Clinical Outcome to Interferon Therapy in Chronic Hepatitis C: Insights from Mechanistic Studies

Since the discovery of hepatitis C virus (HCV) 15 years ago, our understanding of the natural history of chronic hepatitis C, the molecular biology of the virus and implementation of effective therapies has developed significantly. Initial treatment of chronic hepatitis C was with conventional interferon-alpha (IFN-α) monotherapy, a treatment that resulted in a sustained virological response (SVR) in only approximately 20% of individuals. However, the introduction of combination therapy with ribavirin significantly increased the SVR to as high as 60% in those individuals infected with genotypes 2 or 3 and 40% in genotype 1 infections [1,2]. The current treatment of choice is combination therapy with pegylated IFN-α (PEG-IFN) and ribavirin, which has increased SVR even more. Recent clinical studies using PEG-IFN and ribavirin therapy in treatment-naive patients has resulted in treatment failure (defined as persistent HCV replication at 24 weeks after completion of therapy) in approximately 20% of patients infected with genotypes 2 or 3, respectively, and in approximately 50% of patients infected with genotype 1 [3,4]. Thus, while modification of IFN therapy is making up some ground in the war against HCV, there are still a significant number of individuals who will not respond to the available therapeutic approaches. The failure of IFNbased therapies in these individuals is not well understood at the molecular level, although it is most probably due to multiple factors involving both the virus and the host. One of the burning questions for clinicians treating patients infected with HCV and for basic researchers interested in the pathogenesis of hepatitis C, is what are the determinants, either viral or host, which determine the outcome as either an SVR or failure with the current combination therapy. While it is known that viral factors probably play a role in the outcome of infection, host factors including genetic susceptibility may contribute to the variable manifestations of the disease and treatment response. Viral factors such as HCV genotype and viral load are strongly associated with a poor response to IFN therapy [1,5]. Individuals infected with genotype 1 (the predominant genotype in the USA and Europe) and those with a high viral load prior to treatment are more resistant to therapy compared with individuals infected with other genotypes and those with low viral loads. The exact viral determinants conferring IFN ‘resistance’ or failure have yet to be identified but are most probably a result of modulation of the antiviral effect and immunomodulatory functions of IFN. One candidate that has received a lot of attention for this modulation is the HCV non-structural protein 5A (NS5A). The exact role of NS5A in the HCV life cycle is unknown. However, a relationship has been identified between the sequence of the central region (40 amino acids) of NS5A, termed the interferon sensitivity-determining region (ISDR), and an SVR in genotype 1-infected patients [6–8]. Most recently, it has also been shown that the lack of an SVR correlates with the sequence of a variable region V3, positioned at the C-terminal part of NS5A [9,10]. It has been shown in vitro that NS5A, in particular the ISDR, can inhibit the action of protein kinase R (PKR) [11–13], a protein with potent antiviral activity that is induced by IFN-α. This inhibition of PKR, at least in vitro, is thought to be due to direct interactions with NS5A [12,13]. However, the role of the ISDR in inhibition of the action of IFN is controversial, with one study [14] showing no association of NS5A and PKR. As suggested by Pawlotsky [15], it is possible that NS5A/PKR interactions may play a role in IFN resistance in the setting of naturally secreted IFN-α but it is unlikely to play a role in IFN-α-based treatment in which high levels of IFN are used.