ribavirin nonresponders with daily dosing of consensus interferon

Category 5d." l~ral Hepatitis." Hepatitis C Clinical investigate whether there was any evidence to suggest that the natural history of their infections might vary with the infecting type. Data on clinical outcomes were extracted from the HCV National Register and mortality data were taken from death certification. Sera were available for 749 cases who had been enrolled in the U K HCV National Register. HCV RNA-positive specimens were genotyped and HCV RNA-negative specimens were serotyped. Logistic regression analysis was used to investigate the effect of HCV type on viral clearance and histological stage of liver disease. 444 of the sera were found to carry- HCV RNA. The most prevalent HCV types were 1 (52%), 3 (29%) and 2 (16°/3). Of the 305 specimens found to be HCV RNA-negative, it was possible to serotype 160 of them; serotypes 1 (58%o), 3 (24%) and 2 (13%) were the most common. There was no evidence of any association between viral type and: mortality, signs and symptoms of liver disease or histological grade of liver disease. A significant association was observed between viral type and response to treamlent, with type 1 infections being associated with poor response to treatment when compared to types 2 or 3 (P=0.003). Viral type was independently associated with spontaneous viral clearance, with type 1 being more likely to clear spontaneously than non-1 types (OR 0.50, 95%CI: 0.30-0.84, P = 0.009). Viral type was also independently associated with histological stage of liver disease, with type 1 being associated with stage scores above the median when compared to non-1 types (OR 2.03; 95%CI: 1.07-3.83; P=0.03). The results of this study suggest that HCV type 1 infection is more likely to be associated with spontaneous clearance but is clinically more aggressive than type non-1 infection when it persists.

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TOLERABILITY AND IMMUNOGENICITY OF HCV E1 THERAPEUTIC VACCINATION IN PATIENTS WITH CHRONIC HEPATITIS C ON INTERFERON PLUS RIBAVIRIN

Y. Horsmanslj R. Brenard I , P. St2irkel I , S. De Schepper 2, A. De Brauwer2, C. Vander Stichele 2, F. Hulstaert2, G. Maertens 2 . 1UCL Saint-

Luc, Brussels, Belgium," 2Innogenetic's, Gent, Belgium Background: In patients with chronic hepatitis C, opendabel E1 therapeutic vaccination monotherapy has been shown to be well tolerated, irmnunogenic, and associated with improvement in liver histology. Aim: This prospective open-labd study was conducted to explore tile immunogenicity and tolerability of E1 therapeutic vaccination in patients who had already started standard interferon/ribavirin therapy for at least 10 weeks. Methods: Seventeen patients were enrolled; one patient was ineligible. Sixteen patients with chronic hepatitis C [10 male, 6 female; mean age 46.4 years; genotype 1 or 3; median duration of IFN-based therapy 15 weeks (range 10 37 weeks); 11 previously treatment-naive] received 6 intramuscular injections of 20 lag HCV E1 at. three-week intervals with a 4-week follow-up. T-cell responses were measured by proliferation assays, cyto!dnes and anti-E1 antibodies by ELISA. Quality of life (QoL) was assessedwith the RAND 36 questionnaire before and after E1 vaccination. Results: HCV E1 induced both El-specific humoral and cellular immune responses. Tile mediarl values of anti-E1 antibody levels increased from 87mU/ml at baseline to 185 at study end. Of the 10 patients tested, nine developed a positive Y cell response (SI ~>3) with a strong increase in IFN-¥ and IL-5 secretion. With the exception of local side effects at the site of vaccine injection, no unusual side effects were observed. Interestingly, a trend towards improvement was observed for 4 out o f 8 QoL scales and for Health Transition. Of the trine patients with an elevated ALT value at the start of vaccination, three normalized serum ALT levels. Of tile 10 patients who still had detectable virernia at the start of vaccination, 3 became negative during combined treatment. Conclusion: A course of 6 HCV E1 injections was well tolerated and was associated with an El-specific immune response as well as a trend towards improvement in QoL in patients with chronic hepatitis C who already

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received at least 10 weeks of standard therapy. Some "late" biochemical and viral responses were observed. Whether such responses can be induced by the addition of HCV E1 therapeutic vacdnation to standard therapy remains to be investigated in larger controlled studies.

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DOSE OPTIMIZATION AND SAFETY OF THE THERAPEUTIC HEPATITIS C VIRUS (HCV) PEPTIDE VACCINE IC41 IN HEALTHY SUBJECTS

C. Klade ~, E. Tauber ~, V. Buerger 1, S. Jelovcan 1, M. Buschle I , J. Frisch I , C. Firbas 2, B. Jilma 2 . lIntercell AG, Vienna, Austria," 2Department of

Clinical Pharmacology, Medical University of Vienna, Nenna, Austria Induction of HCV-specific T-cells holds promise for therapy of patients not responding to or relapsing from standard therapy. Therapeutic vaccination with synthetic peptides and the novel synthetic T-cell adjuvant poly-L-arginine has been shown to induce interferon (IFN)-¥ secreting cytotoxic and helper T-cells. IC41 is a novel fully synthetic vaccine containing 5 peptides harbouring several cytotoxic (human lymphocytic antigen (HLA)-A*0201) and promiscuous T-helper epitopes of HCV The aim of this study was to compare the safety and efficacy of different doses of the vaccine and of different ratios of pepti de to poly-L-arginine. Healthy volunteers (n = 128) were enrolled into a randomized, placebo controlled, single-blind, parallel group phase 1 study to determine the optimal close for immunological T-cell response. Cryo-preserved peripheral blood mononuclear cells were used in IFN-'/ enzyrne-linked immunospot (ELIspot), T-cell proliferation and HLA-tetrarner assays. Safety assessments were local and systemic tolerability and routine laboratory parameters. ICA1 was well tolerated and the local reactions were of transient nature and of mild to moderate degree. In terms of T-cell induction, ICA1 induced significant responses in all peptide/poly-L-arginine groups, with higher responder rates (up to 75%) and more robust responses in higher dose groups. Poly-L-arginine was required for induction of IFN-¥-secreting T-cells. With increasing number of vaccinations higher responder rates and more robust responses were found. In conclusion, IC41 is a safe, well-tolerated fully synthetic therapeutic peptide vaccine capable of inducing both HCV specific IFN-y-secreting cytotoxic and helper T-cells in humans.

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SUCCESSFUL RETREATMENT OF INTERFERON/ RIBAVIRIN N O N R E S P O N D E R S WITH DAILY DOSING OF C O N S E N S U S INTERFERON

S. Kaiser, H.G. Hass, M. Gregor. Department of Medicine I, University Hospital of Tuebingen, Tuebingen, Germany Retreatrnent of nonresponders with conventional interferon o~ arid ribavirin leads to very low sustained response rates of only about 7%. These rates are not significantly changed with the use ofpegylated interferons. In the present study, the efficacy of CIFN daily (losing and induction therapy followed by ribavirin combination treatment in combination therapy nonresponders was evaluated. 182 patients (92% Genotype 1) were included. Patients were either treated with CIFN at a dosage of 27, 18 or 9ug for 4 weeks, followed by a reduced CIFN dosage by 9 u g in the two higher dosed arms for 8 weeks. The CIFN 9 ug arm remained unchanged. Thereafter, treatment was continued in all groups with CIFN at 9 ug QD with ribavirin at 10-15mgjkg/d for another 36 weeks. Data show that after the initial 24 weeks of CIFN/ribavirin therapy a primary response was observed in 43-71%. The sustained virological response rates (SVR) were 3 8 4 5 % for standard interferon/ribavirin nonresponders (n= 121) and 27-31% for peginterferon/ribavirin (n = 61) nonresponders. The CIFN dose had to be dose-reduced in 16-21% of patients and discontinued in 7-9% of patients. The most common cause were reductions in WBC and platelet counts, especially in the 27 ug CIFN group, while no growth factors were used in this study. The overall tolerability of the CIFN 9 and 18 ug regimen

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Posters

were of comparable tolerability to a standard therapy with peg3zlated interferon and ribavirin, while the CIFN 27/18/9ug regimen was less tolerable during the high dose induction period. However, drop out rates were not different between the dosing regimen. It is concluded, that CIFN daily dosing/induction therapy together with subsequent ribavirin combination therapy shows promising response rates in previous combination therapy non-responders including nonreponders to standard as well as peginterferons. Although a significant proportion o f patients experienced a relapse after cessation of therapy, the overall sustained response rates are nevertheless promising. It is concluded that CIFN may be an effective treatment modality for this diffficult-to-treat patient group.

~GENE EXPRESSION PROFILES IN HCVIHIV COINFECTION: CLASS PREDICTION ANALYSES PRIOR TO TREATMENT PREDICTS OUTCOME OF HCV THERAPY AMONG HIV CO-INFECTED INDIVIDUALS

R. Lempicld 1, J. Yang 1, M. McLaughlin 3, C. Koratich3, L. Wu 3, C. Refim3, H. Masur 2, M.A. Polis3, S. Kottilil 3. 1SAIC, NCI-Frederick,

NIH, DHHS, Frederick, MD, USA; 2CCMD, CC, NIH, DHHS, MD, USA; SLIR, NIAID, NIII, DHIIS, MD, USA Background: HW-infected patients co-infected with HCV have modest responses to anti-HCV therapy. Tile purpose of the study is to examine gene expression patterns in PBMC of HIV/HCV co-infected patients to predict the treatment outcome of anti-HCV therapy. Methods: PBMC gene expression profiles from 23 patients, pre- and post-anti-HCV therapy were determined using the Afl}'metrix U133A GeneChip (~22,000 genes). Patients were grouped as non-responders (n= 10), relapsers, those with an end of treatment response (ETR), but no sustained virologic response (SVR) (n 9), or SVR (n 4) based on HCV viral load following therapy. Gene expression values were determined using MAS5 and significant differences in gene expression determined by ANOVA. Differentially expressed genes were grouped using K-means clustering and functional category enrichment was performed using EASE analysis. PAlM software was used to perform class-prediction. Results: A cluster of 278 genes exclusively up-regulated in non-responders prior to therapy contained genes associated with immune activation. Elevated immune activation in non-responders prior to therapy was confirmed by elevated levels of %CD4+CD25+ cells, %CD4+CD45RO+ cells, serum ALT, and AST. Using 10× cross-validations, we identified 193 genes that correctly classified all non-responders, and misclassified only 1 relapser and 1 SVR as non-responders, resulting in an overall correct classification of 91%. Class prediction analyses of post treatment gene expression comparing relapsers and SVR identified 109 genes that correctly classified all samples (100%). Conclusions: Gene expression and clinical monitoring profiling of samples from HIV/HCV-co-infected patients suggests a link between elevated immune activation and resistance to anti-HCV therapy. Class prediction analysis using PBMC gene expression patten~s prior to treatment was able to predict the outcome with an overall accuracy of 91% of all patients while analyses of post treatment gene expression patterns o fpatients with an ETR was able to predict the ultimate outcome in all patients (100%). Validation of this bioinfomaatics approach in larger clinical trials would be extremely valuable in tile management of HCV therapy arnong HIV coinfected individuals to specifically target persons who may be amenable to therapy, or in whom therapy, with its attendant toxicities, should be avoided.

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POPULATION-BASED ANALYSIS OF ACUTE HEPATITIS C VIRUS (HCV) INFECTIONS AND SPONTANEOUS VIROLOGICAL RESOLUTION BASED ON GENDER AND AGE IN BRITISH COLUMBIA, CANADA

R. Shadrnani ~, B. Pourbohloul ~,3, G. Butt 1, D. Cook 1, G. McNabb 1, M. Petric 1,2, M. Krajden 1,2. 1British Columbia Center for Disease

Control (BCCDC), Vancouver, BC, Canada," 2Department of Pathology, University of British Columbia, Vancouver, BC Canada," SDepartment of Health Care and Epidemiology, University of British Columbia, British Columbia, Canada, Vancouver, BC, Canada Background: The spontaneous rate of HCV resolution is 25%, range 15% to 45%. The BCCDC laboratory performs >95% of anti-HCV tests and >75% of HCV PCR for the province of British Columbia, population 4 M. Between 1992-2002 it performed 580,726 anti-HCV tests on 452,326 people and 7558 qualitative PCR tests on treatment naive individuals which provides comprehensive population based data. Aims: To determine the rate of acute infection based on seroconversions/new infection (seronegative 6 mo previously) and the rate of spontaneous virological resolution based on clearance of HCV-RNA. Methods: Anti-HCV reactivity was determined by a dual testing algorithm using 2nd then 3rd gen assays (Abbott and Ortho). Qualitative HCV-PCR was by Cobas AMPLICOR v2.0. Indeterminate specimens were excluded. Results: Between 1992 2002, 580,726 anti-HCV tests were performed on 452,326 individuals; 45,644 were anti-HCV reactive of whom 2168 demonstrated seroconversion/new infection. PCR was available on 7558 individuals, 4694 males (M), 2864 females (F). Although tile rate of antiHCV testing in F was higher than in M (1035 vs 964/100,000) the rate of infection was twice as high in M. Acute cases predominated in those 15 39 yra old [80%, F 731 (83%): M 987 (78%)] vs 19% in those ~>40 yrs old [F 147 (17%): M 269 (21%)]. 48% of chronic cases were 15 39 yrs old [F 7543 (52%): M 12,803 (46%)] and 50% were >~40 yrs old [F 6645 (46%): M 14,345 (52%)] (p <0.0001). For F 15 59yrs the rates of active infection (PCR +re) were 56%-84% (mean 73%, n 2568) and were always lower than in M, for all age intervals, whose rates were 780/085% (mean 80%, n=4354) (p < 0.05). In contrast, for those />60yrs the rates of active infection in M&F were similar (range 74%-86%, n=457, mean 81%). Conclusions: Females in British Cohlmbia undergo more frequent antiHCV testing, have similar acute rates of infection but demonstrate a consistent pattern of spontaneous HCV resolution that is 1% to 22% higher, mean rate of 7% than M between the ages of 15 to 59 (p < 0.05). This may explain the preponderance of males with active HCV in the general population.

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HIGH EARLY VIROLOGIC RESPONSE IN PATIENTS WITH CHRONIC HEPATITIS C, GENOTYPE 1 TREATED WITH PEGINTERFERON AND RIBAVIRIN; THE IMPACT OF GROWTH FACTORS

M. Kugelmas I , V~J. Sernon2, G. Spiegelman3, R. Reindollar 4. 1South

Denver Gastroenterology, Denver, CO, USA," 2Iowa Digestive Diseases Center, Des Moines, IA, USA," SGary Spiegelman Gastroenterology, Knoxville, IN,, USA,"4Carolinas Center for Liver Diseases, Charlotte, NC, USA Baekground: Hematologic toxicity" is one of the most common reasons for dose reduction or discontinuation when treating chronic hepatitis C. In turn, these dose reductions negatively affect chance of achieving early virologic response (EVR) during therapy of patients with genotype 1 chronic hepatitis C (HCV-1) (Davis, Hepatology 2003). Aims and Methods: We are comparing standard of therapy (ST) with pegylated interferon ~-2b (IFN) plus weight-based ribavirin (RBV) in patients with HCV-1 to an adjuvant therapy" (AT) regimen where anemia