Date: 5 May 15, 2005

Abstract ID: S1585

The Effect Of Hematologic Growth Factors (GF) on the Rate Of Sustained Viral Response (SVR) in Chronic Hepatitis C.

S. Zubair, R. Rullan, K. Gendreau, D. D'Agostino, L. Marshall, K. Coleman, S. Mehta, L. Shick

Purpose

To retrospectively determine the effect of GF on the rate of SVR for the treatment of chronic HCV.

Background

Hematologic cytopenias often complicate treatment of chronic HCV. The reduction in medication doses has been associated with lower rates of SVR. GF is often successful in treating these cytopenias and improving quality of life. The current assumption is that GF helps to sustain SVR by maintaining appropriate doses of PEG-interferon and ribavirin. There is no published data on the effect of GF on SVR for the treatment of chronic HCV.

Methods

A retrospective analysis was performed of all patients with chronic HCV that received treatment with PEG-interferon and ribavirin (2002-present) at UMass Memorial Medical Center. Patients receiving maintenance dosing and those who have not completed the six month post-treatment follow-up period were excluded. Data on the use of G-CSF, erythropoietin and oprelvekin were recorded. SVR was compared in genotype 2/3 chronic HCV patients versus non-genotype 2/3 patients.

Results

215 patients were analyzed. Thirteen patients were excluded because they had not completed the six month post-treatment follow-up period. One patient was excluded due to maintenance dosing. 31% of all patients were female and 69% were male. 77% were Caucasian and 13% were non-Caucasian. GF use included erythropoietin (24 patients), G-CSF (9 patients), and oprelvekin (1 patient). The overall rate of SVR was 58.2%. The rate of SVR in non-genotype 2/3 chronic HCV patients and genotype 2/3 patients was 47.7% and 78.2%, respectively. Non-genotype 2/3 chronic HCV patients receiving erythropoietin achieved a higher rate of SVR (70.8% vs. 42.6%, p=0.01). Among non-genotype 2/3 chronic HCV patients, those who received GF showed a trend towards a higher rate of SVR (61.2% vs. 43.6%, p=0.08). In a linear regression analysis, when controlling for gender, there was a relationship between SVR and the use of any GF (p=0.05). Females who did not receive GF, were more likely to not achieve SVR (73.3% vs. 26.7%). The use of GF did not appear to have a significant effect on the rate of SVR in patients with genotypes 2/3 HCV.

Conclusion

In non-genotype 2/3 chronic HCV patients, the use of erythropoietin for anemia may increase the rate of SVR. Furthermore, the use of any GF showed a tendency towards higher rates of SVR. Prospective trials should be planned to confirm these findings.

Abstract ID: S1569

Correlation of Immune Stimulation with Antiviral Response to Interferon Therapy in Hepatitis C Patients

M. Silva, J. Poo-Ramirez, F. Wagner, M. Jackson, D. Cutler

Introduction

Neopterin, a byproduct of tryptophan metabolism by macrophages and dendritic cells, has been associated with immune stimulation through interferon alpha pathway(s). The relationship between neopterin production and antiviral response, and the potential differences in neopterin production in patients chronically infected with hepatitis C virus (HCV) genotype 1 receiving peginterferon alfa-2b (PEG2b) and alfa-2a (PEG2a) were investigated.

Methods

Patients (n=36) were randomized to receive PEG2b 1.5μg/kg/wk or PEG2a 180μg/wk alone for 4wk, and then with ribavirin 13mg/kg/d for 4wk. Neopterin levels were measured at 0h (baseline), 6h, 10h, 12h, 24h, 48h, 72h and 120h after dose 1 and 4. Cmax is the maximal change from baseline during 1wk or 4wk. AUC is the cumulative change from baseline during 120h of sampling. Responders were defined as patients whose HCV viral load was reduced by at least 2.0 log10 after 8wk.

Results

Baseline neopterin levels at 1wk and 4wk were not significantly different between the two peginterferons, nor between the responders and nonresponders. Table shows change in neopterin production by responder status and treatment following administration of peginterferon alfa.

Conclusions

There is significant association between magnitude of increase in neopterin production in response to peginterferon treatment and antiviral effects. Tachyphylaxis occurs with repeated dosing (magnitude of increase at 4wk is lower than at 1wk), and was greater with PEG2a. Findings are consistent with an overall association of HCV viral decline to interferon alpha treatment with neopterin production and upregulation of interferon alpha response genes.

Parameter	Wk1		Wk4
	Cmax	AUC	Cmax	AUC
>=2.0 log10 decline in HCV at 8wk	4.44*	355.4	1.4*	78.4*
<2.0 log10 decline in HCV at 8wk	3.17	272.5	0.5	10.5
PEG2b	4.86*	383.1*	1.8*	108.9*
PEG2a	3.1	267.8	0.4	-2.3

*p<0.05 t-test, responder vs nonresponder and PEG2b vs PEG2a

Abstract ID: S1557

A Pilot Study Of Etanercept Treatment for Inhibition Of Fibrotic Progression in Chronic Hepatitis C Infection.

R.J. Marrero, A. Sobhonslidsuk, P. Mendez, M. Torres, P. Bejarano, C. O'Brien, E.R. Schiff

Background

There is no established treatment that prevents the progression of fibrosis in patients who failed interferon-based combination antiviral treatment. Tumor necrosis factor (TNF) alpha is an important mediator in the development of fibrosis, thereby implicating a possible role for the inhibition of TNF alpha in the treatment of chronic Hepatitis C (CHC).

Aim

To asses the efficacy of etanercept treatment on the necroinflammatory and fibrotic change in patients with CHC infection, genotype 1, nonresponders to interferon-based combination antiviral treatment.

Methods

Ten patients with CHC, genotype 1, nonresponders to antiviral treatment with pegylated interferon and ribavirin were enrolled. Active HCV infection was documented by a positive HCV RNA by PCR (Cobas Amplicor). Etanercept was administered for 24 weeks duration at a dose of 25 mg subcutaneously twice weekly. A liver biopsy prior and post etanercept treatment was obtained and reviewed by an independent pathologist using the METAVIR score. Patients were followed monthly for evaluation of side effects and liver related blood tests for a period of 32 weeks.

Results

Of the ten patients enrolled 50% (5/10) were women of mean age 50 years, and 50% (5/10) were men of mean age 40 years. One patient was withdrawn due to abnormal elevation in serum alanine aminotransferase (ALT); one patient was lost to follow up. Eight post treatment liver biopsies were evaluated; 12% (1/8) had an improvement in the stage of fibrosis, 88% (7/8) had no change in fibrosis. The mean baseline platelet count (PLT) and ALT level were (177,000 MCL/120 U/L) respectively. None of the differences between platelet count and ALT levels at baseline and at follow up achieved statistical significance (p >0.05). Even tough one patient had an improvement in the stage of biopsy after treatment; these results did not reach statistical significance.

Conclusion

This is the first analysis of etanercept treatment for inhibition of hepatic fibrosis in patients with chronic HCV, genotype 1, nonresponders to combination antiviral therapy. There was no significant histological or biochemical improvement.

Abstract ID: S1565

Predictors Of Treatment Failure in Patients With Hepatitis C Genotypes 2 or 3 Infections.

A.M. Qadri, K.M. Edwards, C.K. Zein, D.M. Wachsberger, N.N. Zein

Background/Aims

Sustained virologic response (SVR) following antiviral therapy in genotype 2 and 3 HCV patients is accomplished in most cases although a small number of patients fail to respond (NR) or relapse (Rel) after discontinuation of therapy. Understanding predictors of treatment failure in this “highly treatment-sensitive” population may allow the development of novel therapeutic approaches. Our aim was to assess predictors of treatment failure (NR and Rel) in patients with HCV genotypes 2 and 3.

Methods

All treatment-naive Caucasian patients with chronic HCV genotype 2 and 3 infection at The Cleveland Clinic Foundation between 2001 and 2004 were identified (59 patients). Those who received at least one dose of peginterferon (fixed dose PEG2a or weight-based PEG2b) and ribavirin were included whereas liver transplant recipients, co-infected hepatitis B and/or HIV patients were excluded. Identification of variables associated with treatment failure was done by comparing variables of interest between SVR and non-SVR groups using Wilcoxon test for continuous variables and Chi-Square for categorical variables. Individual logistic regression was done to obtain Odds Ratios (OR). Multivariate modeling was done to identify independent predictors of treatment failure.

Results

Overall, 14/59 (24%) patients failed to achieve SVR (7 NR and 7 Rel). Male gender (p=0.01, OR=6.2, 95% CI 1.5-43.3), history of alcohol abuse (p=0.003, OR=8.2, 95% CI 1.4-39.6), non-weight-based therapy (p=0.01, OR=5.7, 95% CI 1.4-39.6), and presence of histologically advanced disease (p=0.04, OR=3.9, 95% CI 1.1-16.7) were identified as predictors of failure to achieve SVR by univariate analysis. Multivariable logistic regression analysis model (whole model p=0.0006) identified history of alcohol abuse (p=0.009; OR=9.3, 95% CI 2.1-67.6) and non-weight-based treatment (p=0.028; OR=6.7, 95% CI 1.4-49.3) as significant independent predictors of failure to achieve SVR in these patients. More patients with genotype 3 failed to achieve SVR although not statistically significant.

Conclusions

A subgroup of Caucasian HCV patients with genotype 2 and 3 infections less likely to achieve SVR may potentially benefit from weight-based peginterferon therapy. Excessive alcohol intake appears to contribute to treatment failure in patients infected with HCV genotype 2 or 3 infections. Novel therapeutic approaches such as longer duration of treatment may lead to better outcomes in this population.

Abstract ID: S1539

Final Results Of a Double-Blind, Placebo-Controlled Trial Of the Antifibrotic Efficacy Of IFN Gamma-1b in Chronic Hepatitis C Patients With Advanced Fibrosis or Cirrhosis

P.J. Pockros, L. Jeffers, N. Afdhal, Z.D. Goodman, D. Nelson, R. Gish, R. Reddy, R. Reindollar, M. Rodriquez-Torres, S. Faris-Young, S. Sullivan, L.M. Blatt

Introduction

IFN-γ 1b is a pleiotropic cytokine that displays antifibrotic, antiviral, and antiproliferative activity. Preliminary data in pulmonary and liver fibrosis suggest that
IFN-γ 1b has antifibrotic effects in vivo. As a result, a Phase 2, double-blind,
placebo-controlled randomized study was initiated to assess the antifibrotic efficacy of IFN-γ 1b in HCV patients with advanced fibrosis/cirrhosis.

Methods

502 patients with compensated liver disease and Ishak Fibrosis Score (ISHAK) 4–6 were randomized to IFN-γ 1b 100 g SC 3´/week (Group1: N = 173), IFNγ1b 200 μg SC 3´/wk (Group 2: N = 163), or placebo (Group 3: N= 166) for 48 wk. Posttreatment liver biopsies were assessed in a blinded fashion for a reduction of 1 or more ISHAK points (primary endpoint).

Results

All analyses are presented as ITT. Of the 420 patients with pre-and posttreatment liver biopsies, 83.6% had ISHAK = 5 or 6 at baseline. Overall, there was no difference in the number of patients who had a 1-point improvement in ISHAK score among the three treatment groups (12.1%, 11.7%, and 15.7% of patients in Groups 1-3 respectively; P value = NS). Five patients in the IFN-γ treatment groups became HCV RNA undetectable on treatment compared with none in the placebo group. Analysis of IFN-γ–inducible biomarkers revealed that when iTAC, an IFN-γ–inducible CXCR3 chemokine, was evaluated as an independent predictor of stable or improving ISHAK score using univariate and ROC analysis, a cutoff of >59% induction was significantly associated with a favorable outcome (P = 0.0118).

Safety

IFN-γ 1b was well tolerated. Predictable IFN–associated side effects were more frequent in the treatment arms and included flu-like symptoms and neutropenia. A similar number of deaths occurred in the 3 arms (5, 5, 4, respectively) of which most were related to complications of cirrhosis.

Conclusions

IFN-γ 1b as a monotherapy for 48 wk is not effective at reversing advanced fibrosis or cirrhosis. IFN-γ 1b appears to have some antiviral effect in a minority of patients and to be well tolerated in most patients. The biomarker iTAC may be useful to determine if subgroups of patients with ISHAK <5–6 may benefit from IFN-γ 1b alone or in combination with IFN-alpha. The study did not explore the impact of longer durations of IFN-γ 1b therapy with or without concomitant HCV antiviral therapy on liver fibrosis, nor the impact of IFN-γ 1b therapy on earlier-stage fibrosis.

Abstract ID: S1571

Hepatitis C Viral Load Declines With Peginterferon Alfa Therapy: Association With Inteferon Alpha Gene Expression

M. Silva, M. DeLorenzo, M. Grace, J. Poo-Ramirez, F. Wagner, M. Jackson, D. Cutler

AIMS

To determine the relationship of interferon alpha response gene upregulation in PBMCs between initial administration of peginterferon alfa and 8wk antiviral therapy effects, in patients with chronic hepatitis C virus (HCV) genotype 1. To explore potential differences in interferon alpha response gene upregulation between peginterferon alfa-2b (PEG2b) and alfa-2a (PEG2a).

Methods

Patients (n=36) were randomized to receive PEG2b 1.5μg/kg/wk or PEG2a 180μg/wk alone for 4wk, then with ribavirin 13mg/kg/day for further 4wk. mRNA was extracted from whole blood at 0h (baseline), 6h, 24h, 48h and 72h. 31 patients had sufficient mRNA to determine increase from baseline by PCR. Assays were blinded to treatment and responder status. Cmax was maximal increase in mRNA from baseline in 72h; AUC was total increase in mRNA in 72h. Responders were defined as ³2.0 log10 decline in HCV-RNA at 8wk.

Results

17/31 patients were responders (55%). Table shows upregulation of five interferon alpha response genes by responder status and treatment.

Conclusions

There was greater upregulation of interferon alpha response genes with PEG2b compared with PEG2a, and responders compared with nonresponders. This was consistent with more patients achieving ³2.0 log10 decline in HCV-RNA with PEG2b (13/18) than PEG2a (8/18).

Parameter	IP10		ISD15		PKR		2'5' OAS		ISG54
	Cmax	AUC	Cmax	AUC	Cmax	AUC	Cmax	AUC	Cmax	AUC
Responders at 8wk	247.1*	4564.1*	87.7	3495.5	11.0*	492.8*	20.5	1072.5*	39.9*	1327.0*
Nonresponders at 8wk	78.7	1593.5	40.1	1844.8	6.5	306.6	13.4	666.3	16.4	611.4
PEG2b (n=14)	237.3	4408	99.3	3922.8	11.0*	505.7	22.5*	1176	44.9	1468
PEG2a (n=17)	126.4	2426.9	41.9	1886.7	7.5	345.1	13.3	682	18	678.9

*p<0.05 by Wilcoxon Rank Sum Test, responders vs nonresponders and PEG2b vs PEG2a

Abstract ID: S918

Consensus Interferon (IFN Alfacon-1) Alone or in Combination with IFN Gamma-1b Suppresses Replication Of a PEG IFN-Alpha-2b--Resistant Hepatitis C Virus Replicon

A. Kaup, C. Wang, M. Gale, Jr

Background

Treatments for chronic hepatitis C virus (HCV) infection employing pegylated interferon (IFN) alpha 2 plus ribavirin are successful in ~50% of all treated patients, suggesting that HCV may evade the antiviral actions of contemporary IFN therapy and demonstrating a need for more effective therapy application. We evaluated the in vitro biochemical, antiviral response and anti-HCV efficacy imparted by IFN-α-2a, PEG IFN-α-2b, consensus IFN (IFN alfacon-1) or a combination of IFN alfacon-1 and IFN-γ 1b in cultured human hepatocytes or hepatoma cells that harbor genetically distinct HCV RNA replicons with differential sensitivity to the antiviral actions of IFN-a-2a.

Methods

IFNs were applied to cultured cells using relevant dosing based upon the pharmacologic attainable in vivo serum maximum (C_max) IFN concentration. Gene expression and antiviral properties were measured using protein and RNA quantification assays.

Results

At C_max concentrations of each IFN we found that ISG56 and PKR, interferon stimulated genes (ISGs) with demonstrated antiviral properties, were maximally expressed following IFN alfacon-1 treatment. Treatment with IFN-α-2a or PEG IFN-α-2b resulted in the slower accumulation and an overall lower level of ISG expression. Importantly, we found that while replication of an IFN-α-2a–sensitive HCV 1b subgenomic HCV replicon in cultured hepatoma cells was equally suppressed by IFN alfacon-1, IFN-α-2a, and PEG IFN-α-2b, only IFN alfacon-1 effectively suppressed the replication of an IFN-α-2a–resistant HCV replicon variant at relevant C_max dosing. When combined with the therapeutically relevant C_max dose of IFN-g 1b, IFN alfacon-1 induced a unique ISG expression profile marked by the induction of interferon regulatory factor (IRF)-1 and IRF-7, and resulted in further enhancement of antiviral action against the IFN-α-2a–resistant HCV replicon.

Conclusion

The application of IFN alfacon-1 alone or in combination with IFN g-1b induces a cellular antiviral response distinct from that induced by IFN-α-2a or PEG IFN-α-2b. This distinction may provide an advantage for the treatment of chronic HCV in infected individuals who do not respond to pegylated interferon alpha-2–containing regimens.

Abstract ID: S1537

Response Of Chronic Hepatitis C PEG IFN-2 + Ribavirin Nonresponders To Treatment With IFN Alfacon-1 (15 Mcg) and IFN Gamma-1b (50 Mcg)

C. Leevy, C. Chalmers, L.M. Blatt

Introduction

The elimination of serum HCV RNA following IFN-based therapies displays biphasic kinetics with the first order attributed to the direct antiviral effects of IFN-a and the second order attributed to an immune-mediated clearance of infected cells by induction of T_H1 cytokines, primarily IFN-g. Patients who have not had >2 log₁₀ reduction in serum HCV RNA by wk 12 have a 97–100% chance of not responding. We have demonstrated that antiviral effects and T_H1 responses are enhanced by combining IFN-g and IFN-ain in vitro systems. Given these data, we conducted a retrospective study of nonresponders to PEG IFN-a-2 + ribavirin (RBV) who were re-treated with IFN alfacon-1 and IFN-g 1b without ribavirin.

Methods

All patients (N = 50) received PEG IFN-γ-2 and RBV for 12 wk and did not achieve >2 log₁₀ drop in HCV RNA. With no washout, patients were retreated with IFN alfacon-1 15 μg SQ daily, and IFN-g 1b 50 μg SQ TIW for 48 wk. Serum HCV RNA was assessed at wk 8, 12, 24, 48 (EOT), and 60 (12 wk posttreatment) to determine virologic response on- and off-treatment and will be assessed at wk 72 to determine SVR.

Results

Virologic responses are shown below (Amplicore qualitative assay, Roche Diagnostics):

Week	8	12	24	48 (EOT)	60 (12 Wk Posttreatment)
HCV RNA Negative %(N)	36% (18/50)	40% (20/50)	46% (23/50)	46% (23/50)	35% (13/37)

One patient interrupted therapy due to constitutional symptoms while all others tolerated therapy well. By wk 48, 13 patients (26%) required filgrastim for reductions in ANC to below 0.75 X 10⁹/L. After 12 wk of PEG IFN-a-2 and RBV therapy the mean hemoglobin level was 11.6 ± 0.7 g/dL. By wk 8 all of IFN alfacon-1 and IFN-g 1b patients recovered hemoglobin levels to normal with no use of erythopoeitin.

Conclusions

Retreatment of PEG IFN-a-2 + RBV nonresponders with the combination of IFN alfacon-1 and IFN-g1b is well tolerated, and preliminary analysis of posttreatment virologic response suggests that this treatment may be of potential benefit in these difficult-to-treat patients. This combination did not interfere with hemoglobin recovery, indicating a differential safety profile with respect to RBV containing regimens. Further analysis will assess SVR and a larger dose-finding study of the combination of IFN alfacon-1 and IFN-g1b is ongoing.

Abstract ID: S1580

Identification Of Barriers To Antiviral Therapy in Hepatitis C (hcv)-Infected Patients With Active Substance Use (su) and Mental Health Illness (mi).

S. Wongcharatrawee, H. Hashem, C. Eggers, A. Anwar, M. Sernyak, G. Garcia-Tsao

Introduction/ Aim

Active SU and MI are no longer considered contraindications to antiviral therapy for HCV. However, it is important to determine whether certain baseline characteristics of this special patient population are predictive of show-up rate, completion of workup and initiation of therapy.

Methods/Patients

As part of a prospective cohort study of HCV patients with active SU and/or MI, 201 patients were referred to a multidisciplinary HCV clinic between 2/03 and 8/04. The median age is 51 (23-78); 98% are male; 55% are Caucasian, 33% Black and 9% Hispanic; 37% have MI, 25% SU and 38% both.

Results

Only 105 (52%) showed up for a 1^st appointment (mail), 33 showed up for a 2^nd appointment (phone and mail) and 14 showed up for a 3^rd appointment (phone and mail); 49 (24%) did not show up despite 3 appointments. When comparing patients who kept a clinic appointment vs. those who did not, there were no differences in age, sex or race, clinic or provider referring the patient. However patients with active SU (with or without MI) had a lower show-up rate (85/127 or 56%) compared to patients with active MI (67/74 or 90%)(p<0.001). In fact, of 49 patients who did not show up, 86% had active SU. Among 152 patients who kept a clinic appointment, 80 completed workup necessary to come to a decision on antiviral therapy (including viral load, genotype, education session, liver biopsy, psychiatric evaluation, HIV status); 31 did not complete workup and it is pending in 41. Comparing patients who completed workup vs. those who did not, there were no differences in age, sex, race, HIV status, or psychiatric status (MI/SU), however patients who kept their first appointment were more likely to complete workup (60/76 or 79%) than those who showed up at the 2^nd or 3^rd appointments (20/35 or 57%) (p=0.023). Twelve patients were excluded from antiviral therapy, 40 started antiviral therapy and 29 elected not to start therapy. Black patients (p=0.036 vs. non-Black patients) and those with early stages (0-1) of liver disease (p=0.01 vs. stages 2-4) were less likely to initiate therapy.

Conclusions

A high no-show rate to an HCV clinic was demonstrated for this special patient population, with active SU being the only “no-show” predictor. However, patients with active SU who keep the initial appointment are as likely as others to complete workup and initiate antiviral therapy. This stresses the importance of initial engagement and patient education at the pre-HCV clinic level, particularly in SU clinics.

Abstract ID: S1604

Noninvasive Evaluation Of Liver Fibrosis With Ast To Platelet Ratio Index in Patients With Chronic Hepatitis C, Non-Alcoholic Steatohepatitis and Autoimmune Hepatitis

A.M. Loaeza-del Castillo, Dr, F.P. Pineda, Dr, F. Vargas-Vorácková, Dr

Introduction

AST to platelet ratio index (APRI) is a novel non-invasive method developed for the evaluation of liver fibrosis in chronic hepatitis C patients. The non-specificity of its components raises the question as to how generalizable its diagnostic usefulness might be to other chronic liver diseases.

Aim

To comparatively assess APRI diagnostic performance in patients with chronic hepatitis C, non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AH).

Patients and methods

Adult patients with chronic hepatitis C (n=108), NASH (n=30) or AH (n=42), who had a liver biopsy taken before treatment were included. Liver fibrosis was assessed by means of the METAVIR score. Significant fibrosis was defined as a METAVIR > 2. AST value and platelet count were taken at the time of liver biopsy. APRI was calculated as: [AST(/ULN)/platelet count (10⁹/L)] x 100.

Results

180 patients were included. Their mean age was 48.7, 43.1 and 28.4 years in the hepatitis C, NASH and AH groups, respectively. Cirrhosis was present in 38, 0 and 9 patients in the same groups. Irrespective of fibrosis score, median AST values were highest in the AH group, whereas median platelet counts were highest in the NASH group. Median APRI values for patients with METAVIR < F2 vs > F2 was 0.6 vs 1.3 for chronic hepatitis C (p<0.001), 0.4 vs 0.6 for NASH (p<0.547), and 3.3 vs 6.1 for AH (p<0.295). The area under the ROC curve (AUC) for the diagnosis of significant fibrosis was 0.734, 0.564, and 0.602, respectively. The AUC for the diagnosis of cirrhosis was 0.8 in chronic hepatitis C, with an optimal cut-off point of 0.76 (sensitivity 89% and specificity 63%).

Conclusions

Our results confirm APRI usefulness for the diagnosis of significant fibrosis and cirrhosis in patients with chronic hepatitis C. APRI, however, does not appear to be useful for liver fibrosis staging in NASH and AH. This is probably due to a differential impact of etiology on the mechanisms of liver damage progression.

Abstract ID: S1562

Safety and Tolerability Of Combination Therapy Of Low Dose Ribavirin and Pegylated Interferon for Patients With Hepatitis C Virus and End-Stage Renal Disease on Dialysis

J. Park, D. Carriero, J. Lucas, A. Uriel, D.T. Dieterich

Introduction

Hepatitis C virus (HCV) is associated with an increased prevalence of renal disease. Standard treatment for HCV is pegylated interferon (Peg-IFN) and ribavirin (RBV). However, there is no recommendation regarding anti-HCV treatment in patients (pts) with end-stage renal disease (ESRD). In pts with ESRD on dialysis, combination Peg-IFN and RBV therapy is contraindicated because of concern about its accumulation and side effects in addition to anemia. Effectiveness and safety of low dose RBV and Peg-IFN combined with erythropoietin is still unknown.

Objective

To determine the efficacy and safety profile of a modified combination of Peg-IFN and RBV in pts with HCV and ESRD on dialysis.

Methods

This is an open label, prospective cohort study involving eight pts with HCV and ESRD with dialysis three times a week. All pts were started on combination of Peg-IFN alpha 2a 135mcg-weekly and ribavirin 200-mg daily. The pts remained on erythropoietin 10,000 units three times a week and low dose iron supplements. These pts were followed biweekly to monitor tolerability and treatment response.

Baseline Characteristics

Mean age of cohort was 50.7 years (+10.9 SD), mean weight was 73.6 kg (+14.3 SD). There were 7 males (87.5%), 7 African Americans (87.5%), and 1 Hispanic (12.5%). 100% of cohort was genotype (GT) 1 with median HCV RNA 318,500 IU/ml (IQR 190,000-809,000), median ALT 30.5 U/L (IQR 18-76), median albumin 3.85 (IQR 3.8-4.1), median hemoglobin 12.25 g/dL (IQR 10-13.4), and median platelet 196.5 (164-240). Liver biopsy scores were mean grade of 1 and fibrosis stage of 1. All pts have reached week 12 of the study.

Results

Median hemoglobin decrease was 0.5 g/dL at week 12. 4 out of 8 patients (50%) achieved an early virological response (EVR), 3 had undetectable HCV RNA PCR (<100 cps/ml) and one pt had a 3 log drop in HCV RNA by week 12. 3 pts had < 2 but >1 log drop in HCV RNA by week 12. One pt had no change in HCV RNA and therapy was discontinued. There were no statistically significant changes in laboratory values including ALT, albumin, and platelets. The treatment was uniformly well tolerated. The most common reported side effect was malaise.

Conclusions

Our data demonstrate that a combination therapy of Peg-IFN alpha 2a and low dose RBV daily can be well tolerated and effective in pts with HCV and ESRD.

Abstract ID: S930

The Impact Of a Multi-Faceted Educational Intervention on the Knowledge Of Primary Care Physicians Regarding Diagnosis, Evaluation, and Treatment Of Hepatitis C Patients

A.R. Daniel, MD, S. Paruthi, MD, A.M. Jankowski, T.M. Shehab, MD

Introduction

Despite the large impact of hepatitis C virus (HCV) on gastroenterology practices, the majority of HCV patients remain undiagnosed. Previous studies have shown significant knowledge deficits and deficiencies in management of HCV by primary care physicians (PCPs). Given the benefits of early diagnosis and treatment, it is important to optimize PCP knowledge and practice.

Aim

The aim of this study is to determine the impact of a multi-modality intervention on the knowledge and practice of PCPs.

Methods

A validated survey assessing knowledge of HCV risk factors, testing and basic treatment was administered to all primary care teaching faculty and internal medicine residents in a community based hospital. A baseline survey was followed by an 8 week intervention (article distribution, lectures, chart and email prompts);cohort was then resurveyed.

Results

91% (72/79) of the physicians participated in this study. 56% were female and 22% were teaching faculty. At baseline, 62% of physicians had not made a new diagnosis of HCV in the past year and 57% reported HCV was of only moderate importance. Although PCPs self-identified their role in caring for HCV patients as screening and diagnosis, only 56% reported testing for HCV in patients with high risk. 77% would order antibody testing, while 20% would order PCR testing as the initial diagnostic test. 93% counsel HCV patients to avoid alcohol and 71% recommend hepatitis A and B vaccine. For treatment, 3% recommend Interferon monotherapy, 40% Interferon/Ribavirin, and 57% Pegylated Interferon/Ribavarin. 12% of physicians overestimated, while 42% significantly underestimated the current efficacy of multi-drug regimen.

Post intervention data revealed significant improvement in correct identification of risk factors, current standard therapy and rates of treatment response although there was no improvement in ordering the correct diagnostic test. Physicians were considerably more likely to respond that they were confident in caring for HCV patients after the intervention.

Conclusion

This study again demonstrates a number of concerning knowledge deficits among PCPs. However, this is the first study demonstrating significant improvement in PCPs’ knowledge of HCV with a specific intervention. This improvement was seen in risk factor recognition, knowledge of treatment and comfort of managing HCV patients. Future studies should determine if this type of intervention modifies actual patient care.

Abstract ID: S928

Retreatment Of Hepatitis C Is Cost-Effective in a Select Subset Of Patients

M.S. Campbell, J.C. Sun, B.Y. Lee, K. Reddy

Introduction

Combination pegylated interferon/ribavirin achieves only modest rates of sustained virologic response in previous nonresponders to hepatitis C treatment.

Aim

To determine cost-effectiveness of pegylated interferon/ribavirin treatment for hepatitis C patients with advanced fibrosis previously unresponsive to therapy.

Methods

We constructed a 6-state lifetime Markov cost-effectiveness model with 1 year cycle length. Patients cycle between bridging fibrosis, compensated cirrhosis, hepatocellular carcinoma (HCC), decompensated cirrhosis, liver transplantation, and death. Competing age-adjusted mortality is included. Transition probabilities, quality of life measurements based on standard gamble data, and costs were obtained from systematic literature review. Wholesale drug costs are used, and the analysis is from a Medicare payer perspective (2003 US dollars). Cost and effectiveness are discounted at 3%. The base case reflects patients from the HALT-C trial (Shiffman et al Gastroenterology 2004): age 50, 89% genotype 1, 39% cirrhosis and 61% bridging fibrosis. Non-responders to prior interferon monotherapy and interferon/ribavirin have 28% and 12% response rates, respectively. Lack of early virologic response prompts treatment discontinuation. Monte Carlo microsimulation and sensitivity analyses were performed.

Results

Retreatment of prior non-responders to interferon monotherapy and interferon/ribavirin increases quality adjusted life-years (QALY) by 0.11 and 0.05 respectively, with incremental cost-effectiveness ratios (ICER) $164,274 and $352,007 per QALY, respectively. Sensitivity analysis showed that age accounts for 85% of model uncertainty. Initial state (% bridging fibrosis vs % cirrhosis) and rate of progression to HCC account for another 12%. Patients < age 41 failing interferon monotherapy have ICER < $50,000 (age 35, ICER $31,985; age 40, ICER $48,538). Increasing the initial prevalence of cirrhosis and the rate of HCC development also lower ICER, but have less effect than initial age.

Conclusions

Our comprehensive Markov model suggests that for hepatitis C patients with advanced fibrosis, retreatment achieves modest gains in QALY, though at relatively high cost. We found a striking effect of age on retreatment benefit, reflecting competing risks of age-adjusted mortality. Retreatment of young patients unresponsive to prior interferon monotherapy appears to be cost-effective, especially among cirrhotics.

Abstract ID: S1555

Controlled Therapy Interruption, CTI: a Novel Approach Harnessing Immune Memory Response for the Control Of Chronic Hepatitis C Viremia

G. Lake-Bakaar, J. Zagorski

Introduction

Memory cells are virus specific T cells that survive acute infection. They rapidly re-acquire cytotoxic activity on re-exposure to antigen. In chronic viral infections, high antigen load or poor CD4 help, cause memory cells to become partially exhausted or deleted. HAART, followed by intermittent re-exposure to virus through structured therapy interruptions (STI), induced modest immune control in early but not late HIV disease, reflecting irreversible CD4 impairment, which is uncharacteristic of HCV infection. Controlled therapy interruption, CTI, a modification of STI might generate protective immunity in chronic HCV infection.

CTI Protocol

Cycle #1 starts with initiation of pegylated interferon and ribavirin (P+R) therapy, continued until HCV RNA becomes undetectable (TMA <5 iu/ml), maintained at this level for at least two weeks and then stopped. If virological relapse ensues, therapy is restarted without delay, before VL rises significantly above 7500 iu/ml and continued until two weeks after VL < 5 iu/ml. Cycle #2 can be started as soon as relapse occurs and continued for two weeks beyond TMA negativity. Cycling continues until SVR is achieved.

Results

We describe in detail, the results of treatment in one patient who has completed three cycles of CTI. Patient BB is a 52 year old male with chronic HCV liver disease genotype 1 and a history of alcohol abuse with biopsy proven cirrhosis who first presented in 2001 with mild ascites. Initial treatment with P + R was followed by virological relapse after just two weeks (Treatment Free Remission, TFR), with concomitant increase in LFTs.

Therapy (cycle #1) was started and required eight weeks for HCV to become undetectable by TMA. Treatment was stopped with prompt relapse within five weeks (TFR). Therapy was restarted and HCV RNA dropped to undetectable levels (cycle #2) within eight weeks, accompanied by a marked paradoxical increase in total serum bilirubin from 1.11 up to 5.71 mg/dl and ALT from normal levels to 204 U/L. Therapy was discontinued when TMA became undetectable (end of cycle #2). Bilirubin and ALT normalized. HCV RNA remained undetectable for a post cycle #2 TFR of 13 weeks.

With cycle #3, TMA became undetectable after only two weeks of therapy and TFR for cycle #3 was > 10 weeks.

Conclusion:

CTI is associated with prolonged periods of aviremia without treatment and suggests a potential role for the control of chronic hepatitis C viremia.

Abstract ID: S1582

Short Period Interferon Beta Induction Therapy in the Patient With Interferon Resistant Chronic Hepatitis C

T. Yoshida, Y. Matsuzaki, A. Honda, K. Ikezawa, I. Makino, N. Tanaka

Introduction / Aim

It has been reported that disappearance of HCV-RNA from blood in early period of interferon (IFN) therapy is important for sustained virological response in chronic hepatitis C (CH-C). IFN-beta is more potent to reduce HCV-RNA level in early period than IFN-alpha. However, clinical problems for IFN-beta therapy were noted that; 1. Longer hospitalized period is required to compare with IFN-alpha therapy. 2. Characteristic adverse effects, such as proteinuria, increase of the ALT level, are observed. To reduce these disadvantages, we conducted short period IFN-beta induction therapy and observed virological response and the occurrence of adverse effects for this therapy.

Methods

Eight patients (6 males and 2 females, 45.1 +/- 13.2 years old) with CH-C were treated with IFN-beta prior to IFN-alpha therapy. All patients were genotype 1b and their HCV-RNA level were more than 100 kIU/mL. Written informed consent was obtained from all patients and this study was conducted with Helsinki declaration of 1975 (1983 revision). The treatment regimen was as follows; A 3 MU of Natural IFN-beta was administered every 12 hours intravenously. Each infusion time was taken for 2 hours. The injection period was for 2 weeks. After completion of IFN-beta induction, either IFN-alpha with rivabirin combination therapy or IFN-alpha monotherapy was started sequentially.

Results

1. The serum HCV-RNA levels before treatment were ranged from 320 to more than 5000 kIU/mL (1603 +/- 1778 kIU/mL). At day 8, serum HCV-RNA was not detected in 3 cases. The HCV-RNA levels in the rest of 5 cases were ranged from 7 to 1963 kIU/mL (403.8 +/- 871.6 kIU/mL). At day 15, serum HCV-RNA was not detected in 4 out of 8 cases. The HCV-RNA levels in the rest of 4 cases were ranged from 1 to 2 kIU/mL (1.4 +/- 0.5 kIU/mL).

2. All cases were accomplished for IFN-beta induction therapy and continued IFN-alpha therapy sequencially. Serious adverse effect was not observed during IFN-beta induction. Both elevation of serum ALT level (from 58 to 581 IU/mL) and moderate proteinuria were observed in a case at day 15, although these were improved after completion of IFN-beta therapy.

Conclusions

Serum HCV-RNA was strongly diminished by IFN-beta with 2-hour injection every 12 hours for 2 weeks. This IFN-beta induction therapy prior to IFN-alpha with rivabirin combination therapy may be useful for the patients with IFN resistant CH-C.

Abstract ID: S1556

Safety and Efficacy Of Antiviral Therapy in Patients With Decompensated Cirrhosis Associated With Chronic Hepatitis C Infection

J.K. Lim, J.C. Imperial

Background/Aims:

Decompensated liver disease associated with chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the U.S. Although interferon-based regimens are frequently used in compensated cirrhosis, the role of antiviral therapy in the treatment of patients with decompensated cirrhosis remains poorly defined.

Methods:

We evaluated the safety and efficacy of antiviral therapy in 32 patients with decompensated HCV cirrhosis. At the time of inclusion, 25.0% of patients were Child-Pugh A, 59.4% were Child-Pugh B, and 15.6% were Child-Pugh C, with a mean Child-Pugh score of 8.03 +/- 1.75 (95% CI 7.40-8.66). Most patients were white (87.5%) and male (74.2%), with a mean age of 54.9 +/- 7.2 years (95% CI 52.28-57.47) and mean weight of 92.2 +/- 24.4 kg (95% CI 83.41-101.0). Thrombocytopenia (90.6%), fluid retention (62.5%), esophageal varices (46.9%), and hepatic encephalopathy (21.9%) were the most common decompensation events. All patients underwent an intensive pretreatment regimen to optimize hepatic function prior to antiviral therapy (e.g. eradication of varices, resolution of ascites), and were monitored closely throughout therapy within a major university transplant program. Patients were treated with pegylated interferon/ribavirin (78.1%), pegylated interferon monotherapy (12.5%), or interferon/ribavirin (9.4%), for a mean of 37.8 +/- 17.1 weeks (95% CI 31.55-44.13).

Results:

Sustained virologic response (SVR) was achieved in 10/32 patients (31.3%), including 21.1% in genotype 1 and 53.8% in non-genotype 1 patients. Normalization of ALT was achieved in 40.6% of patients. The mean CTP score following end-of-treatment was 6.06 +/- 1.22 (95% CI 5.62-6.50). Most patients (84.4%) experienced adverse events; six (18.8%) required withdrawal of antiviral therapy, and one (3.1%) experienced liver decompensation. Anemia requiring erythropoietin support (50.0%), neutropenia requiring G-CSF support (15.6%), depression (18.8%), and infections (9.4%) were the most common adverse events. Five patients (15.6%) were removed from transplant listing due to clinical improvement. No patients died during treatment.

Conclusion:

Antiviral therapy appears to be safe and effective in carefully selected patients with decompensated cirrhosis associated with chronic HCV infection. Treatment may result in SVR in nearly one-third of patients, and lead to improvements in biochemical markers and liver synthetic function.

Abstract ID: S1535

Statins Are Protective Against Hepatocellular Cancer in Patients With Hepatitis C Virus Infection: Half a Million Us Veterans' Study

V. Khurana, A. Saluja, G. Caldito, C. Fort, E.R. Schiff

Aim

To investigate the effect of HMG CoA Reductase Inhibitors (statins) on the development of hepatocellular cancer (HCC) in patients with hepatitis C virus (HCV) infection in the US veteran population.

Design

VISN 16 data warehouse, which contains clinical and demographic information about all veterans (>1.4 million patients) cared for at the 10 VA Medical Centers in 4 states comprising the South Central VA health Care Network in the mid-south region of the US, was queried from Oct 1998 to June 2004. Retrospective case control design was used. Multiple logistic regression analysis was used with calculation of odds ratios and 95% confidence intervals were used universally. Statistical analysis was performed using SAS software version 9.0 (Chicago, IL).

Results

A total of 480,306 patients with 91.7% Men, mean age 61.1±14.8 years were queried. Data on race revealed 37% white and 13.3 % black. A total of 14,021 (2.92%) patients had HCV infection (ICD-9 codes 070.51, 070.41, 070.54 or 070.44). HCC (ICD-9 155) was noted in 409 (0.09%) patients. A total of 164,250 (34.2%) were on statins. Patients using statins prior to diagnosis of HCC were included in the study group. HCV infection was a significant risk factor for the HCC prior to adjusting for statin use (OR 15.69, 95% CI for OR 12.33 -20.0, p <0.0001) and after adjusting for statin use (OR 10.81, 95% CI for OR 8.37-13.37, p <0.0001). Age was also a significant risk factor for HCC (OR 1.034, 95% CI for OR 1.027 - 1.042, p <0.0001). After controlling for age and HCV infection, statin use was associated with a significant risk reduction for HCC. (OR 0.52, 95% CI for OR 0.41- 0.67, p<0.0001).

Discussion

Statins are commonly used cholesterol-lowering agents that are noted to suppress tumor growth in several animal models. Studies have shown the beneficial effect of pravastatin in patients with advanced HCC, however clinical data for a chemoprotective role of statins against HCC is lacking. An internal consistency of the database is reflected by an increased risk associated with documented risk factors. The results should be interpreted with caution given the limitations of population, the database and retrospective design. Furthermore, dose, duration and nature of particular medication was not factored into the analysis.

Conclusion

Statin use was found to have a significant protective effect against hepatocellular cancer after controlling for age and Hepatitis C Virus infection.

Abstract ID: S916

All-Trans-Retinoic Acid for Treatment Of Patients With Chronic Hepatitis C and Non-Response To Interferon Alfa / Ribavirin

W.O. Bocher, C. Wallasch, T. Herget, B.M. Klebl, D. Strand, P.R. Galle

Introduction

In vitro studies, submitted in parallel by Herget et al, have shown that all-trans retinoic acid (ATRA) induces upregulation of selenium dependent gastrointestinal-glutathione peroxidase in HCV-subgenomic RNA replicon cells leading to drastic downregulation of the replicon, that was further enhanced by interferon alfa. Based on these findings, a clinical pilot trial was performed in HCV non-responder patients.

Methods

20 patients with chronic HCV infection and non-response to IFN alfa and ribavirin (pos. PCR at week 12) were randomly assigned to treatment with daily 45 mg/m2 ATRA p.o. and 30 mcg/d selenite (arm A) or 45 mg/m2 ATRA and selenite combined with 180 mcg/week peg-interferon alfa2a (arm B). All patients had serotype-1, elevated ALT levels and 9 patients had F3 fibrosis or cirrhosis. Mean IFNa pretreatment duration was 14 months, 9 patients were Peg-IFN nonresponders. ATRA treatment was continued for 12 weeks and followed for additional 12 weeks after end of treatment (ETR). HCV RNA was assessed by quantitative real time PCR.

Results

The intend-to-treat analysis of virological response rates is shown in the Table:

VL		Arm	A				Arm	B
reduction	wk 2	wk 4	wk 8	wk 12	EFU	wk 2	wk 4	wk 8	wk 12	EFU
≥ 2 log	0/10	1/10	1/10	2/10	1/7	1/10	4/10	5/10	4/10	0/5
PCR neg	0/10	1/10	1/10	2/10	1/7	0/10	0/10	4/10	4/10	0/5

Treatment was rather well tolerated. Three patients discontinued prematurely because of headache (2, arm A) or attempted suicide (arm B); one patient (arm A) had an intermittent ATRA dose reduction due to headaches. Other side effects were dry lips and nasal mucosa (15 of 19) and hypertriglyceridemia (3/20 >3xULN). No liver toxicity was observed. At the meeting, follow up data of all patients will be presented.

Conclusions

ATRA monotherapy shows significant antiviral activity against HCV with a more than two log decrease in viral load (VL) in 2/10 patients. However, a much faster and stronger antiviral activity was shown in combination with Peg-IFN alfa leading to transient viral clearance (neg. PCR) in 4/10 patients. Thus, a prolonged treatment with a triple combination of ATRA, interferon alfa and ribavirin might offer a new treatment option for previous non-responders with chronic hepatitis C.

Abstract ID: S1534

Treatment Of Chronic Hepatitis C Patients With Child a and B Cirrhosis With a Low Ascending Daily Dosing Regimen With Consensus Interferon and Ribavirin Results in Significant Viral Eradication Rates

S. Kaiser, H. Hass, M. Gregor

Objective

Antiviral treatment response in patients with chronic hepatitis C and liver cirrhosis is considerably lower than in non-cirrhotic patients and therapy is complicated by high drop-out rates, less tolerablity of side effects and high rates of hematological complications. Pegylated interferons have shown higher response rates than standard interferons, however, also higher dose-reduction and drop-out rates due to lower tolerability, especially regarding thrombocytopenia, thus resulting in an overall only minor benefit. Consensus interferon (CIFN) is an interferon with a relatively low half-life, but stronger antiviral potency as shown by high efficacy in nonresponders.

Methods

The efficacy of CIFN together with ribavirin (RBV) was evaluated in 58 patients with chronic hepatitis C and cirrhosis Child A and B. All patients had histologically proven cirrhosis, elevated ALT values and were viremic, with 73% having genotype 1. Patients were treated with CIFN 9 ug TIW for 6 weeks, followed by 9 ug QD for another 6 weeks. Continuing treatment consisted of CIFN 9 ug QD with RBV with a stepwise increase from 400 mg to 1000 mg QD at 4 week intervals for a total of another 48 weeks. Based on tolerability the dosing of RBV was increased to a weight-based dosing.

Results

At 48 weeks therapy an undetectable HCV-RNA was observed in 57% (n=33) of patients (ITT) with a drop out rate of 21% (n=12). Data regarding sustained response rates show a 47 % response (n=36). Due to side effects CIFN had to be dose reduced in 31%, mainly due to low platelet counts. SVR rates were significantly higher in Child A patients (61%) as compared to Child B patients (23%). As growth factors erythropoetin as well as G-CSF was used. Three patients experienced grade III and one patients a grade IV thrombocytopenia. Overall tolerability of the CIFN QD regimen was comparable to a standard therapy with pegylated IFN and RBV, while CIFN even as QD treatment resulted in a lower rate of thrombocytopenias.

Conclusions

CIFN as a low ascending and finally daily dosing regimen with subsequent RBV shows significant response rates in Child A and B cirrhotic patients. Therapy is also safe, however, a significant portion of patients was unable to even tolerate low doses of CIFN or RBV. These data suggest that for a subgroup of cirrhotic patients even in stage Child B a combination therapy of CIFN and RBV may lead to viral eradication.

Abstract ID: S1576

Modulation Of Cytokine Response in Chronic Hepatitis C (CHC) Patients Treated With Combination Antiviral Therapy

M. Trapero , J. Moreno-Monteagudo, M. Vitón, C. Muñoz, M. Borque, L. García-Buey, X. Salcedo-Mora, R. Moreno-Otero

Introduction

T cells produce IFNg and TNFa which, potentially suppress hepatitis C virus (HCV) replication.

Aims

1. To analyse the cytokine profiles in peripheral blood mononuclear cells (PBMCs) from patients with CHC during combination therapy.

2. To correlate the cytokine production with sustained virological response (SVR).

Methods

A total of 44 caucasian genotype 1 naive patients with CHC received PegIFNa2a (weekly) plus RBV (1-1.2 g/day) for 48 weeks. The production of IL-4, IFNg and TNFa, and surface CD8+ marker from PBMCs, both resting and stimulated, were measured using flow cytometry. SVR was defined as HCV-RNA negativity after 6 months follow-up. Statistics: Student´s t test, c² test and ANOVA test.

Results

At present, 28 patients (mean age 45±8 years), have finished follow-up. During treatment, IL-4, IFNg and TNFa levels fall progressively in all patients. After follow-up, 12 patients had SVR (43%), 13 relapsed (47%) and 3 were non-responders (10%). At third month during treatment, stimulated-IL-4 levels were lower in patients with SVR than in those who did not (0.97 vs 2.58; p=0.1); no statistically differences appeared with IFNg and TNFa. At the end of treatment, the induced IFNg production was higher in patients with SVR (20 vs 8; p<0.05). Conversely, IL-4 production was higher in NR patients although without reaching statistical significance (p <0.1). No differences were found with TNFa (14 vs 7; p<0.2).

Conclusions

IFNg production by CD8+ T lymphocytes (cytokine response type 1) during combination treatment is associated with SVR suggesting the replication control and later clearance of HCV.

Abstract ID: S1566

Baseline Fibrosis Score Does Not Predict Sustained Virological Response To Peginterferon Alfa-2a (40KD) Plus Ribavirin in Patients With Chronic Hepatitis C and Persistently ‘normal’ Alt Levels

R. Reindollar, D. Prati, H. Pérez-Gómez, M. Shiffman, P. Lardelli, S. Blotner, R. Koff , C. Berg

Introduction

Patients (pts) with chronic hepatitis C and advanced fibrosis/cirrhosis have lower sustained virological response (SVR) rates to interferon-based therapies. We aimed to determine whether there was a correlation between baseline fibrosis score and SVR rates in noncirrhotic pts (Ishak stage 0-4) with persistently ‘normal’ ALT levels.

Methods

Pts with persistently ‘normal’ ALT levels on ≥3 occasions over 18 months were randomized to 24 or 48 weeks of treatment with peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 800 mg/d, or no treatment in a multinational trial. The study was initiated before the optimal RBV dose (1000/1200 mg/d) for genotype 1 was known. The primary endpoint was SVR (undetectable HCV RNA, <50IU/mL, after 24 wks untreated follow-up). Results were retrospectively analysed according to baseline fibrosis score and genotype (1 or 2/3).

Results

422 noncirrhotic pts were randomized (402 were infected with genotype 1 or 2/3). No untreated control pts cleared HCV, thus they are not represented in our analysis. There was no significant correlation between baseline fibrosis score (table) or baseline necroinflammatory score (data not shown) and SVR. Baseline fibrosis and necroinflammation scores were not significant predictors of SVR according to multiple logistic regression analysis.

Conclusions

In noncirrhotic pts (stage 0-4) with persistently ‘normal’ ALT levels, baseline fibrosis scores (excluding 5-6) do not predict the outcome of treatment with peginterferon alfa-2a (40KD) plus RBV. These data suggest that liver biopsy result should not be the sole determinant of the decision to treat such patients, and aruge against a conservative watchful-waiting strategy. Indeed, these data provide support for the recommendation in the US National Institutes of Health guidelines that all patients with chronic hepatitis C are potential candidates for antiviral therapy.

These findings support the early use of peginterferon alfa-2a (40KD) plus ribavirin therapy in patients with chronic hepatitis C irrespective of baseline ALT level.

The decision to treat should involve consideration of the probability of eradicating HCV infection, the likelihood of disease progression, risk of HCV transmission and quality of life considerations.

Correlation between baseline fibrosis score and SVR rate
HCV genotype	Treatment duration in weeks	Baseline Ishak fibrosis stage (n)	SVR, n (%)	Pearsons correlation coefficient
1 (n=285)	24 (n=144)^a	0/1 (98)	14 (14)	0.045
		2 (28)	4  (14)
		3/4 (16)	1 (6)
	48 (n=141)^a	(104) 0/1	39 (38)	-0.086
		2 (26)	14 (54)
		3/4 (10)	4  (40)
2/3 (n=117)	24 (n=58)	(36)  0/1	25 (69)	0.017
		2 (13)	11 (85)
		3/4 (9)	6   (67)
	48 (n=59)^a	(33)  0/1	24 (73)	-0.139
		2 (16)	14 (88)
		3/4 (8)	7  (88)
Baseline biopsies were obtained within 36 months of enrolment. ^aStage unavailable for 5 patients. One patient had a fibrosis score >4 and is not included. SVR = undetectable HCV RNA (<50 IU/mL by COBAS AMPLICOR HCV Test v2.0) after 24 weeks of follow-up

Abstract ID: S1554

Differential Activities Of Interferon-Alpha Subtypes Against Intracellular Hepatitis C Virus Replication

T. Koyama, N. Sakamoto, Y. Tanabe, M. Nakagawa, Y. Itsui, Y. Takeda, S. Kakinuma, Y. Sekine, Y. Yanai, M. Kurimoto, M. Watanabe

Background

Interferon (IFN)-alpha, which is essential for current therapies against HCV, is represented by a large family of structurally related genes expressing at least 14 subtypes. These subtypes of IFN show different antiviral (Yanai, J Interferon Cytokine Res 2001) and anti-tumor effects (Yanai, Cancer Letters 2002). In the present study, we have analyzed effects of five IFN alpha subtypes on intracellular HCV replication using HCV subgenomic replicon system and investigated on the difference of mechanisms of action.

Materials and methods

A cell line transfected with HCV replicon expressing selectable chimeric reporter protein of neomycin phosphotransferase and firefly luciferase was used (Huh7/Rep-Feo; Tanabe, J Infect Dis 2004). Five subtypes of recombinant human IFNs (IFN alpha1, 2, 5, 8, and 10) and IFN-alpha con1 were added into medium of Huh7/Rep-Feo by various concentrations (0.01 to 100 IU/ml), and analyzed levels of HCV replication by luciferase assay. To study effects of IFNs on cellular signal transduction pathways, reporter assays were done using ISRE-, GAS-, AP1-, CRE-, and SRE- luciferase plasmids.

Results

Replication level of HCV replicon was significantly suppressed by each IFN subtype in dose-dependent manner. Fifty percent inhibitory concentrations (IC50) were 0.39 IU/ml (130 pg/ml) for alpha1, 0.115 IU/ml (1.6 pg/ml) for alpha2, 0.18 IU/ml (4.5 pg/ml) for alpha5, 0.104 IU/ml (0.36 pg/ml) for alpha8, 0.19 IU/ml (3.9 pg/ml) for alpha10, and 0.110 IU/ml (0.053 pg/ml) for alpha con1, respectively. On the contrary, the reporter assays showed that there was no significant difference in induction velocity of ISRE and GAS activity between IFN subtypes. IFNs showed no significant effects on AP1, CRE and SRE activities.

Conclusion

Antiviral effect of HCV replicon was strongest in IFN alpha8. The dissociation between cellular ISRE responses and antiviral effect implies other pathways where IFN-activated JAK-STAT pathway is not involved.

Abstract ID: S1572

‘Real’ World Experience With Peginterferon Alfa-2a (40KD) Plus Ribavirin in Chronic Hepatitis C: Results Of a Multicenter Open-Label Expanded Access Program in Canada

E. Yoshida, J. Heathcote, R. Bailey, F. Anderson, K. Kaita, M. Krajden , M. Deschênes, V. Bain, S. Lee, M. Sherman, K. Peltekian, S. Simonyi

Introduction

Patients (pts) in clinical trials are highly selected. Whether similar responses can be achieved in routine practice is unknown. We evaluated peginterferon alfa-2a (40KD) (peg-IFNα-2a) + ribavirin (RBV) in treatment-naïve pts and in relapsers (REL) or nonresponders (NR) to previous IFN-based therapy in a multicenter, open-label expanded access program in a routine clinical setting.

Methods

Anti-HCV-antibody-positive adults with HCV RNA >600 IU/mL were eligible. Pts with advanced fibrosis (F3/4) and compensated liver disease, and previous REL and NR were also eligible. Pts were assigned to peg-IFNa-2a 180 µg/wk + RBV 800 mg/d for 24 or 48 wks at the investigator’s discretion. The program started before optimal regimens for genotype-1 and 2/3 were known. ITT analyses were conducted.

Results

863 pts were enrolled and treated. More NR had genotype 1 infection (84%). 47% of REL and 50% of NR had advanced fibrosis. Most treatment-naïve (380/508, 75%) and previously treated pts (323/355, 91%) were assigned to 48 wks treatment. Highest SVRs were obtained in treatment-naive, non-cirrhotic patients, and the lowest in NR. Among NR to monotherapy and combination therapy, respectively, 9/42 and 30/153 genotype 1 pts had SVRs, and 4/10 and 7/21 genotype 2/3 pts had SVRs. The incidence of serious AEs was similar across groups (5-8%).

Conclusion

Overall SVRs in treatment-naive pts reflect those obtained in phase III trials with peg-IFNα-2a (40KD) + RBV. These ‘real world’ results in a large cohort also demonstrate that it is possible to cure previous NR and REL to IFN-based therapy. Optimal regimens may yield even higher SVRs in these difficult-to-treat pts.

Pt group, N	Baseline characteristics						SVR by genotype, n (%)
	age (yr)	male (%)	Prior therapy (if known) mono; combo	HCV genotype (%)
				1	2/3	other	all	1	2/3
Treatment-naïve pts:
Noncirrhotic, 334	42	222 (66)	–	196 (59)	127 (38)	11 (3)	186 (56)	81 (41)	98 (77)
Cirrhotic, 174	48	113 (65)	–	118 (68)	53  (30)	3  (2)	71 (41)	40 (34)	31 (58)
Previously treated pts:
Relapsers, 119	47	83 (70)	35; 80	78  (66)	37  (31)	4 (3)	48 (40)	27 (35)	19 (51)
Nonresponders, 236	48	169 (72)	53; 180	198 (84)	31  (13)	6 (3)	54 (23)	39 (20)	11 (35)
SVR = HCV RNA <50 IU/mL 24wks after end of treatment. NR did not have a viral response at any time during prior IFN or IFN/RBV therapy; REL had an on-treatment viral response during previous therapy. Advanced fibrosis = bridging fibrosis or cirrhosis

Abstract ID: S1564

Predictability Of An Early Virological Response With Peginterferon Alfa-2a (40KD) Plus Ribavirin in the ‘real World’: Results Of a Multicentre Open-Label Expanded Access Program for Patients With Chronic Hepatitis C in Canada

K. Peltekian, M. Krajden , M. Deschênes, V. Bain, F. Anderson, K. Kaita, J. Heathcote, R. Bailey, M. Sherman, S. Lee, E. Yoshida, S. Simonyi

Introduction

The absence of an early virological response (EVR) at wk 12 of peginterferon alfa-2a (40KD) (peg-IFNa-2a) + RBV therapy has a high negative predictive value (NPV, 97%) for the probability of achieving a sustained viral response (SVR, Fried. NEJM 2002). We determined how well this criterion applies in an everyday clinical setting.

Methods

Adult chronic hepatitis C pts with detectable HCV RNA (>600IU/mL) were eligible. Pts with advanced fibrosis and compensated liver disease, and previously treated pts were also eligible. Pts were assigned to peg-IFNa-2a 180µg/wk + RBV 800mg/day for 24 or 48 wks at the investigators discretion. The program began before the optimal treatment for genotype 1 and 2/3 were determined. EVR = undetectable HCV RNA (≤50 IU/mL) or ≥2-log drop by quantitative PCR (limit of quantitation 600 IU/mL) at wk 12. SVR = undetectable HCV RNA 24 wks after the end of treatment.

Results

863 pts were enrolled and treated (EVR data missing for 36). NPV values ranged from 94-95% in treatment naive pts. Data for genotype 1 pts are shown in the table. An EVR was achieved by 94-96% of genotype 2/3 pts who were treatment-naive (166/174) or relapsers (33/35), and by 80% of nonresponders (24/30). No previously-treated pt had an SVR without an EVR (NPV=100%), thus EVR is predictive of SVR in groups other than naive pts.

Conclusion

Our results in treatment-naive pts are consistent with those obtained in a multinational phase III trial. As expected, pts who failed to respond to previous treatment had the lowest EVR and SVR rates. Almost all pts who achieved a cure had an EVR, thus pts without an EVR are highly unlikely to achieve an SVR. In the absence of an EVR, the goals of treatment should be reviewed and discussed with pts.

	EVR, n (%)	SVR, n (%)	PPV %	NPV %
Treatment-naïve, n
Noncirrhotic, 319	266 (83)	182 (57)	68	94
genotype 1, 185	137 (74)	78 (42)	57	94
Cirrhotic, 167	122 (73)	68 (41)	56	94
genotype 1, 114	75 (66)	38 (33)	51	95
Previously treated, n
Relapsers, 113	101 (89)	47 (42)	47	100
genotype 1, 75	65 (87)	26 (35)	40	100
Nonresponders, 228	139 (61)	54 (24)	39	100
genotype 1, 196	108 (55)	39 (20)	36	100
EVR data were not reported for 22 naive and 14 previously treated pts. NPV = probability of not achieving an SVR in pts without an EVR; PPV (positive predictive value) = probability of an SVR in pts with an EVR. Nonresponders did not respond at any time during prior IFN or IFN/RBV therapy; relapsers had an on-treatment virological response during a prior course of IFN or IFN/RBV

Abstract ID: S1542

Efficacy Of 24 Weeks Of Treatment With Peginterferon Alfa-2b 1.5 µg/kg/week Plus Ribavirin 800-1400 Mg/day (p/r) in Patients Infected With Chronic Hepatitis C With Genotype 1 Of Low Viral Load (lvlg1)

S. Zeuzem, R. Esteban-Mur, M. Buti-Ferrer, P. Ferenci, J. Sperl, Y. Horsmans, J. Cianciara, E. Ibranyi, O. Weiland, E. Manesis, M. Rizzetto, R. Sola-Lamoglia, S. Noviello, C. Brass

Background

Previous 48 week treatment studies suggest that LVLG1 patients have high sustained virologic response rates (SVR) similar to genotype 2/3 patients. Recent data demonstrated that genotype 2/3 patients respond similarly with 24 weeks of therapy as historical 48-week treated controls; no similar data exist for LVLG1 patients. The aim of this study was to compare the efficacy of 24 weeks of P/R with an historical control treated for 48 weeks with peginterferon alfa-2b plus a similar ribavirin dose (>10.6 mg/kg) (Manns et al., Lancet 2002).

Methods

For 24 weeks, treatment-naïve LVLG1 patients (≤2 million copies/mL) were treated with peginterferon alfa-2b 1.5 µg/kg/week subcutaneously plus oral ribavirin 800-1400 mg/day based on body weight. Plasma HCV RNA was determined at treatment weeks 4, 12, 24 and follow-up weeks 12 and 24 using quantitative Taqman assay (sensitivity 29 IU/ml). Genotype was determined by sequencing the PCR product. 

Results

235 LVLG1 patients were treated (237 enrolled). End of treatment (EOT) virologic response was 81% and SVR was 50% with 24 weeks treatment. The 48 week historical control had similar EOT of 74% but higher SVR of 71%. This difference was due to high virologic relapse rate after 24 weeks of therapy (37%) compared to historical control (4%). In a subset of patients who became HCV RNA negative at week 4, a similarly high SVR (89%) with 24 weeks treatment was seen versus historical control (85%). In contrast, SVR was low (25%) and relapse high (75%) in patients who first had an undetectable HCV RNA at week 12. Discontinuation and dose reductions for adverse events were lower with 24 weeks treatment (3%, 25%) than the historical control (14%, 49%).

Conclusion

Overall, 24 week treatment with P/R in LVLG1 patients achieves similar EOT response, but lower SVR compared to a 48-week treated historical control.  However, for patients who become HCV RNA negative at week 4, treatment for 24 weeks has similar high efficacy with superior safety compared to 48 week therapy.

SVR and relapse rates based on time to 1st negative HCV RNA

		24 WK TX		48 WK TX*
Time to 1st neg HCV RNA	% of Patients	SVR	Relapse**	SVR	Relapse
Week 4	47%	89% (98/110)	8% (9/106)	85% (11/13)	8% (1/12)
Week 12	26%	25% (15/61)	75% (44/59)	93% (14/15)	0% (0/14)
Week 24/EOT	10%	17% (4/24)	80% (16/20)	67% (2/3)	0% (0/2)
All		50% (117/235)	37% (69/185)	71% (27/38)	4% (1/28)

* Manns et al., ** Missing follow-up not included

Abstract ID: S1573

Treatment Of Hepatitis C Among HIV/HCV Co-Infected Patients in the Veterans Administration (VA) System

H.K. Tam, S.C. Eaton, R.W. Baran, A. Phippard, S.A. Bozzette

Introduction / Rationale

End stage liver disease is a leading cause of morbidity and mortality in HIV-infected patients since the introduction of HAART. Hepatitis C virus (HCV) infection accelerates the progression to end stage liver disease among HIV co-infected patients. Previous reports indicate 38% HCV seroprevalence among 12,216-screened veterans who had received HAART and CD4/viral load monitoring from 1997-2002 (Backus, 11^th CROI). We performed a retrospective cohort study to characterize the prevalence and treatment of HCV infection among individuals receiving HIV care in the VA.

Methods

Data for this study were extracted from the Quality Enhancement Database, an HIV database derived from the VA Immunology Case Registry containing medical and pharmacy data on all patients receiving HIV care in the VA. All veterans who received HIV care between January 1, 2001 and June 30, 2003 were included. Identification of HCV coinfection was based on ICD-9 codes, a positive HCV antibody test, or a quantitative or qualitative HCV RNA determination. Interferon therapy was identified according to outpatient prescriptions dispensed.

Results

Among 22,824 veterans who received HIV care during the study period, 7,921 (35%) were co-infected with HCV. Comparing the coinfected to the whole population, 4680 (62%) vs. 6830 (48%) patients were black (p<.001), and 6742 (85%) vs. 9883 (66%) patients were over 45 years old. Among the coinfected, 479 (6%) received outpatient interferon. Outpatient interferon was more common among whites than blacks (8% vs. 5%, P<.001) and among patients who ever received antiretroviral therapy compared to those who never did (7% vs. 4%, P<.001), but was similar among patients over 45 compared to those 45 or younger (6% vs. 5%, P=.13). Among the coinfected, Kaposi’s sarcoma was more prevalent among patients who had received an interferon prescription (5% vs. 3%, P=.02); other cancers commonly treated with interferon were not (3% for both groups; P=.42).

Conclusion

Although HCV co-infection is highly prevalent among HIV patients in the VA, HCV treatment rate was very low during the study period . With increasing evidence of the efficacy of peg-interferon therapy among co-infected patients, trends in treatment and outcomes should be monitored. Additional analyses on this cohort are planned.

Abstract ID: S1543

Reduced Hemoglobin A1c Values in Diabetic Patients During Hepatitis C Combination Therapy Are Due To Ribavirin-Induced Hemolysis and Do Not Reflect Glycemic Control

A.S. Rosman, P.D. Greenberg, L.S. Eldeiry, Z. Naqvi, N. Bräu

Introduction

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 lower exposure of hemoglobin (Hb) to plasma glucose. Ribavirin (RBV) used in combination with interferon (IFN) to treat chronic hepatitis C causes dose-dependent, 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 of hemoglobin A1c and hemoglobin: before, during, and after HCV therapy (minimum of 3 months).

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% (mean paired diff., +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) suggesting that glycemic control remained unchanged during HCV therapy. During IFN + RBV therapy, mean Hb 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 Hb. level (p=0.081, t-test; ANOVA, p<0.001). The maximum decrease in A1C level during therapy was not correlated to the maximum change in Hb concentration (r=0.14, p=0.94), nor to any other baseline measure including pre-Rx Hb level (p=0.41), RBV dose in mg (p=0.17) or in mg/kg (p=0.95), weight (p=0.26), and BMI (p=0.60). Maximum decreases in HgA1c levels were similar between patients who had an end-of-treatment viral clearance to <100 copies/mL (n=10, -2.04%) vs. those who did not clear the virus (n=22, -1.99%, p=0.91).

Conclusion

Reductions of A1c levels by a mean of 2.0% during hepatitis C therapy with IFN + RBV are due to RBV-induced hemolysis and do not reflect improved glycemic control. These reductions cannot be predicted by RBV-induced changes in Hb concentrations. A1c levels should not be measured during hepatitis C treatment with IFN + RBV since they are inappropriately low.

Abstract ID: S1551

Repetition of Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma and Prolongs the Long-Term Survival in Patients With Chronic Hepatitis C

K. Iyoda, M. Kato, N. Yuki, K. Yamamoto, Y. Izumi, T. Ueda, T. Nakamura, N. Shirahata, E. Satomi, T. Michida, M. Ikeda

Introduction/Aim

The development of hepatocellular carcinoma (HCC) is significantly reduced in sustained responders in chronic hepatitis C patients who received interferon (IFN) therapy. However, the long-term, especially more than ten years, the efficacy of IFN retreatment is not clear. We investigated whether IFN therapy prevents the development of HCC and improves prognosis. And we decided to evaluate the risk factors for liver carcinogenesis and the long-term survival in patients with chronic hepatitis C.

Methods

Five hundred and forty two patients with chronic hepatitis C were received interferon therapy in Osaka National Hospital from 1987 to 2001. These patients were followed from 24 to 191 months after IFN therapy. The HCC appearance rate and the survival rate were analyzed using Kaplan-Meier technique and the log rank test. Independent factors associated with them were studied using the stepwise Cox regression analysis.

Results

After 6 months from the end of initial IFN therapy, sustained virological response (SVR) with HCV RNA clearance was found in 187 patients, transient response (TR) with alanine aminotransferase (ALT) normalization was found in 217 and no response (NR) in 138. In TR and NR, retreatment (RT) with 2nd IFN therapy was found in 111 patients and no retreatment (NRT) in 244. During observation period, forty two developed HCC, of whom 6 were SR, 10 were TR and 26 were NR. And twenty six died. The cumulative incidence of HCC in TR was almost equal to that in SVR, but it was significantly higher in NR than in SVR or TR (p=0.0006 or 0.0002). The cumulative survival rate in TR was also equal to that in SVR, but it was significantly lower in NR than in SVR or TR (p=0.0035 or 0.0006). The cumulative incidence of HCC in RT was almost equal to that in SVR, but it was significantly higher in NRT than in SVR or RT (p=0.0071 or 0.0222). The cumulative survival rate in RT was also equal to that in SVR, but it was significantly lower in NRT than in SVR or RT (p=0.0173 or 0.0408). Univariate analysis associated the risk for HCC and the survival with the effect of IFN and age.

Conclusion

In sustained and transient responders by IFN therapy the risk for HCC was significantly suppressed and the long-term survival was prolonged. Moreover, there was little risk of the incidence of HCC in the patients who received IFN retreatment. Repetition of IFN therapy ameliorated the survival rate in chronic hepatitis C patients.

Abstract ID: S1549

Differences Of Host Immunological Background Between Responders and Nonresponders To IFN Therapy Among Patients With Chronic Hepatitis C

K. Ishii, K. Matsumaru, K. Higami, Y. Fujita, K. Sasao, N. Wakui, K. Momiyama, M. Shinohara, H. Nagai, M. Watanabe, K. Miki, Y. Sumino

Background/Aim

IFN alone (IFN) and IFN combined with ribavirin (R+IFN) are active against chronic hepatitis C virus (HCV) infection, although there are some nonresponders. The goal of this study was to investigate differences in baseline immunological parameters between responders and nonresponders to IFN or R+IFN among patients with chronic hepatitis C (CHC).

Patients and Methods

One hundred and twenty-two adults with biopsy-proven CHC were studied. Baseline serum HCV-RNA was quantified by RT-PCR (Amplicor Ver.2.0; Roche). HCV was divided into 2 serotypes: type 1 (genotypes 1a and 1b) was detected in 61 patients and type 2 (genotypes 2a and 2b) was found in 61 patients. A regimen of IFN-alpha 2b (6 MU daily for 2 weeks followed by 6 MU thrice weekly for 22 or more weeks) and ribavirin (600–800 mg/day for body weight for 24 weeks) was given to 50 patients, comprising 33 men and 17 women with a median serum HCV-RNA of 470 KIU/ml before therapy. The other 72 patients (53 men and 19 women with a median serum HCV-RNA of 200 KIU/ml before therapy) were treated with consensus IFN or IFN-alpha alone (18 MU daily or 6 MU daily for 2 weeks followed by 18 MU or 6 MU thrice weekly for 22 weeks, respectively). Twenty-four weeks after the end of therapy, responders were defined as patients whose serum HCV-RNA was negative by a qualitative method (Amplicor Ver 2.0), and nonresponders were defined as patients whose serum HCV-RNA was positive. Flow cytometry was used to assess cytoplasmic IFN-gamma and IL-4 expression by peripheral CD4 + T cells, and the percentage of IFN-gamma + and IL-4 - (Th1) cells as well as IFN-gamma - and IL-4 + (Th2) cells, was calculated. NK cells in peripheral blood and serum levels of IL-18 and 2-5AS were measured before the start of therapy.

Results

The responders were 65 patients (48 men and 17 women with and a median serum HCV-RNA of 201 KIU/ml before therapy), while the nonresponders were 57 patients (38 men and 19 women with a median serum HCV-RNA of 435 KIU/ml before therapy). The percentage of peripheral blood Th1 cells and the serum IL-18 level of the responders were significantly lower than those of the nonresponders, while the percentage of peripheral blood Th2 cells and the serum 2-5AS level did not differ between the two groups.

Conclusion

Our results suggest that patients whose immunity system is not activated by chronic HCV infection before IFN therapy can respond to various IFN therapies. This is besides well-known predictors such as lower viremia, histopathologically less fibrotic change, and infection with genotype 2.

Abstract ID: S1574

The Neuropsychological Impairment and Decreased Regional Cerebral Blood Flow By Interferon Treatment in Patients With Chronic Hepatitis C

H. Tanaka, S. Maeshima, H. Ueda, H. Hamagami, M. Ichinose

Introduction

Interferon (IFN) has various side effects. Serious side effects include psychotic symptoms such as depressive state. In addition, some studies have reported that decreased regional cerebral blood flow (rCBF) was observed in patients with depression.

Methods

In this study, we compared the neuropsychological impairment and the rCBF using single photon emission computed tomography (SPECT) between patients with chronic hepatitis treated with and without IFN-ƒ¿. Subjects and methods: The subjects were eight patients with chronic hepatitis. 4 patients were treated with IFN-ƒ¿2b (IFN group) and 4 patients were not treated (no-IFN group). All patients were excluded if they had psychological disease and received other cytotoxic drugs such as steroids. Neuropsychological tests conducted included the mini-mental state examination (MMS), Kana-hiroi test, word fluency test (WFT), auditory-verbal learning test (AVLT), and the Raven's colored progressive matrices (RCPM) test. The self-rating depression scale (SDS) and the stste-trait anxiety inventory (STAI) also were completed by subjects. In addition, cerebral SPECT (3DSRT) was performed to all patients. Neuropsychological tests and SPECT were performed to IFN-group at 2 month during IFN treatment.

Results

Though the significant difference did not show in comparison about neuropsychological tests between IFN group and no-IFN group, AVLT as memory function in IFN group showed decreased tendency. The significant reduction of rCBF in IFN group was observed in two cerebral region (lt-angular and lt-temporal region) (p<0.05), which are associated with memory function.

Conclusion:

The decrease of rCBF by IFN treatment was shown, suggesting that the neuropsychological impairment as side effects by IFN treatment may be associated with the decrease of rCBF.

Abstract ID: S1581

High Serum Leptin Is An Independent Risk Factor for Non-Response To Antiviral Treatment in Chronic Hepatitis C

M. Yatsuda, Y. Eguchi, T. Mizuta, T. Kumagai,

Introduction/Aim

This study aimed to determine whether serum leptin level and/or body weight were independent predictors of response to antiviral treatment in patients with chronic hepatitis C.

Methods

A retrospective evaluation was performed of one hundred thirty three patients with chronic hepatitis C treated with interferon (IFN) from 1996 to 2000. Sustained response was defined as negative by hepatitis C virus (HCV) RNA analysis with PCR and normal transaminase at 24 weeks after cessation of IFN therapy. Patients who remained positive for HCV RNA at the end of IFN treatment were defined as resistant to IFN therapy. Sex, age, body mass index (BMI)(>=25 versus >25), complication of diabetes mellitus, serum leptin level (>=8.0 ng/ml versus <8.0 ng/ml), and the stage of liver fibrosis by needle biopsy (F1/F2 versus F3/F4) were examined

Results

Sustained respond was achieved in 33 patients (23.7%), while others failed to show a response to IFN. Overall, the factors associated with sustained antiviral effects were HCV-RNA load, HCV serotype, serum leptin level, and stage of liver fibrosis evaluated by univariate analysis. BMI was not associated with any therapeutic effect of IFN. Multivariate analysis indicated that HCV-RNA load was a significant risk factor, but among the patients with low viremia (HCV-RNA less 100KIU/ml), leptin level was an independent risk factor for IFN resistance. Namely, a high level of serum leptin attenuated the effect of IFN on patients with low viremia.

Conclusions

This study demonstrated the possibility that among host factors serum leptin level can be a significant negative predictor for IFN-response in chronic hepatitis C, but does not address the issue if pretreatment intervention to decrease serum leptin level before IFN therapy would compensate for the low response rate in patients with a high serum leptin level. It was suggested that serum leptin level was an important factor for INF response, although viral load was most critical for INF therapy.

Abstract ID: S1533

Accelerated Vaccination Schedule Using a Combination Hepatitis a and B Vaccine (Twinrix) Is Effective in Patients With Hepatitis C

A.T. Hewlett, V. Kalidindi, S. Fehmi, H. Doshi, D. Lau

Background

Immunogenicity to standard HBV vaccination in HCV patients is generally lower compared to healthy subjects with a primary nonresponse rate between 30 and 40%. Recently, an accelerated vaccination schedule (0, 7, 21days) of a combined hepatitis A/B vaccine (Twinrix, GSK) was found to be associated with a more rapid onset of seroprotection for HBV.

Objective

To prospectively compare the safety and effectiveness of Twinrix at an accelerated schedule (0, 7, 21days with a booster at month 3) between HCV patients and healthy volunteers.

Methods

Subjects without any HAV and HBV serologic markers were enrolled and anti-HBs seroprotection (>10mIU/ml) were monitored at 1, 3, 4, 6 and 12 months. Detailed demographic and clinical information were obtained. A standardized questionnaire was used to document adverse events.

Results

To date, 76 of 100 target subjects (Male: N=25, Female: N=51) were enrolled and 39 (HCV: N=18, Control: N=21) completed month 6 visits. Anti-HBs seroprotection was observed as early as Month 1 in 33% of controls and 22% HCV patients and the rates increased to 57% and 39% respectively at Month 3 (p=0.19). Significant rise in anti-HBs titers was observed after the Month 3 booster dose. The anti-HBs seroprotection rose to 90% for controls and 67% for HCV patients when measured at month 4 (p=0.07). This favorable trend was maintained in both groups by month 6. The vaccine was well tolerated and there was no significant adverse event reported. Mild symptoms such as soreness at injection site, fatigue and headaches were noted in 46% of controls and 56% of HCV patients, and the difference was not significant. In both groups, response was not influenced by age, gender, smoking, and BMI. Among the 12 HCV patients with liver biopsy results, those with higher fibrosis stages (F>2) had similar response (p=0.3) compared to those with no or stage 1 fibrosis (p=0.6).

Conclusions

The accelerated dosing of Twinrix vaccine is safe and well tolerated. This therapeutic approach is at least as effective as the conventional vaccination schedule for HCV patients. Its major advantage is to provide faster HBV seroprotection and increase compliance due to the shorter intervals between vaccine administration. Another theoretical advantage of the accelerated schedule is to ensure completion of the HBV vaccine series prior to interferon-based therapy. There is controversial evidence that interferon may affect the HBV vaccine response.

Abstract ID: S1552

The Use and the Effect Of Psychiatric Medications in US Veterans With Hepatitis C Receiving Interferon Based Therapy.

Authors: A. Jakiche, S. Tannan, E. Paredez, V. Sontag, D.T. Blair, C. Qualls, E. Dettmer, C. Geppert

Introduction

Interferon (IFN) based therapy in patients with hepatitis C (HCV) may cause new psychiatric symptoms or worsening of existing psychiatric condition. The aim of this study is to evaluate the use and the effect of psychiatric medications during IFN based therapy in patients with psychiatric history (Psych Hx) in comparison to patients without such history (Control).

Methods

All patients with (HCV) treated with IFN based therapy at our clinic since January 02 who reached the end of planned treatment were analyzed (n=79). Patients were evaluated following a standardized template to collect clinical and psychiatric data at baseline, weeks 2,4,8,12 and every 6 weeks thereafter. Depression was measured at each visit by obtaining the CES-D (Center for Epidemiologic Studies-Depression) score. A psychiatric medication intervention (PMI) was defined as the addition or increase in the dose of a psychiatric medication. PMIs were further divided to those with sedatives/hypnotics (S/H), anti-depressants (AD), and neuroleptics (NE). Patients were divided to two groups: +Psych Hx (n=46) and Control (n=33).

Results

61% of +Psych Hx and 82% of Control patients required PMI. The number of PMIs per patient in the two groups was 0.6 vs. 0.7 for S/H, and 0.57 vs. 0.76 for AD respectively. Only few PMIs with NE were needed. The mean time for the first PMI in the +Psych Hx and Control patients was at weeks 11.4 vs. 6.6 for S/H, and at weeks 8.9 vs. 11.6 for AD. The effect of PMIs on CES-D score in the two groups is summarized in the table below. There were no differences between the two groups in rates of: treatment completion (83% vs. 85%), end of treatment response (57% vs. 70%), and sustained viral response (47% vs. 41%).

		CES-D Score
		Baseline (Pre-IFN)	4 to 6 weeks Pre-PMI	PMI	4 to 6 weeks Post-PMI	8 to 12 weeks Post-PMI
Psych Hx	S/H	16.72	19.21	22.63	19.71	18.54
	AD	17.06	21.47	28.29	24.24	23.12
Control	S/H	9.00	12.55	19.75	17.65	15.05
	AD	5.70	10.05	22.45	16.35	13.90

Conclusions:

1. Patients with Psych Hx were less likely to require a psychiatric medication intervention.

2. S/H and AD resulted in improvement of depression in the two groups, although the CES-D score at 8-12 weeks post PMI continued to be higher than baseline.

3. Control Patients required PMI with S/H earlier than patients with Psych Hx.

Abstract ID: S1545

Correlation Between Lipid Profile and Outcome Of Hepatitis C Treatment

K. Gopal, T.C. Johnson, S. Gopal, A. Walfish, C.T. Bang, P. Suwandhi, H.N. Pena-Sahdala, D.J. Clain, H.C. Bodenheimer, Jr., A.D. Min

Introduction

Low-density lipoprotein receptor (LDLR) has been proposed as the candidate receptor for hepatitis C virus (HCV). In vitro experiments have shown a competitive inhibition of HCV binding to LDLR by LDL. If similar inhibition occurs in vivo, the elevated serum concentration of beta lipoproteins may reduce the rate of hepatocyte infection by competing with the virus. Our aim is to investigate the role of the baseline lipid profile in influencing the outcome of HCV treatment.

Methods

Charts of all patients >18 yrs of age, treated with interferon-based regimen between 1998 and 2004 at Beth Israel Medical Center, NY were reviewed. Patients with HIV, HBV, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, along with patients on lipid modifying drugs were excluded from the study. Those without pretreatment lipid profile and triglyceride (TG) levels over 400mg/dl were also excluded. Data were analyzed with 2-sided independent sample t-test.

Results

Of 107 patients enrolled in the study, 45 patients (42%) had HCV genotype-1 (mean LDL 100 + 31.3), 50 patients (47%) had genotype 2 or 3 (mean LDL 111 + 39.3) and for 12 patients (11%) genotype was unknown (mean LDL 78 + 33.8). Early viral response (EVR), end of treatment response (ETR) and sustained viral response (SVR) were documented in 70, 58 and 50 patients respectively. Patients with positive SVR were younger (46.4 + 7.4) than non-responders (52.4 + 11.1), p= 0.023. Pretreatment LDL and cholesterol levels were found to be higher in patients with positive EVR, ETR and SVR when compared to corresponding patients with negative EVR, ETR and SVR, respectively (see Figure 1 & 2). This difference remained significant independent of age (p<0.01). There was no significant correlation between high density lipoprotein or TG levels and treatment outcome.

Conclusions:

Patients achieving SVR are younger and have higher serum LDL and cholesterol levels than non-responders. Thus, higher pretreatment serum LDL and cholesterol levels may be good prognostic indicators for treatment outcome in chronic hepatitis C.

Figure 1: Figure 2:

Abstract ID: S1563

Hematopoiesis Suppression With Different Pegylated and Nonpegylated Interferon-Alpha Regimens for Chronic Hepatitis C

M. Peck-Radosavljevic, M. Schmid, E. Formann, M. Homoncik, C. Datz, A. Gangl, P. Ferenci

Background/Aims

Investigate haematotoxic effects of four interferon (IFN)-α and ribavirin (RIB) regimens in chronic hepatitis C.

Methods

Patients (n=133) received IFN-α2b 5MU TIW alone (IFN2b; 36wk) or with RIB 1000-1200mg/d (IFN2b/R; 38wk), or pegylated IFN-α2a 180μg/wk (PEG2a/R; 48wk) or pegylated IFN-α2b 1.5μg/kg/wk (PEG2b/R; 24wk) both with RIB 1000-1200mg/d. Erythropoiesis [hemoglobin (HB), erythropoietin (EPO)], thrombopoiesis [platelets (PPC), thrombopoietin (TPO)] and leukopoiesis [leukocytes] were monitored.

Results

HB decreased in all combination groups after 4wk (p<0.001 vs baseline); remained diminished throughout. HB decreased slightly in IFN2b at 8wk (p<0.05). EPO increased after 4wk in all combination groups (p<0.001); remained significantly above baseline throughout. PPC decreased in all groups after 4wk (p<0.05); remained below baseline throughout in IFN2b, PEG2a/R and PEG2b/R; recovered to baseline at 16wk in IFN2b/R. In all groups, leukocyte counts decreased after 4wk; remained low throughout. Neutrophil and lymphocyte counts were similar across IFN2b, IFN2b/R and PEG2b/R, but significantly lower in PEG2a/R (p<0.01 any week and p<0.05 therapy end, respectively). After therapy, neutrophil count returned to baseline in 4wk in PEG2b/R and in 24wk in PEG2a/R and IFN2b/R.

Conclusions

All regimens were associated with decreases in the three hematopoietic processes. PEG2a/R had a similar suppressive effect on erythropoiesis and thrombopoiesis to PEG2b/R, but a significantly more suppressive effect on leukopoiesis. Neutrophil recovery was faster after PEG2b/R than after PEG2a/R. No major infections were recorded in either group.

Abstract ID: S1579

A Descriptive Assessment of the Current Treatment Patterns for Hepatitis C in a Health Benefits Company Population

J.E. Whitworth, D.R. Vanderpoel, B. Miller

Introduction

Estimates state that approximately four million US citizens are infected with the Hepatitis C Virus (HCV), yet only half of these cases have been diagnosed. Approximately 75% of all subjects infected with HCV develop chronic hepatitis, with 30% of those later developing cirrhosis. Despite the availability of effective pharmaceutical treatment options, notable gaps currently exist in the provision of optimal therapy to all who could benefit.

Objective

The primary objective of this study was to descriptively assess the demographic characteristics and current pharmaceutical treatment patterns for subjects diagnosed with Hepatitis C in a health benefits company population.

Methods

A retrospective database analysis was completed with the pharmacy and medical claims dataset of a large health benefits company. Eligible participants included subjects of all ages with a diagnosis of Hepatitis C, identified by ICD-9 coding, between 1 January 2003 and 31 July 2003. Eligible participants were also required to maintain continuous plan enrollment throughout the study period. An index date was assigned to all subjects based on their first medical claim for Hepatitis C within the identification period. Subsequently, 12-months of post-index claims data were evaluated for all eligible subjects.

Results

Out of a total sample of 3059 subjects diagnosed with Hepatitis C, 636 (20.8%) were actively treated within the 12-month study period. Females accounted for 42.9% (1312 subjects) of the total study population. A total of 1106 subjects (36.2%) were hospitalized within the study period, yet significantly more non-treated (40.2% [973 subjects]) were hospitalized when compared to the treated (20.9% [133 subjects]). The most frequently identified co-morbidities were similar between treated and non-treated subjects, yet proportions of prevalence varied: depression (36.8% and 25.4%), cirrhosis (21.4% and 24.9%), and diabetes (14.5% and 23.9%). Finally, 62.3% (396 subjects) of the treated and 47.8% (1159 subjects) of the non-treated (1159 subjects) were seen by a gastroenterologist within the study period.

Conclusion

o The results of this retrospective database analysis of a health benefits company population suggest that a significant proportion of those diagnosed with Hepatitis C do not receive active treatment for their illness.

o Differences were found to exist between treated and non-treated study subjects in the following areas of interest:

o Hospitalizations

o Treatment by gastroenterologists

o Concomitant medication utilization

o This observational study was limited by the relatively small sample size, as well as the inherent limitations that exist with medical claims databases (i.e. under-coding, over-coding)

o Additional observational research is needed in the area of hepatitis C treatment to validate the results of these findings, as well as to identify the reasons for gaps in therapy and the specific barriers to treatment.

Abstract ID: S917

Identification and Outcomes Of Psychiatric Patients in a Chronic Hepatitis C Clinic Using a Co-Located Psychiatric Clinical Nurse Specialist.

E. Dieperink, S. Heit, J. Durfee, K. McCarthy, M. Wingert, M.L. Willenbring, J. Johnson, P. Thuras, S.B. Ho

Introduction

Psychiatric and substance use disorders are common in hepatitis C patients and represent barriers to antiviral treatment. We prospectively evaluated the utility of routine psychiatric and substance use screening, followed by referral to a psychiatric clinical nurse specialist (CNS) co-located in a chronic hepatitis clinic.

Methods

221 consecutive patients seen in a hepatitis C clinic were screened using the Alcohol Use Disorders Identification Test-C (AUDIT-C), Beck Depression Inventory (BDI), Urine drug screen (UDS), and posttraumatic stress disorder-primary care (PTSD-PC) screening tool. Patients not already followed in mental health and who scored over the following cut-off scores were referred to the CNS (AUDIT-C >4; BDI > 9; Positive UDS or Positive PTSD-PC). Primary endpoint was the percentage of patients starting antiviral therapy.

Results

All patients were HCV antibody and PCR-positive veterans seen in a HCV clinic from 10/03 through 4/04. Of these, 107/221 (48%) met the criteria for referral for psychiatric evaluation and were designated “high risk”; 114/221(52%) were not referred and designated as “low risk.” Thirty-nine (36.4%) of the high-risk patients did not return for follow-up. High-risk patients included 72/88 (82%) with genotype 1 and, of the 70 who had liver biopsies, 47 (67%) had > stage 2 fibrosis. Low risk patients included 80/96 (83%) with genotype 1 and 52/72 (72%) having ³ stage 2 fibrosis. High-risk patients had higher mean BDI scores 14.1(SD 10.3) vs 13.1 (SD10.8), AUDIT-C scores 3.3 (SD 3.9) vs. 2.0 (SD 3.1) and were more likely to screen positive for PTSD 45% (48/107) vs. 39% (44/114) than low risk patients. 34/81 (42%) of high-risk patients had a positive UDS vs. 27/85 (32%) of low risk patients. Cannabis was the most common drug found using the UDS. To date, 41/107 (38%) of high-risk patients have started antiviral therapy, compared with 43/114 (38%) of low risk patients. No differences in adherence to treatment have been observed between the high and low risk patient groups during an initial three months of follow-up on antiviral therapy.

Conclusions

Referral of patients at high risk for psychiatric and substance use disorders (based on the results of standardized screening tools) to a psychiatric CNS in a chronic hepatitis C clinic resulted in initiation of antiviral treatment at similar rates among high risk patients as among concurrent low risk patients at the same clinic.

Abstract ID: S1550

Re-Treatment As Well As Initial Treatment With Interferon Improved Survival Of Patients With Chronic Hepatitis C

Y. Iwasaki, R. Terada, T. Nishida, B. Shoji, Y. Miyake, H. Taniguchi, S. Fujioka, H. Kobashi, K. Sakaguchi, Y. Shiratori

Background & Aims

The effects of interferon therapy including re-treatment in chronic hepatitis C patients on survival are unclear. We analyzed survival among chronic hepatitis C patients treated once or more with interferon.

Methods

We analyzed 513 patients with chronic hepatitis C who were treated with interferon monotherapy between 1985 and 2001. The median dose and duration of interferon administration was 480 million units and 168 days, respectively. Survival status was confirmed by medical records. The effect of interferon therapy on survival was assessed by standardized mortality ration (SMR) based on published mortality among the Japanese general population.

Results

Of 513 patients treated with interferon, one of 147 sustained virologic responders and 13 of 366 nonresponders to initial treatment died in 4.8 years. Thirteen of 14 patient deaths were due to liver diseases. Compared with the general population, liver-related mortality was not high among interferon-treated patients (SMR: 0.81, CI: 0.43-1.38). Liver-related mortality was low in responders (SMR: 0.20; CI: 0.01-1.12) but not in nonresponders (SMR: 1.08; CI: 0.56-1.88). Of 366 nonresponders to the initial treatment, 109 (30%) were re-treated with interferon and 20 (18%) of re-treated patients achieved sustained virologic response. Five of 109 re-treated patients died in 5.1 years and three of five patient deaths were due to liver diseases. Liver-related mortality was reduced among 109 re-treated patients (SMR: 1.03, CI: 0.21-3.01) compared with 257 patients without re-treatment (SMR: 1.18, CI: 0.61-2.07). In the re-treated patients, the mortality was markedly low among responders (SMR: 0.00, CI: 0.00-5.67) as compared with nonresponders (SMR: 1.32, CI: 0.27-3.87).

Conclusions

Interferon therapy improved survival of patients with chronic hepatitis C by preventing liver-related deaths. Re-treatment as well as initial treatment with interferon improved survival of patients with chronic hepatitis C.

Abstract ID: S1583

Filgrastim for the Neutropenia Associated With Combination Therapy in Chronic Hepatitis C

D. Farmer, R. Collantes, S. Makay, J.P. Ong, H. Gujral, L. Farquhar, M.L. Carniello, R. Sjogren, Z. Younossi

Introduction

Adherence to the optimal dose of combination therapy [Pegylated Interferon (PEG-IFN) and Ribavirin (RBV)] may enhance sustained virologic response (SVR).

Aim

To assess the potential role of filgrastim in reducing the incidence and severity of PEG-IFN-associated neutropenia during anti-HCV therapy.

Methods

In an open-label study, patients with chronic hepatitis C were treated with a combination of PEG-IFN-alfa2b (1.5 mg/kg/week) and RBV (weight-based dosing: 800 mg to 1400 mg/day). To avoid PEG-IFN dose reduction [absolute neutrophil count (ANC) £750], patients were started on filgrastim with the dose titrated from 300 mcg SQ weekly to thrice weekly.

Results

Of 100 patients enrolled, data is available for 57 (age 48.12±7.87, 58% male, 67% Caucasians, 72% HCV genotype 1, baseline HCV RNA 3.9±5.2 million IU/mL, and baseline Hb 14.70±1.33 g/dL. Of 57 patients, 21 (37%) were started on filgrastim, 33% of whom required 300 mcg thrice weekly and the remainder of these patients received bi-weekly to weekly dosing regimens. After initiation of filgrastim, ANC (Median) increased from 0.9 to 6.8 (Figure). Additionally, no one required dose reduction of PEG-IFN due to neutropenia. To date, no SAE can be attributed to filgrastim. Data on SVR is currently being collected.

Conclusions: These data suggest that filgrastim can effectively treat PEG-IFN induced neutropenia and prevent PEG-IFN dose reduction. Final analysis and the impact of dose maintenance on SVR are currently being completed.

Abstract ID: S1536

High Dose Consensus Interferon and Ribavirin Is Effective for Treatment Of Chronic Hepatitis C Infection in Patients Who Are Resistant To Peg-Interferon and Ribavirin

K.D. Rothstein, R. Koka, A.A. Fernandez, S. Singh, H. Hargove, V. Araya, S. Munoz

Background

The majority of nonresponder and relapser patients with chronic hepatitis C are unable to achieve a sustained virologic response (SVR) with the combination of PEG-Interferon (PEG-IFN) and ribavirin (RBV), especially those who have genotype 1 and advanced disease. Consensus interferon (Interferon alfacon-1, CIFN) is a bio-optimized alfa interferon that exhibits increased in-vitro antiviral activity than the naturally occurring alfa interferons 2a and 2b. Improved response rates have been reported with high-dose CIFN therapy and RBV for patients who have failed to respond to PEG-IFN / RBV.

Aim

Evaluate efficacy and safety of high-dose daily CIFN and RBV in HCV patients who failed therapy with PEG-IFN / RBV.

Methods

Patients who had been treated with PEG-IFN/ RBV for HCV but did not obtain a SVR were eligible for treatment if they: 1) tolerated treatment with PEG-IFN / RBV, and 2) had advanced liver disease (bridging fibrosis or cirrhosis). Patients were given 27 ug of CIFN daily and RBV 400 mg BID during the first four weeks, followed by 18 ug daily and ribavirin 400 mg BID daily for the next eight weeks. At 12 weeks, CIFN was decreased to 15 ug daily while RBV was increased to 1,000-1,200 mg daily for 36 weeks.

Results

Thirty three patients have been enrolled in the study, 76% male with a mean age of 52 years old. 94% had genotype 1 and 39% of patients had cirrhosis.19 patients (60%) have achieved an early virologic response (EVR) at 12 weeks. Sixteen (52%) were undetectable at 24 weeks and 8 patients (35%) achieved an End-of-Treatment response. 6 patients were dose reduced and 3 patients stopped therapy due to adverse effects. A total of 10 patients required either Epogen and/or Neupogen.

Conclusion

For HCV patients with advanced histologic disease who had previously failed therapy with PEG-IFN and RBV, the combination of high-dose CIFN and RBV is a well-tolerated and effective option.

Abstract ID: S1520

Impact Of HIV Coinfection on the Development Of Steatosis in Patients With Chronic Hepatitis C Virus Infection

I. Gaslightwala, E.J. Bini

Background

Although steatosis is common in HCV-infected patients, the impact of HIV infection on the development of steatosis in these individuals is not known. The aims of the present study were to determine the prevalence of steatosis in HIV/HCV coinfected patients and to evaluate whether steatosis is associated with HIV viral load, CD4 count, or treatment with highly active antiretroviral therapy (HAART).

Methods

Consecutive patients who were scheduled for liver biopsy were prospectively identified and were interviewed by a research assistant who obtained detailed demographic and clinical data. Fibrosis was scored on a scale from 0 - 4; steatosis was scored according to the percent of hepatocytes involved: 0 (no steatosis), 1 (<33%), 2 (33% - 66%), or 3 (>66%) using the Brunt system.

Results

708 patients (mean age 50.2 ± 5.7 years) were enrolled, including 154 with HIV/HCV and 554 with HCV alone. There were no differences between the groups with regard to age and gender, although coinfected patients were more likely to be black (61.7% vs 40.1%, P <0.001) and weighed less (78.2 vs 88.4 kg, P <0.001). Among coinfected patients, the median CD4 count was 429 cells/mm3, 50.6% had undetectable HIV RNA, and 84.4% were taking HAART. Stage 3/4 fibrosis (43.6% vs 30.0%, P <0.001) and steatosis (72.1% vs 52.0%, P <0.001) were more common in coinfected patients. The steatosis score (0, 1, 2, 3) in coinfected patients (27.9%, 24.0%, 37.0%, 11.0%) was significantly more severe (P <0.001) than in those with HCV (48.0%, 31.8%, 17.1%, 3.1%). Of patients with steatosis, the type of steatosis (micro, macro, or mixed) in HIV/HCV patients (18.0%, 36.0%, 45.9%) and HCV monoinfected patients (1.4%, 88.9%, 9.7%) differed significantly (P <0.001). Among coinfected patients, the prevalence of steatosis was more common in patients with CD4 counts <350 cells/mm3 (83.1% vs 64.0%, P = 0.009) but did not differ between patients with undetectable vs detectable HIV RNA (75.6% vs 68.4%, P = 0.32) or between those who were and were not taking HAART (73.8% vs 62.5%, P = 0.26).

Conclusion

· Steatosis significantly more common in coinfected patients and presents at a more advanced stage than in patients with HCV alone.

· Steatosis is more likely to be mixed in coinfected patients, whereas steatosis is typically macrovesicular in monoinfected patients.

• Steatosis is associated with a lower CD4 count but not associated with the use of antiretroviral therapy or HIV viral load.

Abstract ID: S1570

The Effect of Weight on Exposure in Hepatitis C: Peginterferon Alfa-2b and Peginterferon Álfa-2a

M. Silva, D. Cutler, J. Poo-Ramirez, F. Wagner, M. Jackson, C. Cullen

Objective

To determine the impact of patient weight on exposure and virological outcome during therapy with peginterferon alfa-2b (PEG2b) or peginterferon alfa-2a (PEG2a) in patients chronically infected with hepatitis C virus (HCV) genotype 1.

Methods

36 treatment-naïve patients were randomized to receive PEG2a 180μg/wk or PEG2b 1.5μg/kg/wk alone for 4wk, and then with ribavirin 13mg/kg/day for an additional 4wk. Intensive pharmacokinetic sampling for peginterferon alfa concentration was carried out at 1wk and 4wk. All samples were assayed blindly with two different standards (PEG2b and PEG2a). Patients who achieved a at least a 2.0 log10 HCV-RNA decline at the end of the monotherapy period (4wk) were classified as responders.

Results

Weight had virtually no effect on exposure to PEG2b, which was administered on a weight basis (Figure; note large difference in y-axis values). There was a reduction in exposure with increasing weight in patients receiving the fixed dose of PEG2a. There were 9/18 (50%) and 6/18 (33%) responders in the PEG2b and PEG2a groups, respectively. The mean weights for responders and nonresponders in the PEG2b group were 72.2kg and 66.9kg (p=0.473), respectively. Corresponding mean weights in the PEG2a group were 64.2kg and 74.5kg (p=0.084), respectively.

Conclusions

There was a difference in weight between responders and nonresponders in the PEG2a group. No such difference was evident in the PEG2b group.

Abstract ID: S1548

Relationship Between Early HCV Clearance From Serum and Interferon Receptor (IFNAR-2) Expression on Leukocytes in Chronic Hepatitis C Patients Treated With Various Interferons

K. Ishii, K. Matsumaru, K. Higami, Y. Fujita, M. Shinohara, H. Nagai , M. Watanabe, K. Miki, M. Sano, S. Morita, Y. Sumino

Backgroun/Aim

Ligand-induced receptor down-regulation,as inTFN-alpha and its receptor, is a well-known phenomenon. Type 1 interferon (IFN) may be linked to type 1 IFN receptor expression on cell surface. The goal of the present study was to examine IFNAR-2 expression on leukocytes in patients with chronic hepatitis C (CHC) during treatment with IFN cocktail.

Patients and Methods

Thirty-six adults with biopsy-proven CHC were studied. HCV was divided into 2 serotypes; type 1 (genotypes 1a and 1b) was detected in 18 patients and type 2 (genotypes 2a and 2b) in 18 patients. A twenty-four-week regimens using varied IFNs was administered. IFNs was given daily for 2 weeks followed by thrice weekly administration for 22 weeks. IFN-alpha (6 MU), consensus IFN (18 MU), and IFN-alpha 2b (6 MU) combined with ribavirin (600-800 mg/day for 24 weeks) were given to 9 patients (A group), 9 patients (B group), and 18 patients (C group). Serum HCV-RNA was assessed by a qualitative method( Amplicor Ver 2.0; Roche) at week 2, and became negative in 7, 8, and 4 patients from the A group, B group, and C group, respectively. These 19 patients were defined as the early-loss group, and the other 17 patients as the non-loss group. Blood samples were collected on days 3, 7,and 14 during therapy. FNAR-2 expression by leukocytes was determined by flow cytometry and expressed as the mean fluorescence intensity (MFI) of anti-IFNAR-2 antibody staining. Serum 2-5AS activity was also measured by the standard procedures.

Results

Stained leukocytes were divided into lymphocytes (Ly), monocytes (Mo), and granulocytes (Gr) by flow cytometry. The baseline MFI of Ly, Mo, and Gr showed no significant differences between groups. The MFI of Mo and serum 2-5AS activity peaked on day 3 and thereafter gradually decreased, showing a significant change (P < 0.05 by Friedman�fs test) in both groups. On days 3, the MFI of Mo and serum 2-5AS activity were significantly higher in the early-loss group than in the non-loss group. The MFI of Gr gradually decreased after the start of IFN therapy, also showing a significant change (P < 0.05) in both groups. The MFI of Ly did not significantly change in the early-loss group, but gradually decreased during therapy in the non-loss group during therapy.

Conclusions

These results suggest that up-regulation of IFNAR-2 on Mo and suppression of ligand-induced receptor down-regulation of IFNAR-2 on Ly are related to HCV early loss from the serum.

Abstract ID: 2

Virologic Response and Safety Outcomes in Therapy-Naive Patients Treated for Chronic Hepatitis C with Viramidine in Combination With Pegylated Interferon Alfa-2a

R.G. Gish, Dr., D. Nelson, Dr., S. Arora, Dr., M.W. Fried, Dr., K.R. Reddy, Dr., Y. Xu, Dr., M.C. Kim, Dr., B.S. Murphy, Dr.

Introduction

Dose-limiting anemia can be a prominent adverse event of therapy with pegylated interferon and ribavirin. This dose-ranging study examined whether viramidine, a liver-targeting prodrug of ribavirin, may be a safer alternative when used in combination with pegylated interferon alfa-2a (PEG-IFN).

Methods

Of 180 HCV therapy-naive patients enrolled in the study, 171 received full-dose viramidine (400 mg BID: n = 47; 600 mg BID: n = 43; 800 mg BID: n = 44) or ribavirin 1000-1200 mg/d (n = 37) in combination with PEG-IFN 180 µg/wk SC. Patients were predominantly male (64%), Caucasian (76%), and genotype 1 (72%), with a median HCV RNA of 6.5 log10 copies/mL. Analyses assessed the incidence of anemia (hemoglobin <10 g/dL) and HCV RNA levels (Bayer TMA assay; sensitivity to 5 IU/mL) among patients without dose reduction due to anemia to evaluate the intrinsic activity of viramidine versus ribavirin without the confounding effect of dose reduction.

Results

Among patients with no dose reduction due to anemia through the end of treatment (EOT), no significant differences were noted between viramidine (400, 600, and 800 mg BID) versus ribavirin in the proportion of patients with undetectable HCV RNA levels (55%, 63%, 55%, and 62%, respectively). Rates of anemia through EOT for the viramidine 400, 600, and 800 mg groups were 0%, 2%, and 11%, respectively, versus 27% for the ribavirin arm. Of the evaluable patients at EOT, the percent of patients experiencing a decline in hemoglobin of at least 25% from baseline was higher in the ribavirin group (48%) compared to all the viramidine groups (400 mg: 14%; 600 mg: 18%; 800 mg: 15%). Other types of adverse events were similar between treatment arms.

Conclusions

At EOT in this Phase 2 study, viramidine demonstrated antiviral activity comparable to that of ribavirin when used in combination with pegylated interferon alfa-2a among patients with no dose reduction due to anemia. Patients in the viramidine arms also had a significantly lower incidence of anemia compared to those patients in the ribavirin arm. Data lock for the Phase 2 will occur on December 1, 2004 and sustained response and final safety data will be available for presentation at the time of this meeting.

Abstract ID: 87

Double-Dose Peginterferon Alfa-2b Plus Weight-Based Ribavirin for Re-Treatment Of African-American Non-Responders With Hepatitis C

J.B. Gross, S.M. Johnson, T. Therneau, P.Y. Kwo, R. Investigators

Introduction

12% of IFN+ribavirin(R) nonresponders (NR) re-treated with peginterferon (PEG)+R have a sustained viral response (SVR). African-Americans (AA) with hepatitis C have an inherently low rate of response to therapy.

Aim

Among AA NRs to IFN+R, see if the SVR rate after re-treatment with PEG+R improves with high-dose PEG alfa-2b and weight-based R.

Methods

RENEW is a national trial in which we re-treated IFN+R NRs with PEG alfa-2b, either 1.5 or 3 mcg/kg/wk, plus R 12-15 mg/kg/d (<1400 mg/d) x 48 wk; SVR was assessed 24 wk later. Stratifications: genotype 1/non-1, fibrosis F0-2/F3-4, ethnic group AA/other. We summarize the results among the AA participants.

Results

Over 900 patients enrolled in RENEW, including 131 AA. Of these, 110 were confirmed as starting treatment (54 on 1.5, 56 on 3 mcg/kg/wk). The two AA groups were similar with regard to age, sex, genotype, and liver fibrosis; the 3-mcg group had more patients over 105 kg (25% vs 9%, p=0.04). The rate of SVR was higher among those on the high-dose treatment (table). SVR was not associated with body weight or liver fibrosis. Rates of dose reduction and discontinuation were the same in both groups.

Conclusions

Among AA NRs to IFN+R: 1) Re-treating with a double dose of PEG alfa-2b plus weight-based R improves the rate of SVR significantly. 2) Tolerability on PEG alfa-2b 3 mcg/kg/wk is comparable to 1.5 mcg/kg/wk. 3) High body weight is not a factor when using an aggressive weight-based regimen.

Relevance

We have demonstrated that intensive treatment of a patient group with an inherently low response rate can achieve a re-treatment response rate comparable to other groups, with good tolerability. The combination of high-dose PEG alfa-2b + weight-based R should be investigated in other hard-to-treat patient populations.

	1.5 mcg	3 mcg	p
RNA(-) at 48 wk	6%	18%	NS
SVR	2%	14%	0.032
D/R in 1st 24 wk	24%	21%	NS
D/C for AE	15%	11%	NS
Neutropenia	26%	38%	NS

Abstract ID: 88

Cerebral Metabolic and Neuropsychiatric Effects Of Pegylated Interferon(PIFN)therapy in Hepatitis C.

V. Byrnes, A. Miller, C. Weinstein, Dr, E. Hill, Dr, R. Lenkinski, Dr, D. Alsop, Dr, N.H. Afdhal, Dr

Introduction

Cerebral dysfunction in HCV positive patients treated with pegyalated IFN (PIFN) has not been well characterized.

Aim

The aim of this study was to determine the cerebral metabolic and neuropsychiatric effects of PIFN in HCV positive subjects.

Materials and Methods

HCV positive subjects due to start a course of PIFN underwent an MRI and ¹H–MRS (spectroscopy) of the brain in addition to neuropsychological evaluation (neuropsychometric tests, Beck’s depression inventory, quality of life and self-reported cognitive dysfunction questionnaires), prior to, and 12 weeks following initiation of PIFN. MR studies were performed on a 3.0-T scanner (Signa, GE). MR spectra were acquired from the basal ganglia (caudate nucleus) and from the frontal gray and white matter. Concentrations of the neuronal metabolite N-acetyl aspartate (NAA), and the glial metabolites choline (CHO) and myoinositol (MI) were measured and expressed as a ratio of the control metabolite, creatine (Cr). Major exclusion criteria were cirrhosis, HIV co-infection, active alcohol or drug abuse, and gross white matter changes on baseline MRI.

Results

10 subjects have been enrolled in the study to date. Baseline NAA and MI were similar in all subjects, mean 1.45 (SD,0.27), and 0.72 (SD,0.15). Baseline CHO was higher in the basal ganglia and frontal cortex of subjects with a high viral load > 2 million IU/ml (0.95, 0.64) than in those with a low viral load < 2 million IU/ml (0.46, 0.23). NAA and MI remained relatively unchanged after 12 weeks of PIFN when compared to baseline values, whereas CHO concentration decreased after 12 weeks of PIFN and HCV viral clearance (mean change in basal ganglia 0.99 to 0.24, frontal cortex 0.64 to 0.25) Subjects demonstrated impairments in the cognitive domains of executive functioning, language skills and fine motor co-ordination but not attention and memory. Depression scores increased, QOL was reduced and all patients reported subjective complaints of cognitive difficulties (CAARS).

Conclusion

This study demonstrates neuronal preservation and reduced glial activation following 12 weeks of successful PIFN therapy and increases the evidence for HCV cerebral infection. However, HCV clearance is offset by cognitive decline and reduced QOL. Novel ‘neuroprotective” agents may play a future role in preventing cognitive dysfunction during treatment with PIFN.

Abstract ID: 86

Impact of Asian Race on Response to Combination Therapy with Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C

S.B. Missiha, Dr., E.J. Heathcote, Dr., T. Arenovich, K. Khan, Dr.

Background

Prior investigation has identified factors associated with response to treatment of hepatitis C including viral genotype, viral load, body weight, fibrosis, and adherence to therapy. The lower response rate of African-Americans relative to Caucasians has been established, but studies of other racial or ethnic groups remain limited.

Methods

Data on 472 treatment-naive patients from a large multicenter trial of combination therapy with peginterferon alfa-2a (180 mg SC each week) and ribavirin (800 mg daily) were retrospectively analyzed to determine predictors of a sustained virological response (SVR), defined as an undetectable serum HCV RNA at least 24 weeks after completion of therapy. This trial was designed prior to the determination of optimal ribavirin dose.

Results

SVR occurred in 45% of 417 Caucasians and 67% of 55 Asians (p = 0.0022). In a multivariable logistic regression analysis that adjusted for viral genotype, adherence to drug therapy, and other known factors associated with treatment response, Asian race remained independently associated with a higher probability of achieving an SVR (OR 2.23, 95% CI 1.07 – 4.63). Other factors associated with SVR in this study included viral genotype, body mass index, degree of fibrosis, and adherence to drug therapy, but not age, gender, or baseline viral load.

Conclusions

There is a higher rate of sustained virological response to treatment with peginterferon alfa-2a and ribavirin in Asian patients than Caucasian patients with chronic hepatitis C.

Abstract ID: 89

Interim Analysis Of a Randomized, Controlled Study Comparing the Efficacy Of 40KD Peg-Interferon Alfa2a in Combination With 800mg or 400 Mg Ribavirin/day in Chronic Hepatitis C, Genotype 2/3

P. Ferenci, H. Brunner, H. Laferl, U. Czizek, M. Rosenbeiger, R. Stauber, A. Maieron, G. Fischer, P. Steindl-Munda

Background

At present, the standard treatment of patients with chronic hepatitis C genotype 2 or 3 is the combination of peginterferon-alfa2 qw and 800mg ribavirin/d for 24 weeks. Recent observations suggest, that duration of treatment can be further reduced. Other approaches like decreasing the dose of ribavirin may be useful to improve adherence by avoiding unnecessary side-effects and to decrease treatment costs.

Aim

To compare the sustained virological response rates in patients receiving either 800 or 400 mg ribavirin (COPEGUS), Roche, Basel, CH)/d in combination with 180 µg 40KD peginterferon-alfa2a (PEGASYS), Roche, Basel, CH) qw for 24 weeks. This interim analysis was requested by the IRB after completing treatment of 1/3 of the planned patients.

Methods

163 de novo patients (male: 96, female 67; mean age: 36.2 years) with chronic hepatitis C due to genotype 2 (n=24) or 3 (n=139) were randomized to receive 180 µg PEGASYS; either with 800 mg (n=81) or 400 mg (n=82) ribavirin/d for 24 weeks. At randomization patients were stratified according to genotype and viral load (> or < 850,000 IU/ml). After end of treatment patients were followed for another 24 weeks. Efficacy was assessed by qualitative PCR (AMPLICOR; HCV Test v2.0).

Results

At the time of writing this abstract, there were 18 drop outs (9 in each in group), 86 patients have completed the 24 week treatment period, and 53 the 24 weeks of follow up. 59 are still on treatment. End of treatment (EOT) response rates were (intent to treat): 79.2 and 82.3%; (treated per protocol): 96.2 and 100%; (both non significant) in the 800mg and the 400 mg groups, respectively. Full EOT data will be available at the time of the meeting. The SVR rates (intent to treat) in the patients who have completed follow up so far are 67.7% (95% CL: 48.6-83.3) and 65.6% (46.8-81.4) in the 800mg and the 400 mg groups, respectively.

Conclusions

Reduction of the dose of ribavirin to 400 mg/d did not decrease efficacy of antiviral combination therapy in patients with “easy to treat” HCV genotypes.

Abstract ID: 84

Peginterferon Alfa 2-B Therapy for 8 Weeks in Acute Hepatitis C Genotypes 1 and 4: a Pilot Study

S. Kamal, A. Ismail, A. AL Tawil, S. Hakam, Q. He, J. Rasenack, A. EFouly, M. Madwar

Background/Objective

The efficacy and duration of peginterferon treatment in acute hepatitis C have not been adequately evaluated. This study was designed to determine the efficacy, safety, long term outcome and cost-effectiveness of 8 weeks peginterferon alfa (PEG IFN) therapy in patients with acute hepatitis C virus (HCV) genotypes 1 or 4.

Methods

This intent to treat, controlled multicenter trial was designed to treat patients with acute hepatitis C with detectable HCV-RNA at 8 weeks after the first positive PCR. Sixty-two patients with proven acute HCV genotypes 1 (n= 23) and 4 (n=39) were enrolled and prospectively followed. Ten subjects refused treatment but were followed through the study. Fifty-two patients without spontaneous recovery at week 8 were assigned to receive 1.5 mg/kg peginterferon alfa-2b S.C.once weekly for 8 weeks while patients who still have detectable HCV-RNA after 8 weeks of treatment continued therapy until 12 weeks. The primary end point was sustained virological response (SVR), defined as undetectable HCV RNA 48 weeks after end of treatment. All patients were followed for 3 years after therapy.

Results

Four untreated subjects (40%) had spontaneous recovery. Among the 52 treated patients, 41 (79%) patients (genotype 4: 32 patients, genotype 1: 9 patients) had undetectable HCV-RNA after 8 weeks therapy and treatment was stopped while 11 patients (genotype 1) had persistent viremia so treatment was continued until 12 weeks. The overall SVR in all treated patients was 92.3% [39/41 (90%) in the 8-week treatment group and 10/11 (91%) 27 in the 12-week treatment group]. SVR after 8 weeks peginterferon alpha-2b therapy was achieved more frequently among genotype 4 patients irrespective of viral load while in genotype 1 patients SVR after 8 weeks was more likely in patients with low viral load compared with those with high viral load. Peginterferon alfa-2b therapy was well tolerated in both groups and was associated with significant improvement in the quality of life. None of patients with SVR had detectable HCV-RNA 3 years after completing treatment.

Conclusions

Peginterferon alfa-2b monotherapy for 8 weeks induces high sustained virologic response rates in patients with acute hepatitis C virus with genotype 1 and 4. HCV genotype 1 with high viral load may require longer treatment duration. Peginterferon a therapy in acute hepatitis C seems cost effective as it reduces the incidence of chronicity and improves the quality of life.