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Impact of IL28B gene polymorphisms on interferon-?3 plasma levels during pegylated interferon-?/ribavirin therapy for chronic hepatitis C in patients coinfected with HIV.

ABSTRACT: OBJECTIVES:The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein [interferon (IFN)-?3] plasma levels may vary according to IL28B genotype and/or following pegylated IFN-?/ribavirin therapy. PATIENTS AND METHODS:A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-?/ribavirin therapy were examined. Sustained virological response (SVR) was achieved by 56% of patients. IL28B rs12979860 alleles were genotyped using the 5' nuclease assay with specific TaqMan probes. A specific enzyme immunoassay was used to measure IFN-?3 plasma levels before initiating anti-HCV therapy and at week 4 of treatment. RESULTS:No significant differences between CC and non-CC IL28B carriers were found at baseline, either in the proportion of patients with detectable IFN-?3 plasma levels or in their median values. In contrast, median IFN-?3 plasma levels at week 4 of therapy significantly increased with respect to baseline in CC carriers [34.3 (16.7-56.3) versus 15.6 (15.6-30.3) pg/mL, respectively; P < 0.0001], but not in CT/TT carriers. Unexpectedly, increases in IFN-?3 at week 4 of therapy did not predict SVR. CONCLUSIONS:The exogenous administration of IFN-? may induce IFN-?3 release in IL28B CC carriers, but not in CT/TT carriers. However, this finding does not account for the link between IL28B polymorphisms and treatment outcome.

SUBMITTER: Rallon NI

PROVIDER: S-EPMC3695611 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Impact of IL28B gene polymorphisms on interferon-λ3 plasma levels during pegylated interferon-α/ribavirin therapy for chronic hepatitis C in patients coinfected with HIV.

Rallón Norma I NI Soriano Vincent V Naggie Susanna S Restrepo Clara C McHutchison John J Vispo Eugenia E Benito José M JM

The Journal of antimicrobial chemotherapy 20120201 5

<h4>Objectives</h4>The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein [interferon (IFN)-λ3] plasma levels may vary according to IL28B genotype and/or following pegylated IFN-α/ribavirin therapy.<h4>Patients and methods</h4>A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-α/ribavirin therapy were examined. Sustaine ...[more]

PMID: 22294646

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Project description:BackgroundRecent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.MethodsClinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.ResultsThe most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.ConclusionsIL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.

Project description:Background and aim: Conventional hepatitis C treatment using pegylated interferon (PEG-IFN) and ribavirin is associated with significant side effects. IL28B polymorphism can predict response to treatment, with CC genotype having a better response. ITPA gene deficiency protects against clinically significant anaemia induced by treatment. The purpose of this study was to determine IL28B polymorphism and ITPA variation among hepatitis C genotype 1 patients who have undergone therapy with PEG-IFN and ribavirin and their association with sustained viral response (SVR). Methods: All hepatitis C genotype 1 patients who had been treated with PEG-IFN and ribavirin over the past 10 years were identified by available medical records and were contacted by letter of invitation to participate in the study. Blood samples for IL28B and ITPA genotyping were obtained. Medical records were reviewed for verification of treatment response, development of anaemia and if treatment reduction was required during the treatment. Results: A total of 61 patients with hepatitis C genotype 1 were treated with PEG-IFN and ribavirin, of whom 42 agreed to participate in the study. Mean age was 45.6±12.9 years at time of treatment, and 83.3% of patients were males. Thirty-three (78.6%) had IL28B CC genotype, of whom 25 (75.8%) obtained SVR compared with only 3 of 9 (33.3%) non C/C genotype patients who achieved SVR (P=0.041). Eleven (26.1%) patients had ITPA AC genotype, and 30 (71.4%) had CC genotype. There was no statistically significant difference between ITPA AC and CC genotypes in predicting clinically significant anaemia (45.5% vs 63.3%, P=0.302). Even among patients who developed anaemia, 70.8% still managed to achieve SVR. Treatment reduction also had no impact on SVR. Conclusion: Hepatitis C genotype 1 patients should be informed of the response rate for treatment with PEG-IFN and ribavirin in a population with favourable IL28B genotype before consideration of newer therapeutic options.

Dataset Information

Impact of IL28B gene polymorphisms on interferon-?3 plasma levels during pegylated interferon-?/ribavirin therapy for chronic hepatitis C in patients coinfected with HIV.

Publications

Impact of IL28B gene polymorphisms on interferon-λ3 plasma levels during pegylated interferon-α/ribavirin therapy for chronic hepatitis C in patients coinfected with HIV.

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