Abstract
Background IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.MethodsOptimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.ResultsFrequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.Conclusion IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.
Highlights
With estimated 150 million people chronically infected worldwide and 3–4 million new infections each year [1], hepatitis C virus (HCV) infection is one of the major causes for liver cirrhosis and subsequent development of hepatocellular carcinoma
For optimized prediction of sustained virologic response (SVR) by treatment with dual combination or first generation protease inhibitors (PIs) triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%
In many countries triple therapies with HCV NS3 protease inhibitors telaprevir (TVR) or boceprevir (BOC) and/or dual combination of pegylated interferon alfa (PEG-IFN) and ribavirin will remain the standard of care for the years before newer direct acting antiviral agents (DAAs) containing regimens are approved or reimbursed [7,8,9,10]
Summary
With estimated 150 million people chronically infected worldwide and 3–4 million new infections each year [1], hepatitis C virus (HCV) infection is one of the major causes for liver cirrhosis and subsequent development of hepatocellular carcinoma. This often leads to liver failure and to liver transplantation. In many countries triple therapies with HCV NS3 protease inhibitors telaprevir (TVR) or boceprevir (BOC) and/or dual combination of pegylated interferon alfa (PEG-IFN) and ribavirin will remain the standard of care for the years before newer DAA containing regimens are approved or reimbursed [7,8,9,10]. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources
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