P58 Genetic, virological and immunological pre-treatment predictors of therapy response to Peg-IFN/ribavirin in children with chronic hepatitis C
Authors: I. Carey, M. Bruce, S. Bansal, S. Tizzard, D. Joshi, D. Vergani, G. Mieli-Vergani
Journal: Gut (2011)

<h3>Introduction</h3> Vertically acquired chronic hepatitis C (CH-C) is a mild disease in childhood but may accelerate in adolescence. Effective early therapy with pegylated interferon (Peg-IFN) and ribavirin (Riba) prevents progressive liver damage. Control of HCV infection depends on both innate and adaptive immunity. Little is known about treatment predictors in children with CH-C. <h3>Aim</h3> To assess whether single nucleotide polymorphisms (SNP) near IL28B gene rs12979860 and rs8099917, HCV genotype (G) and pre-treatment innate and adaptive immunity [frequency/phenotype of natural killer (NK) cells, HCV-specific T cell responses, frequency/phenotype of T regulatory cells (T-regs), plasma levels of IFN-γ inducible protein 10 (IP-10)] predict therapy response in children with CH-C. <h3>Method</h3> <b>Patients:</b> 32 children with CH-C (19 males, median age 12 yrs, 53% G1) treated according to genotype with Peg-IFN (60 μg/m<sup>2</sup>/week) and riba (15 mg/kg/d) were divided into responders (22, R), relapsers (4, Rel) and non-responders (6, NR). <b>Methods:</b> rs12979860 and rs8099917 were tested by direct sequencing; baseline numbers of NK cells (CD3<sup>-</sup>CD56<sup>+</sup>) and their subsets CD56<sup>dim</sup>/CD56<sup>bright</sup>, CD3<sup>−</sup>CD56<sup>+/−</sup>CD16<sup>+/−</sup><sub>,</sub> of CD4+cells expressing programmed death receptor (CD4<sup>+</sup>PD1<sup>+</sup>) and of T-regs (CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>) by flowcytometry on peripheral blood mononuclear cells (PBMC). PBMC IFN-γ and IL-10 production after exposure to HCV-core, NS3, NS4, NS5 antigens was evaluated by intracellular cytokine staining. Baseline IP-10 plasma levels [pg/ml] were measured by ELISA. All presented as median. <h3>Results</h3> rs12979860 haplotype CC was present in 34% (91% R and 9% NR), CT in 47% (73% R, 7% Rel and 20% NR) and TT in 19% (17% R, 50% Rel and 33% NR); rs8099917 haplotype TT was seen in 50% (88% R and 12% NR), GT in 44% (50% R, 29% Rel and 21% NR) and GG in 6% (50% R and 50% NR) patients. Non-G1 CH-C was linked with better response than G1 (53% vs 80%, p=0.02). Baseline number of CD56<sup>bright</sup> NK cells was higher in R than Rel &amp; NR (3.7% vs 1.8% and 1.3%, p=0.05). Compared to R, Rel and NR had higher numbers of CD3<sup>-</sup>CD56<sup>-</sup>CD16 cells (17.4% vs 12.9% &amp; 10.7%, p=0.05), of HCV-core-specific IL-10 producing cells (CD4<sup>+</sup>/IL-10: 4.4% and 3.8% vs 1.7%, p=0.03), of CD4+PD1+ cells (7.1% and 6.9% vs 4.3%, p=0.03) and of T-regs (4.2% and 3.0% vs 1.4%, p=0.04). Baseline plasma IP-10 levels were higher in NR than Rel and R (85 vs 34 and 15, p&lt;0.01). By multivariate analysis only possession of CC rs12979860 and TT rs8099917 haplotypes and low baseline IP-10 levels were associated with response to therapy. <h3>Conclusion</h3> Possession of both major haplotypes CC rs12979860 and TT rs8099917 for IL28B gene SNPs and low baseline IP-10 levels predict successful therapy response in children with CH-C.