- Email: [email protected]
613 Cytokine response in chronic hepatitis C (CHC) patients treated with pegylated interferon plus ribavirin
05G. Viral Hepatitis
(g) Hepatitis C
losartan administration. A significant increase was observed in albumin level and platelet counts in the treated patients. Acute (3 h) and chronic (one month) decreases in systolic arterial pressures in supine position were observed after losartan administration. Nevertheless, only one patient referred a single episode of mild orthostatic hypotension. No differences were observed in renal function tests. Conclusion: chronic AT1R blockade may reduce liver fibrosis in chronic hepatitis C patients.
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Clinical therapy
$227
CHRONIC HEPATITIS C IN PATIENTS WITH END STAGE RENAL DISEASE: CHARACTERIZATION OF LIVER HISTOLOGY AND R E S P O N S E TO INTERFERON T H E R A P Y BEFORE RENAL TRANSPLANTATION
R. Teixeira 1'2, R.L. Almeida 1'2, A.H. Silva 1'2, R.S. Brandgo 1'2, T.C. Espindola 1'2, M.L. Oliveira 1, R.D. Cambraia 1, E.M. Figueiredo 1, W. Medeiros Junior 1, E.O. Menezes 1, E. Bassetti-Soares 1, L.R Fonseca2, V.H. Rios2, L.O. Cangussu 1, J.M. Penido 1, G.C. Oliveira 3. llnstituto
Alfa de Gastroenterologia, Hospital das Cl{nicas, UFMG, Brazil," 2Departamento de Cl{nica Mddica, Faculdade de Medicina, UFMG, Brazil," 3Fundaf~to Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil I-~
P O O R PROGNOSTIC FACTORS IN HEAVIER PATIENTS WITH CHRONIC HEPATITIS C (CHC) RESULT IN LESS FAVOURABLE TREATMENT O U T C O M E S
M.G. Swain 1 . G.R. Fostel2, S.J. Hadziyannis 3, E.J. Heathcote 4, D. Jensen5, S.S. Lee 1, RJ. Pockros6, M. Sulkowski7, R. Reddy 8, C. Trepo9. 1University of Calgary, Calgary, AB, Canada," 2Digestive
Disease Researeh Centre, QMUL, London, UK," 3Henry Dunant Hospital, Athens, Greece," 4University of Toronto, Toronto, ONT, Canada," 5University of Chicago Hospitals', Chicago, IL, USA," 6The Scripps Clinic, La Jolla, CA, USA," 7johns Hopkins University, Baltimore, MD, USA," 8University of Pennsylvania, Philadelphia, PN, USA," 9H@ital de l 'Hotel-Dieu, Lyon, France Background: Bodyweight influences sustained virological response (SVR) rates to interferon-based regimens. In this analysis, we assessed the complex relationships between bodyweight, other baseline factors, and treatment outcomes in patients treated with peginterferon alpha-2a (40KD) (PEGASYS | plus ribavirin (COPEGUS | in two phase III studies [Fried. NEJM 2002;347:975; Hadziyannis. Ann Int Med 2004;140:346 55]. Methods: Baseline characteristics of all randomised patients weighing ~<75.5 kg or >75.5 kg were analysed by multiple logistic regression (MLR) analysis. Data from patients treated for 48 weeks with peginterferon alpha-2a (40KD)/ribavirin 1000/1200 mg/day were pooled and outcomes in patients weighing ~<75.5 kg or >75.5 kg compared. Results: MLR analysis identified several poor prognostic factors (male gender, black race, cirrhosis, genotype 1 infection) that were independently associated with weight >75.5 kg (Table). 48 weeks of peginterferon alpha-2a (40KD)/ribavirin 1000/1200 mg/day resulted in an overall SVR rate of 67% in patients weighing ~<75.5 kg vs. 56% in >75.5 kg patients (59% vs. 41% in HCV genotype 1). Although serious adverse events were more common in heavier patients, there was no difference in withdrawal rates as a result of adverse events.
Background: HCV infection in patients with end-stage renal disease (ESRD) in hemodialysis (HD) represents an important cause of morbidity and mortality after renal transplantation (RT). However, the natural history of liver disease in HD patients remains to be defined and there is only limited data about interferon alpha (IFN) therapy in these patients. Aims: To assess the liver histology, virological response and side effects of IFN therapy in HD patients awaiting RT. Methods: The study included patients with confirmed HCV infection and ESRD patients in HD (n 40) awaiting RT or normal renal function (NRF) (n 57). Patients with HBV or HIV coinfection, alcohol use, metabolic or autoimmune liver diseases were excluded. Both groups were matched for age, gender and estimated duration of HCV infection. Results: The mean age was 47 years and most patients were male (ESRD group 29/40, 72%; NRF group 30/57, 53%). The mean duration of HCV infection was 12.88 (• years in ESRD group and 15.12 (• years in NRF group (p NS). Although similar estimated duration of HCV infection, histological stage (Metavir score) in patients with ESRD was significantly lower than that observed in NRF group (ESRD: F0 F2: 34/40, F3 F4: 6/40; NRF: F0 F2: 37/57, F3 F4: 20/57; p 0.003). Twenty ESRD (50%) patients were selected for treatment with IFN before RT (3MU SC, 3 times a week after HD for 48 weeks). 10/20 (50%) have already concluded the period of six months after treatment. 7/20 (35%) stopped the treatment due to adverse events and 3/20 (15%) treatments are ongoing. 6/10 (60%) were non-responders (all genotype 1), 1/10 (10%) was relapser, and 3/10 (30%) are sustained responders (genotype 1 n 1; genotype 3 n 2). Conclusion: Compared to NRF patients, those with ESRD had significantly less histological liver disease suggesting that chronic hepatitis C is not rapidly progressive in most patients. IFN monotherapy while on dialysis is associated with lower tolerance and high drop-out rate. However, the virological response may benefit patients by preventing higher morbidity due to HCV infection after RT. Further studies are warranted to define the natural history of hepatitis C and optimal viral treatment for ESRD patients.
Factors independently associated with bodyweight >75.5 kg in the final MLR model Baseline factor
Odds ratio
95% CI
P value
Male vs. female gender Cirrhosis vs. no cirrhosis US vs. non-US centre Black race vs. white/other Asian race vs. white/other Genotype 1 vs. non-1 ALT ratio >3 vs. ~<3
7.478 1.390 3.776 1.974 0.200 1.312 1.283
6.033 9.269 1.092 1.770 3.067 4.648 1.133 3.438 0.128 0.313 1.084-1.587 1.050 1.569
<0.0001 0.0075 <0.0001 0.0163 <0.001 0.0052 0.0149
Conclusions: Bodyweight has a complex relationship with a range of patient characteristics in patients with chronic hepatitis C. This results in a clustering of poor prognostic characteristics in heavier patients, which may explain, in part, the lower SVR rates in heavier patients observed with all interferon-based regimens, including pegylated interferons.
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CYTOKINE R E S P O N S E IN CHRONIC HEPATITIS C (CHC) PATIENTS TREATED WITH PEGYLATED INTERFERON PLUS RIBAVIRIN
M. Trapero-Marugan 1, L. Garcia-Buey 1, C. Mufioz 2, J.A. MorenoMonteagudo 1, M.J. Borque 3, X. Salcedo-Mora 1, R. Moreno-Otero 1.
1Gastroenterology and Hepatology Service, 2Immunology Service, 3Molecular Biology Unit, Hospital Universitario de la Princesa, Madrid,
Spain Aims: (1) To compare the cytokine profiles in peripheral blood mononuclear cells (PBMCs) from patients with CHC and healthy controls. (2) To analyse the cytokine profiles in CHC patients during combination therapy. (3) To correlate the cytokine production with sustained virological response (SVR). Methods: 44 caucasian genotype 1 naive patients with CHC received PEGIFN~2a (weekly) plus ribavirin (1 1.2g/day) for 48 weeks. 16 healthy
POSTERS
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controls were studied. The intracytoplasmic expression of IL-4, IFN7 and TNF~, and surface CD4 and CD8 markers from PBMCs, resting and stimulated, were measured using flow-cytometry. SVR was analysed after 6 months of follow-up. Results: All 44 patients finished the study. Healthy controls presented a higher percentage of CD8 than CHC patients (22.1• vs 16.9• 10;p < 0.004), higher expression of IFN7 by resting CD4 (0.03• vs 0.8• <0.02), higher expression of TNF~ by CD8 (29.8• vs 19.5• 17.3;p < 0.05) and CD4 stimulated T cells (36.3• vs 26.7• p < 0.02) and lower of IL-4 by CD4 T cells (1.3• vs 2.7• < 0.01). After follow-up, 26 patients had SVR (59.1%), 13 relapsed (29.5%) and 5 were non-responders (11.4%). At the first month, expression of TNF~ by CD4 was higher in patients with a SVR than in NR (36.46• vs 17.2• < 0.01). At the third month, the percentage of CD4 was lower in patients with a SVR (34• vs 44• p <0.04), stimulated-IL-4 expression by CD4 cells was lower in patients with SVR than in nonresponders (1.9• vs 3.9• < 0.05) and TNF~ expression by CD4 was higher in SVR patients (48.8 • vs 31.2 • < 0.01). At the end of treatment, expression of IFN7 by CD8 and CD4 stimulated cells was higher in SVR respectively (17.3• 14 vs 10• p < 0.04 and 10.7• vs 5.9 • p < 0.03). Predictive factors of SVR: CD4 T cells and expression of TNFa by CD4 stimulated T cells at first month, expression of IFN7 by CD4 T cells at third month, and expression of TNFa and IFN7 by CD8 stimulated T cells at the end of treatment. Conclusions: IFN7 and TNF~ expression by CD4 and CD8 T cells (cytokine response type 1) during combination treatment is associated with SVR suggesting the replication control and later clearance of HCV.
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KINETIC ANALYSIS OF INSULIN RESISTANCE A N D S E R U M A D I P O C Y T O K I N E S LEVELS D U R I N G P E G I N T E R F E R O N A L P H A - 2 A PLUS RIBAVIRIN T H E R A P Y IN N O N - D I A B E T I C HCV PATIENTS
G. Venezia 1, O. Lo Iacono 1, S. Petta 1, P.L. Almasio 1, C. Mineo 1, M. Amato 2, A. Mattina 2, V. Di Marco 1, S. De Lisi 1, A. Licata 1, D. Ferraro 3, A. Cra-x{1. 1 Gastroenterology and Liver Unit, 2Endocrinology
Unit, 3Virology Unit, University of Palermo, Italy Background and Aims: Insulin resistance (IR), steatosis and adipocytokines levels have been associated with severity and progression of liver fibrosis. Aims of this study were to evaluate, in non-diabetic HCV patients, the role of host metabolic factors in determining the progression of liver fibrosis and response to antiviral therapy (AVT), and to investigate the changes of IR and adipocytokines levels related to AVT. Methods: Forty-eight naive patients with biopsy-proven CHC (28M/20F; age: 50• years, genotype 1 4: 66.7%), were treated according to genotype for 24 48 weeks with standard schedule of Peginterferon ~-2a (Pegasys, Roche) plus Ribavirin. Biochemical and virological assessment, HOMA-IR and serum leptin, adiponectin and resistin were determined, after an overnight fasting, at baseline, after 3 months, and at the end of therapy (ET) and follow-up (FU). Results: Mean BMI of patients was 26.4• kg/m2 and visceral obesity (according to ATP III definition) was present in half of them. At multivariate analysis, grade 2 3 liver steatosis was associated with older age (RR 1.1; 95%CI: 1.01 1.2), visceral obesity (7.8; 1.3 46.1) and serum insulin (1.4; 1.08 1.9). Independent variables associated with hepatic fibrosis (F2 F4) were higher necroinflammatory activity (27.5; 2.7 277.8) and grade 2 3 of steatosis (6.4; 1.1 38.2). A SVR was achieved in 62.5% (30/48) of patients and was associated with younger age (p < 0.01), genotype non-1 (p < 0.04) and absence of visceral obesity (p < 0.01). When we compared basal vs. end of follow-up levels we observed a significant decrease of insulin (12.09• vs 5.6• p <0.000), HOMA-IR (2.8• vs 1.3• p <0.000) and an increase of adiponectin levels (19.65• vs 26.11• 17.6; p < 0.02). Leptin levels significantly decreased only during AVT (basal: 19.9• vs ET: 9.4• p <0.000) but returned to basal levels after stopping therapy. Mean levels of these variables
did not differ among patients with SVR and non responders. Resistin levels did not significantly changed during and after therapy when compared to basal. Conclusions: Visceral obesity and clinical expression of IR have a major role to determine the severity of liver steatosis and fibrosis. Independently from the outcome, AVT produces significant changes of IR and adipocytokines levels. Visceral obesity is an independent predictor of SVR and maybe another target in the management of CHC patients.
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TREATMENT C O M P A R I S O N OF PATIENTS WITH C H R O N I C HEPATITIS C A N D ELEVATED ALT VS PATIENTS WITH PERSISTENTLY N O R M A L ALT - P R E L I M I N A R Y RESULTS OF A P R O S P E C T I V E O P E N TRIAL
W. Vogel 1, H. Brunnel2, M. Rosenbeigel2, I. Graziadei 1, A. Maieron 3, K. Jilek4, R. Stauber5, D. Wolkersdorfer6, H. Ulmer7. For the Austrian
Hepatitis' Study Group., 1Unia Clinic for Internal Medicine, University Innsbruclc Innsbruck, Austria," 2Department of Internal Medicine I, Hospital Lainz Vienna, Vienna, Austria," 3Internal Department, Hospital Elisabethinen, Linz, Austria," 4Department for Gastroenterology, Hospital Leoben, Leoben, Austria," 5Medical University clinic Graz, Graz, Austria," 6AESCA Pharma GmbH, Traiskirehen, Austria," 7Department for Biostatistics, University of Innsbruck, Innsbruck, Austria There is evidence that patients with persistently normal ALT (PNALT) respond similarly to those with elevated ALT to treatment with interferon and ribavirin, however, further studies are needed. In this prospective, multicenter, open-labeled clinical trial 240 de novo patients with biopsyproven CHC with normal or elevated ALT levels received PegIntron 1.5 gg/kg/wk & Rebetol 0.8 1.2g/d for 48 weeks (genotype 1/4) or 24 weeks (genotype 2/3). Study design: Patients were stratified according to elevated or normal (>3 measurements over >3 months) ALT, high or low viral titer (cutoff 800,000 IU/ml, bDNA HCV RNA 3.0 assay; Bayer Diagnostics) and genotypes (GT) 1/4 or 2/3. Baseline data are available from 225 patients: 107 patients with PNALT (83 patients with GT 1/4, median ALT was 29 U/l, 24 patients with GT 2/3, median ALT was 25 U/l) and 118 patients with elevated ALT (88 patients with GT 1/4, median ALT was 79U/1, 30 patients with GT 2/3, median ALT was 135). Results: There was no statistical significant difference in pretreatment characteristics between the two groups. 65.1% of patients with PNALT had a viral load lower or equal 800,000 IU/ml vs 66.4% of patients with elevated ALT. For 114/225 patients viral load was determined after week 4: 51.8% had undetectable RNA (49.2% PNALT and 54.9% high ALT; 37% of GT 1/4 pts. and 93% of GT 2/3 pts). After week 12 167/225 pts. were evaluated: 71.3% had undetectable RNA (76.3% PNALT and 67% high ALT; 66% of GT 1/4 and 90% of GT 2/3). 195 patients have so far completed the study. 14.4% of these patients withdrew because of AEs; 4.1% had a breakthrough on therapy, and 14.9% did not show a 2 log drop at week 12. Of these 195 patients 71.3% had undetectable RNA at end of treatment (74.1% normal ALT and 69.1% high ALT; 64% GT 1/4 and 89% GT 2/3). The differences in responses between the normal and high ALT group are not significant. Conclusions: Patients with elevated or normal ALT stratified for genotypes and viral load show at least the same ETR receiving PegIntron 1.5 gg/kg/wk & Rebetol 0.8 1.2 g/d.
(g) Hepatitis C
losartan administration. A significant increase was observed in albumin level and platelet counts in the treated patients. Acute (3 h) and chronic (one month) decreases in systolic arterial pressures in supine position were observed after losartan administration. Nevertheless, only one patient referred a single episode of mild orthostatic hypotension. No differences were observed in renal function tests. Conclusion: chronic AT1R blockade may reduce liver fibrosis in chronic hepatitis C patients.
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Clinical therapy
$227
CHRONIC HEPATITIS C IN PATIENTS WITH END STAGE RENAL DISEASE: CHARACTERIZATION OF LIVER HISTOLOGY AND R E S P O N S E TO INTERFERON T H E R A P Y BEFORE RENAL TRANSPLANTATION
R. Teixeira 1'2, R.L. Almeida 1'2, A.H. Silva 1'2, R.S. Brandgo 1'2, T.C. Espindola 1'2, M.L. Oliveira 1, R.D. Cambraia 1, E.M. Figueiredo 1, W. Medeiros Junior 1, E.O. Menezes 1, E. Bassetti-Soares 1, L.R Fonseca2, V.H. Rios2, L.O. Cangussu 1, J.M. Penido 1, G.C. Oliveira 3. llnstituto
Alfa de Gastroenterologia, Hospital das Cl{nicas, UFMG, Brazil," 2Departamento de Cl{nica Mddica, Faculdade de Medicina, UFMG, Brazil," 3Fundaf~to Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil I-~
P O O R PROGNOSTIC FACTORS IN HEAVIER PATIENTS WITH CHRONIC HEPATITIS C (CHC) RESULT IN LESS FAVOURABLE TREATMENT O U T C O M E S
M.G. Swain 1 . G.R. Fostel2, S.J. Hadziyannis 3, E.J. Heathcote 4, D. Jensen5, S.S. Lee 1, RJ. Pockros6, M. Sulkowski7, R. Reddy 8, C. Trepo9. 1University of Calgary, Calgary, AB, Canada," 2Digestive
Disease Researeh Centre, QMUL, London, UK," 3Henry Dunant Hospital, Athens, Greece," 4University of Toronto, Toronto, ONT, Canada," 5University of Chicago Hospitals', Chicago, IL, USA," 6The Scripps Clinic, La Jolla, CA, USA," 7johns Hopkins University, Baltimore, MD, USA," 8University of Pennsylvania, Philadelphia, PN, USA," 9H@ital de l 'Hotel-Dieu, Lyon, France Background: Bodyweight influences sustained virological response (SVR) rates to interferon-based regimens. In this analysis, we assessed the complex relationships between bodyweight, other baseline factors, and treatment outcomes in patients treated with peginterferon alpha-2a (40KD) (PEGASYS | plus ribavirin (COPEGUS | in two phase III studies [Fried. NEJM 2002;347:975; Hadziyannis. Ann Int Med 2004;140:346 55]. Methods: Baseline characteristics of all randomised patients weighing ~<75.5 kg or >75.5 kg were analysed by multiple logistic regression (MLR) analysis. Data from patients treated for 48 weeks with peginterferon alpha-2a (40KD)/ribavirin 1000/1200 mg/day were pooled and outcomes in patients weighing ~<75.5 kg or >75.5 kg compared. Results: MLR analysis identified several poor prognostic factors (male gender, black race, cirrhosis, genotype 1 infection) that were independently associated with weight >75.5 kg (Table). 48 weeks of peginterferon alpha-2a (40KD)/ribavirin 1000/1200 mg/day resulted in an overall SVR rate of 67% in patients weighing ~<75.5 kg vs. 56% in >75.5 kg patients (59% vs. 41% in HCV genotype 1). Although serious adverse events were more common in heavier patients, there was no difference in withdrawal rates as a result of adverse events.
Background: HCV infection in patients with end-stage renal disease (ESRD) in hemodialysis (HD) represents an important cause of morbidity and mortality after renal transplantation (RT). However, the natural history of liver disease in HD patients remains to be defined and there is only limited data about interferon alpha (IFN) therapy in these patients. Aims: To assess the liver histology, virological response and side effects of IFN therapy in HD patients awaiting RT. Methods: The study included patients with confirmed HCV infection and ESRD patients in HD (n 40) awaiting RT or normal renal function (NRF) (n 57). Patients with HBV or HIV coinfection, alcohol use, metabolic or autoimmune liver diseases were excluded. Both groups were matched for age, gender and estimated duration of HCV infection. Results: The mean age was 47 years and most patients were male (ESRD group 29/40, 72%; NRF group 30/57, 53%). The mean duration of HCV infection was 12.88 (• years in ESRD group and 15.12 (• years in NRF group (p NS). Although similar estimated duration of HCV infection, histological stage (Metavir score) in patients with ESRD was significantly lower than that observed in NRF group (ESRD: F0 F2: 34/40, F3 F4: 6/40; NRF: F0 F2: 37/57, F3 F4: 20/57; p 0.003). Twenty ESRD (50%) patients were selected for treatment with IFN before RT (3MU SC, 3 times a week after HD for 48 weeks). 10/20 (50%) have already concluded the period of six months after treatment. 7/20 (35%) stopped the treatment due to adverse events and 3/20 (15%) treatments are ongoing. 6/10 (60%) were non-responders (all genotype 1), 1/10 (10%) was relapser, and 3/10 (30%) are sustained responders (genotype 1 n 1; genotype 3 n 2). Conclusion: Compared to NRF patients, those with ESRD had significantly less histological liver disease suggesting that chronic hepatitis C is not rapidly progressive in most patients. IFN monotherapy while on dialysis is associated with lower tolerance and high drop-out rate. However, the virological response may benefit patients by preventing higher morbidity due to HCV infection after RT. Further studies are warranted to define the natural history of hepatitis C and optimal viral treatment for ESRD patients.
Factors independently associated with bodyweight >75.5 kg in the final MLR model Baseline factor
Odds ratio
95% CI
P value
Male vs. female gender Cirrhosis vs. no cirrhosis US vs. non-US centre Black race vs. white/other Asian race vs. white/other Genotype 1 vs. non-1 ALT ratio >3 vs. ~<3
7.478 1.390 3.776 1.974 0.200 1.312 1.283
6.033 9.269 1.092 1.770 3.067 4.648 1.133 3.438 0.128 0.313 1.084-1.587 1.050 1.569
<0.0001 0.0075 <0.0001 0.0163 <0.001 0.0052 0.0149
Conclusions: Bodyweight has a complex relationship with a range of patient characteristics in patients with chronic hepatitis C. This results in a clustering of poor prognostic characteristics in heavier patients, which may explain, in part, the lower SVR rates in heavier patients observed with all interferon-based regimens, including pegylated interferons.
I•
CYTOKINE R E S P O N S E IN CHRONIC HEPATITIS C (CHC) PATIENTS TREATED WITH PEGYLATED INTERFERON PLUS RIBAVIRIN
M. Trapero-Marugan 1, L. Garcia-Buey 1, C. Mufioz 2, J.A. MorenoMonteagudo 1, M.J. Borque 3, X. Salcedo-Mora 1, R. Moreno-Otero 1.
1Gastroenterology and Hepatology Service, 2Immunology Service, 3Molecular Biology Unit, Hospital Universitario de la Princesa, Madrid,
Spain Aims: (1) To compare the cytokine profiles in peripheral blood mononuclear cells (PBMCs) from patients with CHC and healthy controls. (2) To analyse the cytokine profiles in CHC patients during combination therapy. (3) To correlate the cytokine production with sustained virological response (SVR). Methods: 44 caucasian genotype 1 naive patients with CHC received PEGIFN~2a (weekly) plus ribavirin (1 1.2g/day) for 48 weeks. 16 healthy
POSTERS
$228
controls were studied. The intracytoplasmic expression of IL-4, IFN7 and TNF~, and surface CD4 and CD8 markers from PBMCs, resting and stimulated, were measured using flow-cytometry. SVR was analysed after 6 months of follow-up. Results: All 44 patients finished the study. Healthy controls presented a higher percentage of CD8 than CHC patients (22.1• vs 16.9• 10;p < 0.004), higher expression of IFN7 by resting CD4 (0.03• vs 0.8• <0.02), higher expression of TNF~ by CD8 (29.8• vs 19.5• 17.3;p < 0.05) and CD4 stimulated T cells (36.3• vs 26.7• p < 0.02) and lower of IL-4 by CD4 T cells (1.3• vs 2.7• < 0.01). After follow-up, 26 patients had SVR (59.1%), 13 relapsed (29.5%) and 5 were non-responders (11.4%). At the first month, expression of TNF~ by CD4 was higher in patients with a SVR than in NR (36.46• vs 17.2• < 0.01). At the third month, the percentage of CD4 was lower in patients with a SVR (34• vs 44• p <0.04), stimulated-IL-4 expression by CD4 cells was lower in patients with SVR than in nonresponders (1.9• vs 3.9• < 0.05) and TNF~ expression by CD4 was higher in SVR patients (48.8 • vs 31.2 • < 0.01). At the end of treatment, expression of IFN7 by CD8 and CD4 stimulated cells was higher in SVR respectively (17.3• 14 vs 10• p < 0.04 and 10.7• vs 5.9 • p < 0.03). Predictive factors of SVR: CD4 T cells and expression of TNFa by CD4 stimulated T cells at first month, expression of IFN7 by CD4 T cells at third month, and expression of TNFa and IFN7 by CD8 stimulated T cells at the end of treatment. Conclusions: IFN7 and TNF~ expression by CD4 and CD8 T cells (cytokine response type 1) during combination treatment is associated with SVR suggesting the replication control and later clearance of HCV.
I-~
KINETIC ANALYSIS OF INSULIN RESISTANCE A N D S E R U M A D I P O C Y T O K I N E S LEVELS D U R I N G P E G I N T E R F E R O N A L P H A - 2 A PLUS RIBAVIRIN T H E R A P Y IN N O N - D I A B E T I C HCV PATIENTS
G. Venezia 1, O. Lo Iacono 1, S. Petta 1, P.L. Almasio 1, C. Mineo 1, M. Amato 2, A. Mattina 2, V. Di Marco 1, S. De Lisi 1, A. Licata 1, D. Ferraro 3, A. Cra-x{1. 1 Gastroenterology and Liver Unit, 2Endocrinology
Unit, 3Virology Unit, University of Palermo, Italy Background and Aims: Insulin resistance (IR), steatosis and adipocytokines levels have been associated with severity and progression of liver fibrosis. Aims of this study were to evaluate, in non-diabetic HCV patients, the role of host metabolic factors in determining the progression of liver fibrosis and response to antiviral therapy (AVT), and to investigate the changes of IR and adipocytokines levels related to AVT. Methods: Forty-eight naive patients with biopsy-proven CHC (28M/20F; age: 50• years, genotype 1 4: 66.7%), were treated according to genotype for 24 48 weeks with standard schedule of Peginterferon ~-2a (Pegasys, Roche) plus Ribavirin. Biochemical and virological assessment, HOMA-IR and serum leptin, adiponectin and resistin were determined, after an overnight fasting, at baseline, after 3 months, and at the end of therapy (ET) and follow-up (FU). Results: Mean BMI of patients was 26.4• kg/m2 and visceral obesity (according to ATP III definition) was present in half of them. At multivariate analysis, grade 2 3 liver steatosis was associated with older age (RR 1.1; 95%CI: 1.01 1.2), visceral obesity (7.8; 1.3 46.1) and serum insulin (1.4; 1.08 1.9). Independent variables associated with hepatic fibrosis (F2 F4) were higher necroinflammatory activity (27.5; 2.7 277.8) and grade 2 3 of steatosis (6.4; 1.1 38.2). A SVR was achieved in 62.5% (30/48) of patients and was associated with younger age (p < 0.01), genotype non-1 (p < 0.04) and absence of visceral obesity (p < 0.01). When we compared basal vs. end of follow-up levels we observed a significant decrease of insulin (12.09• vs 5.6• p <0.000), HOMA-IR (2.8• vs 1.3• p <0.000) and an increase of adiponectin levels (19.65• vs 26.11• 17.6; p < 0.02). Leptin levels significantly decreased only during AVT (basal: 19.9• vs ET: 9.4• p <0.000) but returned to basal levels after stopping therapy. Mean levels of these variables
did not differ among patients with SVR and non responders. Resistin levels did not significantly changed during and after therapy when compared to basal. Conclusions: Visceral obesity and clinical expression of IR have a major role to determine the severity of liver steatosis and fibrosis. Independently from the outcome, AVT produces significant changes of IR and adipocytokines levels. Visceral obesity is an independent predictor of SVR and maybe another target in the management of CHC patients.
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TREATMENT C O M P A R I S O N OF PATIENTS WITH C H R O N I C HEPATITIS C A N D ELEVATED ALT VS PATIENTS WITH PERSISTENTLY N O R M A L ALT - P R E L I M I N A R Y RESULTS OF A P R O S P E C T I V E O P E N TRIAL
W. Vogel 1, H. Brunnel2, M. Rosenbeigel2, I. Graziadei 1, A. Maieron 3, K. Jilek4, R. Stauber5, D. Wolkersdorfer6, H. Ulmer7. For the Austrian
Hepatitis' Study Group., 1Unia Clinic for Internal Medicine, University Innsbruclc Innsbruck, Austria," 2Department of Internal Medicine I, Hospital Lainz Vienna, Vienna, Austria," 3Internal Department, Hospital Elisabethinen, Linz, Austria," 4Department for Gastroenterology, Hospital Leoben, Leoben, Austria," 5Medical University clinic Graz, Graz, Austria," 6AESCA Pharma GmbH, Traiskirehen, Austria," 7Department for Biostatistics, University of Innsbruck, Innsbruck, Austria There is evidence that patients with persistently normal ALT (PNALT) respond similarly to those with elevated ALT to treatment with interferon and ribavirin, however, further studies are needed. In this prospective, multicenter, open-labeled clinical trial 240 de novo patients with biopsyproven CHC with normal or elevated ALT levels received PegIntron 1.5 gg/kg/wk & Rebetol 0.8 1.2g/d for 48 weeks (genotype 1/4) or 24 weeks (genotype 2/3). Study design: Patients were stratified according to elevated or normal (>3 measurements over >3 months) ALT, high or low viral titer (cutoff 800,000 IU/ml, bDNA HCV RNA 3.0 assay; Bayer Diagnostics) and genotypes (GT) 1/4 or 2/3. Baseline data are available from 225 patients: 107 patients with PNALT (83 patients with GT 1/4, median ALT was 29 U/l, 24 patients with GT 2/3, median ALT was 25 U/l) and 118 patients with elevated ALT (88 patients with GT 1/4, median ALT was 79U/1, 30 patients with GT 2/3, median ALT was 135). Results: There was no statistical significant difference in pretreatment characteristics between the two groups. 65.1% of patients with PNALT had a viral load lower or equal 800,000 IU/ml vs 66.4% of patients with elevated ALT. For 114/225 patients viral load was determined after week 4: 51.8% had undetectable RNA (49.2% PNALT and 54.9% high ALT; 37% of GT 1/4 pts. and 93% of GT 2/3 pts). After week 12 167/225 pts. were evaluated: 71.3% had undetectable RNA (76.3% PNALT and 67% high ALT; 66% of GT 1/4 and 90% of GT 2/3). 195 patients have so far completed the study. 14.4% of these patients withdrew because of AEs; 4.1% had a breakthrough on therapy, and 14.9% did not show a 2 log drop at week 12. Of these 195 patients 71.3% had undetectable RNA at end of treatment (74.1% normal ALT and 69.1% high ALT; 64% GT 1/4 and 89% GT 2/3). The differences in responses between the normal and high ALT group are not significant. Conclusions: Patients with elevated or normal ALT stratified for genotypes and viral load show at least the same ETR receiving PegIntron 1.5 gg/kg/wk & Rebetol 0.8 1.2 g/d.