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 (Cmax) IFN concentration. Gene expression and antiviral properties were measured using protein and RNA quantification assays.

 

Results

 At Cmax 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 Cmax dosing. When combined with the therapeutically relevant Cmax 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 TH1 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 TH1 responses are enhanced by combining IFN-g and IFN-ain 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)