Abstract
ID: S1531
W.
Bocher, M. Fuchs, P. Buggisch,
S. Kaiser, R. Link, J. Nalop, C. Antoni,
J. Schlaak, T. Witthöft,
P.R. Galle, H.F. Löhr
Introduction
Consensus
interferon (CIFN) is a synthetic type 1 interferon with enhanced in vitro
activity compared to conventional
IFN-alfa (IFNa). In the prospective, randomized multicenter PegIntron-Against-Consensus-Trial
(PACT), the efficacy and safety of daily CIFN-treatment and ribavirin is
compared to peg-IFNa2b plus ribavrin.
Methods
400
patients with chronic HCV infection and serotype-2 or -3 will randomly be
assigned to treatment with 9 mcg qd CIFN sc. (group
A) or peg-IFNa2b (1,5 mcg/kg body weight once weekly, group B), each in
combination with ribavirin (>10,6 mg/kg body weight) for 24 weeks. Treatment
is interrupted for primary non-response, if viral load drops by less than 2 log
until week 12 or drops by more than 2 log but remains positive at week 16.
Follow up includes further 24 weeks. Viral response rates are analysed by the Roche COBAS Amplicor
HCV Monitor v2.0 test. 129 patients out of 199 patients enrolled before
November 2004 reached at least the end of treatment at week 24 and represent
the base of this interim analysis. At the Meeting, ETR data of 170 patients
will be presented.
Results
There
were no significant differences in patient baseline characteristics between
both treatment groups concerning age, gender, genotype and viral load. The
virological response rates analysed as
intend-to-treat are shown in the Table:
|
|
|
Group |
A |
|
Group |
B |
|
|
wk 12 (n=67) |
wk 24 (n=68) |
wk 48 (n=43) |
wk 12 (n=60) |
wk 24 (n=61) |
wk 48 (n=38) |
|
PCR neg |
99% |
93% |
95% |
92% |
94% |
95% |
Thus,
end-of treatment response (ETR) rates as well as sustained virological response
(SVR) rates were very high and identical in both treatment groups. This was
also true for all subgroup analyses, including analysis according to baseline
viral load (< vs. ≥ 800.000 IU/ml) gender, body weight (< vs. ≥
75 kg) and age (< vs. ≥ 60 yrs). Treatment was rather well tolerated
in both treatment groups, as there were no significant differences in the
numbers of serious adverse events or preterm treatment discontinuations.
Conclusions
In
treatment-naive patients with chronic hepatitis C and serotype-2 or -3
infection, daily treatment with CIFN combined with ribavirin has the same
antiviral efficacy and safety profile as weight adjusted peg-IFNa2b. Further
analyses will show, whether some subgroups might preferentially benefit from
one or the other interferon.
Abstract
ID: S1546
G.
Hammoud, J. Li, K. Vega, P. Wludyka,
B. Rodwick, D. Parks, M. Davis, R. Berggren, R. Emgunsnov, R. Eng, D. Lintz, K.
Casey, D. Mayorga, L. Lambiase
Background
African American
monoinfected patients are known to have a lower response to hepatitis C virus
therapy in comparison to Caucasian patients. Moreover, HIV/HCV coinfected
patients have a lower response to HCV therapy than
monoinfected patients. We investigated the difference in response to HCV
combination therapy using two different doses of peginterferon α-2b in
HIV-infected African American (AA) patients.
Aim
To evaluate the efficacy of the standard dose
peginterferon α-2b versus the low dose peginterferon α-2b in addition
to a weight based ribavirin in HIV/HCV coinfected naïve and non-responder African
American patients.
Methods
Originally, this study
was designed to investigate the response to two different doses of
peginterferon α-2b among different racial groups. We present a
sub-analysis of the response among African American subjects in the two arms.
Sixty three patients were enrolled and randomized to low dose (LD, n=32)
peginterferon alpha-2b 1.0 mcg/kg administered once/week and standard dose (SD,
n=31) peginterferon alpha-2b 1.5 mcg/kg administered once/week. Both groups
received ribavirin at 13±2 mg/kg administered twice daily for 48 weeks. Five
Latino patients were excluded from this analysis (SD=3, LD=2). The remaining 58
patients are (African American = 31, males=20, LD=15, SD=16, naïve=20, genotype
1=29, median HCV viral load 850,000 IU/ml), (Caucasians=27, males=20, LD=15,
SD=12, naïve=18, genotype 1=20, median HCV viral load=837,140). HCV was
measured by a quantitative PCR assay at baseline, week 12, 24, 48 and 72.
Sustained virologic response (SVR) is defined as
undetectable HCV six months post therapy.
Results
Seven patients (12%)
achieved sustained viral response (AA = 2 (3%) and Caucasians = 5 (9%), p =
0.16). None of the AA patients with genotype non-1 (6%) achieved SVR while only
two Caucasian patients (7%) with genotype non-1 had SVR on low dose (22%),
(p=1.0). One previous non-responder AA patient (3%) achieved SVR on HD (2%),
while non of the previous non-responder Caucasian patients had SVR and only
four naïve Caucasian patients (15%) achieved SVR on low dose (p=0.09).
Conclusion
African American
patients had a better response with standard peginterferon α-2b especially
in a previous non-responder to standard interferon, while Caucasian patients
had a better response with low dose peginterferon α-2b, however, this did
not reach statistical significance due to the small number of patients with SVR
in both arms.
Abstract
ID: 5
T.
Poynard, E. Schiff, R. Terg,
F. Goncales, S. Flamm, M. Diago, J. Reichen, R. Moreno, H. Tanno, J. McHutchison, H. Fainboim, T. Berg, A. Mattos, K. Burak, P. Mukhopadhyay, P. Bedossa, L. Griffel, M.
Burroughs, C. Brass, J. Albrecht
Introduction
EPIC3 is a
large, prospective, controlled trial designed to understand 1) the efficacy of
treatment with PEG-Interferon a2b and
ribavirin weight based dosing for 48 weeks in previous treatment failures to
any interferon-a
and ribavirin therapy and 2) for non-responders to PEG-Interferon a2b
and ribavirin, to determine the efficacy of PEG-Interferon a2b
0.5 mg/kg/week
compared to no treatment in either delaying progression of hepatic fibrosis or
preventing end stage liver disease in cirrhotics.
Aim
The SVR rate in a
similar population (HALT-C) retreated with PEG-Interferon alfa-2a plus
ribavirin was low (12%). This led us
to examine the SVR to PEG-Interferon
a2b and
ribavirin weight based dosing in the first 575 patients in EPIC3. Additionally, we evaluated the ability of
early virologic response (EVR [>2 log10
decrease or undetectable HCV-RNA at week 12]) to predict the likelihood of
achieving SVR (undetectable HCV-RNA at follow up [FU] weeks 12 or 24).
Methods
HCV +
patients that did not respond (NR) or had relapsed after previous treatment
with any interferon-a
and ribavirin received PEG-Interferon
a2b 1.5 mg/kg
subcutaneously once weekly plus ribavirin 800-1400 mg/day weight based dosing for
up to 48 weeks. All patients had pre-treatment biopsies scored by a single
reviewer using METAVIR criteria. Plasma HCV-RNA was determined at weeks 12, 24
and 48 of therapy and FU 12 and 24 using a quantitative Taq-Man
assay (SPRI; sensitivity 29 IU/mL). Genotype was determined by sequencing the
PCR product.
Results
Of the first 575
patients enrolled in the combination therapy trial, 21% achieved SVR. Of those
who attained EVR, 38% achieved SVR: 61% of those that were HCV-RNA (-) at week
12 achieved SVR, but only 5% of those who attained EVR with detectable viral
load. SVR was higher in genotype 2/3 patients (54%) compared to genotype 1
patients (16%) and greater in previous relapsers (39%) compared to NRs (15%). SVR was higher in F2/3 (27%) patients compared
to F4 patients (14%). NRs and relapsers who were
HCV(-) at week 12 were equally likely to achieve an SVR (61% vs. 59%). SVR was
higher in G2/3 than G1 NRs (47% vs. 12%) and
relapsers (58% vs. 29%).
Conclusions
Retreatment
with PEG-Interferon a2b plus
weight based ribavirin achieves sustained virologic
response in a substantial proportion of interferon-a and ribavirin treatment failures who are
HCV-RNA (-) at treatment week 12.
Abstract
ID: S1575
K. Tang, E. Paulon, E. Herrmann, N. Tatman, s. Zeuzem, R.
Williams, N. Naoumov
Background
Hepatitis C virus (HCV)
genotype is the major determinant for the duration and success rate of
antiviral therapy in chronic hepatitis C (CHC). Better understanding of viral
and host factors associated with these differences is needed to develop more
effective treatment regimens.
Aims
To analyse
and compare early HCV kinetics and HCV-specific T-cell reactivity during
peginterferon-a2a/ribavirin treatment (P2aR) in patients with CHC-G1, G3 and
G4.
Methods
Twenty, treatment-naïve,
non-cirrhotic patients with CHC (10 HCV-G1; 5 HCV-G3a; 5 HCV-G4a) were treated
with P2aR. HCV viral load was quantitated by
real-time RT-PCR at days: 0, 1, 2, 3 and weeks 1, 2, 4, 8, 12 after treatment
initiation. Peripheral blood lymphocytes were obtained serially and CD4+ T-cell
reactivity to HCV Core, NS3 and NS4 antigens was assessed by IFNg ELISpot assays. Mathematical
modelling was employed to determine the patterns of
viral kinetics. Results: Similar baseline characteristics existed between the 3
genotype groups. The mean (±SEM) antiviral efficacy ‘e’ (phase 1 viral decline)
was significantly lower for G1 (72.1%±6.0) compared with G3 (94%±3.6, p=0.002)
and G4 (76.4%±19.1, p=0.01). Infected cell loss (Md)
was greatest among G3 patients (1.5±0.8/day), followed by G4 (0.7±0.3/day),
then G1 (0.3±0.3/day). A further analysis, using a previously determined
threshold Md value correlating with SVR (0.25/day),
identified two subsets of G1 patients: 5 fast responders (G1-FR) and 5 slow
responders (G1-SR). All 5 G3 and 3/5 G4 patients were fast responders. The mean
Md value of G1-FR (0.5±0.1) was similar to G4
(0.7±0.3; p=0.6), whereas the Md of G1-SR (0.1±0.04)
was significantly lower than G3, G4 and G1-FR (all p<0.01). During therapy
no changes in HCV-specific T-cell reactivity were detected in G3 or G4 patients,
but temporal enhancement of T-cell reactivity was demonstrated amongst G1-FR,
peaking at TW12, compared to baseline reactivity (p = 0.016), but not in G1-SR
patients who had persistent viremia.
Conclusions
Early viral kinetic
profiles differ markedly between HCV genotypes during P2aR combined therapy.
The early on-treatment HCV decline is greatest in G3, followed by G1-FR and G4,
and lastly G1-SR. Rapid early HCV clearance, rather than strong antiviral
immunity, appears to be the main determinant for a high treatment response in
CHC G3; however, enhanced cellular immunity is associated with early viral
clearance only in the subset of CHC-G1 fast-responders.
Abstract
ID: S1578
A.J.
Uriel, Dr, L. Moorehead, J.
Park, Dr, D. Carriero, J. Lucas, M. Sulkowski, Dr, D.T. Dieterich
Background
Use of Pegylated
Interferon (Peg-IFN) and Ribavirin (RBV) for chronic Hepatitis C Virus (HCV)
infection is commonly associated with a reversible hemolytic anemia.
Individuals co-infected with Human Immunodeficiency Virus (HIV) and HCV, due to
the myelotoxic effects of HIV and/or antiretroviral
therapy (ART), may be at increased risk for developing anemia during HCV
therapy.
Aim
To assess the factors
associated with fall in hemoglobin (Hb) in a cohort of HIV/HCV patients (pts)
undergoing therapy with Peg-IFN and RBV
Methods
A retrospective analysis
of 89 HIV/HCV pts enrolled in a HCV re-treatment study (HRN 004) using Peg-IFN a2a and
optimized weight based RBV was undertaken. Nadir Hb levels in the first 8 weeks
were compared to baseline. Glomerular filtration rate
(GFR) was estimated using the MDRD formula of Levey
et al, and proteinuria on baseline urinalysis was
noted. Incidence of severe anemia (Hb < 10 g/dl), RBV dose reduction and
treatment cessation due to anemia during the first 24 weeks of therapy were
recorded. Linear regression was utilized to investigate the risk factors for
fall in Hb on therapy.
Results
Mean age of the cohort
was 48.5 years (+/- 6.1), 75 (84%) were male, 77 (87%) had HCV genotype 1 or 4,
median HCV RNA was 694812 IU/ml (IQR 449,004-5,266,006). Median CD4 count was
539 cells/mm3, 85% of the cohort was on ART, 30% were on zidovudine
(AZT). Median RBV dose was 13.1 mg/kg/day (IQR 12.4 –13.6). Median GFR was 96.7 mls/min
(84.8 – 112.4), 4 pts had proteinuria. Mean baseline
Hb was 14.7+/- 1.4 g/dl; mean fall in Hb by week 8 of therapy was 2.63g/dl +/-
1.47 with mean time to Hb nadir of 4 weeks. Using an intention to treat
analysis of outcomes at week 24 of therapy, 12.5% of pts had a fall in Hb to
< 10g/dl, 18% required RBV dose reduction, and 3 pts discontinued therapy
due to anemia. On multivariate analysis, female gender (p=0.0118) and GFR
(p=0.041) were significant negative predictors of anemia, whilst AZT use
(p<0.0001) and proteinuria (p=0.015) were
significant positive predictors. RBV dose was not a significant predictor of
anemia.
Conclusion
In this HIV/HCV cohort
on Pegasys plus ribavirin:
1.
The incidence of severe
anemia was similar to that reported in the HCV moninfected
(12.5%)
2.
Only 3% required
discontinuation of therapy due to anemia
3.
Males and subjects with
lower baseline GFR and/or proteinura had a greater
risk of anemia
4.
AZT use was a highly
significant risk factor with fall in HgB on therapy.
Patients with these risk
factors may require closer monitoring during therapy with Peg IFN and
ribavirin. Consider switching patients
to a non-AZT containing regimen prior to starting HCV therapy.
Abstract
ID: S1568
M.L.
Shiffman, M.W. Fried, P. Marcellin,
S. Govindarajan, J. Lopez-Talavera,
P.J. Pockros
Introduction
Treatment with peginterferon and ribavirin (PEGIFN/RBV) is the standard of
care for patients with hepatitis C virus (HCV) infection. Patients with chronic
HCV and advanced fibrosis or cirrhosis (CX) are at risk for developing disease
progression and hepatic decompensation and are therefore candidates for
treatment. In contrast, the risk:benefit ratio of
PEGIFN/RBV therapy is controversial for patients with mild or no fibrosis (NoF), particularly patients with HCV genotype 1 who have a
lower overall rate of sustained virologic response
(SVR). We therefore examined the relationship between liver histology, SVR and
the incidence of Laboratory abnormalities (LA) during treatment with PEGIFN
alfa-2a/RBV in patients with HCV genotype 1.
Methods
Data were reviewed from
328 patients with chronic HCV genotype 1 treated with PEGIFN alfa-2a (180 mg/week)
plus RBV (1000/1200 mg/day) for 48 weeks in two registration trials. All
patients had a baseline liver biopsy. A subset of the biopsies were assessed
for fibrosis by a local pathologist and staged as either NoF,
portal (PF), incomplete septa (IS) or CX. HCV RNA titer was determined by Roche
Amplicor. SVR and LAs were
examined as a function of baseline fibrosis score.
Results
The number of patients and SVR for each fibrosis
group are listed in the TABLE. Patients with NoF/PF
had an SVR of 56% (136/241) whereas 43% (37/87) of patients with IS/CX achieved
SVR (p<0.03). No significant differences in gender (73% male), race (82%
Caucasian), or baseline HCV RNA titer >800,000 IU/ml (67%) were present
between the 2 groups. In contrast, patients with IS or CX were older
(p<0.001). Only grade 3 thrombocytopenia was more frequent in patients with
IS/CX than noF/PF (10 % vs
2%; p<0.001). No grade 4 thrombocytopenia was observed.
Conclusion
o Among patients infected with HCV genotype 1, those with
early fibrosis achieved a superior SVR rate compared with patients with
advanced fibrosis when receiving treatment with peginterferon
alfa-2a and ribavirin
o These findings suggest that patients infected with HCV
genotype 1 and NoF/PF may benefit from early
treatment with peginterferon alfa-2a plus ribavirin
therapy because fibrosis progression appears to reduce the probability of SVR
o These findings support earlier reports of higher fibrosis
score predicting a lack of virologic response.
o The risk of hematopoietic adverse
events was lower in patients with early-stage fibrosis (NoF/PF)
than in patients with late-stage fibrosis (IS/CX)
|
Baseline Fibrosis score, N=328 |
N (%) |
SVR |
Age, Mean ± SD |
ALT, Mean ± SD |
|
NoF |
65 |
34 (52%) |
38 ± 10 |
84 ± 50 |
|
PF |
176 |
101 (57%) |
43 ± 10 |
114 ± 113 |
|
IS |
51 |
25 (49%) |
48 ± 10 |
133 ± 99 |
|
CX |
36 |
12 (33%) |
50 ± 8 |
151 ± 134 |
Abstract
ID: S1540
K. Reddy, J. Rakela, J. Lopez-Talavera, P.J. Pockros
Background
In patients with chronic
hepatitis C treated with peginterferon alfa-2a plus
ribavirin, a rapid virological response (RVR) is frequently an indication of
early virologic response (EVR) at week 12, and can
predict sustained virological response (SVR). Previous studies have shown that
patients who do not have a rapid and early decrease in HCV RNA may profit from
more extended treatment [Berg, et al AASLD 2004; Sanchez-Tapias,
AASLD, 2004]. We have analyzed the relationship between HCV RNA response at
week 4 and week 12 and SVR.
Patients and Methods
Data from 569
treatment-naïve patients infected with HCV genotype 1 and randomized to 48
weeks of treatment with peginterferon alfa-2a 180 mg/week
plus ribavirin 1000/1200 mg/day were analyzed. HCV RNA was assessed by
quantitative assay and qualitative PCR at weeks 4 and 12 and by qualitative PCR
at weeks 24 and 72.
Results
The overall EVR rate for the patients in this
analysis was 80.3% (457/569). The SVR rate for patients with EVR was 59.7% (273/457).
The relationships between week 4 and week 12 virologic
responses and SVR are shown in the Table. Patients with markedly lower SVR
rates were those with a ³1 and <2 log
decrease in HCV RNA at week 4 and those with a ³2 decrease in HCV RNA but ongoing viremia
at 12 weeks. An additional 133 patients had a > 2 log decrease
at week 12, 80 of whom were HCV RNA
negative by 24 weeks; this group had the lowest SVR rate.
Conclusions
o EVR (12-week viral response) is a better predictor of SVR
than RVR 4-week viral response)
o Patients who have a greater than or equal to 2 log decrease
but still have detectable HCV RNA at week 12 have a high rate of viral
re-emergence
o Additional clinical studies may determine the benefit of
prolonged treatment with peginterferon alfa-2a plus
ribavirin in those patients who have a greater than or equal to 2 log decrease
but still have detectable HCV RNA at week 12.
|
Virologic Response |
N=569 n, (%) |
HCV RNA undetectable at Week
24, n (%) |
SVR, n (% ) |
|
Week
4 |
|
|
|
|
>1
and <2 log decrease, HCV RNA+ |
121
(21.3) |
66 (54.5) |
34
(28.1) |
|
>2
log decrease, HCV RNA+ |
242
(42.5) |
215 (88.8) |
151
(63.4) |
|
Undetectable HCV RNA |
90
(15.8) |
83 (92.2) |
78 (86.7) |
|
Week
12 |
|
|
|
|
>2
log decrease, HCV RNA+ |
133
(23.4) |
80 (60.2) |
37
(27.8) |
|
Undetectable |
324
(56.9) |
301 (92.9) |
236
(72.8) |