Date: 5 May 15,
2005
Abstract ID: S1585
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
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
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
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
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
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
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
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) |