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IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin.

ABSTRACT: BACKGROUND:A single nucleotide polymorphism (SNP) upstream of the IL28B gene (rs12979860) predicts sustained virological response (SVR) to peginterferon-ribavirin therapy in chronic hepatitis C patients. There is scarce information regarding the influence of this IL28B SNP on early viral kinetics during therapy, particularly in patients coinfected with HIV, in whom treatment response is lower than in hepatitis C virus (HCV)-monoinfected patients. METHODS:We selected 196 HIV/HCV-coinfected individuals who had completed a course of peginterferon-ribavirin therapy, and a validated outcome for SVR. Association of IL28B SNPs with rapid, early and end-of-treatment virological responses [rapid virological response (RVR), early virological response (EVR) and end of treatment virological response, respectively] was assessed in univariate and multivariate analyses. RESULTS:Rate of SVR in the study population was 54%. Frequency of the IL28B CC genotype was 44%. The distribution of HCV genotypes was as follows: HCV-1 57%, HCV-2 1%, HCV-3 30% and HCV-4 12%. Compared to CT/TT, the CC genotype was associated with significantly higher rates of all on-treatment viral outcomes, after adjusting for other predictors of viral response as serum HCV-RNA, HCV genotype and liver fibrosis staging. IL28B CC genotype kept its predictive power of SVR in patients who did not achieve RVR or cEVR. The association between IL28B SNP and viral kinetics and treatment outcomes was significant only for HCV genotypes 1 and 4. CONCLUSION:IL28B CC genotype is a strong predictor of virological response to therapy in HIV/HCV-coinfected patients. This effect is mediated by an increase in viral clearance during the first 12 weeks of treatment and is mainly seen in patients infected with HCV genotypes 1 and 4.

SUBMITTER: Rallon NI

PROVIDER: S-EPMC4892378 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin.

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

AIDS (London, England) 20110501 8

<h4>Background</h4>A single nucleotide polymorphism (SNP) upstream of the IL28B gene (rs12979860) predicts sustained virological response (SVR) to peginterferon-ribavirin therapy in chronic hepatitis C patients. There is scarce information regarding the influence of this IL28B SNP on early viral kinetics during therapy, particularly in patients coinfected with HIV, in whom treatment response is lower than in hepatitis C virus (HCV)-monoinfected patients.<h4>Methods</h4>We selected 196 HIV/HCV-co ...[more]

PMID: 21505315

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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

IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin.

Publications

IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin.

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