The Pre-treatment Gene Expression Profile of Chronic Hepatitis C (CH-C) Patients with IL28B T* Host Genotype and HCV Genotype 1 (G1) Suggest an Intrinsic Deregulation in the Inflammatory Response Mechanism

Abstract

Purpose: HCV Genotype 1 patients with IL28B T* host genotype have significantly lower SVR rates after PEG-IFN/RBV treatment as compared to IL289B CC. We assessed the genes differentially expressed at the pretreatment and during IFN/RBV treatment in CHC patients with CC vs T* genotype. Methods: 43 G1 CH-C patients were included. Blood samples were collected into PAXgene™ RNA blood tubes (PreAnalytiX): prior to treatment, day 1, week 1, weeks 4, and weeks 8 after the first dosing. Whole blood was used for IL28B genotyping. Genomic DNA was extracted using QIAamp DNA Blood Mini kit (Qiagen). IL28 B genotyping was performed by tetra-primer amplification and electrophoresis and used for profiling 160 mRNAs involved in cytokine response and used for profiling of differentially expressed genes were determined using Mann-Whitney test (p-value<0.05). For each time point differentially expressed genes were separated into up/down-regulated gene lists according to the IL28B allele (CC or no-CC) and SVR. Results: After a course of treatment overall SVR rate was 37%. Of 43 G1 patients, 27 had IL28B T* genotype and 16 had IL28B CC genotype. SVR rates within cohorts were 22% for IL28B T* and 62% for IL28B CC. EVR rates within cohorts were 42% for IL28B T* and 100% for IL28B CC. Comparison of IL28B T* cohort with IL28B CC cohort: 55% were female [versus 18% (p=0.0180)], 29% were AA [versus %6 (p=0.0685)], 74% had a high viral load [versus 68% (p=0.7067)], 19% had cirrhosis [versus 31% (p=0.3744)], 40% were obese [versus 68% 9p=0.0757)] and 11% had DM [versus 6% (p=0.5957)]. At pretreatment, genes in the IL28b T* cohort were upregulated as compared to the IL28B CC genotype (CEBPB; IKBKG; IRF4; IRF8; LYN; PRDM1; TGFB1; TLR2). All of these genes are known to be involved in the initiation / propagation of the inflammatory and immune response. Surprisingly, following day 1 of treatment with PEG-IFN/RBV this subset of genes becomes downregulated and start emerging again on and following day 7, suggesting an innate deregulation in the inflammatory response mechanism of CH-C genotype 1 patients carrying the Il28B T* allele. Conclusion: At pre-treatment, genes differentially expressed in HCV genotype 1 patients with IL 28B T* genotype suggest intrinsic deregulation in the inflammatory response mechanism with this host genotype and is associated with a substantially worse SVR rate as compared to the IL28B CC genotype. Upon further validation, the genes identified in this study may prove to be a useful aid to clinicians in designing treatment plans.