prospects for personalizing antiviral therapy for hepatitis c virus with pharmacogenetics个性化的前景与药物基因学抗病毒治疗丙型肝炎病毒.pdfVIP

Tavis et al. Genome Medicine 2011, 3:8 /content/3/2/8 R E V I E W Prospects for personalizing antiviral therapy for hepatitis C virus with pharmacogenetics 1,2 1,2 1 2,3 2,3 John E Tavis* , Maureen J Donlin , Rajeev Aurora , Xiaofeng Fan and Adrian M Di Bisceglie Abstract Chronic hepatitis C virus (HCV) infection is a major cause of liver disease worldwide. HCV infection is currently treated with IFNα plus ribavirin for 24 to 48 weeks. This demanding therapy fails in up to 50% of patients, so the use of pharmacogenetic biomarkers to predict the outcome of treatment would reduce futile treatment of non-responders and help identify patients in whom therapy would be justied. Both IFNα and ribavirin primarily act by modulating the immune system of the patient, and HCV uses multiple mechanisms to counteract the antiviral eects stimulated by therapy. Therefore, response to therapy is inuenced by variations in human genes governing the immune system and by dierences in HCV genes that blunt antiviral immune responses. This article summarizes recent advances in understanding how host and viral genetic variation aect outcome of therapy. The most notable human associations are polymorphisms within the IL28B gene, but variations in human leukocyte antigen and cytokine genes have also been associated with treatment outcome. The most prominent viral genetic association with outcome of therapy is that HCV genotype 1 is much less sensitive to treatment than genotypes 2 and 3, but genetic dierences below the genotype level also inuence outcome of therapy, presumably by modulating the ability of viral genes to blunt antiviral immune responses. Pharmacogenetic prediction of the outcome of IFN-based therapy for HCV will require integrating the ecacies of the immunosuppressive mechanisms of a viral isolate, and the