الفهرس 
Introduction
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Abstract
Up till now, the combination of pegylated interferon (IFN)-α and ribavirin is the approved and well accepted standard-of-care (SoC) for chronic hepatitis C. Pegylated IFN-α and ribavirin treatment duration can be tailored to the on-treatment virological response whatever HCV genotype. The likelihood of SVR is directly proportional to the time of HCV RNA disappearance. There is no well settled definition for treatment failure in chronic HCV. It was considered by some as failure to achieve an SVR and classified it into; null response, slow response (>2-log10 reduction in HCV RNA after 12 weeks of therapy but detectable), breakthrough and relapse. Others considered both primary non-response and post-treatment relapse as treatment failure. There are many factors that have been attributed to treatment failure. These factors may be either baseline factors such as ethnicity, gender, body weight and histologic parameters or factors during antiviral therapy like viral kinetics and adherence to treatment. Severe IFN and ribavirin side effects may reduce adherence to therapy and may result in dose modifications that result in a less optimal response. Several measures to improve treatment success rates can be done such as: full adherence to both pegylated IFN-α and ribavirin schedules, body weight reduction in overweight patients prior to therapy, abstain from alcohol during antiviral therapy and administration of recombinant erythropoietin when the hemoglobin level falls below 10 g/dl. Insulin resistance may promote hepatic fibrosis in chronic hepatitis C (HCV) and has been considered as a cofactor in treatment failure. However, no prospective trials of relevant size have been published to date to prove the efficacy of a therapeutic intervention aimed at improving insulin resistance in SVR. Recent genome-wide association studies (GWAS) have identified genetic variations near the IL28B gene which are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A commercially available test of the IL28B rs12979860 genotype was developed. Determination of these polymorphisms may be useful to assess a patient’s likelihood of response to treatment with pegylated interferon alpha and ribavirin. Differential expression of genes implicated in the mechanism of response to PEG-IFN and ribavirin can explain the variation of the treatment efficiency. Many studies demonstrated that ISG (INF-stimulated genes) transcript levels are basally elevated in non-responder liver tissue compared to responders. Further understanding of the HCV life cycle and of structural features of the HCV proteins, resulted in development of many direct-acting antiviral agents (DAA). DAA aim towards higher efficacy, shortened treatment, easier administration, and improved tolerability and patient adherence. Phase III studies have been reported for two NS3/4 protease inhibitors, telaprevir and boceprevir, in combination with pegylated IFN-α and ribavirin in both naïve and non-responder patients infected with HCV genotype 1. FDA has recently approved boceprevir (Victrelis) making it the first new drug for HCV in 20 years. Also, FDA has approved telaprevir (Incivek) for treatment of HCV genotype 1, making it the second new protease inhibitor to win agency approval for HCV. Interferons with a longer half-life and sustained plasma concentrations (e.g., albinterferon) have shown no overall benefit with respect to SVR rates. PEG-IFN lambda (λ)-1 has a promising effect with an expected less frequent related side effects.