 2b), which can be combinedwith other molecules, such as polyethylene glycolor, morerecently, albumin [5,6]. The only difference between IFN- α 2aand IFN- α 2b is in the amino acid present at position 23 of theprotein: IFN- α 2a has a lysine at that position, whereas IFN- α2b has an arginine [7].After the binding with its specific receptor (IFNAR) onthe surface of the target cells, IFN- α activates an intracellularsignaling cascade, which takes the induction of IFN-stimulatedgenes (ISGs), establishing a non-virus-specific antiviral stateinside the cell [3,7]. The principal signaling mechanism usedby IFN- α is the so-called Janus kinase/signal transducers andactivators of transcription (Jak/STAT) pathway [3]. Therefore,two cytoplasmatic proteins with the activity of tyrosine kinaseassociated with IFNAR, activated Jak1 and tyrosine kinase 2(Tyk2), are activated by the dimerization of the receptors.Activated Jak1 and Tyk2 perform the phosphorylation ofSTAT1 and STAT2, respectively. The phosphorylated STAT1and STAT2 bond with the protein p48 forming IFN-stimulatedgene factor 3 (ISGF3), which translocates into the nucleusand bonds with IFN-stimulated regulatory element in thesequences which promote a variety of genes inducible byIFN-α including antiviral proteins such as 2’5’-oligoadenylatesynthetase (2’5’OAS), protein kinase RNA, and Mx protein[1,3,7,8].The absorption of IFN-α (2a or 2b) is high (above 80%)when administrated intramuscularly or subcutaneously. Theconcentration typically peaks at 3-12 h after administration [9].The metabolism and elimination of IFN- α occurs principallyvia the kidneys, with a half-life of 3-8 h [9].