Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin

Abstract

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG-IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1-infected patients. Several viral and host factors have been associated with non-response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non-responders, some interferon-stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG-IFN plus ribavirin) to 70% (for patients treated with a combination of PEG-IFN plus ribavirin plus telaprevir). Different elements are associated with non-response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non-response, to overcome it and to identify factors that can help to predict the response to anti-HCV therapy.

Fig. 1

Factors associated to non-response to pegylated interferon plus ribavirin treatment.

Fig. 2

Hepatitis C virus (HCV) and immune response. Activation of toll like receptor 3 (TLR3) leads to the recruitment of IκB kinase (IKK)-related kinases, TANK-binding kinase 1 (TBK1) and IKKi. These kinases, together with adaptators TANK and NAP1, catalyse the phosphorylation of interferon (IFN) stimulatory factor-3 (IRF-3). Phosphorylated IRF-3 forms a dimer, translocates into the nucleus, binds to DNA in collaboration with transcription factor AP-1 and NF-κB and regulates the expression of IFNβ. The HCV NS3-4A serine protease may block the phosphorylation and effector action of IRF-3. After recognition of viral RNA, RIG-I and Mda5 recruit IFNβ promoter stimulator-1 (IPS-1) via caspase recruitment domain (CARD-CARD) interaction. IPS-1 is localized in the mitochondria and acts as an adaptator that plays a critical role in the activation of IRF-3 and IRF-7. IPS-1 is targeted and inactivated by the serine protease NS3/4A from HCV. IRF-7 forms a dimmer and translocates into the nucleus to induce IFN α/β. Endogenous IFN α/β bind to a common receptor (IFNAR-1/2) expressed at the cell surface of target cells. Receptor engagement leads to recruitment of Tyk2 and Jak1. Together with IRF-9 the two kinases induce activation of STAT1 and STAT2 which, together with ISGF3G/IRF9, bind to cis-acting IFN stimulated elements (ISREs), thereby activating the transcription of IFN α/β-inducible genes such as PKR, IL-8, OAS. The HCV core protein has been shown to induce the expression of SOCS3 (suppressor of cytokine signalling 3), which can suppress Jak/STAT.

Fig. 3

Definition of response to pegylated interferon (PEG-IFN) plus ribavirin treatment. The kinetic of HCV RNA level during PEG-IFN plus ribavirin therapy helps to predict the response. Rapid virological response (RVR) is defined as a HCV RNA negative at treatment week 4. Early virological response (EVR) consists in a reduction of HCV RNA >2 log compare to HCV RNA baseline, at week 12. A complete EVR is defined as a negative HCV RNA at the end of the 24 or 48 weeks of the treatment. Sustained virological response (SVR) is characterized by an absence of HCV RNA, up to 24 weeks after cessation of treatment. Reappearance of HCV RNA in the serum during the treatment is defined as a breakthrough. The term of relapse is used when HCV RNA level is again detectable when the therapy is discontinued. Finally, patients who do not respond to the treatment are described as (i) non-responders when they fail to clear HCV RNA after 24 weeks of therapy, or (ii) Null responders when they fail to clear the HCV RNA level up to 2 log at week 24 of the therapy, or (iii) Partial responders when they achieved a EVR and show HCV RNA level still detectable at week 24 of the therapy.