Background and Aim: Multiple viral (HCV genotype, HIV-HBV coinfections and occult HBV infection) and host factors (age at infection, gender,metabolic syndrome, alcohol intake, intrahepatic expression of interferonstimulated genes [ISGs] and genetic variation at the IL28B/IFN-λ3 region) might influence treatment response to PEG-IFNα and ribavirin combination therapy. Aim of this work was to analyse ISGs liver expression profile according to IL28B genotype and the response to treatment in a well characterized, real-life prospective cohort of Italian naïve genotype 1 chronic hepatitis C patients. Methods: The Multicenter Italian Group for the Study of Hepatitis C cohort enrolled 853 patients [670 with HCV infection alone; 362 with HCV genotype 1 infection]. The RNA expression of 96 direct IFNα/STAT2 target genes, including all the predictive ISGs [according to Chen, 2005; Chen 2010; Sarazin-Filipovicz 2008; Asselah 2008] was analyzed in the pre-treatment liver biopsies from 68 monoinfected patients by real-time PCR using a validated custom TaqMan Low Density Array (TLDA). The frequencies of IL28B SNPs rs8099917 (SNP917) and rs8099860 (SNP860) (TT, GT and GG alleles and CC, CT and TT alleles, respectively) were assessed by real time OCR using the allelic discrimination-based assays from AB Systems. Results: 33/68 (48%) patients on dual therapy reached a sustained virological response (SVR) [SVR=44% in the entire genotype 1 cohort]. Seven ISGs [CXCL10, HERC5, IFI27, IFI44, IFI6, Mx1 and RSAD2/Viperin], significantly over-expressed in patients reaching SVR (p<0.05) as compared to non-responder and relapse patients, were already present in one or more predictive ISGs lists. Two new predictive overexpressed ISGs [CXCL11, PKR] were further identified. The overexpression of the IFI27/ISG12 gene, previously included together with ISG15, RSAD2, and HTATIP2 among the SVR predictive ISGs, was rather associated in our cohort with an Early Virological Response (EVR). SVR correlated with the IL28 genotype (70% in the rs12979860 CC patients, 25% in CT patients and 28% in TT patients). IFI27, IFI44 e IFI6 were overexpressed IL28B TT patients. Conclusion: Pre-treatment ISGs expression levels in the liver were confirmed as strong predictors of SVR, and some also associated to EVR. Good response IL28B variants are strongly associated with lower level expression of most ISGs, suggesting that IL28B genotype may explain at least in part the relationship between hepatic ISG expression and HCV treatment outcome.
IL28B genotype, differential expression of intrahepatis interferon-stimulated genes and response to PEG-IFN and ribavirin therapy in an Italian prospective cohort of genotype 1 hepatitis C patients in “real life”.
FATTOVICH, Giovanna;
2012-01-01
Abstract
Background and Aim: Multiple viral (HCV genotype, HIV-HBV coinfections and occult HBV infection) and host factors (age at infection, gender,metabolic syndrome, alcohol intake, intrahepatic expression of interferonstimulated genes [ISGs] and genetic variation at the IL28B/IFN-λ3 region) might influence treatment response to PEG-IFNα and ribavirin combination therapy. Aim of this work was to analyse ISGs liver expression profile according to IL28B genotype and the response to treatment in a well characterized, real-life prospective cohort of Italian naïve genotype 1 chronic hepatitis C patients. Methods: The Multicenter Italian Group for the Study of Hepatitis C cohort enrolled 853 patients [670 with HCV infection alone; 362 with HCV genotype 1 infection]. The RNA expression of 96 direct IFNα/STAT2 target genes, including all the predictive ISGs [according to Chen, 2005; Chen 2010; Sarazin-Filipovicz 2008; Asselah 2008] was analyzed in the pre-treatment liver biopsies from 68 monoinfected patients by real-time PCR using a validated custom TaqMan Low Density Array (TLDA). The frequencies of IL28B SNPs rs8099917 (SNP917) and rs8099860 (SNP860) (TT, GT and GG alleles and CC, CT and TT alleles, respectively) were assessed by real time OCR using the allelic discrimination-based assays from AB Systems. Results: 33/68 (48%) patients on dual therapy reached a sustained virological response (SVR) [SVR=44% in the entire genotype 1 cohort]. Seven ISGs [CXCL10, HERC5, IFI27, IFI44, IFI6, Mx1 and RSAD2/Viperin], significantly over-expressed in patients reaching SVR (p<0.05) as compared to non-responder and relapse patients, were already present in one or more predictive ISGs lists. Two new predictive overexpressed ISGs [CXCL11, PKR] were further identified. The overexpression of the IFI27/ISG12 gene, previously included together with ISG15, RSAD2, and HTATIP2 among the SVR predictive ISGs, was rather associated in our cohort with an Early Virological Response (EVR). SVR correlated with the IL28 genotype (70% in the rs12979860 CC patients, 25% in CT patients and 28% in TT patients). IFI27, IFI44 e IFI6 were overexpressed IL28B TT patients. Conclusion: Pre-treatment ISGs expression levels in the liver were confirmed as strong predictors of SVR, and some also associated to EVR. Good response IL28B variants are strongly associated with lower level expression of most ISGs, suggesting that IL28B genotype may explain at least in part the relationship between hepatic ISG expression and HCV treatment outcome.
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