F-47 Clinical and genetic factors of response to antiviral treatment of chronic hepatitis C virus infection

F-47 Clinical and genetic factors of response to antiviral treatment of chronic hepatitis C virus infection

S46 Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48 Result: 397 subjects (10%) showed hypertransamina...

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S46

Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48

Result: 397 subjects (10%) showed hypertransaminasemia while 3632 (90%) were normal. No differences in age were seen between the two groups, while differences were observed in sex [78% of G1 subjects where male vs 22% female; P<0.001], bilirubin (mg/dl) [G1 0.71±0.36 vs G2 0.65±0.38;P=0,001], GGT (U/l) [G1 61.4±71.8 vs G2 21.2±20.7;P=0,001] and platelets [G1 230±56 vs 245±57);P=0,001]. The presence and severity of fatty liver at US significantly correlates with transaminases level (P<0.001). Cirrhosis was diagnosed in 8 subjects. Definitive diagnosis: non alcoholic fatty liver disease (NAFLD): 272 subjects, alcoholic hepatitis: 14, alcohol + methabolic disorder: 58, HCV-related hepatitis: 25, HBV-related hepatitis: 8, other: 11 (including hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, celiac disease and thyroiditis); cryptogenetic hypertransaminasemia: 9. Conclusions: Our data show that NAFLD and heavy alcohol intake are actually significant causes of liver disease in the general population of Italy.

F-45 Rapid virologic response (RVR), IL28B single nucleotide polymorphism (SNP) rs12980275 and HCV genotype are independent predictors of sustained virologic response (SVR) in HIV/HCV coinfected patients treated with pegylated interferon and ribavirin M. Puoti 1 , L. Covolo 2 , P. Nasta 4 , F. Gatti 4 , F. Suter 5 , C. Mussini 6 , R. Bruno 7 , C. Ferrari 7 , T. Santantonio 7 , V. Di Marco 3 , A. Craxì 3 1 Infectious

Diseases, AO Ospedale Niguarda Ca’ Granda, Milano, Italy; of Hygiene and preventive Medicine, University of Brescia, Brescia, Italy; 3 Dept of Gastroenterology, University of Palermo, Palermo, Italy; 4 Dept of Infectious Diseases, University of Brescia, Brescia, Italy; 5 Department of Infectious Diseases, Ospedali Riuniti, Bergamo, Italy; 6 Department of Infectious Diseases, University of Modena Reggio Emilia, Modena, Italy; 7 Multicenter Italian Group for the Study of Hepatitis C, Palermo, Italy 2 Department

Background: SNPs associated with IL28B influence the outcome of peginterferon-α/ribavirin therapy of chronic hepatitis C virus (HCV) infection. We analyzed the interaction between IL28B SNPs and sustained virologic response in 138 HIV/HCV coinfected patients enrolled in a prospective observational study aimed to identify predictors of SVR. Methods: IL28B SNPs rs8099917, rs12979860, and rs12980275 were genotyped in 138 HCV treatment-naïve HIV coinfected Caucasian patients (48% genotype 1 or 4), who received peginterferon-α2a (180 μg weekly) and ribavirin (1000-1200 mg daily) with serial HCV-RNA quantifications. Associations between IL28B polymorphisms and SVR, were analyzed accounting for relevant covariates (age, gender, liver enzymes, HOMA, Cholesterol, triglycerides.FIB4, presence of cirrhosis, steatosis, necroinflammatory activity, HCVRNA levels, HIVRNA levels, CD4, HCV Genotype). RVR was assessed in 114 patients Results: SVR was observed in 48% (66/138) pts: 18% (12/67) HCV G1-4 and 76% (54/71) with HCV G2-3. In the univariate analysis the T allele of rs12979860 and the G allele of rs12980275 were significantly associated with lack of SVR (respectively with p=0.002 and <0.00001) together with HCVRNA at baseline >400.000 IU/mL, (p=0.036) HCV Genotype 1 or 4 (p<0.001) and lack of RVR (p<0.001). In the multivariate analysis HCV genotype 2 or 3 (AOR(?) 8.1 95% CI 2.6-25.2 p=0.0003), RVR (AOR 15.1 95% CI 3.4-67.1 p=0.004) and AA SNP rs12980275 (rs12980275 AA genotype) (AOR 4.6 95%CI 1.5-14.1; p=0.0075) were independent predictors of SVR. In pts with no predictors SVR was 6% (2/34 95% CI 0-14%), in pts with one predictor SVR was 41% (12/29 95% CI 23-59%) in pts with 2 predictors SVR was 81% (25/31 95% CI 66-96%) in pts with 3 predictors SVR was 100% (16/16). Conclusion: IL28B SNP rs12980275 and RVR are independently associated with SVR in HIV/HCV coinfected patients both in favorable and unfavorable genotypes. New Drugs are strongly needed in HIV/HCV coinfected patients with less than 2 of the following characteristics: HCV Genotype 2-3, RVR and G allele of rs12980275.

F-46 Graft survival is worse in HCV positive females transplanted with male donor grafts L. Belli, R. Romagnoli, M. Rossi, G.E. Gerunda, A.D. Pinna, S. Agnes, M. Spada, M. Colledan, G. Tisone, L. De Carlis, U. Baccarani, V. Mazzaferro, G.M. Ettorre, U. Cillo, F. Calise, O. Cuomo, L. Lupo, S. Ginanni Corradini, F. Zamboni, T. Marianelli, A. Risaliti, D. Patrono, S. Li Petri, F. Tagliabue, J.M.E. Mangoni, B. Antonelli, C. Sposito, E. Gringeri, G. Rompianesi, D. Sforza, A. Cucchetti, L. Miglioresi, M. Donataccio, M. Gelli, C. Gavrila, A. Nardi, M. Angelico, for the Liver Match investigators Italian Liver Transplant Ctrs and Italian Association for the Study of the Liver, and Dept. of Mathematics, Tor Vergata University, Rome Liver Transplantation (LT) for HCV-related disease is associated with suboptimal outcomes. Better donor-recipient match could improve LT results in this setting. We analyzed this issue within the Liver Match, a prospective observational cohort study on LT ongoing in Italy. Methods: Donor/recipient data on 1530 adult LT (year 2007-2009) were analyzed, including 699 (45.9%) in HCV+ recipients, in whom 159 Graft Losses (GL) occurred within a median f.u. of 721 days. Results: HCV-positive recipients with GL had slightly higher MELD (mean 17.0 vs 15.6, p=0.195) and were more often females (24.5% vs 17.0%, p=0.038) than those without. Kaplan-Meier two-year graft survival was 0.68 (s.e. 0.045) vs 0.79 (s.e. 0.018) in female vs male LT recipients, respectively (p=0.046), being unrelated to donor gender (p=0.939). Median donor age was 59 vs 55 (p=0.0038) among LT with/without GL. At Cox regression, predictors of GL were: donor age (HR: 1.132 per 10 years, p=0.0096); MELD (HR: 1.275 per 10 units, p=0.018); donor HBcAb positivity HR: 1.502, p=0.031) and interaction between donor and recipient gender (p=0.035). Inclusion of donor-recipient gender matching in the Cox model showed that allocation of male donors to female recipients carried a greater GL risk compared with male-to-male allocation (HR: 2.126, 95% c.l.1.264-3.576). Conclusion: In HCV-related LT the risk of GL is greater with increasing donor age, HBcAb positivity and recipient MELD and is more frequent in females receiving a liver from male donors. These variables need careful consideration to optimize liver allocation.

F-47 Clinical and genetic factors of response to antiviral treatment of chronic hepatitis C virus infection M. Masarone 2 , R. Russo 1 , A. Gambale 1 , V. Rosato 2 , R. Lebano 2 , V. La Mura 2 , S. Tartaglia 2 , A. Iolascon 1 , M. Persico 2 1 Ceinge, Naples, Italy; 2 Internal Medicine and Hepatology, SUN, Naples, Naples, Italy

Background: The response to antiviral treatment of chronic hepatitis C virus (HCV) infection is determined by clinical and genetic factors. The most representative clinical factors are: age, sex, BMI, liver fibrosis and steatosis extent, ALT, HCV genotypes and viral laod, metabolic syndrome and/or diabetes. Between the genetic factors of response to antiviral treatment, an high interest has been recently given to the Single Nucleotide Polymorphism (SNP) of IL28B, that has been associated with Sustained Virological Response (SVR) in genotype 1 HCV patients (genotype CC). This SNP has been evaluated in various geographical settings reporting different prevalences. Our group recently demonstrated a link between the response to antiviral treatment and the suppressor cytokine signaling3 (SOCS3) gene, which was over-expressed in genotype 1b HCV non-responder (NR) in confront to genotype 2 infected patients Aims: To evaluate clinical and genetic factor of response to antiviral treatment in a HCV population (N=90, 46 HCV-1 and 44 HCV-2) from Southern Italy, in order to correlate them with the response to antiviral therapy. Patients: Of every patient was evaluated: age, sex, BMI, extent of liver fibrosis and steatosis, ALT, Viral Load and HCV genotype, presence of Metabolic Syndrome and/or Diabetes, IL28B and SOCS3 gene expression and SNP alleles. Moreover, the distribution of IL28B alleles between HCV SVR and NR, and in the total HCV population in confront to a control group of healthy subjects (N=50) were evalated.

Abstracts of the A.I.S.F. Annual Meeting 2012 / Digestive and Liver Disease 44S (2012), S1–S48 Results: At the univariate analysis factors related to SVR were: Genotypes (p: 0.011), Steatosis (p: 0.009), ALT (p: 0.004), Diabetes (p: 0.018), steatosis (p: 0.009), SOCS3-SNP (p: 0.035) and IL28B-SNP (p: 0.004). At the multivariate analysis independent were: HCV Genotype (p: 0,013), IL28B-SNP (p: 0.027) and SOCS3-SNP (p: 0,038). IL28B-SNP rs12979860 allele frequencies in the control group (C allele = 69.0% and T allele = 31.0%) were similar with those observed in HCV population (C allele = 64.6% and T allele = 35.4%). We confirmed the association between CC genotype of HCV patients and SVR (CC=50.9%, CT=41.5%, TT=7.5%; p=0.01 for trend). Conclusions: Genetic factors SOCS3 and IL28B SNP, along with HCV genotypes, seems to be stronger predictors of response to antiviral treatment in confront to clinical ones. No differences in prevalence of IL28B alleles distribution was found between HCV patients and healthy subjects. Our data confirm the association between CC genotype and SVR.

F-48 Genetic predictors of response in the treatment of chronic hepatitis C virus infection: interference between SOCS3 and IL28 R. Russo 1 , M. Masarone 2 , M. Gambale 1 , V. Rosato 2 , R. Lebano 2 , V. La Mura 2 , S. Tartaglia 2 , A. Iolascon 1 , M. Persico 2 1 Ceinge,

Naples; 2 Internal Medicine and Hepatology, SUN, Naples, Italy

Background: The response to antiviral therapy of chronic hepatitis C virus (HCV) infection may be influenced by several genetic factors. In 2008, we identified a link between the response to antiviral treatment and the suppressor cytokine signaling3 (SOCS3) gene, an inhibitor of the JAK-STAT pathway, which was over-expressed in non-responder (NR) patients with genotype 1b HCV versus patients with genotype 2 HCV. Recently, several common single nucleotide polymorphisms (SNPs) in the neighborhoods of three IFN-k genes, were indicated as predictors of response to antiviral therapy in HCV-1 patients. Among these, SNP rs12979860 of IL28B, was associated with SVR (genotype CC). It remains to be evaluated if the IL-28 gene expression vary in HCV patients according to SNP alleles, HCV genotypes and response to antiviral treatment. Moreover it is of high interest to learn if there is an association between SOCS3 and IL28B gene expression. Aim and Methods: We analyzed the IL28B-SNP rs12979860 frequencies and gene expression of SOCS3 and IL28B in a control (N=50) and HCV population (N=90, 46 HCV-1 and 44 HCV-2) from Italy, in order to correlate them with the viral genotype and the response to antiviral therapy. Results: The gene expression analysis performed on 89 HCV patients and 45 healthy subjects (controls, CTR) showed that IL28B is more expressed in CC SNP in respect of other alleles in CTR (p=0.01), and it is induced by viral infection (HCV vs CTR p=0,006). This induction seems to be mediated to a greater extent from the HCV-2 than HCV-1 (p=0.003). The gene expression analysis showed an opposite trend for SOCS3 expression between HCV-1 and HCV-2 patients (p=0.000001), confirming our previous reports. In HCV-1 patients there was a greater expression of IL28 in NR in confront of SVR (p=0,016, Mann Whitney).The correlation analysis between SOCS3 and IL28B gene expression in healthy subjects showed a direct correlation (Spearman’s 0,38, p=0.011). In HCV patients we found an inverse trend (Spearman’s -0.26, p=0.014), but when we evaluated this expression by genotype and response to antiviral treatment we found a direct correlation in HCV genotype 1b patients NR (Spearman’s 0.69, p=0.0002). Conclusions: Our observation about IL28B-SOCS3 correlation in healthy subjects is in agreement with previous studies, which have demonstrated that both INF1 and INF3, stimulate the same pathway, leading to the up-regulation of interferon-stimulated genes (ISGs). Of note, SOCS3 ranks right in the ISGs group. The direct correlation between SOCS3 and IL28B gene expression in HCV genotype 1b NR patients opens a new scenario on the pathogenetic mechanisms in which IL28B and SOCS3 may influence the response to antiviral therapy.

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F-49 Overall survival of patients undergoing liver resection for hepatocellular carcinoma may be predicted by KIR2DL5 and HLA Bw4I80 genotyping E. Cariani 1 , M. Pilli 2 , A. Zerbini 2 , C. Rota 1 , A. Olivani 2 , D. Canetti 2 , P. Zanelli 3 , A. Zanetti 3 , C. Ferrari 2 , G. Missale 2 1 SC Patologia Clinica, Tossicologia e Diagnostica Avanzata, Ospedale Civile S. Agostino-Estense, Modena; 2 UO Malattie Infettive ed Epatologia, Azienda Ospedaliero-Universitaria di Parma, Parma; 3 UO Genetica Medica Azienda Ospedaliero-Universitaria di Parma, Parma

Background and Aims: Killer cell immunoglobulin-like receptors (KIRs) are related to the activation and inhibition of natural killer cells and may play an important role in the innate response against cancer and infections. KIRs have been shown to influence the development of hepatocellular carcinoma (HCC) in post-hepatitic liver cirrhosis. Aim of our study was to evaluate if KIRs can influence HCC disease recurrence and overall survival in patients that had undergone curative resection. Methods: KIR genotyping (2DL1, 2DL2, 2DL3, 2DL5, 2DS1, 2DS2, 2DS3, 2DS5, 3DL1, 3DS1) was performed by PCR with gene-specific primer pairs in a cohort of 41 patients that were also typed for HLA-Bw4 and -Bw6 supertypes. Liver cirrhosis was due to HCV infection in 29/41 (70.7%) of our patient cohort. Results: KIR2DL5 genotype was significantly (p=0.016) associated with longer survival (KIR2DL5 negative: 50% overall survival (OS) 29 months, 75% OS 18 months; KIR2DL5 positive: 50% OS undefined, 75% OS 85 months). The HLA-Bw4I80 genotype was also over-represented in patients with better survival (p=0.046, 75% survival: 73 months for Bw4I80 positives and 15 months for Bw4I80 negatives), whereas Bw4T80 was predictive of worse prognosis (p=0.026, 75% survival: 18 months for Bw4T80 positives and 78 months for Bw4T80 negatives). Conclusion: KIR2DL5 and HLA-Bw4I80 genes association with HCC prognosis supports a role for natural killer (NK) cell activation in HCC progression.

F-50 Increased urinary level of neutrophil gelatinase–associated lipocalin (NGAL) in patients with cirrhosis and type 1 HRS M. Cavallin, S. Fasolato, A. Sticca, E. Gola, A. Bortoluzzi, F. Morando, A. Romano, S. Piano, A. Gatta, P. Angeli Department of Clinical and Experimental Medicine, University of Padova, Italy Background and Aims: Hepatorenal syndrome (HRS) in patients with advanced cirrhosis has been defined as a functional renal failure. Nevertheless there are some new evidence of the presence of renal parenchymal lesions in these patients. Neutrophil gelatinase-associated lipocalin (NGAL) is secreted into the urine by the thick ascending limb of Henle and collecting ducts of the kidney. Thus, urinary excretion of NGAL is increased in parenchymal acute injury (AKI) but not in functional AKI. The aim of the study was to evaluate baseline urinary excretion of NGAL in patients with cirrhosis and type 1 HRS and in patients with cirrhosis and normal renal function. Methods: We tested the baseline urinary excretion of NGAL in 28 patients with cirrhosis and type 1 HRS and in 15 patients with cirrhosis and normal renal function. We defined type 1 HRS according to the International Club of Ascites criteria. We estimated also renal plasma flow (RPF) and glomerular filtration rate by using p-aminohippurate clearance and inulin clearance, respectively. The urine NGAL was measured by ELISA kit (BioPorto Diagnostics, Gentofte, Denmark). Results: Urine NGAL was significantly different in the two groups of patients, with higher levels noted in the type 1 HRS group (175.23±58.62 vs 24.86±6.11 ng/ml, p<0.05). Patients with type 1 HRS were then devided into two subgroups according to the response to treatment with terlipressin and albumin. Complete responders (n=13) showed a lower value of urinary NGAL (59.72±16.60 vs 275.34±103.08 ng/ml, p<0.05), and of serum creatinine (269.33±18.71 vs 353.50±37.67 μmol/l, p<0.05) and an higher level of RPF (214.33±47.45 vs 65.66±11.94 ml/min, p<0.0025) when compared to partial responders and non responders considered as a whole (n=15).