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Substantial Renal Impairment Is Not Infrequent in HCV Patients Under TripleTherapy With Telaprevir or BoceprevirStefan Mauss, Christoph Eisenbach, Renate Heyne, Gero Moog, Thomas Lutz, UweNaumann, Michael Geissler, Matthias Mordeja, Christoph Herold, Karl Georg Simon,Kerstin Milicic-Ouakili, Peter Buggisch, Dietrich Hueppe

Introduction: Until recently experience with telaprevir (TVR) and boceprevir (BOC) wasbased exclusively on clinical trials in selected patients. In late summer 2011 TVR and BOCwere approved in Germany and made available for treatment in clinical practice. Methods:The PAN study is a non-interventional study conducted by the Association of GermanGastroenterologists in Private Practice (bng) in collaboration with Roche. Patients are eligibletreated with peginterferon alfa-2a/ribavirin (PEG/RBV) or triple therapy with TVR or BOC.Here we restrict the analysis to patients having completed at least 12 weeks of treatment.For estimation of glomerular filtration rate (GFR) the recently presented CKD-EPI formulawas chosen as it may be best suited to reflect changes of eGFR in patients with normal ormildly impaired renal function. Results: Overall 907 patients were included, 582 on TVR,214 on BOC and 111 on dual therapy. At week 12 a decrease to , 60 ml/min (=renalinsufficiency stage 3) in patients with an eGFR .60 ml/min at baseline was observed in49/907 (5.4%). Patients on TVR 38/583 (6,5%) and BOC 10/214 (4,7%) experienced morefrequently a decrease in renal function to , 60 ml/min compared to patients on PEG/RBV1/111 (0,9%) (p, 0.05). Risk factors associated with renal insufficiency stage 3 were age(p, 0.001), arterial hypertension (p, 0.001), Diabetes mellitus (p, 0.05) and being ontriple therapy with TVR or BOC (p, 0.05). There was no association with anemia, treatmenthistory or sex. Conclusion: Renal impairment has not been reported as safety signal inclinical trials with TVR or BOC. However in this large cohort including older patients andpatients with risk factors for renal impairment a marked decline in renal function wasobserved in about 5% of patients on triple therapy. In addition to being a safety concern,substantial ribavirin dose reductions have to be considered in these patients.

724

Correction of Vitamin D Deficiency in Patients With Chronic Hepatitis CFacilitated Suppression of Interferon-Gamma-Inducible Protein 10 (IP-10): ARandomized, Double-Blinded, Placebo-Controlled StudyKriangsak Charoensuk, Chintana Chirathaworn, Panarat Thaimai, SirinpornSuksawatamnuay, Kessarin Thanapirom, Kittiyod Poovorawan, Pinit Kullavanijaya,Piyawat Komolmit

BACK GROUND AND AIMS: Vitamin D deficiency, serum IP-10 levels and IL28B polymor-phisms are predictive factors proved to be associated with treatment response of chronichepatitis C (CHC). Vitamin D has a crucial role in immune regulation. In CHC, overexpressionof T-helper 1 related cytokine, IP-10, had negative influence on treatment outcome. Wehypothesized that vitamin D supplement, which shown to improve CHC treatment response,might restore immune dysregulation in CHC patients through a pathway linked to thecytokine, IP-10. The aim of this prospective study was to investigate the association betweenvitamin D supplement and IP-10 level in CHC patients. METHODS: In this double-blinded,placebo-controlled, interventional study; we assigned CHC patients with vitamin D deficiencyto receive vitamin D supplement or placebo for 6 weeks. The patients were measured serum25-hydroxyvitamin D (25(OH)D) and IP-10 levels at baseline and at 6 weeks. Baselinecharacteristics including gender, age, liver function tests, hepatitis C genotype and viral loadwere assessed. RESULTS: A total of 70 CHC patients with vitamin D deficiency wererandomized into two groups, 35 patients in each group. There were no significant differencesin the baseline characteristics between two groups. At pre and post supplement, only the25(OH)D levels in vitamin D group were significantly increased from 21.07 to 48.44 ng/ml, respectively (p,0.001), (Fig.1A).While no significant changes of the IP-10 levels inplacebo group was demonstrated, there were significant decreased in serum IP-10 levels invitamin D group after 6-week of vitamin D supplement (p ,0.01), (Fig.1B). Correlation of

S-960AASLD Abstracts

the changes between serum vitamin D and IP-10 levels were further investigated. The datashowed significant negative correlation between these two parameters (delta values; r = -0.40, p,0.01), (Fig.2). CONCLUSIONS: This study demonstrated that vitaminD supplementand restoration of 25(OH)D level in CHC patients resulted in suppression of serum IP-10levels. These results connected the link and gave one explanation of why vitamin D deficiency,pre-treatment high serum IP-10 levels and by treatment of vitamin D deficiency could haveeffects on CHC treatment responses.

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The Balance Between T Helper 17 and FOXP3+ T Regulatory Cells in PatientsWith Chronic Hepatitis C: Relation to Disease Activity and Hepatic FibrosisHoda El Aggan, Nahala Farahat, Layla K. Younis, Amany Elyamany

Background/Aim: T helper (Th)17 cells, a newly identified subset of Th cells producingmainly interleukin (IL)17A, are major mediators of inflammation-associated disease. Theyhave a reciprocal developmental relationship with the immunosuppressive T regulatory(Treg) cells, which actively restrain the inflammatory response. The present work wasdesigned to study the balance between Th17 cells and Treg cells in patients with chronichepatitis C (CHC) in relation to disease activity and severity of hepatic fibrosis. Methods:Twenty treatment-naive patients with CHC and 20 healthy subjects were included in thestudy. The Th cells, Th17 cells and Treg cell subsets in fresh whole blood samples wereidentified as CD3+CD4+, CD4+IL17A+ and CD4+CD25+FoxP3+ cells respectively usingflow cytometry and expressed as percentages of total lymphocytic count. Serum IL17 levelswere measured using solid phase sandwich enzyme linked immunosorbant assay kit. Liverbiopsies from patients with CHC were examined to assess histological activity grade andfibrosis stage according to METAVIR scoring system. Liver-infiltrating CD4+ (Th cells),IL17A+ cells (Th17 cells) and FoxP3+ cells (Treg cells) were detected by immunohistochemi-cal staining and their proportions were determined as ratios of infiltrating CD4+ Th cells.Results: Patients with CHC showed significant increases in the percentage of Th17 cells,Th17 cells/FoxP3+Treg cells ratio in peripheral blood and serum IL17 levels and a significantdecrease in the percentage of circulating FoxP3+Treg cells compared with healthy subjects(P , 0.01). The percentages of peripheral blood CD4+ Th cells were not statistically differentbetween the two groups (P = 0.284). The proportions of liver-infiltrating IL17A+ cells andFoxP3+ cells of the total intrahepatic CD4+ cell population were inversely correlated andshowed positive correlations with the percentages of circulating Th17 cells and FoxP3+ Tregcells respectively in patients with CHC (P, 0.05). The METAVIR necroinflammation gradeand fibrosis stage [but not serum HCV RNA levels] were directly correlated with the propor-tion of intrahepatic IL17A+ cells and IL17A+ cells/FoxP3+ cells ratio and serum IL17 levelsand were inversely correlated with the proportion of liver-infiltrating FoxP3+ cells (P ,0.05). Conclusions: In patients with CHC, the CD4+ Th cell phenotype is skewed towardsTh17 phenotype more than a regulatory response. The imbalance between Th17 and Foxp3+Treg cells plays an important role in disease progression and hepatic fibrosis in CHC.