Posters – Sunday May 21, 2006 8:00AM
Hepatitis C
HCV Clinical Trials
Abstract
S1057 – Stronger Baseline
HCV-Specific Immunity Is Associated With A Higher Likelihood Of A Sustained
Virological Response to Combination Antiviral Therapy Of Chronic Hepatitis C
J.
R. Burton;
J. Klarquist; K. Im; S. H. Belle; H. R. Rosen
Introduction:
Individuals who spontaneously clear HCV infection have
vigorous HCV-specific cellular immune responses. African Americans (AA) have
lower rates of spontaneous clearance and lower rates of response to antiviral
therapy compared to Caucasians (CA). Aim: Investigate if pretreatment
HCV-specific immune responses are related to race and whether they are
associated with virologic outcome to combination therapy.
Methods:
Virahep-C is a multicenter NIH funded study of response to peginterferon and ribavirin for up to 48 weeks in 205 CA
and 196 AA naďve, genotype 1 patients. Patients with detectable HCV RNA after
24 weeks of therapy were removed from treatment. The primary end-point was a
sustained virological response (SVR) defined as undetectable HCV RNA at 24
weeks after completing therapy. CD4+ T cell responses quantified at baseline in
353 patients (174 CA and 179 AA) using sensative
IFN-γ ELISpot (enzyme linked immunospot)
assays. Briefly, 2.5x105 peripheral blood mononuclear cells (PBMC)
were incubated with HCV core (aa 1-115), E2
(383-715), NS3 (1007-1534), NS4 (1569-1931), NS5 (2054-2995), CMV, negative
control (SDS/SOD) and positive control (PHA/SEB) antigens for 40 hours. Univariate and multivariable regression analyses were
performed to determine factors associated with SVR.
Results:
A combined, baseline HCV antigen response of ≥168
IFN-γ ELISpots/106 PBMC was significantly associated with SVR.
43.2% of patients at or above this threshold experienced SVR vs. 28.2% of those
who did not (RR=1.53; p=0.007). Among CA, 53.3% at or above this threshold
experienced SVR, as compared to 38.5% of CAs who did
not. Among AA, 30.6% at or above this threshold experienced SVR, as compared to
22.5% who did not. Multivariable regression analysis confirmed the independent
association of baseline IFN-γ ELISpot response
with SVR (RR 1.37; p=0.04, see Table 1).
Conclusions:
Baseline HCV-specific immunity is associated with SVR
in patients undergoing antiviral therapy irrespective of race. Further analyses
of the factors associated with more vigorous CD4+ T cell responses to HCV that
correlate with an SVR are needed.
This study is funded by the NIDDK
through a cooperative agreement with partial support from Roche Laboratories
Inc. through a CRADA with the NIH.
|
Variable |
Relative Risk |
95% CI |
p-value |
|
Total IFN-γ ELISpots ≥168 vs. <168 (per 106 PBMC)
|
1.37 |
1.01-1.85 |
0.042 |
|
Baseline viral
level (log 10 IU/ml) |
0.59 |
0.46-0.77 |
<0.0001 |
|
% max pegIFN dose taken in 1st 24 wks (per 10% inc) |
1.38 |
1.18-1.64 |
<0.0001 |
|
CA vs. AA |
1.74 |
1.29-2.37 |
0.0003 |
|
Ishak score |
0.86 |
0.79-0.94 |
0.0006 |
|
Male vs. female |
0.76 |
0.61-0.96 |
0.0226 |
M. Kugelmas; A. L. Sabel-Soteres; G. Spiegelman
Background:
·
When treating patients with chronic
hepatitis C with pegylated interferon and ribavirin, hematologic
toxicity is one of the most common reasons for dose reduction and
discontinuation. These dose reductions
negatively affect the chance of achieving an early virologic response (EVR) during
therapy in patients with genotype 1 chronic hepatitis C infection.
·
EVR, which is defined as ≥
log drop in HCV RNA from baseline at week 12 of treatment, is a recognized
positive predictor of sustained virological respone
(SVR).
Aims
·
To determine whether the use of
growth factors and more lenient platelet cutoff points during anti-HCV therapy
results in better adherence to target doses of peginterferon
alfa and ribavirin, hiher EVR rates, and higher SVR
rate.
Methods:
Treatment-naive patients (N=160) with compensated chronic liver disease
secondary to chronic hepatitis C due to genotype 1 HCV infection were randomly
assigned to 2 treatment groups.
o
Patients who did not achieve a ≥
2 log drop in HCV RNA from baseline by week 12 of treatment were excluded from
the study and considered nonresponders
·
In Group A hemotologic
abnormalities were managed by dose reductions
·
In Group B patients were managed
with the use of group factors (below):
|
Hemotologic Abnormality |
Management |
|
Anemia (hemoglobin
<12 g/dL or decreased >25% from baseline |
|
|
Neutropenia
(absolute neutrophil count (ANC) <900/mm3 |
|
|
Thrombocytopenia |
|
Study End Points
·
Primary end point was assessment of
end-of-treatment response at 48 weeks and SVR after 24 weeks of follow-up
·
Secondary end points
o
Biochemical response (ALT levels)
o
Safety
·
Interim data are presented for
patients who completed at least 12 weeks of therapy.
Results
·
To date, 122 patients are enrolled
in the study
o
Sixty-three patients (n=30 (group
A); n=33 (group B) have completed at least 12 weeks of therapy
·
Patient demographics for the 63
interim-analysis patients are shown below:
o
Gender (42 males; 21 females)
o
Age, 46 ± 8 yo
o
Patients with high viral load
(>800,000 IU/mL) 60.3%
o
Liver biopsy fibrosis score-mean
1.7
o
Weight—mean 80 kg, mean ± 15
o
Race: Caucasian (n=55), African American (n=6),
Hispanic (n=1)
Early Virologic Response
Rates
·
In total, 23 (77%) of 30 patients
in group A and 24 (73%) of 33 patients in group B achieved an EVR
Dose Reduction and
Discontinuations
·
Overall, doses of anti-HCV
treatments were significantly more likely to be reduced in group A than in
group B (33 vs. 12%, respectively;
p=.04)
Group A
·
Ten (33%) of 30 patients in group
A had dose reductions
·
Ribavirin dose was reduced in 5
patients (n=2 (anemia) and n=1 each (flu like symptoms, shortness of breath,
and nondefined side effect))
·
Peginterferon alfa-2b dose was
reduced in 9 patients (n=3 (low ANC); n=2 (thrombocytopenia); n=2 (flu-like
symptoms); and n=2 (weight loss))
Group B
·
Dose reductions occurred in 4
(12%) of 33 patients in group B
o
Two patients required dose
reduction (ribavirin for hemoglobin <10 g/dl and peginterferon
alfa-2b for ANC <750/mm3)
o
Two patients had permanent dose
reductions (ribavirin for nausea and peginterferon
alfa-2b for weight loss)
·
Twenty-one (64%) of 33 patients in
group B received growth factors (darbepoetin
(n=16); filgrastim (n=2); darbepoetin and filgrastim (n=3))
·
In both treatment groups,
hemoglobin levels decreased from baseline through week 12
·
At week 12, hemoglobin levels were
significantly lower in group A than in group B patients (11.1 g/dl vs 12.2 g/dl, respectively; p=.04
Conclusion
·
Use of growth factors prevents
dose reductions of peginterferon alfa-2b and
ribavirin in HCV genotype 1 patients receiving anti-HCV therapy
·
Use of growth factors maintains
more physiologic hemoglobin levels
·
Ongoing results of this study will
show whether use of growth factors allows for higher SVR rates.
Abstract
S1063 – The usefulness of
sPECAM-1 and sVCAM-1 serum
concentrations measurement in the assessment of fibrosis, inflammatory activity
and antiviral therapy effectiveness in chronic hepatitis C
K. Zwirska-Korczala; M. Kukla; A. Ziolkowski; A. Berdowska; E. Janczewska-Kazek;
A. Gabriel; B. Rybus-Kalinowska; I. Korzonek-Szlacheta; T. Brzozowski;
S. J. Konturek
Background:
Platelet/endothelial cell adhesion molecule-1 (PECAM-1) and vascular
cell adhesion molecule (VCAM-1) soluble forms reflect their expression in the
tissue. The study was undertaken to answer the question whether there exists a
correlation of sPECAM-1 and sVCAM-1 serum levels with fibrosis stage and
inflammatory activity and if their levels can predict antiviral therapy
effectiveness.
Material and methods:
We studied 80 patients (40M/40F), aged 53.0±9.9 years, BMI 25.0±0.9
kg/m2 with chronic hepatitis C, receiving peginterferon
and ribavirin. Control groups included 20 HCV Ab-positive
patients with normal AST and ALT levels, without fibrosis and 14 healthy
volunteers age and BMI matched. Scheuer’s scale was
used for liver samples assessment. sPECAM-1 and sVCAM-1 measurements were made
using commercial methods.
Results:
We observed higher sPECAM-1 serum concentration in the patients’ group
compared to the control groups (p<0.001). They were lower in patients with
inflammatory grade 1 than grade 2 or 3 (p=0.03), and in fibrosis stage 3 they
were higher compared to stage 2 (p=0.01). After therapy sPECAM-1 level
decreased (p<0.001) and was slightly but not significantly higher in
non-responders. Serum sPECAM-1 levels correlated positively with inflammatory
activity (r=0.35, p=0.02) and fibrosis stage (r=0.53, p<0.001). Serum sVCAM-1
levels were higher in patients than in the group of healthy volunteers
(p<0.001). There was no correlation between serum sVCAM-1 concentrations and
morphological features in the liver.
Conclusions:
sPECAM-1 serum levels may be fibrosis progression predictor. Further
investigations are necessary to assess the relation between sPECAM-1 serum
fluctuations and therapy effectiveness. Serum sVCAM-1 has limited diagnostic
value in chronic hepatitis C.
Abstract
S1059 – Results of a Phase II dose ranging study of orally
administered celgosivir
as monotherapy in chronic hepatitis C genotype-1 patients.
E. Yoshida; D. Kunimoto; S. S.
Lee; M. Sherman; J. Heathcote; R. Enns
Background:
Celgosivir is a novel antiviral
agent in clinical development for treatment of chronic hepatitis C virus (HCV)
infection. Current standard therapy for HCV is associated with significant side
effects and limited efficacy. Novel treatments for HCV infection must aim to
provide improved efficacy and tolerability. Celgosivir
and its active metabolite castanospermine are potent
inhibitors of alpha-glucosidase I, a host enzyme that
alters the processing of glycoproteins. Inhibition of
this enzyme results in HCV envelope proteins that fail to fold correctly and
inhibition of viral assembly and release. This dose ranging monotherapy study
was designed to provide safety and efficacy data necessary to proceed to
combination therapy studies.
Methods:
This Phase II study was a 12-week, randomized,
dose-response, open-label, multi-center study in treatment-naďve or
interferon-intolerant genotype-1 HCV infected patients. Patients were
randomized to one of three celgosivir treatment
groups:
(i)
200 mg qd (every day),
(ii)
400 mg qd, or
(iii)
200 mg bid (twice a day)
These doses were evaluated tolerability and serum HCV
RNA during the study.
Results:
Forty-three patients were randomized (16-200 mg qd, 15-400 mg qd, 12-200 mg bid)
with 35 (81%) patients completing 12 weeks of therapy.
There was no clinically relevant mean change in viral
load from baseline when celgosivir was used as a
monotherapy at the three dose levels test.
Two patients (5%)
had peak viral load reductions of ≥ 1 log10. The first patient, randomized to the 200 mg
bid group, peaked at Week 4 (-1 log10 drop) and subsequently dropped
out due to non-compliance. The
second patient, randomized to the 200 mg qd group,
had a peak reduction at Week 8 (-1 log 10 drop) and was found to be
non-compliant past Week 10 through to study completeion.
Mild to
moderate gastrointestinal (GI) symptoms were the most frequently reported
adverse events with 67% of patients reporting flatulence, 26% nausea and 49%
diarrhea. Elevated serum creatine kinase
(CK) levels were reported in all treatments groups (47% of patients) and
appeared to be dose related with 12 (80%) patients in the 400 mg qd group compared with 5 (42%) patients at 200 mg bid and 3
(19%) patients in the 200 mg qd group. Elevations
were asymptomatic, reversible and returned to baseline levels within weeks
post-treatment. No serious adverse events were reported. Treatment was
discontinued for adverse events in 4 patients.
Conclusion:
Celgosivir, used as monotherapy in
chronic HCV infection, was well tolerated in all treatment groups with modest
antiviral effect. GI symptoms, particularly mild to moderate diarrhea and
flatulence, were the most frequently occurring adverse events. Elevated serum
CK levels were noted in about half the patients but were reversible, not clinically
significant, and returned to baseline levels post-treatment. Based on
non-clinical synergy data, combination therapy of celgosivir
with peginterferon alfa-2b with or without ribavirin
may produce more significant antiviral activity and is the subject of an
on-going study.
S. Kaiser; H. Hass; B. Lutze; M. Gregor
Objective:
Treatment with
pegylated interferon and RBV for 48 weeks in naive chronic Hepatitis C patients
results in relapse rates of about 20 – 30 %.
Recently improved response rates have been observed in retreatment trials using an extended treatment duration of
72 weeks.
Methods:
The efficacy
of CIFN daily dosing + RBV versus PEG IFN a2a + RBV for 72 weeks in patients
with a prior relapse to 48 weeks of treatment with PEG IFN + RBV was evaluated.
81 patients have been included, with 83% having genotype 1. Average weight of
patients was 78 kg. Patients were either treated with CIFN at 9 ug QD for 72 weeks or with PEG IFN a2a at 180 ug QW for 72 weeks, both in combination with weight-based
RBV.
Results:
Data show that
after the initial 12 weeks a primary response with undetectable serum HCV-RNA
was observed in 83 % of patients in the CIFN QD group and in 78 % in the PEG
IFN 180 ug group. At the end of treatment at week 72,
a negative PCR was observed in 89 % in the CIFN group, and in 76% of the PEG
IFN 180 ug group (diff. not significant). The
sustained viral response rates (SVR) were 69 and 44 %, respectively
(p<0.05), indicating a significantly higher relapse rate in patients treated
with PEG IFN a2a.
No growth factors
were used in this study. Three patients experienced grade III thrombocytopenias, while no grade IV neutropenias
or thrombocytopenias were observed. The overall
tolerability of the CIFN QD regimen was comparable to the PEG IFN a2a therapy,
while the CIFN QD regimen lead to a higher rate of injection site reactions and
a slightly higher drop out rate of 18% versus 12% for the PEG IFN a2a group. In
contrast, hematologic grade III alterations were
higher in the PEG IFN a2a group.
Conclusions:
Extended CIFN
daily dosing combination therapy for 72 weeks shows promising response rates in
comparison to PEG IFN a2a combination therapy in previous relapse patients to
standard PEG IFN / RBV therapy. The data are especially interesting since most
patients were genotype 1 relapsers. Although a significant proportion of
patients experienced a second relapse after cessation of therapy, the overall
sustained response rates are nevertheless promising showing a SVR in up to 70%
of patients. It is concluded that extended treatment with CIFN in combination
with RBV may be an effective treatment modality for this difficult-to-treat
patient group.
Abstract
S1061 – Higher Susceptibility of Peginterferon alfa 2a
versus Peginterferon alfa 2b Nonresponder Patients with Chronic
Hepatitis C to Retreatment with Consensus Interferon
Daily Dosing and Ribavirin
S. Kaiser; H. Hass; B.
Lutze; M. Gregor
Objective:
Current standard treatment with pegylated interferon (PEG
IFN) and ribavirin (RBV) in genotype 1 patients shows sustained response rates
of 31 – 47%, thus leaving more than half of the patients with a relapse or nonresponse to . Recently improved response rates have been
observed in pilot trials using consensus interferon (CIFN) in combination
therapy in PEG IFN / RBV nonresponders.
Methods:
The efficacy of CIFN daily dosing and induction therapy
followed by CIFN / RBV in PEG IFN combination treatment nonresponders was
evaluated. 95 patients have been included, with 9% having genotype 1. Average
weight of patients was 76 kg. Patients were either treated with CIFN at 9 ug QD for 16 weeks or with CIFN 27 ug
QD for 4 weeks, followed by 12 weeks of CIFN 18 ug
QD. Thereafter, treatment was continued in all treatment groups with CIFN at 9 ug QD with weight-based RBV for 32 - 56 weeks, depending
when a patient became first PCR negative, ensuring a treatment period for 48
weeks with a negative PCR.
Results:
Data show that after the initial 12 weeks of CIFN
monotherapy, a primary response with undetectable serum HCV-RNA was observed in
35 % of patients with a prior nonresponse to PEG IFN
a2b and in 51 % in prior PEG IFN a2a nonresponders. At the end of treatment, a
negative PCR was observed in 37 % in PEG IFN a2b nonrespinders,
and in 51% of PEG IFN a2a nonresponders. The sustained viral response rates
(SVR) were 21% and 38% for PEG IFN a2b and PEG a2a nonresponders, respectively.
When response rates were calculated according to the
treatment arm used, the SVR for PEG IFN a2b nonresponders were 18% in the CIFN
9 ug arm and 25% in the CIFN high dose arm. For PEG
IFN a2a nonresponders the SVR were 34% and 41% for the CIFN 9 ug dose and high dose arms, respectively. The overall
tolerability of the CIFN 9 ug regimen was comparable
to a standard therapy with pegylated IFN and RBV, while the CIFN 27/18/9 ug regimen was less tolerable during the high dose
induction period. However, drop out rates were not different between the two
dosing regimen.
Conclusions:
CIFN daily dosing / induction therapy together with
subsequent RBV combination therapy thus shows promising response rates in
previous PEG IFN combination therapy non-responders. Especially PEG IFN a2a
nonresponders appear to have a benefit from CIFN QD retreatment.
It is concluded that CIFN may be an effective treatment modality for this
difficult-to-treat patient group.
J. McHutchison; R. Ghalib; E. Lawitz; B. Freilich; P. Kwo; F. Masciari; J. L. Himes; M.
Al-Adhami; B. Bacon
Background:
CPG 10101 (CPG) is an investigational Toll-like receptor 9
(TLR 9) agonist with antiviral activity. CPG directly activates B cells and plasmacytoid dendritic cells (pDC) and stimulates the innate immune system to produce Th1
cytokines, including those with known antiviral activity (e.g., IFN-α).
This Th1 environment, combined with improved antigen presentation by pDC, promotes HCV-specific adaptive T cell responses.
Standard treatment of chronic HCV with pegylated IFN-α (PEG) and ribavirin
(RVN) for 24-48 weeks, results in sustained viral responses (SVR) in ~ 50%
naďve genotype 1-infected patients. This study investigates CPG’s
potential to exploit immune-mediated HCV infection control mechanisms when used
with standard of care treatment in prior relapse patients.
Methodology:
Sevent-four
HCV genotype 1-infected adults that previously responded to ≥24
weeks PEG + RVN treatment, then relapsed with subsequent detection of HCV RNA
within 6 months, are to be enrolled and randomized equally to five arms:
(i)
Peginterferon plus ribavirin
(ii)
CPG 10101 plus
Peginterferon plus ribavirin
(iii)
CPG 10101 plus pegylated interferon
(iv)
CPG 10101 plus ribavirin
(v)
CPG 10101
Treatment is for 12 weeks:
CPG 101 =0.2 mg/kg SC weekly, Peginterferon =1.5 μg/kg SC weekly; ribavirin =800-1400 mg QD, po).
Hematology and chemistry are assessed at weeks 1, 2, 3, 4, 8
and 12 and HCV RNA (viral load assessed at baseline, weeks 2, 4, 8 and 12.
Summary of 12 week safety
· CPG 10101 was generally
well-tolerated
o
AE were transient and consistent with mechanism
· No grade 2 anemia in any
CPG-contain arm
· No significant increase in
severity of neutropenia following the addition of CPG 10101 to pegylated
interferon with/without ribavirin
· AEs were predominantly mild
in intensity in all groups