Tuesday Poster Sessions,
Topic: Experimental Therapies – R1626
S. Le Pogam; A. Seshaadri; A. Kosaka; S. Hu; H. Kang; J.
Symons; K. Klumpp; N. Cammack; I. Najera
Introduction:
R1626, a prodrug of R1479, is a potent inhibitor of HCV
replication that has shown maximum mean (median) HCV RNA reductions of up to
3.7 (4.1) log10 following 2 weeks of monotherapy study), and 5.2 log10
following 4 weeks in combination with peginterferon alfa-2a (PEG-IFNα-2a)
± ribavirin (RBV) (phase 2A) in patients infected with HCV genotype 1. In vitro
studies have identified NS5B polymerase amino acid substitutions, S96T or
S96T/N142T, that result in 4-5-fold reduced sensitivity to R1479 as determined
in the replicon assay. These mutations also resulted in a ~95% reduction in
replication capacity compared to the wild type replicon.
Aim:
To study resistance development in vivo, phenotypic and
genotypic analyses were performed on multiple serum samples.
Patients
·
Serum
samples from patients involved in two multicenter, randomized clinical studies
designed to evaluate the safety, pharmacokinetics and antiviral activity of
R1626 in treatment-naïve patients chronically infected with HCV genotype (GT) 1
were used to evaluate the in vivo resistance selection:
o
Study 1 was a placebo-controlled, multiple
ascending dose, Phase 1b study with 47 patients who received oral R1626 at
doses of 500 mg, 1500 mg, 3000 mg or 4500 mg or placebo twice daily (bid) for
14 days with 14 days of follow-up
o
Study 2 was a Phase 2a study that
investigated R1626 in combination with PEGASYS and COPEGUS. 103 patients were
randomized to: R1626 (1500 mg bid) plus PEGASYS (Dual Low); R1626 (3000 mg bid)
plus PEGASYS (Dual High); R1626 (1500 mg bid) plus PEGASYS and COPEGUS (Triple
Low); or PEGASYS plus COPEGUS (standard of care) for 4 weeks
Viral resistance evaluation
o
The
viral load profiles of all participants were assessed for a viral rebound
phenotype defined as:
o
A
≥ 0.5 log10 IU/mL increase of viral load from nadir during treatment with
R1626, where nadir is defined as a ≥ 0.5 log10 IU/mL decrease from
baseline (lowest point)
o
Selection
of patient samples for resistance monitoring
o
Samples
from patients who experienced a viral load reduction ≥ 0.5 log10 IU/mL
followed by a viral load rebound were taken before treatment (baseline) and at
the time point after the viral load rebound was observed, which corresponded to
the end of treatment point for most patients. For 2 patients, the rebound
occurred earlier and the end of treatment time point was also included in the
study
o
Measurement
of sensitivity to R1479 in the HCV NS5B phenotypic assay
o
HCV
RNA was extracted from patients’ serum and the NS5B coding region was amplified
and cloned into replicon vectors (GT 1a samples in GT 1a H77 replicon and GT 1b
samples in GT 1b Con1 replicon). Ninety-six clones of each sample were pooled
to represent the viral genetic diversity present in the patients
o
In
vitro transcribed replicon RNA containing the NS5B region from the clinical
isolates was transfected into cured-Huh7 cells
o
R1479
(or medium as a control) was added 24 hours post-transfection in 3-fold
dilutions at a final DMSO concentration of 1%
§
Firefly
luciferase reporter signal was read 72 hours after addition of compounds and
the IC50 values were assessed as the compound concentration at which a 50%
reduction in the levels of firefly luciferase reporter was observed as compared
to control samples in the absence of compound
o
Sequencing
of NS5B coding region
o
The
entire NS5B polymerase coding region was sequenced
o
Detailed
analysis of the NS5B viral quasispecies was performed by sequencing of the 96
molecular clones included in the pool to represent the viral genetic diversity
Results
R1626 showed a time- and dose-dependent HCV RNA reduction in
monotherapy and combination therapy
o
Study
1: Time- and dose-dependent reductions in HCV RNA levels were achieved with
mean HCV RNA reductions of up to 3.7 log10 IU/mL following 2 weeks of monotherapy
o
Study
2: Time- and dose-dependent reductions in HCV RNA levels were achieved with
mean reductions of 5.2 log10 IU/mL in patients treated with Triple Low, 4.5
log10 IU/mL in patients treated with Dual High, 3.6 log10 IU/mL in patients
treated with Dual Low and 2.4 log10 IU/mL in patients treated with SOC after 4
weeks
R1626 resistance
evaluation
o
Among
all 150 participants from all dose groups in both studies, 11 patients
experienced a viral load rebound as follows:
o
3
patients from the 500 mg bid dose group in the monotherapy study
o
8
patients from the combination therapy study:
§
3
in the R1626 1500 mg bid plus PEGASYS group
§
4
in the R1626 3000 mg bid plus PEGASYS group
§
1
in the PEGASYS plus COPEGUS (standard of care) group
o
Among
all participants from all dose groups in both studies, 3 patients did not
respond to the treatment in the 500 mg bid dose group of the monotherapy study
No reduction in sensitivity to R1479 after up to 28
day treatment
o
Phenotypic
characterization of the clinical isolates from patients receiving R1626
monotherapy that experienced a viral load rebound showed no change in
susceptibility to R1479, with a 0.7–1.4-fold shift in IC50 at Day 14 compared
to baseline; these values are well within the 2.6-fold variability of the assay
compared to baseline sample and compared to reference controls (HCV GT 1a H77
and GT 1b Con1 reference strains, data not shown)
o
Phenotypic
characterization of the clinical isolates from patients receiving R1626
combination therapy study showed no change in susceptibility at any of the time
points compared to their respective baseline or to the reference controls
o
Phenotypic
characterization of the clinical isolates from patients receiving R1626
monotherapy that did not respond to the treatment showed no change in
susceptibility to R1479
o
The
patients who had viral rebound in the monotherapy study had low levels of R1479
in plasma as shown by the pharmacokinetic data presented in Table 1. Cmin
values were lower (0.42 to 1.33 μg/mL) than the overall Cmin range (0.86
to 5.98 μg/mL)
o
All
patients who showed viral rebound on combination therapy had discontinued
therapy or had dose reductions.
No known R1479 resistance mutations nor other common substitutions in any of the patients that showed a viral
load rebound during treatment or a non response to R1626
o
In
the monotherapy study, NS5B sequence comparisons between baseline and day 14
time points revealed no pre-existing amino acid substitutions (S96T or
S96T/N142T) known to be responsible for in vitro resistance to R1479 nor common
amino acid changes across the three patients that showed a viral load rebound
before the end of treatment
o
Likewise,
NS5B sequence comparison between baseline and treated time points from the combination
therapy study revealed no known R1479 resistance mutations nor any other common
amino acid substitutions selected upon treatment. Detailed analysis of the
quasispecies of all rebound samples (~1000 NS5B molecular clones) did not show
any known R1479 resistance mutations at baseline or during treatment at low
level (sensitivity of 1%)
o
In
the patients that did not respond to R1626 monotherapy, no known R1479
resistance mutations nor other common substitutions were found. Detailed
analysis of the NS5B viral quasispecies of the baseline sample showed no
pre-existing amino acid substitution responsible for resistance to R1479
No pre-existing amino
acid substitutions were observed at baseline that could be a predictor of
treatment outcome (response or failure)
Conclusions
o
R1626
exhibited a strong HCV antiviral effect in monotherapy and combination therapy.
o
The
absence of evidence for phenotypic and genotypic changes in patients with viral
rebound demonstrates a lack of selection of viral resistance to R1626 after up
to 4 weeks of treatment
o
The
viral load rebound observed in a few patients treated with R1626 was likely due
to inadequate drug levels (all were from the lowest dose arm of the monotherapy
study or following drug dose reduction or discontinuation in patients in the
combination study)
o
Despite
the inadequate plasma levels of R1479 in the studied patients (that could
represent an opportunity for the selection of drug resistant variants), there
was no selection of viral resistance to R1626, neither at a population level
nor at low level in the quasispecies, as evaluated through the extensive study
of molecular clones
o
Sequence
analysis revealed a lack of pre-existing amino acid substitutions at baseline
that could be a predictor of treatment outcome (response or failure)
o
Given
that in vitro studies have shown the poor replication capacity of S96T and
S96T/N142T R1479-resistant replicons,2 the lack of selection of viral
resistance after up to 4 weeks of treatment may indicate that R1626 exhibits a
high genetic barrier to selection of viral resistance
o
R1626,
appears to be a promising agent for treatment of patients chronically infected
with HCV genotype 1
Topic: Diagnostic Tools
C. Sarrazin; M. L. Shiffman; S. J. Hadziyannis; A.
Lin; G. Colucci; H. Ishida; S. Zeuzem
Background:
HCV treatment is rapidly evolving from a fixed duration of
peginterferon alfa-2a (40KD) plus ribavirin (RBV) (48wks for genotype [G] 1;
24wks for G2/3) to response-guided therapy (RGT), adjusting duration according
to on-treatment virologic response at wk4 and wk12; rapid virologic response
(RVR) and complete early virologic response (cEVR), respectively. RGT
originally used sensitive PCR assays (e.g. COBAS Amplicor HCV, v2.0; detection
limit 50 IU/mL). It is unclear how the more sensitive TaqMan assay (COBAS
AmpliPrep/COBAS TaqMan HCV Test: detection limit 15 IU/mL) will influence RGT.
We therefore reanalysed serum samples (stored at –70°C) from two large international
studies, ACCELERATE (G2/3) and NV15942 (G1,2&3),
and compared clinical outcomes when using Amplicor or TaqMan.
Methods:
In ACCELERATE, TaqMan data were available from patients who had
sufficient sample volume at baseline (BL; n=122) and wk4 (n=663). In NV15942,
TaqMan data were available from patients who had BL, wk4, wk12, end of
treatment (EOT) and end of follow-up samples (n=629). RVR rates and sustained
virologic response (SVR) rates in patients with RVR were compared by Amplicor
or TaqMan (HCV RNA <15 IU/mL [undetectable or below the limit of detection]
or Undetectable [true negative]) in G2/3 (ACCELERATE) and G1 (NV15942) patients
treated with peginterferon alfa-2a (40KD) plus RBV standard dose. cEVR (HCV RNA-negative at wk12) and relapse rates were
compared by these two tests in G1 and G2/3 patients in NV15942. BL viral loads
were compared by Amplicor Monitor v2.0 and TaqMan in G2/3 patients in
ACCELERATE.
Results:
RVR and SVR rates were similar when RVR was defined as <50
IU/mL or <15 IU/mL regardless of genotype (Table). RVR rates were slightly
lower when defined as HCV RNA undetectable by TaqMan. cEVR
rates were similar when cEVR was defined as <50 IU/mL or <15 IU/mL. Relapse
rates were lowest when TaqMan undetectable cut-off was utilized to determine
EOT response. BL viral loads were well correlated between the two tests.
Conclusions:
A detection limit of <15 IU/mL by TaqMan serves as a reasonable
definition of RVR and cEVR, along with <50 IU/mL, for RGT, regardless of
genotype. The significance of HCV RNA “undetectable” by TaqMan should be
investigated in prospective trials.
|
Definition of response: |
Amplicor <50 |
TaqMan <15 |
TaqMan UD* |
|
|
RVR SVR(pts with
RVR):16wks Tx SVR(pts with RVR):24wks Tx |
G2/3,n=663 |
50% 82% 91% |
49% 83% 91% |
37% 83% 91% |
|
RVR SVR(pts with RVR):24wks Tx SVR(pts with RVR):48wks Tx |
G1,n=164 |
32% 91% 100% |
32% 90% 94% |
24% 89% 91% |
|
cEVR§ |
G1,n=169 G2/3,n=135 |
77% 97% |
76% 98% |
68% 96% |
|
Relapse rate |
G1:48wks Tx,n=109 G2/3:24wks Tx,n=77 |
18% 9% |
15% 8% |
14% 5% |
RBV standard dose: 1000/1200mg/d
for G1, 800mg/d for G2/3; *UD: Undetectable; §cEVR: –ve at wk12.
Topic: HIV/HCV Coinfection - Pegasys
M. Rodriguez-Torres; F. Torriani; J. Rockstroh; J.
Depamphilis; G. Carosi; D. T. Dieterich
Background:
Patients coinfected with HIV-HCV represent a challenging
population to treat. In the APRICOT study coinfected patients treated with 180
µg/wk peginterferon alfa-2a (40KD) and 800 mg/d ribavirin achieved an SVR rate
of 40% (29% genotype [G] 1; 62% G2/3). These rates compare poorly to those in
monoinfected patients. In monoinfected patients serum samples collected at wks
4 and 12 are increasingly being used to guide therapy decisions
(response-guided therapy). There are limited data in coinfected patients on
whether early treatment responses are also useful to predict rates of SVR and
how rates of SVR in early responders compare between monoinfected and
coinfected patients.
Methods:
Patients included in this analysis were all patients from the
APRICOT study randomised to 180 µg/wk peginterferon alfa-2a (40KD) and 800 mg/d
ribavirin with G1, 2 or 3 HCV. Rates of SVR were determined as a function of
response to therapy at wk 4 and 12. RVR was defined as undetectable HCV RNA
(<50 IU/mL) at wk 4; complete EVR (cEVR) was defined as non-RVR but
undetectable HCV RNA (<50 IU/mL) at wk 12; partial EVR (pEVR) was defined as
non-RVR but ≥2 log reduction from baseline in HCV RNA but remaining
detectable HCV RNA (>50 IU/mL) at wk 12; SVR was defined as undetectable HCV
RNA (<50 IU/mL) 24 wks after the end of therapy.
Results:
Data from 271 patients were included (Table). Rates of SVR
for G1 and G2/3 were greatest in patients achieving an RVR (G1 = 81.8%; G2/3
94.3%), followed by cEVR (G1 = 63.2%; G2/3 69.7%) and then pEVR. Patients not
achieving an RVR or cEVR/pEVR had minimal chance of achieving an SVR.
Considering only patients with pEVR, rates of achieving SVR were influenced by
several baseline and treatment factors indicating that response in this category
of patients is heterogeneous.
Conclusions:
Coinfected patients who achieve an RVR have a similarly high
chance as monoinfected patients of achieving an SVR irrespective of genotype.
Patients that achieve cEVR also have similarly high rates of SVR as in
monoinfected patients. As in monoinfected patients RVR is the strongest
predictor for SVR, but in addition achieving a cEVR is also highly predictive
of achieving an SVR.
|
Early response category |
SVR rate n/N (%) |
|
|
Genotype 1 (n=176) |
Genotype 2/3 (n=95) |
|
|
RVR |
18/22 (81.8) |
33/35 (94.3) |
|
cEVR |
24/38 (63.2) |
23/33 (69.7) |
|
pEVR |
8/46 (17.4) |
2/11 (18.2) |
|
No RVR/EVR |
1/70 (1.4) |
1/16 (6.3) |
Topic: Current Treatment - Pegasys
P. Ferenci; H. Laferl; T. Scherzer; H. Brunner; A.
Maieron; M. Gschwantler; R. E. Stauber; R. Hubmann; K. Staufer; C. Datz; M.
Bischof; H. Hofer; K. Löschenberger ; P. E. Steindl-Munda
Background:
The rate and extent of virological response to therapy in
patients infected with HCV genotypes (G) 1 or 4 is highly variable.
Retrospective analyses show that patients treated with peginterferon alfa-2a
(40KD) plus ribavirin (RBV) who achieve an RVR (HCV RNA <50 IU/mL at wk 4)
may achieve an SVR after only 24 wks, while patients with a slower response may
benefit from prolonged therapy. This prospective study investigated response-guided
therapy of Peg-IFN alfa-2a (40KD) plus RBV in G1 and 4 patients based on RNA
level at wk 4 & 12. We aimed to evaluate whether patients with RVR, EVR
(HCV RNA <600 IU/mL or ≥2-log drop) and non-responders (NR) can be
differentiated at baseline (BL). We will present the final data for the 24 wk
treatment arm (Arm D).
Methods:
Treatment-naive G1 and 4 chronic hepatitis C patients were
treated with Peg-IFN alfa-2a (40KD) 180 μg/wk
plus RBV 1000/1200 mg/day prior to allocation to one of four arms based on RNA
tests at wk 4 & 12. At wk 4, patients with an RVR were assigned to a
further 20 wks of therapy (Arm D). All other patients continued to receive
treatment until wk 12 when RNA was retested. Patients with an EVR were
randomized to a total of 48 (Arm A) or 72 wks (Arm B) of treatment. Wk 12 NRs
were offered to continue treatment for a total of 72 wks (Arm C). Treatment was
stopped if RNA remained detectable at wk 24.
Results:
Of the 580 patients screened 510 patients (G1=443; G4=67) received
treatment and were evaluable. Of these 121/443 (27.3%) G1 patients and 29/67
(43.3%) G4 patients had an RVR and were allocated to Arm D. RVR was associated
with younger age, lower body weight, lower BL viral load, and G4. By multiple
logistic regression analysis viral load (high vs. low OR: 0.26 [95% CI:0.16–0.41]) and genotype (1 vs. 4: OR: 0.29 [95%
CI:0.16–0.56]), body weight and ALT but not fibrosis were significantly
associated with not achieving an RVR. The outcome of patients with RVR is shown
in the table.
Conclusion:
More patients with G4 than with G1 achieved an RVR. Both G1
and G4 patients with RVR achieved high rates of SVR with 24 wks of treatment.
These rates are similar to rates of SVR in G1 patients achieving an RVR with 48
wks of therapy. We confirm that a substantial proportion of patients with G4
and G1 benefit from shortening therapy to 24 wks. Here we show that RVR is
predictive of SVR in G4 patients and that G4 patients with an RVR have an even
greater chance of achieving an SVR compared to G1 patients.
|
Genotype |
Pts with RVR n/N (%) |
Per protocol SVR rate in pts with an RVR (%) |
Per protocol relapse rate in pts with
an RVR (%) |
|
1 |
121/443 (27.3%) |
90/103 (87.4%) |
13/103 (12.6%) |
|
4 |
29/67 (43.3%) |
25/26 (96.2%) |
1/26 (3.8%) |
Topic: Experimental Therapies - HCV-796
S. Villano; D. Raible; D. Harper; P. Chandra; L.
Bazisotto; G. Bichier
Background:
HCV-796 is an inhibitor of hepatitis C virus (HCV)
RNA-dependent RNA polymerase that has demonstrated clinical antiviral activity
across multiple HCV genotypes when administered as monotherapy or in
combination with pegylated interferon alfa-2b (PEG2b). We further evaluated
HCV-796 when administered with pegylated interferon alfa-2a (PEG2a).
Methods:
Evaluations were performed within a randomized, double-blind,
Phase 1 study in adult patients with chronic HCV infection who were naïve to
treatment. In one group, patients were randomized to receive oral HCV-796 or
placebo Q12h for 14 days, and all were to receive PEG2b (1.5 mcg/kg) on day -1
(one day before start of HCV-796/placebo) and day 7. In another group, the
design was the same except the PEG therapy was PEG 2a (180 mcg) on day -1 and
day 7. In each group 12-16 patients were to receive the active HCV-796 (500 mg
Q12h) with one of the PEG therapies.
Results:
The mean baseline HCV RNA level was 6.4-6.5 log10 in each
group and 71% of patients were infected with HCV genotype 1. For both PEG
therapies, combination with HCV-796 reduced plasma HCV RNA levels to a greater
extent than either PEG alone. At day 14, the mean reduction in HCV RNA for
HCV-796+PEG2b was 3.4 log10 vs. 1.6 log10 for PEG2b alone. The mean reduction
for HCV-796+PEG2a was 3.7 log10 vs. 1.1 log10 for PEG2a alone. For both groups,
activity differed by HCV genotype. Mean HCV RNA reductions at day 14 for
genotype 1 was 2.9 log10 for HCV-796+PEG2b and 3.2 log10 for HCV-796+PEG2a. For
genotype non-1 the respective reductions were 4.4 vs. 4.7 log10. Combination of
HCV-796 with either PEG therapy was generally well tolerated. Common adverse
events in all groups were those typically associated with interferons,
including headache, chills, and myalgia.
Conclusions:
The combination of HCV-796 with either PEG2b or PEG2a
provides similar antiviral activity across multiple HCV genotypes over 14 days
of therapy. Results support clinical studies of more long-term administration
of HCV-796 with either PEG therapy.
Topic: Current Treatment - Pegasys
1303.
Peginterferon ALFA-2A and Ribavirin for 12 or 24 Weeks in Patients With HCV Genotype
2/3: The Nordynamic Trial
M. Lagging; C. Pedersen; M. Rauning Buhl; M. Färkkilä;
N. Langeland; K. Mørch; J. Westin; Å. Alsiö; G. Norkrans
Background and Aims:
Prior trials investigating the efficacy of treatment for less
than 24 weeks in HCV genotype 2/3 infected patients have yielded discordant
results. The aim of this study was to compare the efficacy of 12 or 24 weeks of
combination therapy, as well as to identify patients achieving SVR using liver
biopsy evaluation, IP-10 levels,α-interferon
concentrations, ribavirin concentrations, and HCV RNA measurement using Roche
COBAS TaqMan at baseline, day 3, day 7, day 8, week 4, and week 8.
Methods:
Three hundred and eighty-two genotype 2/3 infected patients
at 31 centers in Denmark, Finland, Norway, and Sweden were randomized at
baseline to 12 or 24 weeks of treatment with peginterferon α-2a 180
μg/week plus ribavirin 800 mg/day from February 2004 to November 2005.
Results:
Twelve weeks of combination therapy was inferior to 24 weeks
for patients infected with genotype 2 (SVR rates 56% vs. 82%, p=0.007) and
genotype 3 (58% vs. 78%, p=0.001). Likewise, 12 weeks of treatment was inferior
for patients with non-significant fibrosis (p=0.024) and bridging fibrosis
(p=0.0033), and a similar trend was noted for patients with cirrhosis
(p=0.078). Multivariate analysis demonstrated that age as well as HCV-RNA
levels on day 7 and 29 were independent predictors of SVR following 12 weeks of
therapy. For patients <40 years, no significant difference was noted between
12 and 24 weeks of therapy regardless of HCV-RNA level day 29. Similarly, for patients ≥40 years, no significant difference was
noted between the treatment arms if both HCV-RNA day 7 was below 1,000 IU/mL
and HCV-RNA was undetectable day 29. If both of these two
criteria were unmet for patients ≥40 years, 24 weeks of therapy was
superior (p<0.0001).
Conclusion:
Our findings indicate that 12 weeks of combination therapy
may be acceptable for subgroups of, but not for all patients infected with HCV
genotypes 2 or 3.
Topic: Experimental Therapies - GI-5005
1304.
HCV-Specific Cellular Immunity, RNA Reductions, and Normalization of ALT in
Chronic HCV Subjects after Treatment with GI-5005, a Yeast-Based Immunotherapy
Targeting NS3 and Core: A Randomized, Double-blind, Placebo Controlled
Phase 1b Study
E. R. Schiff; G. T. Everson; N. Tsai; N. H. Bzowej; R.
G. Gish; J. G. McHutchison; I. M. Jacobson; M. J. Tong; D. M. Jensen; G. M.
Lauer; S. Cruickshank; J. Ferraro; A. Haller; R. Duke; T. Rodell; D.
Apelian
PURPOSE:
Evaluation of the efficacy,
immunogenicity, and safety of GI-5005 in subjects with chronic HCV infection.
METHODS:
GI-5005 is a whole heat-inactivated S. cerevisiae immunotherapy
expressing HCV NS3 and Core. Subjects with chronic HCV infection who were
interferon (IFN) partial responders, relapsers, or treatment naïve were
eligible. Five weekly subcutaneous (SC) doses of GI-5005 monotherapy over 29
days were followed by two monthly SC GI-5005 doses and 9 months of
post-treatment follow-up. Dose groups of 0.05, 0.5, 2.5, 10, 20, and 40YU (1 YU
= 10,000,000 yeast cells) were randomized 3:1 treated:placebo.
Discussion:
Safety:
o
GI-5005
was well tolerated, with no dose limiting toxicities (DLTs) through 40YU.
Efficacy:
o
Viral
load reductions from -0.75 to 1.4 log 10 were observed only in GI-5005 treated
patients 6/54 (11%).
o
GI-5005
dose response for ALT normalization reaching 50% in the 40 YU group. No ALT normalization has been observed in the
placebo group.
o
HCV
specific cellular immune response only observed in GI-5005 treated subjects
(9/39, 23%) using stringent criteria for amplitude and breadth of immune
response. The strongest ELIspot
responses (>250 activiated cells per million lymphocytes) were detected only
in the highest GI-5005 doses tested (10YU, 20YU, and 40YU).
These results indicated that a short course of GI-5005
monotherapy is capable of generating an HCV specific immune response that is
associated with viral load reductions of up to 1.4 log10, and ALT
normalizations in up to half of the high dose patients. A Phase 2 trial comparing GI-5005 plus
pegylated interferon/ribavirin vs. pegylated interferon/ribavirin alone is
being initiated at 50 centers in the
Topic: Current Treatment - Pegasys
M. Rodriguez-Torres; M. Sulkowski; R. T. Chung; F.
Hamzeh; D. M. Jensen
Introduction
Rapid virologic response (RVR), defined as undetectable serum
HCV RNA after 4 weeks of treatment, is associated with likelihood of sustained
virologic response. This retrospective analysis assessed the effect of baseline
and demographic factors and drug dose/modification during the first 4 weeks of
treatment on RVR.
Methods
Patients in 5 clinical trials who were infected with HCV
genotype 1 and randomized to 180 μg/wk
pegIFNα-2a/1000-1200 mg/d RBV were included. Baseline factors
utilized for multiple logistic regression analyses included age (≤40 vs
>40 years), gender, race/ethnicity (non-Latino white vs other), BMI (≤27
vs >27 kg/m2), baseline ALT quotient (≤3 vs >3X ULN), baseline
serum HCV RNA (≤400,000 vs >400,000 IU/mL) and cirrhotic classification
(cirrhotic vs non-cirrhotic). On-treatment factors included average daily
exposure to RBV (≤13 vs >13 mg/kg/day) and pegIFNα-2a dose
reductions (yes vs no). Any factor with p≤.2 was considered significant.
Results
Of 1550 treated patients, 234 (15.1%) attained RVR and 1316
(84.9%) did not; 1 (0.4%) and 16 (1.2%), respectively, withdrew for safety
reasons, and 0 and 17 (1.3%), respectively, for non-safety reasons. Of these
1550 patients, 1050 (67.7%) were non-Latino whites, 295 (19.0%) were Latino
whites, 154 (9.9%) were black, and 51 (3.3%) were Other; 1031 (66.5%) were men;
1112 (71.7%) were >40 years old; 797 (51.4%) had BMI >27 kg/m2; 1184
(76.4%) had ALT quotient >3X ULN; 1346 (86.8%) had serum HCV RNA >400,000
U/mL; and 239 (16.4%) were cirrhotic. Multiple logistic regression analysis
showed that white non-Latino race (OR 1.48; 95% CI 1.04-2.12, p=.031), age ≤
40 years (OR 1.63; 95% CI 1.27-2.26, p=.0035), baseline ALT quotient >3X ULN
(OR 1.96; 95% CI 1.40-2.76, p=.0001), baseline serum HCV RNA ≤400,000
IU/mL (OR 8.67; 95% CI 6.13-12.37, p<.0001), non-cirrhotic status at
baseline (OR 1.63; 95% CI 1.01-2.64, p=.0444), male sex (OR 1.37; 95% CI
0.98-1.91, p=.0687) and BMI ≤27 kg/m2 (OR 1.37; 95% CI 0.99-1.91, p=.0545)
were predictive of RVR. After adjusting for significant risk factors, multiple
logistic regression analysis showed that average daily RBV >13 mg/kg/day (OR
2.15; 95% CI 1.41-3.27, p=.0004) was a significant predictor of RVR, whereas
pegIFNα-2a dose reduction was not.
Conclusion
RVR in patients infected with HCV genotype 1 was associated
with younger age, white race, higher ALT quotient, lower serum HCV RNA, absence
of cirrhosis, male sex and lower BMI, and with greater exposure to RBV over the
initial 4 weeks. Patients exposed to ≤13 mg/kg/day RBV over the first 4
weeks were less likely to achieve RVR.
Topic: Current Treatment – Consensus
Interferon
1306.
Treatment of Peginterferon/Ribavirin Nonresponders with daily Dosing of
Consensus Interferon and Ribavirin - Preliminary Results of the
S. Kaiser; W. Boecher; J. F. Schlaak; B. Lutze; B.
Sauter; L. Bissinger; C. Werner; H. Hass; 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 therapy followed by CIFN /
RBV in PEG IFN combination treatment nonresponders was evaluated. 400 patients
have been included, with 92% having genotype 1. Average weight of patients was
79.3 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:
Preliminary data show that after the initial 12 weeks of CIFN
monotherapy, a primary response with undetectable serum HCV-RNA was observed in
37 % of patients with a prior nonresponse to PEG IFN a2b and in 48% in prior
PEG IFN a2a nonresponders (n=189). At the end of treatment, a negative PCR was
observed in 34% in PEG IFN a2b nonresponders, and in 48% of PEG IFN a2a
nonresponders. The sustained viral response rates (SVR) were 16% and 23% for
PEG IFN a2b and PEG a2a nonresponders, respectively (n=143).
When response rates were calculated according to the
treatment arm used, the SVR for PEG IFN a2b nonresponders were 13% in the CIFN
9 ug arm and 19% in the CIFN high dose arm. For PEG IFN a2a nonresponders the
SVR were 19% and 27% 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.
Topic: Experimental Therapies -
PF-03491390
G. Burgess; P. Colman; E. Engmann; H. Bantel; P. N.
Soni
Background:
In patients with chronic HCV infection, the pancaspase
inhibitor, PF-03491390 may minimise hepatocellular (HCC) damage, as reflected
by reductions in elevated ALT and AST levels. As caspase activation plays a
pivotal role in inflammatory and fibrotic liver injury in HCV-infection, we
investigated caspase activation and a range of inflammatory and fibrotic serum
biomarkers during therapy with this agent.
Methods:
204 patients (63% male, 51 yo average age) with chronic HCV infection and liver fibrosis
were randomized to receive placebo or PF-03491390 5 mg, 25 mg, or 50 mg orally
twice daily for 12 weeks in a placebo-controlled, double-blind, parallel-group
study. If ALT and AST levels remained elevated at Week 10, the dose of study
drug was doubled to Week 12. Changes in serum markers of inflammation, fibrosis
and apoptosis are reported.
Results:
At Week 12, compared with placebo, PF-03491390 therapy was
associated with decreases in serum levels of transforming growth factor (TGF)
β1, α-2 macroglobulin, caspase-mediated cytokeratin-18 fragments
(M30-Antigen), active caspases 3/7 and α-fetoprotein. PF-03491390 therapy
was also associated with increases in serum levels of haptoglobulin and Fas
ligand, at Week 12, compared with placebo. PF-03491390 therapy had no apparent
impact on serum levels of the other measured biomarkers (Table 1).
Safety
·
In
total, three (1.5%) subjects withdrew from the study due to treatmentemergent adverse
events.
o
two
subjects in the placebo treatment group;
o
one
with a severe elevated liver function test
o
one with dyspnea, upper abdominal pain, asthenia and palpitations (all
severe).
o
one
subject in the PF-03491390, 5 mg treatment group;
o
with moderate exacerbation of a migraine.
·
During
the study, 139 (68%) subjects reported a total of 443 adverse events.
·
The
most frequently reported treatment emergent events were headache (24 [12%]
subjects) and fatigue (22 [11%] subjects), with the majority of adverse events
being of mild or moderate severity.
HCV viral load
·
No
changes in HCV RNA viral load were observed.
Conclusions:
·
PF-03491390
effectively reduced aminotransferase levels in patients with chronic hepatitis
C. These reductions were evident as early as Day 7 and were sustained for the
full 12-week duration of treatment. ALT/AST normalization rates were low, however,
necessitating increases in the dose of study medication in most patients.
·
Levels
of caspases 3/7 and M30 antibody decreased during 10 weeks’ treatment with
PF-03491390. The decreases in caspases 3/7 were partially dose dependent, but
no dose dependency was observed for the M30 antibody response. These observations
suggest that PF-03491390 may inhibit liver fibrosis via suppression of
pro-apoptotic caspase activation.
·
The
observed decreases in serum levels of caspases 3/7 and M30 antibody are consistent
with those that would be expected if PF-03491390 inhibited the apoptosis of
activated hepatic stellate cells, suggesting that the drug has the potential to
limit hepatic fibrosis.
·
Although
the lack of clear dose dependency observed for the M30 antibody response might
not be expected if PF-03491390 inhibited the apoptosis of activated hepatic
stellate cells, it could indicate the existence of a steep dose response that
reached maximal at the lowest dose tested in this study. It could also indicate
that the initial levels of CK-18 neo-epitope were lower than expected for this
population of patients with chronic liver disease.
·
Levels
of the other markers of inflammation and fibrosis measured in this study showed
little or no change during 12 weeks’ treatment with PF-03491390. These observations
probably reflect low initial levels of these markers and the relatively short
duration of the study rather than a de facto absence of effect of PF-03491390 on
liver inflammation and fibrosis.
·
Larger
and longer-term studies, with a histology endpoint, are required to explore further
the impact of PF-03491390 treatment on serum markers of inflammation, fibrosis
and apoptosis, and their potential implications in clinical practice
Table 1: Median absolute change of serum markers of inflammation, fibrosis and apoptosis from baseline at Week 12
|
Serum marker |
Placebo |
PF-03491390 |
|||
|
|
|
5 mg bid |
25 mg bid |
50 mg bid |
|
|
Fibrosis |
N=47-50 |
N=49–53 |
N=48–50 |
N=44-57 |
|
|
|
M30-Antigen
(U/L) |
-17.0 |
-114.5 |
-93.0 |
-105.0 |
|
|
Active
caspases 3/7 (RLU) |
-46.0 |
-292.0 |
-285.0 |
-464.0 |
|
|
TGFβ1
(ng/ml) |
6.2% |
-14.4% |
-2.9% |
-7.3% |
|
|
α-2
macroglobulin (mg/dl) |
0.5% |
-0.9% |
-0.1% |
-2.5% |
|
|
Haptoglobin
(mg/dl) |
-0.6% |
8.4% |
5.6% |
8.0% |
|
|
Apolipoprotein
A1 (mg/dl) |
0.3% |
-2.1% |
0.3% |
-2.2% |
|
Inflammation |
N=48–51 |
N=49–55 |
N=46–50 |
N=43–48 |
|
|
|
Tumor
necrosis factor-α (pg/ml) |
0% |
5.3% |
0% |
0% |
|
|
C-reactive
protein (mg/dl) |
-7.9% |
-4.4% |
-3.6% |
-13.0% |
|
|
α-fetoprotein
(ng/ml) |
0% |
-12.2% |
-17.0% |
-11.1% |
|
|
Interleukin-6 (pg/ml) |
0% |
16.2% |
-12.4% |
-13.6% |
|
|
Interleukin-8 (pg/ml) |
-3.0% |
0% |
-6.5% |
-7.9% |
|
|
Fas ligand (pg/ml) |
-0.4%
|
2.9% |
4.2% |
3.2% |
|
Mechanism of
Action |
N=25 |
N=28 |
N=29 |
N=20 |
|
|
|
Interleukin-1β
(pg/ml) |
0% |
0% |
0% |
0% |
Topic: Current Treatment - Pegasys
P. Marcellin; D. M. Jensen; S. J. Hadziyannis; P.
Ferenci
Background:
Early on-treatment responses in HCV RNA at wks 4 & 12
post initiation of therapy are increasingly being used to predict those pts
likely to achieve an SVR. Pts achieving an RVR (HCV RNA <50 IU/mL at wk 4
and maintained at wk 12) have a high rate of SVR irrespective of genotype. The
standard definition of an early virologic response (EVR) had been defined as
pts at wk 12 achieving either an undetectable HCV RNA (<50 IU/mL) or a ≥2
log drop in HCV RNA but still detectable. However, rates of SVR in pts
achieving an EVR by this definition are heterogeneous. By further subdividing
pts achieving early responses into RVR, complete EVR (cEVR or non-RVR but HCV
RNA <50 IU/mL at wk 12) and partial EVR (pEVR or non-RVR but HCV RNA ≥2
log drop in HCV RNA at wk 12 but still detectable) it may be possible to
improve the prediction of pts likely to achieve an SVR and may allow for
tailoring of treatment duration. Here we performed a retrospective analysis of
2 large, multinational phase III studies of genotype 1 pts treated with peginterferon
alfa-2a (40KD) in combination with ribavirin (RBV) (Fried et al. NEJM 2002
& Hadziyannis et al. Ann Intern Med 2004).
Methods:
569 pts treated for 48 wks with 180 µg/wk peginterferon
alfa-2a (40KD) and 1000/1200 mg/d RBV were included in the present analysis
(ITT). Early responses were divided into 4 mutually exclusive categories as
defined above: RVR, cEVR, pEVR and non-EVR (<2 log drop at wk 12). Rates of
SVR were then calculated for each category.
Results:
16% (90/569) pts were classified as achieving an RVR, 42%
(240/569) pts a cEVR, 22% (128/569) pts a pEVR and 20% (111/569) non-EVR. Rates
of achieving an SVR in these groups were 87% (78/90) for RVR, 68% (162/240)
cEVR, 27% (34/128) pEVR and 5% (5/111) for non-EVR pts.
Conclusions:
Pts achieving an RVR have high rates of SVR and may benefit
from shortened treatment duration (24 wks; also see Jensen et al. Hepatol
2006). Pts with a cEVR also have high rates of SVR but should be encouraged to
remain on therapy for the standard duration of therapy (48 wks). Pts with a
pEVR have lower rates of SVR with the standard 48 wks of therapy and may
benefit from intensified treatment (72 wks; also see Sánchez-Tapias et al.
Gastroenterol 2006) and pts that are non-EVR at wk 12 have a low chance of
achieving an SVR and consideration should be given to change treatment
strategy. Early on-treatment virologic responses in HCV RNA are highly
predictive of achieving an SVR and subdividing early responses into RVR, cEVR
and pEVR allows for a more precise prediction of achieving an SVR.
Topic: Current Treatment - Pegasys
C. J. Weegink; N. Forestier; P. L. Jansen; S. Zeuzem;
H. W. Reesink
Purpose:
Telaprevir (TVR, VX-950) is a highly-selective peptidomimetic
inhibitor of the hepatitis C virus (HCV) NS3/4A protease that is designed to
block HCV replication. This 14-day study was designed to explore the viral
kinetics and safety during dosing with TVR in combination with
peginterferon-alfa-2a (Peg-IFN). Here we report the final results of patient
status after stopping follow-on standard therapy with Peg-IFN and ribavirin
(RBV).
Methods:
The VX04-950-103 clinical study randomized twenty
treatment-naïve patients with chronic genotype 1 hepatitis C infection to three
dosing arms. Eight patients received TVR (750 mg as tablets q8h) with Peg-IFN
on Days 1 and 8, and eight patients received TVR alone. Four patients received
Peg-IFN alone on Days 1 and 8. At the completion of the 14-day study, off-study
therapy with Peg-IFN and RBV was offered to all patients. Nineteen of 20 patients
began therapy within 5 days of completing the 14-day dosing period. The patient
who refused post-study Peg-IFN/RBV was in the TVR-alone group.
Results:
At week 12 of therapy, all 8 patients in the TVR/Peg-IFN
group and 5 of 7 patients in the TVR alone group had undetectable HCV RNA. At
week 24, all 15 patients who received TVR had undetectable HCV RNA(<10 IU/mL). Ten patients (6/8 TVR/Peg-IFN and 4/7 TVR
alone) chose to stop Peg-IFN/RBV treatment at week 24 and 5 patients chose to
continue Peg-IFN/RBV for a total of 48 weeks. All groups were followed for the
subsequent 24 weeks. In patients who had received TVR-based therapy for 14 days
before starting off-study Peg-IFN/RBV therapy, 7/10 patients treated for a
total of 24 weeks and 2/5 patients treated for a total of 48 weeks achieved a
sustained viral response (SVR) One patient, treated for 48 weeks, was lost to
follow-up. From the group who received Peg-IFN alone before 48 weeks of
Peg-IFN/RBV therapy, 1/4 patients achieved SVR. The side effect profile
observed during the post-study dosing was consistent with the expected profile
of Peg-IFN/RBV therapy. Sequence analysis of the 5 patients who relapsed after
TVR-based therapy is in progress.
Conclusions:
SVR was achieved in 9 of 15 patients treated for 14 days with
TVR or TVR/Peg IFN followed by Peg-IFN/RBV therapy for a total of 24 or 48
weeks. These results suggest that TVR-based regimens may increase SVR rates
compared to current therapies. Large Phase 2 clinical studies of TVR-based
regimens are now ongoing to evaluate this hypothesis and the possibility of
shortening the duration of therapy.
Topic: Current Treatment – Pegasys
S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C.
Werner; H. Hass; 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 treatment-naïve patients
with a slow viral response as well as in retreatment trials using an extended treatment duration of 72 weeks. However, the
optimal retreatment regimen and treatment time remains unclear at present.
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. 120 patients with genotype 1.
Average weight of patients was 79 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 85 % of patients in the CIFN QD
group and in 81 % in the PEG IFN 180 ug group (diff. = n.s.). At the end of
treatment at week 72, a negative PCR was observed in 86 % in the CIFN group,
and in 78% of the PEG IFN 180 ug group (diff. = n.s.). The sustained viral
response rates (SVR) were 69% for the CIFN arm and 42 % for the PEG IFN a2a
arm, respectively (diff. p<0.05), indicating a significantly higher relapse
rate in patients being retreated with PEG IFN a2a.
No growth factors were used in this study. 5 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 19% versus 11% for the PEG IFN a2a group. In contrast, hematologic
grade III alterations were higher in the PEG IFN a2a group.
Conclusions:
Both extended CIFN daily dosing combination therapy and PEG
IFN a2a combination therapy for 72 weeks show promising response and SVR rates
in previous relapse patients to standard PEG IFN / RBV therapy, while relapse
rates are significantly lower in the CIFN retreated patents leading finally to
higher SVR rates. Although a significant proportion of patients experienced a
second relapse in both treatment regimens 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 especially with
CIFN in combination with RBV may be an effective treatment modality for this
difficult-to-treat patient group.
Topic: Current Treatment - Peg-intron
S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C.
Werner; H. Hass; M. Gregor
Objective:
Objective:
Treatment with current standard antiviral therapy leaves
about 50% of patients without viral clearance with the risk of progression of
their liver disease. Recent studies have suggested an antifibrotic effect of
low dose interferon treatment.
Aim:
To evaluate the efficacy and safety
of low-dose PEG-IFN ALFA-2B (PEGINTRON) as maintenance therapy in patients with
chronic hepatitis C and advanced fibrosis or cirrhosis.
Methods:
The efficacy of low dose pegylated interferon alfa 2b with
0.5 ug/kg weekly given for 36 months as monotherapy was evaluated based on
histological examination and liver function in 182 patients with chronic HCV,
nonresponse to antiviral combination therapy and significant fibrosis /
cirrhosis (Ishak staging 3-6) and compared to an observational control group
(n=83). Histology was evaluated at baseline, at 18 months of treatment and 6
months after end of treatment.
Results:
182 patients receiving treatment were enrolled in the study,
and 167 patients were included in the analysis—Although
all patients have completed therapy, 15 patients have not undergone a second
liver biopsy. An additional 83 untreated
patients were enrolled to serve as an observation cohort.
Patient characteristics were balanced in the two groups
except there were more genotype 4 patients in the PEG-INF group compared to the
group of patients who did not receive treatment (3.8% vs. 12.0% respecitively).
The mean fibrosis scores improved during treatment and were
maintained 24 weeks after cessation of treatment in patients receiving PEG-IFN
alfa-2b 0.5 μg/kg/wk. In contrast, fibrosis scores slowly increased
in untreated patients (indicating a progressive histology) during the 36-month
observational period and throughout follow-up.
HCV RNA Levels, Dropout
Rates, and Discontinuation Rates:
·
Overall,
61% of treated patients experienced a >1 log10 decrease in HCV RNA from
baseline during treatment
o
In
10 (6%) of 167 patients, HCV RNA was undetectable at the end of treatment
o
All
patients who received PEG-IFN alfa-2b 0.5 μg/kg/wk experienced relapse
after withdrawal of treatment
·
Among
treated patients, dropout and dose-reduction rates were 3% and 13%,
respectively
o
The
drop out rate was 3% and the dose reduction rate was 13%
Safety
Mean changes in laboratory parameters among patients
receiving PEG-IFN alfa-2b 0.5 μg/kg/wk:
Mean
Decrease During Tx Lowest
Recorded Value During Tx
White blood cell count,
cells/μL 1630 1390
Hemoglobin, g/dL 0.8 8.4
Platelets, cells/μL 45,563 24,000
Alanine aminotransferase, U/L 19 NA
- 22 Serious adverse events were reported
among patients receiving PEG-IFN alfa-2b 0.5 μg/kg/wk, of which 17
were attributed to complications of cirrhosis (Table 3)
- There was no significant
difference in the complication rates between treated and untreated
patients (data not shown)
- At the end of the study, more
patients in the untreated group (n = 3) required transplants than
patients in the treated group (n = 1)
Conclusions:
Low dose therapy with pegylated interferon alfa 2b in
patients with HCV and advanced fibrosis or cirrhosis shows a significant and
persistent decrease in fibrosis in comparison to a control group. In contrast
the also observed significant decrease in the necroinflammatory score is only
temporary as long as treatment lasts. As treatment was well tolerated even for
patients with cirrhosis, this treatment could evolve as a salvage therapy for
patients with advanced liver disease with HCV where standard antiviral therapy
has failed.
Topic: Experimental Therapies - General
C. Cooper; S. Shafran; S. Greenbloom; R. Enns; J.
Farley; M. Neuman; N. Abadir
Background:
High levels of TNFα may contribute to the pathogenesis
of hepatitis C virus (HCV) infection. This study evaluated the safety of
infliximab in HCV-infected patients and assessed the effect of infliximab
induction therapy on early virologic response and sustained virologic response
(SVR). This interim analysis reports viral kinetics during the first 12 weeks
of treatment.
Methods:
This was a randomized, prospective,
open-label trial conducted at 8 academic and community sites in
Results:
This analysis is based on the first 29 randomly assigned
patients (16 Arm A, 13 Arm B) who received 12 weeks' of PEG-2b + RBV; 70% of
participants were male. Infliximab was well tolerated, without excessive side
effects. More infliximab recipients had advanced (F3) fibrosis (38% vs 15%). At
initiation of PEG-2b + RBV, lower mean serum TNFα levels were observed in
patients in Arm A than in Arm B (P=.013). In Arm A, 7/16 (43.8%) patients
attained RVR, compared with 4/13 (30.8%) patients in Arm B. By week 8,
significantly more patients (11/16, 69%) in Arm A had undetectable HCV RNA than
in Arm B (6/13, 46%; P=.024). The number of patients who attained undetectable
HCV RNA at week 12 was similar between study arms (11/16 patients in Arm A [69%]
vs 11/13 patients [85%] in Arm B; P=.183), suggesting that the effect of
infliximab may not be sustained past week 8.
Conclusion:
The anti-TNFα effect of infliximab on HCV may provide
viral decline during the first 8 weeks of HCV therapy. It is unknown whether
infliximab treatment before combination PEG-2b + RBV therapy will translate
into greater SVR rates.
|
|
HCV RNA Log 10 |
|||
|
F1-F2 Patients |
Arm A |
Arm B |
||
|
Visit, wk |
Mean |
SD |
Mean |
SD |
|
1(–3) |
5.9 |
0.78 |
6.09 |
0.33 |
|
2(–1) |
5.82 |
0.68 |
6.08 |
0.43 |
|
3(0) |
5.65 |
0.82 |
5.57 |
1.05 |
|
4(2) |
3.62 |
2.28 |
4.02 |
1.89 |
|
5(4) |
1.84 |
2.78 |
3.07 |
2.36 |
|
6(6) |
1.77 |
2.68 |
2.31 |
2.13 |
|
7(8) |
1.26 |
2.51 |
1.75 |
1.94 |
|
8(12) |
1.23 |
2.44 |
0.52 |
1.66 |
Topic: Current Treatment - General
J. L. Green; K. Heard; G. M. Bogdan; B. Brands; R. C.
Dart
Introduction:
Retrospective accounts question the safety of maximum labeled
daily dose of APAP in alcoholics and in patients with hepatitis C.
Methods:
As part of a larger trial of APAP use in alcoholic patients,
we evaluated the effect of APAP on hepatic tests in alcoholic patients who also
had hepatitis C virus (HCV) antibody. This was a randomized, double-blind,
placebo-controlled trial of recently abstinent alcoholics.
Results:
Patients were randomized 1:1 to APAP (1g every 4 hr for 4
doses x 5 days) or placebo. Exclusion criteria included a baseline serum APAP
> 20 mcg/ml, aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) > 200 IU/L, or international normalized ratio (INR) > 1.5.
Laboratory measures were obtained at baseline and days 2, 4, 6, and 7. Of 141
patients (73 APAP group, 68 placebo group), 50 subjects were positive for HCV
antibody (24 APAP, 26 placebo). Demographics, nutritional status and baseline
measures were similar between groups (p>0.05). Baseline ALT was
significantly higher in the HCV reactive group (59 ± 38 IU/L) than in the HCV
non-reactive group (42 ± 32 IU/L, p>0.05). The ALT in HCV reactive patients
was significantly higher throughout the study than HCV non-reactive patients
(p<0.05), regardless of treatment group assignment. Of the HCV reactive
subjects, the ALT increased during the trial in both groups. However, the ALT
was not different between APAP and control groups. The peak ALT mean of HCV
reactive subjects was on Day 7 (70 ± 55.7 IU/L in APAP group, 48.4 ± 40.4 in
placebo group). Maximum reported ALT was 216 IU/L in APAP group and 246 IU/L in
placebo group. Total bilirubin decreased significantly after Day 2, regardless
of treatment group assignment. The INR was unaffected in either group.
Conclusion:
Short term treatment of alcoholic subjects with hepatitis C
at the maximum labelled daily dose of acetaminophen (4 g/day) does not impact
ALT.
Topic: Current Treatment - PegIntron
S. Pianko; E. M. Yoshida; S. Zeuzem; Y. Benhamou; V.
G. Bain; E. Pulkstenis; J. G. McHutchison; G. M. Subramanian
Background/Aim
This Phase 2b, active controlled study evaluated the efficacy
and safety of albinterferon alfa-2b (alb-IFN)in
IFN-naïve, CHC patients. The effects of alb-IFN on subject quality of life
(QoL) and disability days were compared with those of PEG-IFNa-2a (PEG-IFN).
Methods
458 patients were randomized and treated in 4 groups: PEG-IFN
180mcg Q1w or one of 3 alb-IFN arms (900mcg Q2w, 1200mcg Q2w or 1200mcg Q4w).
The primary efficacy end-point was SVR. SF-36v.2 and the Hospital Anxiety and
Depression Scale (HADS) were used to assess subject QoL and anxiety/depression.
Subject disability days were evaluated by a number of missed work days or days
with impaired activity. Missing data for patient reported outcomes were handled
using LOCF (last observation carried forward).
Results
Based on ITT analysis, SVR rates were comparable (p=NS)
across treatment groups. SVR in the 900Q2 was 58.5% and for PEG-IFN was 57.9%.
Overall, QoL was similar or favorable for all albIFN arms compared to PEG-IFN
at all timepoints assessed. At w12 and w24 on treatment, the 900Q2w cohort
performed better in all 10 SF-36 domains relative to PEG-IFN. Statistically
significant and clinically meaningful differences were observed in mental
health (figure), bodily pain, vitality, and social functioning domains. Changes
in mental health correlated strongly (r=0.7) with changes in HADS and by w12
post-treatment had recovered to baseline in 67% of 900Q2w subjects and 57% of
PEG-IFN subjects. Subjects receiving alb-IFN 900Q2 experienced significantly
fewer days of missed work: at w12 and 24, ~5% of 900Q2w subjects missed at
least 7 days of work the previous month compared to ~20% for PEG-IFN.
Conclusions
The alb-IFN 900mcg Q2w dose was associated with the most
favorable QoL and fewest missed work days while maintaining efficacy at least
comparable to PEG-IFN.
Topic: Current Treatment - Pegasys
M. Yu; C. Dai; J. Huang; L. Lee; M. Hsieh; C. Chiu; N.
Hou; Z. Lin; S. Chen; M. Hsieh; L. Wang; W. Chang; W. Chuang
Background:
Recommended treatment for patients with HCV genotype 1 (G1)
infection is Peg-IFN plus ribavirin (RBV) for 48 wks and 24 wks for HCV G2/3. A
rapid virological response (RVR; <50 IU/mL HCV RNA at wk 4) is a strong
predictor of sustained virological response (SVR; <50 IU/mL HCV RNA 24 wks
after untreated follow-up). SVR rates of >80% with a shorter treatment
duration of 12-16 wks peginterferon alfa-2a (40KD) plus RBV in HCV G2/3 pts
with an RVR have questioned whether shorter treatment duration can yield high
SVR rates for G1 patients with an RVR. Therefore, we determined the efficacy of
24 wks therapy to standard 48 wks treatment in HCV G1 patients with an RVR.
Methods:
In a controlled, multicenter, open-label study in
Results:
Baseline (BL) characteristics were similar in the 24 and 48
wk arms. At BL, respectively for the 24 and 48 wk arms, male patients accounted
for 57/58% of all patients, with a mean age of 49.7/49.1 years, a mean weight
of 65.5/67.5 kg and with 25/19% having a BL diagnosis of advanced hepatic
fibrosis (F3/4). BL log HCV RNA (IU/mL) was 5.43 (24 wk) and 5.66 (48 wk). Overall,
the 48 wk arm had a significantly lower relapse rate and a higher SVR rate than
the 24 wk arm (ITT). Patients with an RVR had a significantly higher SVR rate
than patients without an RVR in both treatment arms. For patients with a lower
BL viral load (LVL, <400,000 IU/mL) and an RVR at wk 4, the rates of relapse
and SVR in the 24 wk arm was comparable to those in the 48 wk arm. MLR analysis
in all patients showed that an RVR was the strongest independent factor
associated with an SVR, followed by treatment duration, adherence and BL viral
load. The 48 wk arm had a significantly higher rate of discontinuation than the
24 wk arm.
Conclusion:
In this study, high SVR rates (>96%) were seen with both
24 and 48 wks of peginterferon alfa-2a (40KD) plus RBV 1000/1200 mg/d in HCV G1
patients with a LVL and an RVR. BL viral load and an RVR at wk 4 could provide
decision-making information for a shorter treatment
duration for HCV G1 patients.
|
Efficacy,
n (%) |
24wks (n=100) |
48wks (n=100) |
p-value |
|
RVR |
45 (45.0) |
42 (42.0) |
0.669 |
|
End of treatment response |
93 (93.0) |
90 (90.0) |
0.447 |
|
Relapse, n/N (%) |
|
|
|
|
Overall Pts with LVL
and RVR Pts with RVR Pts without RVR |
34/93 (36.6) 1/28 (3.6) 5/45 (11.1) 29/48 (60.4) |
11/90 (12.2) 0/24 (0) 0/42 (0) 11/48 (22.9) |
<0.0001 1 0.056 <0.0001 |
|
SVR, n/N (%) |
|
|
|
|
Overall Pts with LVL
and RVR Pts with RVR Pts without RVR |
59 (59.0) 27/28 (96.4) 40/45 (88.9) 19/55 (34.5) |
79 (79.0) 24/24 (100) 42/42 (100) 37/58 (63.8) |
0.002 1 0.056 0.002 |
Topic: Current Treatment – Consensus
Interferon
S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C.
Werner; 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 dropout 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 a lower tolerability. 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 120 patients with chronic hepatitis C and cirrhosis Child A and B
(average Child score 7.9, maximum MELD score 20) . All
patients had histologically proven cirrhosis, elevated ALT values and were
viremic, with 79% having genotype 1. Child A patients
were treated with CIFN 9 ug TIW for 4 weeks, followed by 9 ug QD for another 4
weeks. Continuing treatment consisted of CIFN 9 ug QD with RBV with a stepwise
increase from 400 mg by 200 mg increments at 4 week intervals for a total of
another 52 weeks. For Child B patients the two lead-in phases with CIFN
monotherapy were extended to 6 weeks each, and the starting dose of RBV was 200mg
with an otherwise identical therapy as with Child A patients. Based on
tolerability the dosing of RBV was increased to a weight-based dosing for all
patients.
.
Results:
At 60 weeks therapy an undetectable HCV-RNA was observed in
76% and 47% of Child A and B patients, respectively, with drop out rates of 13%
and 27%. Sustained response rates showed a 57% and 27% response for Child A and
B, respectively. Due to side effects CIFN had to be dose reduced in 17% and
34%, mainly due to low platelet counts. As growth factors erythropoetin as well
as G-CSF was used. 11 patients experienced grade III and 7 patients 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
escalating 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 lower
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.
Topic: Experimental Therapies - TMC435350
R. Verloes; K. Abou Farha; A. van Vliet; G. van 't
Klooster; F. Aharchi; K. Marien; H. de Kock; K. Simmen
Background:
This trial studied the safety, tolerability and plasma
pharmacokinetics (PK) of a novel HCV NS3/4A protease inhibitor, TMC435350,
after single oral dosing and, in a second step, after 5 days of oral dosing in
HCV-negative volunteers.
Methods:
The single ascending dose (SAD) part was studied under fed
conditions using two panels of 9 males or females followed by an investigation
on the effects of fasting. In the multiple ascending dose (MAD) part, 4 panels
of 9 volunteers were included. Each panel was designed to have 6 subjects
receiving TMC435350 solution and 3 subjects receiving placebo. Safety monitoring included physical examination, vital signs,
laboratory parameters (haematology, biochemistry, urinalysis), extensive
cardiovascular safety (ECGs, and additional biomarkers and echocardiography
during the MAD phase), and adverse events. In the SAD study a full PK
profile was evaluated up to 72 h post-dose. In the MAD study, a full PK profile
was studied on Days 1 and 5, with samples taken up to 72 h post-dose.
Results:
In the SAD study, oral doses up to 600 mg were well tolerated
without attaining any dose-limiting toxicity. The plasma exposure increased in
a more than dose proportional fashion. A single dose of 200 mg studied under
fasted conditions was well tolerated and yielded comparable exposure to the fed
condition. TMC435350 displayed good plasma exposure, with a Tmax of 4-6 hours,
which together with a half-life of ~12 hours, supports once daily dosing (qd)
in the MAD phase.
In that phase, a starting dose of 100 mg was given qd for 5
days. Subsequent doses were 200 mg qd, 200 mg bid and 400 mg qd. All doses of
TMC435350 or placebo were well tolerated. There were no grade 3 or 4 adverse
events and no clinically relevant changes from baseline on laboratory
parameters, vital signs, ECG recordings and echocardiographic evaluations.
Minor effects observed were mainly gastrointestinal tract related. Mild,
short-lasting erythema was also noted after sun exposure in a few subjects
receiving the 200 mg bid dose or placebo. The plasma levels of TMC435350
detected 24 hours after the Day 5 dosing were substantially in excess of the
replicon EC50 value for all doses.
Conclusions:
·
In
this phase I study, TMC435350 was safe and well-tolerated when given to
HCV-negative healthy volunteers at single oral doses up to 600 mg, and at 5
days of oral doses up to 400 mg once-daily.
·
The
pharmacokinetic profile of TMC435350 supports once-daily dosing.
·
This
is no food effect.
·
The
plasma levels of TMC435350 24 hours after day 5 dosing are substantially in
excess of the replicon EC50 value for both 100 and 200 mg qd doses.
·
Minor
(grade 1 only) adverse events:
o
Mainly
gastrointestinal tract related.
o
Transient
photosensitive reaction in some subjects (mild, short-lasting erythema).
·
TMC435350
will be further investigate following once-daily
administration in HCV patients.
Mean PK parameters after single doses of TMC435350.
|
Dose |
50 mg |
100 mg |
200 mg |
300 mg |
450 mg |
600 mg |
|
tmax, h |
5 |
5 |
6 |
6 |
6 |
6 |
|
Cmax, ng/mL |
.29 |
.58 |
2.96 |
5.09 |
10.46 |
13.55 |
|
AUC24h, ng.h/mL |
3.35 |
6.28 |
30.05 |
46.38 |
125.0 |
166.70 |
Topic: Current Treatment - Consensus
Interferon
T. Hassanein; R. H. Ghalib; N. N. Zein; K. D.
Rothstein; S. N. Joshi; P. Kwo; J. Hammond
Background:
Relapse rates in HCV treatment-naïve patients treated with
pegIFN/RBV occurs in over 30% of patients. A recent controlled trial of
pegIFN/RBV non-responders retreated with a subsequent course of pegIFN/RBV
showed a relapse rate of more than 80% and a sustained response in only 3% of
patients. While several factors associated with relapse after therapy of naïve
patients with pegIFN/RBV have been identified (genotype 1, high viral load,
advanced histology, and non-adherence to treatment regimen), predictors of
relapse after re-treatment of pegIFN/RBV nonresponders with consensus
interferon (CIFN) and RBV remain unknown. Therefore, viral and host factors associated
with relapse following 48 weeks of therapy with CIFN/RBV in patients who failed
previous pegIFN/RBV treatment were analyzed.
Methods:
The DIRECT clinical trial is Phase 3, multi-center, and open-label
US-based study. 27 genotype 1 patients who had an end-of-treatment response and
received daily CIFN (15μg/d) and RBV (1.0-1.2 g/d) were identified for
this retrospective analysis. 54% of these patients had a high baseline viral
load (VL; ≥850,000 IU/mL), 41% had advanced liver disease/cirrhosis, 44%
had evidence of steatosis, and a mean weight of 89kg. 59% of patients had a
<2log10 drop in VL during their previous course of pegIFN/RBV therapy.
Relapse was defined as VL negative at end of treatment and virus detectable at
anytime within the 24-week follow-up period. No adjunctive growth factors were
used. Patients had a negative VL if virus was undetectable by both bDNA and TMA
assays.
Results:
The relapse rate in the 27 patients was 59%. The relapse rate
in patients with steatosis was 83% compared to 38% in patients who did not have
steatosis. Patients that achieved viral negativity by week 12 had the lowest
relapse rate (33%), followed by patients that were negative by week 24 (45%).
All patients that became viral negative after week 24 relapsed. There was no
apparent difference in relapse rates between patients that had a null response
(<2log10 drop in VL) versus a partial response (>2log10drop in VL but
detectable HCV RNA) to previous pegIFN/RBV therapy (63% vs. 57%, respectively).
Conclusions:
Previous pegIFN/RBV non-responders treated with daily
CIFN/RBV that achieved viral negativity earlier in the course of treatment were
less likely to relapse. The presence of steatosis also appeared to worsen the
relapse rates. Previous response to pegIFN/RBV did not appear to have an impact
on relapse with retreatment with daily CIFN 15µg/d and RBV. To reduce relapse
rates in this population, additional studies evaluating longer duration of CIFN
and higher doses of RBV are warranted.
Topic:
Current Treatment - General
M. L. Shiffman; H. Mansbach; J. Hammond; M.
O'Neill
Background:
Early virologic response (EVR) has been defined as a
>2log10 decline in HCV RNA from baseline or undetectable HCV RNA at
treatment week 12. However, within the context of EVR are patients who are HCV
RNA undetectable at treatment week 12 (complete responders) and a second group
that remains HCV RNA positive at week 12 (partial responders). Previous studies
have suggested that this latter group has a significantly lower chance of
achieving a sustained virologic response (SVR). We, therefore, analyzed a large
database of HCV patients who received either pegIFN alfa-2a or -2b along with
ribavirin (RBV) and determined the impact of EVR, complete, and partial
response on SVR.
Methods:
A retrospective review of the active control arms
(pegIFN/RBV) of two global phase 3, multi-center, randomized, parallel group, double-blinded studies in treatment-naïve patients was
performed. This analysis pooled 392 genotype 1 patients, 204 of whom were treated with pegIFN alfa-2b (1.5mg/kg/wk) and 188
treated with pegIFN alfa-2a (180µg/wk). Both studies used standard weight-based
doses of RBV (1.0-1.2 g/day). Week 12 response was categorized as HCV RNA
negative (complete responder), >2log10 decline but HCV RNA positive (partial
responder), and <2log10 decline in HCV RNA (null responder). Each category
of response was evaluated with respect to its ability to achieve SVR. HCV RNA
was assessed using the NGI SuperQuant assay (sensitivity to 39 IU/mL).
Results:
The patient population was 82% Caucasian; mean body weight
81kg; 71% high viral load (>2 million copies), and 34% with advanced
fibrosis or cirrhosis (F3-4). At week 12, 56% of patients were complete
responders (HCV RNA undetectable), 29% partial responders, and 15% null
responders. 335 patients (85%) achieved an EVR and 54% of these patients went
on to achieve an SVR. 220 of the EVR patients (66%) were complete responders,
and 115 patients (34%) were partial responders. 162 (74%) of complete
responders went on to achieve SVR. In contrast, SVR was achieved by only 18
(16%) of partial responders. Only 1 of 57 (2%) null responders achieved an SVR.
Conclusions:
Approximately 56% of genotype 1 treatment-naïve patients
treated with pegIFN/RBV became HCV RNA undetectable at week 12, and 74% of
these patients achieved SVR. In contrast, only 16% of patients with partial
response at week 12 achieved SVR. A study to determine if SVR can be increased
in partial responders (those with EVR but HCV RNA positive at week 12) by
switching to a more aggressive IFN regimen at week 12 is, therefore, warranted.
Topic: Current Treatment - General
T. Ide; T. Arinaga; I. Miyajima; K. Ogata; R.
Kuwahara; Y. Koga; K. Kuhara; R. Kumashiro; M. Sata
Background and aims:
Standard duration of pegylated interferon and ribavirin
therapy for HCV genotype 1 and high viral load is 48 weeks in
Methods:
83 genotype 1b and high viral load (>100 KIU/ml, Roche
amplicore) patients were randomized at baseline for standard (n=41) or extended
(n=42) treatment group. Standard group patients received 48 weeks of treatment.
Duration of extended treatment was determined by the time of HCV RNA negative
to be HCV RNA negative for 44 weeks (ex. If HCV RNA became negative at week 16,
total treatment duration was 60 weeks.). If HCV RNA is positive at week 24, the
patient was dropped out of the trial.
Results:
Two patients in standard group were lost to follow-up. 9 in
standard group and 8 in extended group were dropped out because of HCV RNA
positive at 24 weeks. 6 in each group discontinued treatment because of the
side effects and other reasons. SVR rates were 56.0% (14/25) in standard group
versus 81.1% (23/28). Especially, in patients who obtained HCV RNA negative at
from week 12 to week 24, SVR rate was significantly higher in extended group
(standard vs extended: 35.3% vs 78.9%, P<0.05).
Conclusion:
Extension of treatment with pegylated interferon plus
ribavirin therapy significantly increased the SVR rate in patients with HCV RNA
undetectable at 12-24 of treatment.
Topic: Current Treatment - PegIntron
M. B. Shah; R. S. Brown; T. Barski; B. Freilich; R. A.
Levine; N. H. Afdhal
Introduction:
Quality of life (QOL) is critical for the utilization of long
term maintenance therapies. The aims of this study were to evaluate baseline
QOL in patients with advanced fibrosis and to evaluate changes with
Peginterferon alfa-2b (PEG-IFN) vs. Colchicine (COLC).
Rationale:
Given side effects of standard doses of PEG-IFN, it is
unclear whether lower-dose maintenance therapy would improve or impair QOL.
Methods:
475 patients with advanced Hepatitis C refractory to
conventional treatment with Interferon and/or Ribavirin were randomized to
receive 0.5μg/kg PEG-IFN alfa 2b weekly vs. COLC 0.6mg PO BID. QOL was
assessed by administering the Medical Outcome Trust’s SF-36© survey annually
throughout the study. Responses were scored using the norm-based scoring
approach, where 50 is the mean for the general population and 10 is the
standard deviation.
Results:
Mental Component Summary (MCS) scores and Physical Component
Summary (PCS) scores were calculated for each of the two groups at baseline,
48-weeks, and 96-weeks. Mean values are reported in Table 1. All demographics
including age, gender, duration of disease, histology,
viral load, biochemical tests, and Child Pugh classification were comparable
between the 2 groups. Mean MCS and PCS scores were not significantly different
between the study groups at baseline. QOL was relatively stable in the groups
with no statistically significant change between baseline and week 96. Mixed
procedure analysis revealed a statistically significant effect of treatment
assignment only on MCS score (p = 0.02) at week 48 in the COLC group, and
values returned to baseline by week 96. The actual difference in score was a
modest 4-point reduction in MCS. There was no significant effect of treatment
assignment on PCS over time (p = 0.16) in either group.
Conclusion:
Surprisingly, cirrhotic patients were not more than 1 SD
below the normal population in either MCS or PCS at baseline. Treatment with
low-dose PEG-IFN did not adversely affect QOL over a 2-year period in patients
staying on therapy, suggesting that it can be tolerated as a maintenance
therapy.
Mean MCS and PCS Scores
|
Randomization |
Week |
N |
MCS Score (Mean ± SE) |
PCS Score (Mean ± SE) |
|
Colchicine |
0 |
161 |
46.4 ± 0.9 |
42.6 ± 0.8 |
|
48 |
88 |
42.6 ± 1.3* |
40.4 ± 1.2 |
|
|
96 |
69 |
46.2 ± 1.2 |
43.9 ± 1.2 |
|
|
PEG-IFN |
0 |
177 |
44.4 ± 0.9 |
42.1 ± 0.8 |
|
48 |
106 |
45.3 ± 1.1 |
41.6 ± 1.1 |
|
|
96 |
76 |
43.7 ± 1.2 |
41.0 ± 1.3 |
Topic: Current Treatment – Consensus
Interferon
F. Rahman; M. Schuchmann; H. F. Löhr; R. Link; P.
Buggisch; M. Fuchs; S. Kaiser; C. Antoni; T. Witthöft; J. Schlaak; P. R. Galle;
W. Bocher
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 PegInterferon (PegIFN) alfa2b plus ribavirin in genotype 2 and 3
patients.
Methods:
262 patients with chronic HCV infection and genotype 2 or 3
were randomly assigned to treatment with peg-IFNa2b (1,5
mcg/kg body weight once weekly, group A) or 9 mcg qd CIFN (group B) for 24
weeks. 194 patients received weight based ribavirin doses, however due to a
later protocol amendment, 68 patients received a fixed ribavirin dose of 800 mg
qd. Follow up was 24 weeks.
Results:
There were no significant differences in patient baseline
characteristics between both treatment groups concerning age, gender, genotype
and viral load. No significant differences were detected between both
treatments at end of therapy (EoT) and for sustained virological response (SVR)
rates in the intent to treat (ITT) and the per protocol (PP) analysis (ITT: 82%
vs. 75% at EoT and 67% vs. 65% SVR; PP: 95% vs. 95% at EoT and 84 vs. 90% SVR).
However, the CIFN group displayed a significantly lower relapse rate than group
A (3% vs. 9%, p = 0,042) resulting in a slightly higher SVR rate in group B in
the PP analysis. Furthermore, no difference in the treatment outcome was found
between weight based or fixed ribavirin dose regimens. Treatment was well
tolerated in both treatment groups, despite more dose modifications for
leucopenia in group B (9% vs. 3%, p = 0,015) without an increased
discontinuation rate.
Conclusions:
In treatment-naive patients with chronic hepatitis C and
genotype 2 or 3, daily treatment with CIFN combined with ribavirin has similar
antiviral efficacy and safety profile as weight adjusted PegIFNa2b.
Topic: Current Treatment – Consensus
Interferon
F. Rahman; M. Schuchmann; H. F. Löhr; R. Link; P.
Buggisch; M. Fuchs; S. Kaiser; C. Antoni; T. Witthöft; J. Schlaak; P. R. Galle;
W. Bocher
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 PegInterferon (PegIFN) alfa2b plus ribavirin.
Methods:
310 patients with chronic HCV genotype 1 infection were
randomly assigned to 48 weeks of treatment with: PegIFNa2b induction regimen
(group A: 2 weeks IFNa2b 10 -> 5 MU qd, followed by 36 weeks peg-IFNa2b 1,5
mcg/kg x week plus ribavirin); PegIFNa2b standard regimen (group B: 48 weeks
Peg-IFNa2b plus ribavirin); CIFN induction regimen (group C: 12 weeks CIFN 27
-> 18 mcg qd, followed by 36 weeks CIFN 9 mcg qd plus ribavirin); or CIFN
standard regimen (group D: 48 weeks CIFN 9 mcg qd plus ribavirin). Follow up
was 24 weeks.
Results:
There were no significant differences in patient baseline
characteristics between treatment groups concerning age, gender and viral load.
In the intent to treat (ITT) analysis, group D displayed reduced sustained
virological response rates (SVR), although due to limited statistical power
this was not statistically significant (A: 39%, B: 40%, C: 37%, D: 29%). Drop
out rates were 13-19% in the qd treatment regimens A, C and D. In the per
protocol analysis (PP), both PegIFN groups had lower end of treatment responses
compared to the CIFN groups (A: 58%, B: 58%, C: 84%, D: 70%). However, due to
higher relapse rates in the CIFN groups, no significant differences were found
in the SVR. All four regimens were similarly well tolerated with 3-9% adverse
events (AE) -related treatment discontinuations. However, group C displayed a
higher rate of dose reductions due to AE, mainly during the induction phase.
Conclusions:
Thus, in treatment-naive patients with chronic hepatitis C
and serotype 1 infection, daily CIFN could not increase SVR rates over those of
PegIFN alfa2b due to higher relapse rates. Moreover, neither IFN alfa2b nor
CIFN induction therapy increased cure rates in these patients compared to the
standard regimen.
Topic: Diagnostic Tools
K. Patel; J. G. McHutchison; Z. D. Goodman; D.
Theodore; A. Webster; M. Schultz; B. Stancil; M. Gartland; S. Gardner
Background:
Non-invasive biomarkers have been proposed as an alternative
to liver biopsy for initial staging and assessing changes in fibrosis with
therapy in chronic hepatitis C (CHC) patients. Our aims were to assess the
utility of the FibroSURE panel in staging fibrosis during screening for
enrollment into a multicenter phase II, placebo-controlled, antifibrotic study
of a PPARγ agonist (Farglitizar) in CHC infection.
Methods:
482 adult CHC non-responder patients with compensated liver
disease had a screening biopsy, and FibroSURE (FS) assay obtained through a
central laboratory. Liver biopsy assessment for Ishak staging was performed
independently by a single central histopathologist; subjects with Ishak stages
2-4 were subsequently randomized into the study. Screening data were analyzed
to determine the accuracy of FS for predicting Ishak fibrosis stage.
Results:
CHC patients were mostly Caucasians (363/482;75%), male
(297/482; 62%) and with a mean age 52 ±6.7 yrs. Mean biopsy length was 22.6
±11.4 mm. Overall Spearman correlation for Ishak stage and FS, r=0.38 (CI,0.31
– 0.47;p<0.0001); weighted Kappa = 0.15 (CI, 0.11 – 0.19; p<0.0001). FS
demonstrated good sensitivity but relatively poor performance for the detection
of moderate-to-severe stage (F3-F6) disease (AUC=0.69). For FS detection of
cirrhosis (F5-F6), AUC=0.73, r=0.25 (95% CI, 0.16 – 0.34). For FS index scores
0.32-0.58 that predicted stage F2-F3 disease, biopsy indicated F0-F1=53/134
(40%), F2-F3=72/134 (54%), and F4-F6 = 9/134 (7%).
Conclusions:
Non-invasive serum biomarkers such as FibroSURE demonstrate
good performance for exclusion of significant disease. However, their utility
in differentiating moderate stage disease is relatively poor, and this may
limit their ability to accurately follow changes in fibrosis stage with
treatment. This will be further evaluated based on follow-up biopsies at the
end-of-treatment in this study.
Performance characteristics of FibroSURE for detection of moderate and advanced disease
|
Ishak Fibrosis stage |
Prevalence |