Tuesday Posters (11/15/2005)– HCV Treatment – 8:00AM – 6:30PM

Abstract ID: 63030

Category: JO7: HCV: Treatment

Negative impact of aging on hepatocarcinogenesis after viral eradication in patients with chronic hepatitis C: A long-term observation study of 1,672 patients and an effect of PEG-interferon/ribavirin therapy.

Y. Asahina, Musashino Red Cross Hospital, Tokyo, Japan, N. Izumi, Musashino Red Cross Hospital, Tokyo, Japan, T. Hosokawa, Musashino Red Cross Hospital, Tokyo, Japan, N. Umeda, Musashino Red Cross Hospital, Tokyo, Japan, K. Ueda, Musashino Red Cross Hospital, Tokyo, Japan, F. Doi, Musashino Red Cross Hospital, Tokyo, Japan, K. Tsuchiya, Musashino Red Cross Hospital, Tokyo, Japan, H. Nakanishi, Musashino Red Cross Hospital, Tokyo, Japan, K. Matsunaga, Musashino Red Cross Hospital, Tokyo, Japan, T. Kitamura, Musashino Red Cross Hospital, Tokyo, Japan, M. Kurosaki, Musashino Red Cross Hospital, Tokyo, Japan, M. Uchihara, Musashino Red Cross Hospital, Tokyo, Japan, S. Miyake, Musashino Red Cross Hospital, Tokyo, Japan

BACKGROUND:

Interferon (IFN) for chronic hepatitis C, in general, has been shown to prevent hepatocellular carcinoma (HCC). However, benefit of viral eradication by PEGIFN/ ribavirin (RBV) in elderly patients is unknown. An increase in the prevalence of elderly patients, which already occurred in Japan, is becoming an imminent problem in other countries where viral spread occurred more recently.

AIMS:

To determine the benefit of IFN and PEG-IFN/RBV on prevention of hepatocarcinogenesis especially in elderly patients.

METHODS:

Consecutive 1,672 patients with chronic hepatitis C who were treated with IFN-based anti-viral therapy were analyzed (mean age, 55 yo; IFN mono=971; IFN/RBV=393, PEG-IFN mono=202, PEG-IFN/RBV=106; mean follow up, 5.1 years). Cumulative incidence of HCC after anti-viral therapy was analyzed by Kaplan-Meier method, and the factors associated with disease-free survival were determined by Cox proportional hazard model.

RESULTS:

Cumulative incidence of HCC at 5 and 10 years after IFN therapy was 4.0% and 9.0%, respectively. Multivariate analysis revealed age, gender, fibrosis and virological response were independent factors for hepatocarcinogenesis. In elderly patients (>65 years old, n=425), cumulative incidence of HCC was significantly higher than younger patients (n=1,247) (10 years: 18.3% vs. 7.0% and logrank test:p<0.0001). Even when stratified by stage of fibrosis, the incidence was significantly higher in elderly patients than younger patients (10 years disease-free survival rate: F1, 6.1% vs. 1.1%; p=0.02: F2, 19.6% vs. 5.0%; p=0.0005; F3, 25.7% vs. 12.1%; p=0.02). Importantly, impact of viral eradication on prevention for HCC was more of a contributing factor in younger patients (10 years: SVR vs. NR in younger patients=1.7% vs. 10%, p=0.005; 12% vs. 20% in elderly patients). In patients with genotype 1b and high viral load who were treated by PEG-IFN/RBV combination therapy, sustained virological response rate was significantly higher in younger patient than elderly patients (53.8% vs. 25%), and rate of discontinuation due to adverse effects was higher in elderly patient (12.6% vs. 8.9%). Other than a decline in HCV during treatment, age was the only other independent factor that contributed to SVR during PEG-IFN/RBV therapy.

CONCLUSION:

Even after stratification by fibrosis stage, the risk of HCC after antiviral treatment was higher in elderly patients. HCV eradication had less of an impact on hepatocarcinogenesis in elderly patients. Although PEG-IFN/RBV is expected to prevent the development of HCC, careful surveillance of HCC should be taken in elderly patients even after viral eradication.

Abstract ID: 63217

Category: JO7: HCV: Treatment

Analysis of Responses to Alpha and Gamma Interferons in Hepatitis C Virus Infected Chimpanzees.

Y. Huang, National Institutes of Health, Bethesda, MD, R. Sapp, National Institutes of Health, Bethesda, MD, L. Blatt, InterMune, Inc, Brisbane, CA, K. Murthy, Southwest Foundation for Biomedical Research, San Antonio, TX, T. J. Liang, National Institutes of Health, Bethesda, MD

More than 50% of HCV-infected patients are resistant to alpha interferon (IFN- α) combination therapy, the current standard of care for chronic hepatitis C virus (HCV) infection. Gamma IFN (IFN-γ) has been shown to exert potent antiviral activity against HCV replication in the replicon system, but failed to exhibit any efficacy in HCV-infected patients. To better understand the nature of and resistance to the IFNs, we examined the dynamic responses to IFN-α; and -γ; in the chimpanzee model in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) from naïve chimpanzees were isolated and treated with human IFN (hIFN)-α and -γ, then compared with similarly treated PBMCs from healthy human donors. Quantitative real-time PCR was performed to evaluate the expression of IFN-stimulated genes (ISGs). The overall dose-dependent and time-related response patterns to both IFNs were comparable in human and chimpanzee. However both IFNs induced higher levels (2-5 fold) of ISGs in humans than chimpanzees, suggesting that chimpanzees do not respond as well as humans to hIFN in vitro. Next, naive and HCV chronically infected chimpanzees were treated with IFN- α; (10 million IU) and IFN- γ; (400 &#956;g). These doses are 3-4 times higher than those for human use, in order to compensate for the lower efficacy of hIFNs in chimpanzees. Expression of the ISGs was analyzed in PBMCs and liver biopsy samples. Although both naive and HCV-infected chimpanzee PBMCs had an earlier response to hIFN- α; and - γ; &#61472;(reaching a peak at 8 hours post-treatment), the response level in HCV-infected chimpanzee was much lower (~4 fold) than that in naive chimpanzee. IFN- α; appeared to induce a transient elevation of ALT and surprisingly, a concomitant increase (>5-fold) in viremia in HCV-infected chimpanzees. Interestingly, both IFN- α; and IFN- γ; induced a strong ISG response in hepatocytes of naive chimpanzees, but not in those of HCV-infected animals. In conclusion, these data indicate a deficiency of response, particularly in hepatocytes, to hIFNs in HCV-infected chimpanzee. Additional experiments are being conducted to study the mechanism of inhibition of IFN pathways by HCV infection in chimpanzees. Elucidation of these pathways in vivo may provide novel insights into the clinical issue of nonresponse to IFN in the treatment of hepatitis C.

Abstract ID: 63228

Category: JO7: HCV: Treatment

Hepatitis C Virus Genotypes and Viral Concentrations in Participants from a General Population Survey in the United States.

O. V. Nainan, Centers for Disease Control and Prevention, Atlanta, GA, M. J. Alter, Centers for Disease Control and Prevention, Atlanta, GA, D. Kruszon-Moran, Centers for Disease Control and Prevention, Hyattsville, MD, F. Gao, Centers for Disease Control and Prevention, Atlanta, GA, G. Xia, Centers for Disease Control and Prevention, Atlanta, GA, G. McQuillan, Centers for Disease Control and Prevention, Hyattsville, MD, H. S. Margolis, Centers for Disease Control and Prevention, Atlanta, GA

Estimates of the long-term benefits of antiviral therapies for chronic hepatitis C are influenced by the frequency of characteristics that affect response in the population treated. This study determined hepatitis C virus (HCV) genotypes and HCV RNA titers among 275 HCV RNA-positive participants in the Third National Health and Nutrition Examination Survey conducted during 1988-1994. Genotypes were determined by sequencing from the NS5b region and HCV RNA was quantified using Amplicor™ Monitor. The HCV genotypes identified included 1a (n=142), 1b (n=73), 2a (n=8), 2b (n=27), 3a (n=17), 4 (n=3), and 6 (n=5). Based on weighted analysis of persons infected with genotypes 1, 2, and 3, genotype 1 predominated in all age groups (75.3%). By racial/ethnic group, genotype 1 was found in 90.9% of non-Hispanic blacks, 69.6% of non-Hispanic whites and 71.2% of Mexican Americans. After adjusting for age and gender, only non-Hispanic black race/ethnicity was independently associated with genotype 1 infection (adjusted odds ratio 4.9, 95% confidence interval [CI] 1.9, 12.8). This difference was primarily due to a higher proportion of genotype 1b infections among non-Hispanic blacks (34.5%, 95% CI 24.2-46.0) than among each of the other racial/ethnic groups (12.5%, 95% CI 5.2-23.9 in non-Hispanic whites, 17.8%, 95% CI 9.7-28.7 in Mexican Americans). Among only persons infected with genotype 1, there was a difference in the distributions of 1a and 1b by age; 1a was more common in persons less than 50 years old (81.3%, 95% CI 71.2-91.5) and 1b in persons aged 50 years or older (72.5%,95% CI 50.4-88.6). The two factors independently associated with genotype 1b were older age (adjusted odds ratio 10.9, 95% CI 3.2-37.6) and non-Hispanic black race/ethnicity (adjusted odds ratio 2.7, 95% CI 1.0-6.9). The overall geometric mean concentration of HCV RNA was 2.1x106 IU/mL; concentrations >2 million IU/mL were found in 53.0% overall and 50.3% of persons with genotype 1. In conclusion, the predominance of genotype 1, even among younger persons, and the disproportionate number of non-Hispanic blacks with genotype 1 in this sample of HCV infected persons from the general population suggest that when current therapies are used more widely, the long-term clinical and economic effectiveness may be lower than previously estimated from clinical patient groups.

Abstract ID: 64025

Category: JO7: HCV: Treatment

Safe Use of peg-IFN and Ribavirin in HCV-cirrhotic Patients Undergoing Partial Splenic Embolization.

A. MORENO, HOSPITAL RAMON Y CAJAL, MADRID, Spain, J. R. FORUNY, HOSPITAL RAMON Y CAJAL, MADRID, Spain, R. BARCENA, HOSPITAL RAMON Y CAJAL, MADRID, Spain, C. QUEREDA, HOSPITAL RAMON Y CAJAL, MADRID, Spain, J. BLAZQUEZ, HOSPITAL RAMON Y CAJAL, MADRID, Spain, L. A. GIL-GRANDE, HOSPITAL RAMON Y CAJAL, MADRID, Spain, J. MORENO, HOSPITAL RAMON Y CAJAL, MADRID, Spain, M. J. PEREZ-ELIAS, HOSPITAL RAMON Y CAJAL, MADRID, Spain, L. MORENO, HOSPITAL RAMON Y CAJAL, MADRID, Spain, A. ANTELA, HOSPITAL RAMON Y CAJAL, MADRID, Spain, J. SANCHEZ, HOSPITAL RAMON Y CAJAL, MADRID, Spain, M. A. RODRIGUEZSAGRADO, HOSPITAL RAMON Y CAJAL, MADRID, Spain, S. MORENO, HOSPITAL RAMON Y CAJAL, MADRID, Spain

Background:

Partial splenic embolization (PSE) is a non-surgical alternative for the treatment of hypersplenism in cirrhotic patients with pancytopenia, specially thrombocytopenia, that precludes the use of interferon (IFN)-based therapies.

Methods:

Between May 2002 and May 2005, 18 HCV-cirrhotic patients underwent PSE a tertiary center in Madrid, Spain, specifically aimed to improve blood parameters enough to allow the use of full-dose peg-IFN and ribavirin (RBV). We report the outcomes of 12 patients (67%) that to date have started HCV therapy following PSE, with complete follow-up data available in 9 (75%).

Results:

The mean MELD score and age before PSE were 14+2.31 (11-18) and 43+10 years, respectively; 8 subjects were male (67%), and 6 were HIV-coinfected (50%). The most frequent HCV genotype was 1 (n=9, 75%). Three patients (25%) underwent PSE and received HCV-therapy following liver transplantation. Prior to PSE, the mean hemoglobin, platelet and neutrophil values were 12,4+1,48 g/dl, 45.275+13.928 cels/ml (below 50.000 cels/ml in 7 cases, 58%) and 1.350+956 cels/ml, respectively. PSE significantly improved the mean platelet (p=0.002), neutrophil (p=0.028) and haemoglobin (p=0.01) levels, and also the mean prothrombin activity (p=0.005) and MELD score (0.049). A mean of 15+9 weeks after PSE all patients started weight-adjusted RBV (mean dose 14,55+3,67 mg/kg/day) and full-dose peg-IFN- α-2b (n=7) or peg-IFN-α-2a (n=5). Baseline mean HCV-RNA was 5,4+0,78 log10 IU/ml. During therapy peg-IFN dose was not reduced in any subject, even in 3 patients (25%) with early withdrawal after 13, 32 and 70 days, respectively. Two patients (17%) received erythropoietin (one of them without RBV dose adjustements) due to Hb levels below 10g/dl, whereas RBV dose was reduced in 3 (25%) after a mean of 21 weeks. Neutropenia below 500 cels/ml was managed with G-CSF in two cases (17%). Three out of 9 patients with complete followup data have achieved SVR (33%), and 2 subjects with histological and biochemical improvement despite treatment failure maintained long-term full-dose combined therapy (73 and 121 weeks, respectively).

Conclusions:

PSE allowed the safe use of full-dose peg-IFN plus RBV in HCV-cirrhotic patients with severe cytopenias who otherwise would have never been treated. The rate of SVR was 33%.

Abstract ID: 64145

Category: JO7: HCV: Treatment

RELATIONSHIP BETWEEN SUSTAINED VIRAL RESPONSE AND LEUKOCYTE INTERFERON RECEPTOR (IFNAR-2) EXPRESSION ON IN CHRONIC HEPATITIS C PATIENTS TREATED WITH SEVERAL INTERFERONS.

K. Ishii, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, Y. Sumino, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, M. Shinohara, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, K. Higami, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, K. Matsumaru, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, T. Ikehara, Division of Gastroenterology, Toho University, Tokyo, Japan, M. Shinohara, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, H. Nagai, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, M. Watanabe, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, K. Miki, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, M. Sano, Laboratory Medicine, Toho University, Tokyo, Japan, T. Morita, Laboratory Medicine, Toho University, Tokyo, Japan

BACKGROUND/AIM:

Type 1 interferon (IFN) receptor consisting of two chains (IFNAR-1 and IFNAR-2) on hepatocytes may influence the response to IFN therapy. We previously reported that IFNAR-2 expression by leukocyte subsets, including lymphocytes (Ly), monocytes (Mo), and granulocytes (Gr), showed changes detectable during IFN therapy (DDW-AASLD 2005). The goal of the present study was to elucidate the significance of changes in IFNAR-2 expression by leukocyte subsets in patients with chronic hepatitis C (CHC) during IFN therapy.

PATIENTS AND METHODS:

Thirty-two adults with biopsy-proven CHC (M/F: 20/12; median age: 51 years) were studied. The baseline serum HCV-RNA level was quantified by Amplicor Ver 2.0 (Roche). HCV was divided into 2 serotypes; type 1 (genotypes 1a and 1b) was detected in 13 patients and type 2 (genotypes 2a and 2b) was found in 19 patients. Therapy was given for 24 weeks using several IFN regimens, in which IFNs were administered daily for 2 weeks followed by thrice weekly for 22 weeks. IFN-alpha (IFN-A; 5-6 MU), consensus IFN (IFN-C; 18 MU), and IFN-alpha 2b (R+IFN; 6 MU) combined with ribavirin (600-800 mg/day for 24 weeks) were given to 12, 9, and 11 patients, respectively. Blood samples were collected on days 0, 3, 7, 14, and 28 during therapy. IFNAR-2 expression on leukocytes was measured by flow cytometry and serum 2-5AS activity was measured. IFNAR-2 expression on leukocyte subsets was determined by calculating the mean fluorescence intensity (MFI) after staining with anti-IFNAR-2 antibody. A sustained responder (SVR) was defined as any patient in whom serum HCV-RNA was negative by a qualitative Amplicor Ver 2.0 at 24 weeks after the end of therapy, while a nonresponders (NR) was defined as any patient in whom serum HCV-RNA was positive. SVR was achieved in 10, 9, and 6 patients from the IFN–A, IFN-C, and R+IFN groups, respectively. Seven patients were non-responders.

RESULTS:

The baseline MFI of Ly, Mo, and Gr showed no significant differences between the NR and SVR groups. The MFI of Mo and the serum 2-5AS activity increased to a peak on day 3 and thereafter decreased gradually, showing a significant change (p < 0.05 by Friedman’s test) in both groups. On day 28, the MFI of Mo underwent re-elevation in the NR group and was significantly higher than in the SVR group. The MFI of Gr decreased gradually after the start of IFN therapy, showing a significant change (p < 0.05) only in the SVR group. The MFI of Ly did not change significantly in either group.

CONCLUSIONS:

Up-regulation of IFNAR-2 expression by Mo on day 28 may predict the failure of IFN therapy, so the IFNAR-2 on Mo may be related to clearance of HCV.

Abstract ID: 65146

Category: JO7: HCV: Treatment

Pharmacokinetics and Response of Obese Patients with Chronic Hepatitis C Treated with Different Doses of PEG-IFN alpha2A(40KD) (PEGASYS®).

B. Bressler, UHN-TWH, Toronto, Canada, K. Wang, Hoffmann-La Roche, Nutley, NJ, J. Gries, Hoffmann-La Roche, Nutley, NJ, E. Heathcote, University of Toronto, Toronto, Canada

Background:

Obesity is a negative predictor of response to treatment for chronic hepatitis C (CHC). This association may in part be a result of altered pharmacokinetics of interferon (IFN) leading to low serum IFN levels.

Aim:

To compare the pharmocokinetics of PEG-IFN a2a in obese patients (pts) with CHC to non-obese pts with CHC. A secondary aim was to determine if increasing the dose of PEG-IFN a2a would lead to higher serum exposures in obese pts with CHC.

Methods:

Non-cirrhotic patients with CHC and a BMI >30kg/m2 participated in a single centre open-label study. Patients were randomized to either:

· Group A: 180μg PEG-IFN a2a plus ribavirin (1000/1200 mg/day) for 48 weeks

· 270μg PEG-IFN a2a + ribavirin (1000/1200mg/day) for 48 wks.

Noncompartmental PK analysis (AUC, Cmax and CL/F) were performed on blood samples drawn post first dose and at wk 12. Trough levels (Ctrough) were determined on wks 2, 4, 8, and 24 wks. Results were compared to Roche data on file in non-obese and obese pts with CHC.

Results:

40 patients were included in this analysis. The two treatment groups were balanced with respect to HCV genotype and BMI.

A total of 39 of 40 patients have completed 24 weeks’ follow-up after completion of treatment. One patient receiving peginterferon alfa-2a (40KD) 270 μg week plus ribavirin withdrew prior to treatment.

Efficacy

An SVR was recorded in 14 of 20 (70%) and 15 of 19 (79%) patients receiving peginterferon alfa-2a (40KD) 180 μg and 270 μg plus ribavirin respectively.

Of the six patients who failed to achieve an SVR following peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin, three had a non-response and three relapsed.

Of the four patients without an SVR following peginterferon alfa-2a (40KD) 270 μg/week plus ribavirin, one had a non-response and three relapsed.

Values for AUC0-168 (ng·hr/mL, mean±SD) at wk 1 and wk 12 for 180μg were 980±352, and 2154±919 respectively, and for 270μg dose were 1403±772, and 3374±1844 respectively. Cmax (ng/mL) at wk 1 and wk 12 for 180μg dose were 7±3, and 14±7 respectively, and for 270μg dose were 9 ± 7, and 22 ± 12 respectively. CL/F (L/hr) at wk 12 for 180μg dose was 0.10 ± 0.05, and for 270μg dose was 0.09 ± 0.04. Steady state exposure was reached at week 8 for both dose groups. The mean Ctrough (pg/mL) for 180μg dose was 11,189 (4397-18,524) and for 270μg dose was 16,056 (414-44,161). These values are similar from the mean Ctrough values from previous studies on 180μg doses in non-obese pts (14,113 [310-24600]) and obese pts (11,202 [125-22600]) with CHC.

Conclusion:

· In this small cohort, both doses of peginterferon alfa-2a (40KD) plus ribavirin resulted in high SVR rates (70-79%).

· In obese patients (BMI > 30 kg/m²), increasing the dose of peginterferon alfa-2a (40KD) from 180 μg/week resulted in higher serum drug exposure.

o The clinical impact of higher exposure in obese patients requires further study.

· Trough concentrations of peginterferon alfa-2a (40KD) in obese patients were 21% lower than in non-obese patients.

What role this modest decrease in exposure plays relative to other negative risk factors associated with this patient population is uncertain; further study is required.

Abstract ID: 65256

Category: JO7: HCV: Treatment

REDUCTION IN HEMOGLOBIN A1C VALUES IN DIABETIC PATIENTS DURING HEPATITIS C COMBINATION THERAPY: A COMBINED EFFECT OF RIBAVIRIN-INDUCED HEMOLYSIS AND DECREASED GLUCOSE LEVELS.

Z. Naqvi, Bronx VA Medical Center, Bronx, NY, L. Eldeiry, Bronx VA Medical Center, Bronx, NY, N. Bräu, Bronx VA Medical Center, Brinx, NY, A. S. Rosman, Bronx VA Medical Center, Bronx, NY, P. D. Greenberg, Bronx VA Medical Center, Bronx, NY

BACKGROUND:

Hemoglobin A1c (A1c) measures glycemic control over the last 3 months. In a state of hemolysis, A1c levels are reduced due to decreased survival of red blood cells and shorter exposure of hemoglobin (Hgb) to plasma glucose. Ribavirin (RBV) used in combination with interferon (IFN) to treat chronic hepatitis C causes dosedependent, reversible hemolytic anemia. This study’s aim was to examine the extent to which treatment with RBV combined with IFN influences A1c levels.

METHODS:

A retrospective chart review in a tertiary care center identified 32 diabetic patients who underwent treatment (Rx) for chronic hepatitis C with IFN (standard or pegylated) and RBV. Each subject had at least 3 measures (before, during, and after hepatitis C virus (HCV) therapy) of A1c (with matching glucose values) and Hgb (with matching LDH, MCV, and reticulocyte counts)

RESULTS:

Patients had a mean age of 54.5 years, a mean body mass index (BMI) of 29.5 kg/m2, and 97% were male. A1c values decreased from a mean pre-Rx level of 7.2% to an on-Rx A1c level of 5.2% (mean paired difference, -2.01% [95% CI, -1.59% to -2.43%], p<0.001, t-test). Post-Rx, A1c levels rose again to a mean of 7.5% (difference, +2.27% [+1.16% to +2.93%], p<0.001, t-test; repeated measures ANOVA, p<0.001). Pre-Rx and post-Rx A1c values were similar (7.2% vs. 7.5%, p=0.38). During IFN + RBV therapy, mean Hgb levels decreased from 15.1 g/dL at baseline to a nadir of 11.7 g/dL (p<0.001) and returned to a post-Rx level of 14.7 g/dL (p<0.001) which was similar to the pre-Rx Hgb level. Increases in LDH levels and reticulocyte counts and constant MCV measures showed that this Hgb decline was due to hemolysis associated with RBV. At the same time, mean glucose levels also fell, from a pre-baseline level of 172 mg/dl to 133mg/dl (mean paired diff., 38.4 mg/dl [95% CI, 13.4 to 63.5 mg/dl], p=0.002). Body weight declined concurrently (pre-Rx, 89.4 kg; on-Rx, 86.2; difference, 3.15 kg [95% CI, 1.69 kg to 4.62 kg], p<0.001). Published correlation curves between A1C and glucose values have shown that for every 10 mg/dl glucose change, there is a 0.28% change in A1C level. This decline in glucose levels of 38.4 mg/dL thus accounts for 1.08% of the A1C decline.

CONCLUSIONS:

Reductions of A1c levels by a mean of 2.0% during hepatitis C therapy with IFN + RBV are due to RBV-induced hemolysis (0.93%) as well as due to decreased glucose levels (1.08%) associated with weight loss, likely due to IFN-induced reduction in appetite and caloric intake. A1c levels should not be measured during hepatitis C treatment with IFN + RBV since they do not adequately reflect glycemic control.
Abstract ID: 65536

Category: JO7: HCV: Treatment

The antiviral effects assessed by interferon induced enzyme, 2_f-5f oligoadenylate synthetase (2-5AS) activity during interferon alpha 2b+ribaviran, peginterferon alpha 2a alone, and peginterferon alpha 2b+ribavirin therapies for chronic hepatitis C.

M. Shindo, Akashi Municipal Hospital, Akashi, Japan, K. Hamada, Kyoto Institutes of Technology, Kyoto, Japan, T. Akatsuka, Saitama University, Saitama, Japan, A. Muramatsu, Akashi Municipal Hospital, Akashi, Japan, T. Morikawa, Akashi Municipal Hospital, Akashi, Japan, T. Okuno, Akashi Municipal Hospital, Akashi

Aim

We have reported that 2-5 AS activity is one of several interferon (IFN) induced enzymes that can be an accurate indicator of the antiviral effect of IFN (Hepatology, 1998). In this study, 2-5AS levels were measured during various types of IFN treatment in patients with chronic hepatitis C virus (HCV) infection in order to determine which IFN induced the most 2-5 AS. The treatments studied were standard IFN plus ribaviran (IntronA 10 MU/d+Rebetol 600-800mg/d for 6 mos), pefinterferon alpha 2a (180ƒÊg/w) (PEGSYS) alone for 1 year, and peginterferon alpha 2b (PEGIntronA, 80-100ƒÊg/w)+ribavirin (600-800mg/d) for 1 year.

Materials and Methods

A total of 50 patients with chronic hepatitis C were studied (interferon alpha 2b+ribaviran(n=10), peginterferon alpha 2a alone(n=20), Peginterferon alpha 2b + ribavirin (n=10), peginterferon alpha 2a+ribavirin(n=10). 2-5AS activity was measured by RIA assay kits (Eiken. Tokyo, Japan) every 1 to 2 weeks.

Results

1) In 10 patients treated with interferon alpha 2b(10MU/d)+ribavirin (800mg/d) for 6 mo, 2-5 AS levels increased 4 to 11 times (average level, 263 pmol /dL) over the pretreatment levels (average 30 pmol/dL) during the therapy. 2) In 10 patients treated with peginterferon alpha 2b+ribavirin, 2-5 AS levels increased to 7-30 times over (average, 415 pmol/dL) the pretreatment levels (30pmol/dL). 3) Six months after the initiation of peginterferon alpha 2a alone therapy, 8 patients (40%) were maintained on the dose of 180ƒÊg/w, however the remaining 12 patients were reduced in dose to 90 ƒÊg/w, and 10 of them were reduced to dosing only every 10 to 14 days due to neutropenia or thrombocytopenia. The average 2-5AS level in patients during peginterferon alpha 2a 180ƒÊg/w was 212 pmol/dL, , 90ƒÊg/w=181, 90ƒÊg/10days=194, and 90ƒÊg/2w=245. There was no significant correlation between 2-5 AS levels and peginterferon alpha 2a dose and schedule after the initial 3 to 6 months of dosing at 180 ƒÊg/w. Once HCVRNA became negative, it sustained negative in spite of dose reductions or prolongation of the interval between doses.

Conclusions

1) 2-5AS levels were significantly higher than in patients treated with peginterferon than in patients treated with conventional IFN therapy, which suggests that peginterferon is more potent at inducing interferon response genes resulting in an improved antiviral effect. 2) From the view of 2-5AS levels, once PEGASYS 180ƒÊg/w was administered for the initial 3-6 months, it appeared to maintain a long-term antiviral effect, thus it could be administered every 10 days to 2weeks in cases of side effects.

Abstract ID: 66093

Category: JO7: HCV: Treatment

Viral and metabolic factors influencing alanine aminotransferase (ALT) activity in patients with chronic hepatitis C receiving peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) in randomized phase III trials.

D. Prati, IRCCS Ospedale Maggiore Milan, and Ospedale A. Manzoni, Lecco, Lecco, Italy, M. L. Shiffman, VCU Medical Center, Richmond, VA, M. Diago , Hospital General Universitario Valencia, Valencia, Spain, E. Gane, Middlemore Hospital, Auckland, New Zealand, K. Reddy, Hospital of the University of Pennsylvania, Philadelphia, PA, P. Pockros, The Scripps Clinic, La Jolla, CA, P. Farci, Università di Cagliari, Cagliari, Italy, C. O'Brien, University of Miami, Miami, FL, P. Lardelli, Hoffmann-La Roche Ltd, Basel, Switzerland, S. Blotner, Hoffmann-LaRoche, Nutley, NJ, S. Zeuzem, Saarland University Hospital, Homburg, Germany

In chronic hepatitis C, serum ALT activity is highly variable. Up to 46% of patients have normal ALT levels, although significant hepatic lesions may be present. To clarify the role and reciprocal interactions of viral and host factors in inducing liver cell injury, we examined associations of several clinical and laboratory variables on serum ALT in patients chronically infected with hepatitis C virus (HCV) with normal and elevated ALT enrolled in randomized multinational phase III trials of peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®). Factors influencing ALT at the end of follow-up in patients with a sustained virological response (SVR) were also analyzed.

Methods

Data from all patients with HCV infection enrolled in three phase III trials of peginterferon alfa-2a (40KD) and ribavirin (two trials in patients with ‘elevated’ ALT [NEJM 2002;347: 975; Ann Intern Med 2004;140:346] and one with persistently ‘normal’ ALT [Gastroenterology 2004; 127:1724]) were included, independent of treatment received. Analyses were carried out with both baseline and end-of treatment variables. Associations between several metabolic and virological factors and baseline ALT activity (log10 values) were analyzed in both males and females using univariate (data not shown) and multivariate linear regression. The same analysis was performed to examine the relationship between metabolic and virological factors and ALT at the end of follow-up in all patients with an SVR.

Results

o Data from a total of 2881 patients were included in the analysis, 480 of whom had persistently ‘normal’ ALT levels.

o According to univariate analysis, ALT activity was significantly (p<0.05) associated with a number of factors including gender, HCV genotype, HCV RNA level, blood pressure and plasma glucose and cholesterol levels at baseline.

o Multivariate analyses indicated that ALT activity was significantly associated with the following factors: gender; infection with HCV genotype 2 or 3; low serum cholesterol or triglyceride levels; high blood glucose; high HCV RNA; and high diastolic blood pressure (DBP).

o Similar results were obtained when the analysis was conducted separately by gender.

o Multivariate analysis to identify baseline covariates (in addition to ALT) showed that the following were directly associated with serum cholesterol level: age, female gender, Caucasian race, serum triglyceride level and DBP. Variables that were inversely associated with cholesterol were: blood glucose, BMI, and genotype 1 or 3 infection.

o Multivariate analysis showed that blood glucose level was directly associated with male gender, age, BMI, triglyceride level, systolic blood pressure (SBP) and Caucasian race (in addition to ALT); and indirectly associated with serum cholesterol level and infection with HCV genotype 2.

o A total of 1403 patients in the pooled analysis of all antiviral treatments achieved an SVR. At the end of follow-up, ALT activity in these patients was significantly associated (p<0.05) with gender, BMI, triglyceride levels and SBP and DBP, according to univariate analysis.

o When multivariate tests were applied, gender, BMI, triglyceride levels and DBP had a direct association with ALT activity at the end of follow-up.

o Separation of data according to gender for patients with an SVR revealed that ALT level was also directly associated with non-Caucasian race in men and with age in women.

Conclusion

o In the overall study population, ALT activity was inversely associated with serum cholesterol and triglyceride levels. Multivariate analysis showed that this relationship was dependent on HCV genotype.

o Before treatment, serum lipids and ALT activity were inversely associated (i.e. high ALT associated with hypolipidemia) but, following successful treatment (SVR), they were directly associated (i.e. blood lipid levels increased substantially after treatment).

o In patients who achieved an SVR, ALT activity was significantly associated with gender, viral factors and indicators of metabolic syndrome.

o In conclusion, heterogeneity in ALT activity in patients with chronic hepatitis C appears to depend largely on the degree of derangement of fat and carbohydrate metabolism. This is the result of an association between the chronicity of the infection and the patient’s individual characteristics. Therefore, decisions regarding patient management should not be based on ALT activity alone, but should rather be individualized following an extensive evaluation of host and viral factors.

Abstract ID: 67062

Category: JO7: HCV: Treatment

Antiviral combination therapy modulates serum levels of markers of hepatic angiogenesis in chronic hepatitis C (CHC) patients.

X. B. Salcedo-Mora, Hospital Universitario La Princesa, Madrid, Spain, P. Sanz-Cameno, Hospital Universitario La Princesa, Madrid, Spain, J. Medina, Hospital Universitario La Princesa, Madrid, Spain, S. Martín-Vílchez, Hospital Universitario La Princesa, Madrid, Spain, M. Trapero-Marugán, Hospital Universitario La Princesa, Madrid, Spain, J. Moreno-Monteagudo, Hospital Universitario La Princesa, Madrid, Spain, M. Borque, Hospital Universitario La Princesa, Madrid, Spain, F. Rodríguez-Salvanés, Hospital Universitario La Princesa, Madrid, Spain, R. Moreno-Otero, Hospital Universitario La Princesa, Madrid, Spain

I

Abstract ID: 67698

Category: JO7: HCV: Treatment

Detection of minimal residual hepatitis C viremia at treatment week 12 is associated with a high probability of relapse.

A. Bergk, Charité, Medical school of Berlin, Department of Gastroenterology, Berlin, Germany, C. Sarrazin, Saarland University, Department of Gastroenterology, Homburg, Germany, G. Teuber, Universitätsklinikum Frankfurt, Department of Gastroenterology, Frankfurt, Germany, P. Buggisch, Universitätsklinikum Hamburg, Gastroenterology, Hamburg, Germany, H. Klinker, Universitätsklinikum Würzburg, Würzburg, Germany, V. Weich, Charité, Department of Gastroenterology, Berlin, Germany, B. Wiedenmann, Charité, Department of Gastroenterology, Berlin, Germany, T. Berg, Charité, Department of Gastroenterology, Berlin, Germany

Introduction:

Treatment outcome of HCV type 1-infected patients still remains unsatisfactory and sustained virologic responses (SVR) can be observed in only 50%. Virologic non-response as well as relapse rates are significantly higher in type 1-infected patients as compared to HCV type 2 and 3. Non-responders can be accurately identified at week 12 by a drop of viral load of less than two logs. However, prediction of viral relapse after completion of therapy remains difficult. In the present study, the predictive value of a minimal residual HCV viremia determined by real-time PCR for a relapse in HCV genotype 1-infected patients was assessed.

Methods:

174 early virologic responders defined by a greater than 2 log HCV RNA decline at week 12 on combination therapy with pegylated interferon plus ribavirin who continued therapy for 48 weeks were included. At week 12, HCV RNA was undetectable by quantitative PCR (Roche Amplicor, detection limit 600 IU/mL) in 162 of the 174 patients. A SVR was achieved in 102 patients, whereas 72 patients experienced a relapse six month after the end of therapy. Week 12 HCV RNA levels (stored serum samples, -80°C) were reanalyzed using a more sensitive real-time PCR (Roche Cobas TaqMan, limit of detection of 10 IU/ml).

Results:

Using real-time PCR a minimal residual hepatitis C viremia at week 12 could be detected in 65 of the 174 early virologic responders (37%). A highly significant correlation was found between the presence of minimal residual viremia and the probability of viral relapse. Only 14.7% (15/102) of the sustained responders had detectable HCV RNA by real time PCR as compared with 69.4% (50/72) of the relapse patients (p<0.001). The relative risk of viral relapse in patients with detectable viremia at week 12 was 3.8 and without detectable viremia 0.26, respectively.

Conclusion:

The presence of detectable residual hepatitis C viremia by highly sensitive real-time PCR is associated with a significantly increased risk of relapse after completion of therapy and could therefore be a valuable prognostic marker to predict the individual treatment outcome. Further studies are necessary to assess the value of an extended treatment duration on the dismal prognosis of those patients.

Abstract ID: 67731

Category: JO7: HCV: Treatment

Impact of HCV therapy vs. no treatment in the progression of fibrosis in patients that are coinfected with HIV.

M. Rodríguez-Torres, Fundación de Investigación de Diego, Santurce, PR, Puerto Rico, J. Rodríguez-Orengo, UPR-Medical Science Campus, San Juan, PR, A. Marxuach-Cuétara, Fundación de Investigación de Diego, Santurce, PR, A. Fernández-Carbia, University Pathologists, San Juan, PR, A. Sotolongo-Fernández, Fundación de Investigación de Diego, Santurce, PR

Human immunodeficiency virus (HIV) coinfected patients have a more severe form of chronic hepatitis C. Progression to end stage liver disease and hepatic failure has become the most important cause of morbidity and mortality in HIV/HCV coinfected patients. We examined the impact of treatment or no treatment, in the progression of fibrosis in a cohort with double biopsies.

Methods:

73 consecutive HCV/HIV coinfected patients with double biopsies were evaluated. Patients had laboratory/virological parameters within (2) months of 1st liver biopsy. Patients received either no-treatment n=8, PegIFN alfa 2-a (Pegasys) and RBV (Copegus) 800mg/daily n=25, PegIFN alfa 2-a monotherapy n=11, IFN and RBV 800mg n=8, or IFN n=21. Second liver biopsy was performed at 23.68 mean months after 1^st biopsy (SD 6.54). Liver biopsies were interpreted by the same experienced hepatopathologist using HAI Ishak (0-6 staging). Fibrosis progression rate (FPR) was calculated by the interval of time between biopsies and both staging values. Patients abstained from alcohol between biopsies and most of the patients had no changes in HAART.

Results:

Cohort is mostly male 75%, with mean age 43.6 years, log HCV 5.90, log HIV 2.76, absolute CD4 cells 474, and high ALT 101. Mean duration of treatment was 9.15 months. Mean staging at baseline (FS1) 4.06, and after treatment FS2 was 4.02; with mean difference of -0.41. There was no difference in duration of treatment between the 4 therapy arms, p=0.706. Within the groups, only the patients that received Pegasys and RBV or Pegasys monotherapy, demonstrated statistically significant decrease in fibrosis between the (2) biopsies, -1.4 for Pegasys/RBV and -0.364 for Pegasys monotherapy, p=0.0077. IFN/RBV, IFN monotherapy and no treatment, all showed increases in fibrosis. Additional analyses with the Pegasys/RBV group demonstrated no differences between SVR and non responders. Both groups benefited from the treatment, although almost half did not clear the virus at 72 weeks. (Table)

Conclusion:

Treatment with PegIFN alfa 2-a and PegIFN alfa 2-a and RBV, achieve significant decreases in fibrosis stage and fibrosis progression rate. This benefit, expected in SVR, is also demonstrated in non responders. These results support HCV therapy as beneficial even when SVR are inferior to those achieved in HCV monoinfected patients and implies a possible beneficial effect of maintenance therapy.

Table

Group n F. Stage difference

Abstract ID: 62857

Category: JO7: HCV: Treatment

Low Body Weight Predicts PEG-Interferon alfa-2a (Pegasys) Induced Neutropenia in Chronic Hepatitis C Patients.

Y. Rotman, Liver Institute, Rabin Medical Center, Beilinson Campus, Petach Tikwa, Israel, Z. Ben-Ari, Liver Institute, Rabin Medical Center, Beilinson Campus, Petach Tikwa, Israel, M. Braun, Liver Institute., Rabin Medical Center, Beilinson Campus, Petach Tikwa, Israel, M. Cohen, Liver Institute, Rabin Medical Center, Beilinson Campus, Petach Tikwa, Israel, O. Cohen-Ezra, Liver Institute, Rabin Medical Center, Beilinson Campus, Petach Tikwa, Israel, V. Manhaim, Liver Institute, Rabin Medical Center, Beilinson Campus, Petach Tikwa, Israel, R. Tur-Kaspa, Medicine D & Liver Institute, Rabin Medical Center, Beilinson Campus, Petach-Tikwa, Israel

Background:

Treatment of chronic hepatitis C with pegylated interferons (PEG-IFN) and ribavirin, the current standard of care, is often complicated by neutropenia, necessitating PEG-IFN dose reductions in about 20% of patients. PEG-IFN α 2a (Pegasys) is administered at a fixed, weight-independent dose owing to its low volume of distribution and pharmacologic profile.

Aim:

To determine if body weight affects rates of dose reduction for neutropenia in patients treated with PEG-IFN α 2a and ribavirin.

Methods:

Participants were part of a prospective, non-controlled, multi-center study on the safety and tolerability of PEG-IFN and ribavirin; our single-center data are reported here. Doses and dose modifications were set according to current guidelines. PEGIFN α 2a dose was reduced when the absolute neutrophil count was <750 cells/ μl.

Results:

The study group included 137 patients of mean age 48 years, mean weight 75.4 kg and mean body-mass index (BMI) 27; 71% were treatment-naïve and the rest were mostly non-responders to previous treatment; 39% had advanced fibrosis on biopsy and 80% were infected with genotype 1. Mean duration of follow-up was 65 weeks (range 10-117). PEG-IFN α 2a doses were reduced in 33 patients (24%), of whom 25 (18%) had neutropenia. Median time to first neutropenic dose reduction was 60 days (range 7-253). The chances of dose reduction for neutropenia were 41% in patients weighing <62kg compared with 11% in those weighing >62kg (χ2=14.6, p<0.001, odds ratio (OR)=5.8, CI=2.2-15.2). The rate of neutropenic dose reduction was monotonically dependent on body weight and body surface area, but not on BMI. On univariate logistic regression, female sex, weight, and height significantly influenced rates of neutropenia. On multivariate analysis, only weight retained significance (OR=0.934, CI=0.84-0.986, p=0.014). Time to first dose reduction was not correlated with body weight. At completion of treatment, a higher rate of response was actually noted in the patients with a dose reduction (58%) than in those without (47%); at 24 weeks post-treatment, the corresponding sustained virologic response (SVR) rates were 27% and 34%. Neither difference was statistically significant.

Conclusion:

Though PEG-IFN α 2a is given at a fixed, weight-independent dose, low body weight greatly increases the risk of treatment-induced neutropenia in patients with chronic hepatitis C. The major predictor appears to be body size, not body fat content. The finding that dose reductions did not impair rates of SVR indicates that a lower PEGIFN α 2a dose may be sufficient for smaller patients.
Abstract ID: 63764

Category: JO7: HCV: Treatment

Treatment of Hepatitis C Virus and Human Immunodeficiency Virus Coinfection : From Large Trials to Real Life.

P. Cacoub, La Pitié-Salpêtrière Hospital, Paris, France, . ROSENTHAL, CHU Nice, Nice, France, P. Halfon , Laboratoire alphabio, MARSEILLE , France, D. Sene, La Pitie Salpetriere hospital, Paris, France, D. Saadoun, La Pitié-Salpêtrière Hospital, Paris, France, c. Perronne , CHU Raymond Poincaré, Garches , France, S. Pol, CHU Necker, paris, France

Despite the frequency and seriousness of HIV-HCV coinfection, as well as recent therapeutic advances, patient access to anti-HCV treatment remains limited.

Aim :

To analyse the barriers to anti-HCV treatment in HIV-HCV coinfected patients.

Patients and Methods :

Seventy-one physicians specializing in infectious disease (39%), internal medicine (27%), HIV/AIDS information and care(17%), haematology (10%), and hepatology (6%) prospectively included patients seen from November 22 to 29, 2004. They were recruited from 50 specialized centres representative of those prescribing antiviral treatment in France. A standard data collection form was used.

Results :

Three hundred and eighty patients with the following characteristics were included: male gender 71%; mean age 41.5 years; European (77%) or African (21%) origin; HIV diagnosed 12 years ago; routes of transmission via injection drug use (78%) or heterosexual transmission (11%); undetectable HIV viral load (235/373, 63%) or <10,000 copies per ml (86/373, 23%); and CD4 >200/ml (76%). HCV RNA was positive in 325/369 (88%) patients; HCV viral load was >800,000 copies/ml (60%); HCV genotype was known in 324 patients (genotype 1 or 4 in 65%); and liver biopsy had been done in 56%. Anti-HCV treatment had been previously prescribed in 100 out of 380 (26%) patients, resulting in a sustained viralogical response in 29%, while 65 (17%) were receiving treatment or repeated treatment. There were several explanations for the nontreatment of HCV in 205 out of 380 (54%) patients : anti-HCV treatment was deemed questionable due to minor hepatic lesions (32%), alcohol consumption (31%), or active drug use (12%); no liver biopsy had been done (n=68); treatment was contraindicated (n=62), mainly for psychiatric reasons; there was physician conviction of poor patient compliance (n=62); and patient refusal (n=33). Patients having received anti-HCV treatment (n=91) compared to those who had never received any (n=205) were most often of European origin (85 vs 70%), were being followed by a hepatologist (47 vs 27%), had an undetectable HIV viral load (75 vs 55%), CD4 >350/mL (56 vs 44%), a liver biopsy done (87 vs 36%), and an HCV viral load >800,000 copies/ml (60 vs 39%) (p < 0.001).

Conclusion :

In "real life" in France in 2004, more than half of HIV-HCV coinfected patients have never received anti-HCV treatment. The main reasons are a treatment which may be deemed questionable (minimal hepatic lesions, alcohol, active drug use), a lack of available liver biopsy, a psychiatric contraindication and physician conviction of poor patient compliance (due to patient reluctance and unfavourable socio-economic conditions).
Abstract ID: 64615

Category: JO7: HCV: Treatment

Interferon therapy completion and response rates for hepatitis C among patients with schizophrenia, schizoaffective disorder, and substance use disorders.

M. S. Huckans, Portland VA Medical Center, Portland, OR, J. M. Loftis, Oregon Health and Science University, Portland, OR, P. Hauser, Portland VA Medical Center, Portland, OR

Background:

Individuals with schizophrenia and substance use disorders are at increased risk for hepatitis C (HCV), yet they have been typically excluded from interferon (IFN) therapy out of concerns that they might not complete treatment or that IFN might exacerbate psychiatric symptoms. Few studies have explored treatment responses empirically.

Methods:

Using a comprehensive medical record database system, information was retrospectively collected on 293,445 veterans seen in the Northwest Veterans Healthcare System. Treatment response and completion rates were compared among three groups: 1) SCHZ Group: n=8,836, all have a history of schizophrenia or schizoaffective disorder, 47% with any comorbid substance use disorder, 2) SUD Group: n=39,922, all have a history of substance use disorder with no history of schizophrenia/schizoaffective disorder, and 3) Controls: n=244,605, no history of schizophrenia/schizoaffective disorder or substance use disorder.

Results:

Within the total sample, 59% of the SCHZ Group, 63% of the SUD Group, and 30% of Controls were tested for HCV. Of those tested, 22% of the SCHZ Group, 27% of the SUD Group, and 5% of Controls tested antibody positive. Of those infected, 11% of the SCHZ Group, 11% of the SUD Group, and 14% of Controls were treated with IFN. If treated, the SCHZ Group was significantly less likely than Controls to complete 24 weeks of IFN (29% vs. 46%, OR=0.5, p=0.001) but equally likely to complete 48 weeks of IFN (13% vs. 15%, OR=0.9, p=0.69). Based on intent to treat, the SCHZ Group achieved a sustained viral response (SVR) at rates comparable with Controls (25% vs. 30%, OR=0.8, p=0.73). If treated, the SUD Group was significantly less likely than Controls to complete 24 weeks (35% vs. 46%, OR=0.6, p< 0.001) and 48 weeks (11% vs. 15%, OR=0.7, p=0.03) of IFN therapy. Based on intent to treat, the SUD Group achieved a SVR at rates comparable with Controls (24% vs. 30%, OR=0.7, p=0.24).

Conclusions:

Results indicate that individuals with schizophrenia/schizoaffective disorder are less likely than controls to complete 24 weeks of IFN therapy but are as likely as controls to complete 48 weeks of IFN therapy. Although individuals with substance use disorders are less likely to complete IFN therapy, the magnitude of differences is not large. In spite of completion rate differences, results indicate that individuals with schizophrenia and substance use disorders have similar SVR rates as controls. Therefore, HCV treatment is warranted for these groups. Future studies should further explore how IFN therapy impacts psychiatric symptoms in these high-risk groups.

Abstract ID: 66913

Category: JO7: HCV: Treatment

Treatment of chronic Hepatitis C virus (HCV) genotype 1 with peginterferon alfa-2b (PEGIFN), high weight based dose ribavirin (RVN) and Epoetin alfa (EPO) enhances sustained virologic response (SVR).

M. L. Shiffman, Virginia Commonwealth University Medical Center, Richmond, VA, A. Price, Virginia Commonwealth University Medical Center, Richmond, VA, S. Hubbard, Virginia Commonwealth University Medical Center, Richmond, VA, M. Wilson, Virginia Commonwealth University Medical Center, Richmond, VA, J. Salvatori, Virginia Commonwealth University Medical Center, Richmond, VA, R. K. Sterling, Virginia Commonwealth University Medical Center, Richmond, VA, R. T. Stravitz, Virginia Commonwealth University Medical Center, Richmond, VA, V. A. Luketic, Virginia Commonwealth University Medical Center, Richmond, VA, A. J. Sanyal, Virginia Commonweakth University Medical Center, Richmond, VA

Introduction

Successful treatment of chronic HCV with PEGIFN and RVN is hampered by adverse events (AEs). One of the most common AEs is anemia and this frequently requires that RVN either be dose reduced or prematurely discontinued. RVN dose reduction, particularly during the first 24 weeks of therapy, is associated with a significant reduction in SVR; particularly in patients with HCV genotype 1. Our HYPOTHESIS was that utilizing EPO at the onset of PEGIFN and RVN therapy would reduce the frequency

of anemia, the need to dose reduce RVN, allow for use of higher RVN dosing and this in turn could enhance SVR.

Methods

150 patients with HCV genotype 1, naïve to prior treatment, were randomly assigned to one of three treatment groups (50/group);

· Group 1: PEGIFN alfa-2b (1.5 mcg/kg/wk) + weight based RVN (WBRBN) 13.3 mg/kg/day (800-1400 mg/day);

· Group 2: PEGIFN alfa-2b + WBRVN + EPO (40,000 U/wk) or

· Group 3: PEGIFN alfa-2b + a higher dose of WBRVN (HDWBRVN) 15.2 mg/kg/day (1000-1600 mg/day) + EPO.

In groups 2 and 3 EPO was initiated at the onset of therapy and titrated

between 10,000 –60,000 U/wk to maintain the hemoglobin (Hb) between 12-15 gm/dl. In all groups, the RVN dose was reduced by 200 mg increments if the Hb declined below 10 gm/dl or for management of other side effects as needed. All patients underwent liver biopsy prior to treatment. HCV RNA was assessed by Taqman PCR.

Results

The mean age of the patient population was 48 years; 60% were male and 34% African American (AA). Mean body weight was 82.4 (49-149) kg, serum Log HCV RNA 5.5 + 0.32 IU/ml and Knodell score was 7.0 + 2.3; 6% of the patients had cirrhosis. Early virologic response (EVR), end-of-treatment response (ETVR), SVR, mean RVN dose and the percentage of patients in each group that required RVN dose reduction are listed (Table).

	Group 1	Group 2	Group 3
EVR	67%	53%	65%
ETR	48%	46%	55%
SVR	27%	24%	45%

No significant difference in either EVR or ETVR was observed between the three groups. In contrast, SVR was higher (p=0.05) in patients who received HDWBRVN + EPO (Group 3) despite the need for dose reduction in 27% of patients. This increase in SVR resulted from a decline in relapse.

Although EVR, ETVT and SVR were all lower in the 51 AA patients; SVR in both AA (31 vs 18%) and non-AA (53 vs 30%) patients were higher in Group 3 (HDWBRVN) compared to Groups 1.

Conclusion

We conclude that a significant increase in SVR can be achieved in HCV genotype 1 patients if treated with higher doses of RVN along with EPO to limit dose reduction.

Abstract ID: 67045

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

DOES AMANTADINE IMPROVE THE VIROLOGICAL SUSTAINED RESPONSE OF NAÏVE PATIENTS WITH CHRONIC HEPATITIS C IN ASSOCIATION WITH PEG-INTERFERON-RIBAVIRIN COMBINATION ? A PROSPECTIVE, RANDOMISED, MULTICENTER, DOUBLE-BLIND STUDY:PRELIMINARY RESULTS IN 200 PATIENTS.

V. CALAY, Liver and Transplantation Unit, MONTPELLIER, France, S. HACHEMANE, Liver and Transplantation Unit, MONTPELLIER, France, G. PAGEAUX, Liver and Transplantation Unit, MONTPELLIER, France, M. BOURLIERE, Hospital, MARSEILLE, France, I. PORTAL, HOSPITAL, MARSEILLE, France, P. MATHURIN, HOSPITAL, LILLE, France, E. VERDIER, Réseau Hépatites Ville-Hôpital, NIMES, France, A. TRAN, HOSPITAL, NICE, France, M. BOZONNAT, IURC, MONTPELLIER, France, J. DAURES, IURC, MONTPELLIER, France, J. ARPURT , HOSPITAL, AVIGNON, France, O. GORIA, HOSPITAL, ROUEN, France, P. CHASSAGNE, Réseau Hépatites Ville-Hôpital, BEZIERS, France, D. LARREY, Liver and Transplantation Unit, MONTPELLIER, France

Background

Pegylated interferon-ribavirin combination is associated with a sustained virological response(SVR) in half of patients with chronic hepatitis C. The interest of amantadine addition to this bitherapy remains very controversial, possibly because previous studies were not designed in a double blind manner.

Aim

To assess whether amantadine combined to pegylated interferon and ribavirin ( tritherapy) may increase HCV eradication.

Patients and methods

Patients with chronic hepatitis C ( proved by liver biopsy and positive for serum HCV RNA), naive of previous treatment were randomised to receive for 48 weeks:

· Group 1: Peg-Interferon alpha-2b,1,5mg/kg/week SC-ribavirin 1000-1200 mg/d orally, with amantadine 200 mg/d

· Group 2: p Peg-Interferon alpha-2b,1,5mg/kg/week SC-ribavirin 1000-1200 mg/d orally plus placebo

The SVR was defined by an undetectable serum HCV RNA, 24 weeks after the end of treatment. Statistical analysis was performed in an intention-to-treat-analysis.

Results

232 randomised patients were given the treatment .We present the preliminary results of 200 patients: 106 in group 1 and 94 in group 2.

Baseline characteristics were comparable in both groups: mean age: 45.6 vs 44.4 years, male: 61% vs 66%, Genotype 1: 69% vs 71%, Genotype 2,3: 21% vs. 18%, histological Metavir score F3-F4 (extensive fibrosis and cirrhosis): 19% vs 18%.

Sustained Virological Response:

	Group 1	Group 2
SVR	43.7%	49.6%
SVR – Genotype 1	35.4%	45.2%
SVR – Genotype 2,3	72.0%	68.0%
SVR – Fibrosis (Metavir) F1-F2	46.9%	52.0%
SVR – Fibrosis (Metavir) F3-F4	31.8%	38.1%
HCV RNA (≤ 625,000 UL/mL)	42.6%	45.2%
HCV RNA (>625,000 UL/mL)	25.0%	45.1%

Conclusion

The addition of amantadine 200mg/d to conventional bitherapy pegylated interferon alpha-2-b-ribavirin not only does not increase the efficacy but might even lower it in naïve patients. This later point deserves to be confirmed on a larger number of patients.

Abstract ID: 66153

Category: JO7: HCV: Treatment

Peginterferon a-2b 1 mcg/kg dose plus ribavirin 800-1200mg for 24-48 weeks, accordingto genotype, in naive patients with chronic hepatitis C: efficacy and cost-effectiveness evaluation.

M. Basso, Dpt Internal Medicine, University of Genova, Genoa, Italy, A. Grasso, Ospedale San Paolo, Savona, Italy, G. Percario, Ospedale San Carlo, Genoa, Italy, E.

Azzola, Ospedale Santa Corona, Pietra Ligure, Italy, S. Artioli, Ospedale Civile S. Andrea, La Spezia, Italy, N. Pelli, Dpt Internal Medicine, University of Genova, Genoa, Italy, F. Torre, Dpt Internal Medicine, University of Genova, Genoa, Italy, A. Picciotto, Dpt Internal Medicine, University of Genova, Genoa, Italy

Background & Aims

A dose finding study on monotherapy demonstrated no significant difference in sustained virological response (SVR) rate between peginterferon alpha-2b 1,5 mcg/kg/week and 1 mcg/kg/week in naive patients with chronic hepatitis C (Lindsay et al. Hepatology, 2001; 34:395-403).

Aim

In the attempt to optimise efficacy and resources, we designed a multi-centre observational protocol, treating chronic hepatitis C naïve patients with peginterferon alpha-2b 1 mcg/kg/week and ribavirin 800-1200mg, according to body weight, for 24 weeks in genotype 2 or 3 and for 48 weeks for genotype 1 or 4 infected patients.

Methods

148 consecutive, unselected naive patients (M/F: 87/61; median age: 49 yrs, range 19-67) were enrolled between 12/2001 and 6/2003 in five regional referring centres in Liguria, Italy. 51.4% had genotype 1/4. None of the patients had clinical sign of cirrhosis. HCV-RNA was assessed at week 2, 4, 12, end of treatment and at the end of follow up.

Results

There were 6 dropouts, two due to intolerance after few injections, 4 due to non-compliance with the treatment. 142 patients were adherent to the protocol and follow-up. No statistically significant differences were presents between the genotype groups for age, sex, ALT levels. Overall, we achieve SVR in 59.4% of patients, with a 5.4% of relapse-responders (RRs) and a 35.2% of non-responders (NRs) (intention to treat). For genotype 1/4 (76 pts, 48 weeks treatment), we had 32.9% SVR, 7.9% RRs, 52.6% NRs

and 6.6% DO. For genotype 2/3 (72 pts, 24 weeks treatment), we had 87.5% SVR, 2.8% RRs, 8.3% NRs and 1.4% DO. Week 2 and 4 HCV-RNA determinations did not prove to be reliable predictors of SVR. No major side effects or adverse events were reported. No dose reduction was needed for peginterferon alpha-2b, while a dose adjustment for anemia was necessary in 5% of the patients.

Conclusions

Peginterferon alpha-2b 1 mcg/kg dose plus ribavirin 800-1200mg

combination treatment was well tolerated in our group. The overall SVR is comparable with the published data (54%, Manns et al, Lancet, 2001; 358:958-965). Whilst in genotype 1/4 our results are slightly below the best-published results (32.9% vs 42%, Manns et al; peginterferon alpha-2b 1.5 mcg/kg plus 800mg ribavirin), for genotype 2/3 we obtained identical results (87.5% vs 82%, Manns et al. with a 48 weeks treatment).

Our results suggest that this combination therapy for 24 weeks can be considered the best option in genotype 2/3 infected patients. With the same SVR ratio, we obtained to reduce significantly length of treatment and side effects, and to halve the costs. Clearly, genotypes 1/4 need more aggressive schedules.