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Predictive value of interferon-lambda gene polymorphisms for treatment response in chronic hepatitis C.

Susser S, Herrmann E, Lange C, Hamdi N, Müller T, Berg T, Perner D, Zeuzem S, Sarrazin C - PLoS ONE (2014)

Bottom Line: 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.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%.

View Article: PubMed Central - PubMed

Affiliation: Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.

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.

Methods: Optimization 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.

Results: Frequencies 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%.

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A-2E: SVR prediction rates in HCV infected patients based on interferon-lambda host genotypes and grouping of such by applying a binary regression tree analysis. Figure 2A: HCV genotype 1 patients treated with dual-therapy (PEG-IFN/RBV). Figure 2B: HCV genotype 1 patients treated with triple-therapy (TVR/PEG-IFN/RBV). Figure 2C: HCV genotype 2 patients. Figure 2D: HCV genotype 3 patients. Figure 2E: HCV genotype 4 patients. The boxes show the proportion of the CC+TT+TT/TT haplotype in all patients having rs12979860 CC, rs8099917 TT, and ss469415590 TT/TT, respectively.
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pone-0112592-g002: A-2E: SVR prediction rates in HCV infected patients based on interferon-lambda host genotypes and grouping of such by applying a binary regression tree analysis. Figure 2A: HCV genotype 1 patients treated with dual-therapy (PEG-IFN/RBV). Figure 2B: HCV genotype 1 patients treated with triple-therapy (TVR/PEG-IFN/RBV). Figure 2C: HCV genotype 2 patients. Figure 2D: HCV genotype 3 patients. Figure 2E: HCV genotype 4 patients. The boxes show the proportion of the CC+TT+TT/TT haplotype in all patients having rs12979860 CC, rs8099917 TT, and ss469415590 TT/TT, respectively.

Mentions: As a next step we tried to find out which single SNP and which combination of SNPs in a best way would be able to predict SVR to antiviral therapy, therefore we calculated classification trees. Not all combinations of the different SNPs were observed in the different groups and some combinations were only present in very few patients. Overall, a grouping of SNPs with intermediate and high SVR rates according to the results of the binary regression trees was possible. Analyzing all HCV genotypes and IFN-L3/IFN-L4 genotypes revealed rs12979860 C/C as the factor, which is highest associated with SVR over all groups. Therefore, all haplotypes including IFN-L3 rs12979860 C/C were assigned in the “high SVR rate” group. As next step, the groups with different HCV genotypes were analyzed individually. Interestingly, in the vast majority of patients with the IL28B rs12979860 C/C genotype also beneficial genotypes of the two other SNPs (IL28B rs8099917 T/T and IFN-L4 ss469415590 TT/TT) were observed (98% in genotype 1 dual, 100% in genotype 1 triple, 96% in genotype 2, 92% in genotype 3, and 98% in genotype 4) (Figures 2A–2E). SVR rates typically were highest in the group with IL28B rs12979860 C/C or IFN-L4 ss469415590 TT/TT (group “high”).


Predictive value of interferon-lambda gene polymorphisms for treatment response in chronic hepatitis C.

Susser S, Herrmann E, Lange C, Hamdi N, Müller T, Berg T, Perner D, Zeuzem S, Sarrazin C - PLoS ONE (2014)

A-2E: SVR prediction rates in HCV infected patients based on interferon-lambda host genotypes and grouping of such by applying a binary regression tree analysis. Figure 2A: HCV genotype 1 patients treated with dual-therapy (PEG-IFN/RBV). Figure 2B: HCV genotype 1 patients treated with triple-therapy (TVR/PEG-IFN/RBV). Figure 2C: HCV genotype 2 patients. Figure 2D: HCV genotype 3 patients. Figure 2E: HCV genotype 4 patients. The boxes show the proportion of the CC+TT+TT/TT haplotype in all patients having rs12979860 CC, rs8099917 TT, and ss469415590 TT/TT, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4231027&req=5

pone-0112592-g002: A-2E: SVR prediction rates in HCV infected patients based on interferon-lambda host genotypes and grouping of such by applying a binary regression tree analysis. Figure 2A: HCV genotype 1 patients treated with dual-therapy (PEG-IFN/RBV). Figure 2B: HCV genotype 1 patients treated with triple-therapy (TVR/PEG-IFN/RBV). Figure 2C: HCV genotype 2 patients. Figure 2D: HCV genotype 3 patients. Figure 2E: HCV genotype 4 patients. The boxes show the proportion of the CC+TT+TT/TT haplotype in all patients having rs12979860 CC, rs8099917 TT, and ss469415590 TT/TT, respectively.
Mentions: As a next step we tried to find out which single SNP and which combination of SNPs in a best way would be able to predict SVR to antiviral therapy, therefore we calculated classification trees. Not all combinations of the different SNPs were observed in the different groups and some combinations were only present in very few patients. Overall, a grouping of SNPs with intermediate and high SVR rates according to the results of the binary regression trees was possible. Analyzing all HCV genotypes and IFN-L3/IFN-L4 genotypes revealed rs12979860 C/C as the factor, which is highest associated with SVR over all groups. Therefore, all haplotypes including IFN-L3 rs12979860 C/C were assigned in the “high SVR rate” group. As next step, the groups with different HCV genotypes were analyzed individually. Interestingly, in the vast majority of patients with the IL28B rs12979860 C/C genotype also beneficial genotypes of the two other SNPs (IL28B rs8099917 T/T and IFN-L4 ss469415590 TT/TT) were observed (98% in genotype 1 dual, 100% in genotype 1 triple, 96% in genotype 2, 92% in genotype 3, and 98% in genotype 4) (Figures 2A–2E). SVR rates typically were highest in the group with IL28B rs12979860 C/C or IFN-L4 ss469415590 TT/TT (group “high”).

Bottom Line: 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.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%.

View Article: PubMed Central - PubMed

Affiliation: Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.

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.

Methods: Optimization 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.

Results: Frequencies 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%.

Show MeSH
Related in: MedlinePlus