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 |
FS Index Score |
Sensitivity |
Specificity |
PPV |
NPV |
AUC(SE) |
|
F3-F6 |
40% |
≥0.32 (n=386) |
0.90 |
0.27 |
0.45 |
0.80 |
0.69(0.02) |
|
F4-F6 |
15% |
≥0.59 (n=252) |
0.80 |
0.53 |
0.23 |
0.93 |
0.70(0.03) |
|
F5-F6 |
8% |
≥0.73 (n=151) |
0.70 |
0.72 |
0.19 |
0.96 |
0.73(0.03) |
AUC,
Area under ROC curve
Topic:Treatment
- General
1326. A 52 week
multi-centre, randomized, double-blind placebo-controlled trial evaluating the
efficacy and safety of glycyrrhizin in patients with chronic hepatitis C not responding
to IFNα or PEG-IFN plus ribavirin therapy
M. P. Manns; I. G. Bakulin; N. P. Blokhina; N. I.
Khomutjanskaja; H. Wedemeyer; T. Roskams; H. P. Dienes; M. Hasebe; J. V.
Platon; F. Baschiera
Background:
A significant number of patients with chronic hepatitis C
genotype 1 fail to respond to the standard therapy of PEG-IFN-α plus RBV,
or cannot be treated for various reasons. There are no options for
non-responders to previous standard therapies. Glycyrrhizin (GL) is used in
Objectives:
Confirm efficacy (based on ALT and histology) and safety of
GL in non-responders to combination therapy.
Methods:
The trial consists of 2 phases (12 plus 40 weeks). Phase 1 is
a randomized, double-blind, placebo-controlled, parallel group comparison of
i.v. injections of GL (200 mg glycyrrhizic acid), administered intravenously
5x/ and 3x/ week, or 5x/ week placebo, for 12 weeks. The following phase 2 is a
randomized, open comparison of GL 200 mg administered iv
5x/ versus 3x/ week, for 40 weeks (no placebo for ethical reasons). Adaptive
design plan and 2 primary efficacy endpoints: 1 - proportion of patients with ≥
50% ALT reduction after 12 weeks, and 2 - proportion of patients (>60%) with
improved necroinflammation score after 52 weeks. Inclusion criteria: pos.
HCV-RNA, non-response or relapse to IFNα or PEG-IFN plus ribavirin,
abnormal ALT, liver biopsy at entry or performed within 6 months. In this study
were enrolled 374 patients from 2002 to 2004, (5x/week GL, 3x/week GL, and
placebo with N= 123, 127, and 129, respectively.), carrying genotype type 1 in
73 % of cases. Baselines (mean, SD): ALT 77 ±49 IU/L, necroinflammation score
7.6 ± 2.5, fibrosis score 3.1 (±1.8).
Results:
The rate of ALT reduction ≥ 50% after 12 weeks was
significantly higher with 5x/week GL (30%, p = 0.000003) and 3x/week GL (32%, p
= 0.000001) compared to placebo (6%). Significant ALT (mean; 95% CI) decrease
under active treatment (-33 % -40 to -25) and (-27 %; -33 to -21) respectively,
but not under placebo (1 %;
The rate of patients with an improvement in HAI
necroinflammation score after 52 weeks of treatment was 34.6% in the 5x/week GL
(n=53 patients, p = 1.000) and 32.2% in the 3x/week GL group (n=48 patients,
p=1.0). Thus, the second formal primary
endpoint (>60% of patients with improved necroinflammation) could not be
reached. Considering cases with no
further deterioration as success, rates increased to 63% and 61% respectively.
Fibrosis score (architectural changes, fibrosis and
cirrhosis): Improvement or no further
deterioration in 67% of patients.
Improvement was higher with 5x/week GL compared to
3x/week GL (37% vs. 29%).
There were no remarkable changes in HCV viral load during the
double-blind and open phase and no remarkable differences between treatment
groups.
Quality of life including health change assessments showed
slight improvements in all treatment groups during both treatment phases. Improvements appeared to be more pronounced
in patients receiving GL than receiving placebo (double-blind phase) and more
pronounced in patients receiving 5x/week GL than those receiving 3x/week
GL.
Conclusion:
The study results show a statistically significant (compared
to placebo) reduction of elevated ALT-levels by GL, which was maintained during
the entire study duration. Treatment with 5x/week GL appeared to be slightly more effective than
3x/week GL (mean ALT reduction -33% vs.-27%, NS). The results of the liver biopsies showed
positive effects of GL on necroinflammation and fibrosis if ‘no worsening’ is
considered a positive effect-which should be, since chronic hepatitis C in
general is a progressive disease.
Topic: Current Treatment - Pegasys
F. Mecenate; G. Barbaro; A. Pellicelli; A. Barlattani;
E. Mazzoni; M. Bonaventura; M. Romano; L. Nosotti; P. Arcuri; A. Picardi; G.
Barbarini; F. Soccorsi
Background:
In chronic hepatitis C (CHC) patients with genotype 2 or 3,
24 weeks treatment with peg-interferon and ribavirin induces a sustained
virological response (SVR) in about 80% of the cases. Recent trials have shown
that a similar response rate may be obtained with a shorter treatment period
(12 or 16 weeks), especially in patients with rapid virologic response (RVR).
Aim:
Primary endpoint of the study was to assess whether 12 week
treatment with peg-interferon and ribavirin is as efficacious as 24 week
treatment in inducing a SVR in CHC patients with genotype 2 or 3. Secondary
endpoint was the rate of relapsers among groups.
Methods:
We performed a multicenter, prospective, randomized trial on
180 histologically confirmed CHC patients with genotype 2 or 3 enrolled in 11 italian centers. All patients were treated with
peg-interferon alpha2a (180 mcg/week) and ribavirine (800-1200mg/day). After 4
weeks of treatment, the patients with HCV-RNA <600 UI/ml (RVR) were
randomized either to 12 weeks (Group A1; n=60) or to 24 weeks (Group A2; n=60)
of combination therapy in a 1:1 ratio. The patients without RVR continued
standard 24 weeks combination therapy (Group B n=60). In all groups of patients
HCV-RNA was checked 12 and 24 weeks after the end of therapy.
Results:
At the end of the study period SVR was observed in 84% of
patients of Group A1, in 74% of patients of Group A2 and in 54% of patients of
Group B (P<0.05 vs Groups A1 and A2). Relapsers rate at the end of the study
period was 3% in Group A1, 2% in Group A2 and 6% in Group B. Logistic
regression analysis showed that baseline HCV-RNA< 1 million/UI/ml (OR: 3.5;
P<0.001), a baseline histological inflammation score <7 (OR:2.5;
P<0.001), a fibrosis score <2 (OR: 3.3; P<0.001) and a RVR <4 week
(OR: 3.5; P<0.001) were the strongest covariates predictive of SVR.
Conclusions:
In CHC patients with genotype 2 or 3, 12 week combination
therapy is as efficacious as 24 week therapy. A RVR is an independent covariate
predictive of SVR along with low baseline HCV levels and a low baseline
histological inflammation and fibrosis score without significant differences in
the rate of relapsers.
Topic: Current Treatment - Pegasys
1329. Viral
Kinetics Of HCV Genotype 4 During Pegylated
Interferon Alpha 2a –Ribavirin Therapy
M. F. Derbala; N. Z. El Dweik; S. R. Al Kaabi; A. D.
Al Marri; A. Bener; F. Shebl; A. M. Amer; M. T. Butt; R. Yakoob; M. Al
Mohanadi; M. Al Khinji
Background:
Kinetics of Hepatitis C virus (HCV) during pegylated
Interferon (PEG-IFN) and early monitoring of viral decline were recently
described to predict treatment outcomes and in turn reduce the course of
treatment, adverse effects and cost. There is limited information on the viral
dynamics of HCV-4.
Aim:
To follow the HCV-RNA kinetics during Peg-IFN-α2a and
Ribavirin therapy and the best time for predicting SVR in genotype 4 patients.
Methods: Serum HCV-RNA levels before initial dosing, 24h
later then at weeks 1, 4, 12, 24, 48 and 72 were assessed in 84 HCV genotype 4
patients treated weekly by PEG-IFN alpha2a 180microgram and daily
Ribavirin(1000-1200mg).
Results:
At the end of treatment, out of the 84 treated patients, 19
(22.6%) were non-responders while 65 (77%) showed end of treatment response
(ETR). However 9 patients relapsed (9.5%), thus the sustained viral response
(SVR) was observed in 57 patients (67.9%). Younger patients were more likely to
attain SVR, where the odds of SVR increased by a factor of 0.94 for each year
increase in age (95% CI 0.90, 0.99, p=0.019). Although a significant negative
correlation between stage of fibrosis and rate of viral decline at week 1
&4 (p <0.005 & 0.001, respectively) was seen, neither fibrosis stage
(X2 =3.4882, p>0.1) nor grade of inflammation (X2= 0.0057, p >0.1)
significantly predicted response to treatment. Non-responders had no or only a
limited decline at week 1 and week 4, whereas sustained virological responders
had a significant decline both at week 1 and week 4.Area under (ROC) curve
revealed that week 12 is better than any other time point in predicting SVR
(AUC 0.97; 95% CI 0.94, 1.01), (sensitivity 98.3%; 95% CI 90.7, 99.9),
(specificity 88.5%; 95% CI 71.0, 96.0), positive predictive value (PPV) of
94.9% and negative predictive value (NPV) of 95.8%. A drop of more than 1.17
log viral load at week 1 and viral clearance or decline >3log at week 4 were
considered as the earliest predictors of SVR.
Conclusion:
In genotype 4 patients, while failure to achieve an EVR at
week 12 predicts non-response, and RVR at week1 &
week 4 98% guaranteed SVR. These findings further re-enforce the value of week
12 in the course of IFN treatment. Genotype 4 patients who show significant
viral clearance (>1.17 log viral load) by the first week of treatment and
viral clearance >3log by week 4 are expected to show SVR and would therefore
be assigned to a shorter drug regimen lasting for 24 weeks. Those unfortunate
cases who do not achieve viral clearance by week 1 or week 4 should not be
deprived from treatment but rather given more time till week 12 before being
classified as non-responders.
Topic: Disease Progression
G. Teuber; A. Schaefer; J. Rimpel; K. Paul; C.
Keicher; M. Scheurlen; S. Zeuzem; M. R. Kraus
Background and Aims:
Health-related quality of life (HRQoL) is significantly
impaired in patients with chronic hepatitis C. However, only few studies have
been published investigating the relationship between the stage of liver
disease and quality of life and revealed conflicting results. Therefore, we
investigated HRQoL and fatigue in patients with chronic hepatitis C virus (HCV)
infection in relation to the degree of fibrosis while controlling for the
influence of relevant demographic and medical variables.
Patients and Methods:
HRQoL and fatigue were assessed in a cross-sectional
multi-center study including a total of 215 consecutive outpatients (92 women
and 123 men, mean age 46.7) with chronic HCV infection using the Medical
Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the German version
of the Fatigue Impact Scale (FIS-D). Applying multiple linear regression
analyses, the contribution to the variability of these psychometric scores was
evaluated for the degree of fibrosis (Ishak Score) as well as viremia, gender,
age, mode of transmission, genotype, and ALT.
Results:
Concerning HRQoL, there was a strong negative association
between the degree of liver fibrosis and the physical SF-36 summary score
(p=0.016), mainly due to the subscale “general health” (p=0.046). No such
relationship was found with respect to the mental domain of SF-36. These
effects were independent of the covariate age, also significantly predicting
physical HRQoL (p=0.001). Similarly, the absolute FIS score – including the
subscale “physical functioning” (p=0.011) – was significantly increased in
patients with advanced fibrosis (p=0.043), indicating a higher burden of
fatigue symptoms. A further noticeable finding was the more pronounced
impairment of the mental SF-36 summary score (p=0.007) and fatigue (p=0.017) in
females. However, the psychometric scores of HRQoL and fatigue were found to be
unrelated to viremia, mode of transmission, genotype and ALT levels.
Conclusions:
The present study suggests a significant association of the
physical aspects of both HRQoL (SF-36) and fatigue (FIS-D) with the extent of
fibrosis in patients with chronic hepatitis C while viral factors such as
viremia and genotype exert no significant effect. Female HCV patients were
particularly affected by impaired mental components of HRQoL and fatigue,
possibly indicating gender-specific aspects of coping. Our findings stress the
need for considering fibrosis stage for the identification and management of
HCV patients at risk for reduced physical HRQoL.
Topic: Experimental Therapies - Thymosin
K. E. Sherman; S. C. Gordon; R. Iftikar; M.
Rodriguez-Torres; V. K. Rustgi; A. M. Di Bisceglie
Background:
Management of HCV-infected treatment non-responders remains a
significant clinical challenge. Early pilot studies suggested that an
immunomodulatory peptide, thymosin alpha-1 (TA-1) may play a role in enhanced
viral clearance, histologic improvement and sustained viral response (SVR). We
performed two parallel randomized controlled trials to evaluate efficacy of
TA-1 in this difficult to treat population.
Methods:
Both trials had similar designs. Patients were randomized to
receive either pegylated interferon alfa 2a 180 mcg (PEG) SQ qweek + TA-1 for
48 weeks, or PEG with placebo TA-1 for 48 weeks. One trial (803) permitted
subjects with mild fibrosis through bridging fibrosis (Metavir F1-3) while the
other (804) enrolled subjects with more advanced baseline fibrosis (F3 or F4).
Each trial planned enrollment of at least 500 subjects with a 1:1 randomization
between TA-1 and placebo TA-1. Baseline and post-treatment liver biopsies were
obtained.
Results:
Cumulative enrollment in the two trials was 1061 subjects.
Nearly all were genotype 1 (93.5%), and 83% had previously failed treatment
with interferon alfa + ribavirin and 17% with interferon alfa alone. HCV RNA
viral load at baseline was similar between the two trials and averaged log 6.2
copies/ml. 71% of subjects were male and their mean age was approximately 50
years. By intention-to-treat analysis (ITT), viral clearance at week 48
occurred in 74/533 (13.9%) of subjects treated with PEG + TA-1 vs. 76/528
(14.4%) in the control arm. SVR was observed in 13 subjects (2.4%)in the active treatment arm and 9 subjects (1.7%) in the
placebo arm (not significant). The proportion of patients demonstrating an
improvement of Knodell Histologic Activity Score (HAI) by 2 or more points was
similar in treatment and control groups. Decreases in circulating CD4
lymphocytes were lower among subjects with more advanced fibrosis who received
TA-1 vs those receiving placebo. Treatment emergent toxicities were similar
between treatment groups.
Conclusion:
·
Among
treatment experienced subjects with HCV infection, retreatment with PEG + TA-1
resulted in a similar sustained virologic response when compared to use of PEG
monotherapy, and is not effective in the management of prior non-responders.
·
Studies
utilizing PEG, TA-1 and ribavirin are in progress.
Topic: Current Treatment – Consensus
Interferon
1332.
S. B. Ho; B. Aqel; E. Dieperink; L. Tetrick; Y.
Falck-Ytter; C. A. de Comarmond; C. I. Smith; D. McKee; A. A. Mihas; W. Boyd;
C. C. Kulig; M. Pedrosa; E. J. Bini
Introduction:
Patients in the
Purpose:
To determine the efficacy and safety of daily CIFN+RBV for
initial treatment of patients with HCV genotype 1 and other
“difficult-to-treat” characteristics.
Methods:
Patients with HCV genotype 1 were prospectively enrolled in 7
Veterans Affairs (VA) and 2 private medical centers. Patients were randomized
to treatment with daily CIFN (15 mcg/d sq) and RBV (1-1.2 gm/d PO) given for
(A) 52 weeks, vs (B) 52 to 72 weeks (from time of initial virologic response +
48 wks). Treatment is discontinued if HCV RNA is detectable at wk 24.
Results:
64 patients initiated treatment (92% male, 33% African
American, 78% VA, 67% high viral load, 59% stage III-IV fibrosis, mean body
weight 92.5+2.1 kg). ITT analysis of 64 patients with virologic data through 24
wks indicated that 43 (67%) achieved undetectable viral levels; overall 21
(33%) demonstrated a rapid virologic response (RVR) at 4 wks, 16 (25%) were
early virologic responders between 8-12 wks, and 6 (9%) were late virologic
responders between 12-24 wks. During treatment 27 (42%) patients required CIFN
dose reduction and 18 (28%) required RBV dose reduction. Five patients were
discontinued at 24 weeks due to virologic non-response. Overall early
discontinuation of treatment before 24 wks occurred in 22/64 (34%) patients (9
due to intolerance; 10 due to noncompliance; 1 due to chest pain; and 2 due to
cellulitis). This is comparable with the 32% discontinuation rate reported in a
large VA cohort treated with interferon alfa-2b+RBV (J Viral Hep 2006;13:242). Final ETR and SVR data are pending.
Conclusions:
Patients with hepatitis C genotype 1 and “difficult-to-treat”
characteristics treated with daily CIFN+RBV demonstrated a high RVR rate, with
33% virus-negative at 4 wks and 67% virus negative by 24 wks. This compares
favorably with RVR rates of 19-22% for genotype 1 patients treated with
pegylated interferon alfa-2a and ribavirin (Gastroenterology 2006;130:1086 and 131:451). Although adherence and tolerability
are limitations, these data indicate that daily CIFN+RBV for initial treatment
of
Topic: HIV/HCV Coinfection - Pegasys
F. Torriani; M. Rodriguez-Torres; J. Rockstroh; E.
Snoeck; K. Jorga; D. T. Dieterich
Background:
It is now well established that HCV genotype 1 (G1)
mono-infected patients benefit from starting RBV at a dose of 1000/1200 mg/d
instead of the lower 800 mg/d dose used in earlier studies. In the APRICOT
trial, HIV-HCV co-infected patients were treated with peginterferon alfa-2a
(40KD) plus RBV 800 mg/d for 48 weeks. The 800 mg/d dose of RBV was selected to
minimize hematologic toxicity and the potential for drug–drug interactions with
nucleoside reverse transcriptase inhibitors. In APRICOT, the rate of SVR was
40% overall and 29% in G1 patients. We modeled the probability of SVR and
anemia in co-infected G1 patients and predicted the outcomes for treatment with
RBV 1000/1200 mg/d.
Methods:
Binary data from 176 G1 patients in APRICOT were incorporated
into an existing generalized additive model (GAM) established with data from
817 mono-infected G1 patients enrolled in two phase III clinical trials. The
effect of prognostic factors on SVR and anemia (Hgb <10 g/dL) were analyzed
and simulations run with the updated GAM to predict SVR and the incidence of
anemia in co-infected G1 patients treated with peginterferon alfa-2a (40KD)
plus RBV 1000/1200 mg/d. Uncertainty was quantified by ‘bootstrapping’.
Results:
After incorporating data from APRICOT, significant predictors
of SVR retained in the model included baseline (BL) viral load, RBV dose
(mg/kg), age, BL ALT quotient, histological diagnosis (cirrhosis vs no
cirrhosis) and HIV status (yes vs no). BL factors predictive of anemia included
BL Hgb level, RBV dose (mg/kg), age, sex, HIV status, BL ALT quotient and BL
viral load. Use of RBV 1000/1200 mg/d in co-infected G1 patients is predicted
to increase the SVR rate by 8% (from 29% to 37%) and the incidence of anemia
from 14% to 23% (Table).
Conclusions:
Our simulations suggest that increasing RBV dose to 1000/1200
mg/d, would improve SVR rates in patients co-infected with HIV and HCV G1.
However, higher doses of RBV would also be associated with a higher incidence
of anemia. Therefore, Hgb levels should be monitored closely and the RBV doses
should be decreased in small decrements to preserve chances for higher end of
treatment responses and to prevent relapses.
Predicted outcomes after 48wks treatment with PegIFN alfa-2a/RBV in G1
|
RBV dose (mg/d) |
800 |
1000 (<75kg) or 1200 (≥75kg) |
|
Predicted median SVR (%, 95% CI) |
|
|
|
HCV mono-infection |
41 (36-45) |
49 (45-53) |
|
HIV-HCV co-infection |
29 (23-35) |
37 (29-45) |
|
Predicted median incidence of anemia (%, 95% CI) |
|
|
|
HCV mono-infection |
7 (5-9) |
13 (11-15) |
|
HIV-HCV co-infection |
14 (11-17) |
23 (18-30) |
Anemia=Hgb
<10 g/dL; SVR=undetectable HCV RNA (<50 IU/mL) at wk72
Topic: Experimental Therapies - R7025
B. Brennan; R. Robson; I. Rodriguez; J. Symons; J.
Huang; M. Chan; S. Blotner; N. Jennings; B. Rawal; M. Brunda; G. Hooper; A.
Rakhit
Background:
Pegylated interferon (PEG-IFN) in combination with ribavirin
is the standard of care for patients with chronic hepatitis C (CHC). However,
treatment is not yet optimal in patients infected with HCV genotype 1 with
sustained viral response rates of ~50%. R7025 is a novel human pegylated
IFNα molecule generated using DNA Shuffling (Maxygen, Inc.) technology
that exhibits ~50-fold higher antiviral activity compared to PEG-IFNα-2a,
but only 2- to 10 fold greater antiproliferative activity in vitro. R7025
contains the identical branched chain 40KD PEG molecule used in the synthesis
of PEG-IFNα-2a. The primary objective of this study was to evaluate the
safety, tolerability, PK and PD activity of single ascending doses of R7025 in
healthy volunteers.
Methods:
In each cohort, subjects were randomized to receive a single
dose administered subcutaneously in the abdomen according to the following
scheme: 8:R7025, 2:placebo, 2:180 μg PEG
IFNα-2a. Subjects were evaluated frequently for safety, tolerability, PK
and PD assessments. The following dose levels were evaluated 1, 5, 20, 40, 80
and 120 µg.
Results:
12 subjects were enrolled and completed the study:
·
8
received R7025
·
2
received placebo
·
2
received pegylated interferon alfa-2a 180 ug (positive control)
The PD markers, serum neopterin and 2’,5’-oligoadenylate
synthetase (2,5 OAS) levels were increased in subjects who received a 20- 120
µg dose of R7025. Doses of 40 µg and higher produced a similar level of PD
induction as a 180 μg dose of PEG IFNα-2a. Serum exposure (Cmax and
AUC) of R7025 increased with dose and was sustained over 168 hrs, supporting a
minimum of once weekly dosing. Doses up to 80 µg were well tolerated with most
adverse events rated (AEs) as mild or moderate. No serious AEs have been
reported. In the 120 µg group, 4/8 R7025 treated subjects experienced severe
flu-like symptoms, which were adequately controlled with analgesics and fully
reversible. Most subjects who received 20-120 µg of R7025/placebo exhibited a
reversible decrease in neutrophils but only grade 1/2 changes in neutrophils
were observed.
Conclusions:
·
R7015 doses ≥
20 ug produced similar levels of PD marker induction to 180 ug dose of
pegylated interferon alfa-2a
·
Most adverse
events were mild and consistent with those absorbed after administration of
other IFNa’s
·
At a dose ≥ 120 ug
transient severe flu-like symptoms were observed.
·
Changes in
haematological parameters observed across all doses were mild and
reversible.
Topic: Treatment – Herbal Treatment
1383.
Botanical Medicines for Hepatitis C
S. J. Polyak; J. Wagoner; O. Kane; M. Austin; D. Lee;
C. Morishima
Background:
A striking feature of hepatitis C virus (HCV) infection is
its propensity to establish a chronic disease state. Because state-of-the art
antiviral treatments are costly, have serious side-effect profiles, and
moderate probabilities for durable cures, many patients opt for complementary
and alternative medicine (
Methods:
In the current study, we examined two widely used botanicals,
silymarin and sho-saiko-to (SST), for antiviral and immunomodulatory actions.
Results:
Silymarin inhibited expression of TNF-α in anti-CD3
stimulated human PBMC and NF-κB dependent transcription in human hepatoma Huh7
cells. Moreover, both silymarin and SST dose-dependently inhibited infection of
Huh7 and Huh7.5.1 cells by JFH-1 virus. Both compounds also displayed
prophylactic and therapeutic effects against JFH-1 infection, and when combined
with IFN-α, inhibited HCV replication more than IFN-α alone.
Antiviral effects induced by Silymarin involved Jak-Stat dependent and
independent signaling, while SST enhanced ISRE transcription via p38 MAP kinase
activation. HPLC fractionation of the herbal preparations permitted
identification of the components eliciting antiviral actions.
Conclusions:
The data demonstrate that standardized silymarin and SST have
antiviral action against in vitro HCV infection, and that silymarin has
immunomodulatory and anti-inflammatory actions. Therefore, CAM-based approaches
may assist in the management patients with chronic hepatitis C.
Topic:Treatment
- General
P. Halfon; G. Pénaranda; M. Bourlière; A. Tran; D.
Botta-Fridlund; I. Portal; C. Renou; M. Picon; C. Wartelle; J. Arpurt; M.
Antoni; M. Guisset; C. Gueyffier; P. Delasalle; D. Ouzan
Background:
Previous studies demonstrated that viral load (VL) is an
important predictor for treatment outcome in patients with chronic hepatitis C
virus (CHC). We looked at pre-treatment (BL) VL, and
week 4 VL (W4) to assess a predictive score achieving probability of sustained
virological response (SVR) in CHC genotype 1 patients: the SVRScore.
Patients-Methods:
113 CHC genotype 1 patients were included in the study among
which 86 patients achieved complete 48 weeks treatment (54 had an SVR).
Patients were treated with PEG-IFN alpha2b+RBV. Serum HCV RNA was measured using
COBAS TaqMan HCV Test (TaqMan HCV; Roche Molecular Systems Inc.,
Results:
In univariate analysis BL VL and W4 VL were both associated
with SVR (p<.0001 and p<.01 respectively). In multivariate analysis, BL
VL and W4 VL were both independent predictors of SVR (respective odds ratio
0.29 (95% CI 0.09-0.95), and 0.39 (0.24-0.63). From the binary logistic
regression, we calculated the SVRScore combining BL VL and W4 VL (cf. formula
below).
Area under the ROC curve for SVR prediction was of 0.89 and
positive predictive value of SVR was 86% (44/51).
Conclusions:
·
We
developed the SVRScore, a new, simple, and highly predictive score for SVR
prediction in CHC genotype 1 infected patients.
·
With
high predictive values the SVRScore remain useful for the treatment management
of CHC infected patients.
·
In
the near future an analysis will be conducted to validate the SVRScore on an
independent cohort.
Topic: Experimental Therapies - GS-9190
I. Vliegen; J. Paeshuyse; E. Marbery; B. Peng; I.
Shih; L. S. Lehman; H. Dutartre; B. Selisko; B. Canard; S. Bondy; W. Tse; H.
Reiser; E. De Clercq; W. A. Lee; G. Puerstinger; W. Zhong; J. Neyts
Background and Aims:
Following lead optimization of a novel series of substituted
imidazopyridines, GS-9190 was identified as a promising drug candidate based on
its potent inhibition of in vitro HCV RNA replication and excellent selectivity
index. The aim of this study was to characterize the biological activity of
GS-9190 against HCV replicons of different genotypes and against various drug
resistant mutants. GS-9190 was also studied in combination with known anti-HCV
agents.
Methods:
The antiviral activity of GS-9190 was evaluated in HCV
genotypes 1b, 1a and 2a replicon cells, in the JFH1 (genotype 2a) infectious
system, and against several related and unrelated viruses. Cytotoxicity of
GS-9190 was determined in a panel of cell lines. A transient replication assay
using Lunet cells (Huh-7) was used to characterize susceptibility of known drug
resistant mutants to GS-9190. Combinations of GS-9190 with other HCV agents
were evaluated in the genotype 1b (Con-1) replicon cells.
Results:
GS-9190 is a potent inhibitor of HCV genotype 1b and genotype
1a replicon replication (EC50 = 0.6 and 2.5 nM, respectively). The 50%
cytostatic concentration of GS-9190 in various cell lines is > 50µM,
illustrating a high degree of selectivity (SI > 20,000). GS-9190 has lower
potency against a genotype 2a replicon or against the JFH1 infectious virus
(EC50 ~ 1 µM) and is inactive against a number of related and unrelated
viruses. Replicons resistant to various HCV protease and polymerase inhibitors
remained fully susceptible to GS-9190. The combination of GS-9190 with either
IFN-α or several HCV protease and polymerase
inhibitors resulted in an additive antiviral activity. The combination of
GS-9190 with a protease inhibitor was more efficient in clearing hepatoma cells
from their replicon than either agent alone. Following long-term culture with
increasing concentrations of GS-9190, resistant replicons were selected.
Transfection of naïve Lunet cells with total RNA isolated from the GS-9190res
replicon cells transferred drug resistance, indicating that resistance is
associated with the viral genome. In biochemical assays, GS-9190 is inactive
against HCV NS3 serine protease, NS3 RNA helicase, and NS5B polymerase (either
in initiation or elongation assays).
Topic: Experimental Therapies - ITM-191
P. Rajagopalan; S. Stevens; A. Stoycheva; B.
Brandhuber; H. Zhang; M. Gale; L. M. Blatt; S. Seiwert; K. Kossen
Background:
Combination therapy for chronic hepatitis C with pegylated
interferon alfa and ribavirin (SoC) results in a Sustained Virologic Response
(SVR) rate of approximately 50%. Direct antiviral agents may improve the rate
of SVR when used in combination with SoC or in novel regimens. A desired
characteristic of potential therapeutics is the ability to function against
multiple HCV genotypes. ITMN-191 is a potent HCV NS3/4A protease inhibitor in
clinical development. Previous studies demonstrate that ITMN-191 binds genotype
1b NS3/4A in a two-step mechanism, inhibits with picomolar potency, and that
the enzyme-inhibitor complex is stable for hours. The biochemical potencies and
inhibition kinetics of ITMN-191 against proteases from multiple HCV genotypes
are defined here.
Methods:
Coding sequences for genotype 1a, 1b, 2b, 3a, 4, 5, and 6
variants of NS3 were cloned and used to express full-length proteins in
baculovirus infected cells. A continuous fluorometric assay for NS3/4A protease
activity was used under conditions that maximize sensitivity and protease
stability. ITMN-191 dissociation was studied by examining recovery of protease
activity following dilution of the pre-formed NS3/4A-ITMN-191 complex. Results
were interpreted in light of structural data obtained via X-ray
crystallography, homology modeling, and inhibitor docking.
Results:
A kinetic characterization of genotype 1-6 proteases suggests
that ITMN-191 binds the majority of these proteins through a two step mechanism
similar to that previously proposed for a replicon-derived protease sequence.
In this mechanism, ITMN-191 forms an initial complex with NS3/4A that
subsequently isomerizes to a more stable species from which ITMN-191
dissociates slowly. IC50 values for genotype 1a, 1b, 4, 5 and 6 proteases are
similar to the 0.8nM potency previously obtained with a replicon-derived
protease when assays are conducted with minimal preincubation of enzyme and
inhibitor. Under these conditions, the genotype 2b and 3a proteases show 3 and
19 fold reduced sensitivity to ITMN-191, respectively. In assays that monitor
the recovery of activity following dilution of a preformed enzyme-inhibitor
complex, all tested proteases show evidence for slow dissociation of ITMN-191
with the exception of genotype 3a. Structural and computational analyses of
ITMN-191 binding implicate key sequence differences between the 3a isolate and
other genotypes.
Conclusions:
ITMN-191 is a highly potent, slowly dissociating inhibitor of
the HCV NS3/4A protease. The strong inhibition of genotype 1-6 proteases supports
the use of ITMN-191 to treat multiple genotypes of HCV.
Topic: Experimental Therapies - General
1387. A
Hepatitis C T-Cell Vaccine Candidate Covering HCV Genotype Complexity and HLA
Type Diversity
A. Van der Aa; V. Goossens; K. Allosery; G. Verheyden;
S. Southwood; C. Dahlberg; D. McKinney; M. Newman; H. M. Diepolder; G.
Maertens; M. Buyse
Background:
Viral clearance of HCV has been shown to be associated with
multi-specific, strong CD8+ T-cell (CTL) responses together with strong CD4+
T-cell (HTL) responses. A candidate therapeutic polyepitope T-cell vaccine able
to induce such potent specific T-cell responses could ultimately lead to viral
clearance. Also, by taking human HLA as well as HCV genotype diversity into
account, such a vaccine should be applicable to the majority of infections.
Methods:
HCV-derived CTL and HTL epitopes for a wide range of HLA
class-I and HLA-DRB1 alleles were identified applying different algorithms on
the full HCV genome. Further selection was made based on in vitro HLA binding
affinity of the peptides, immunogenicity in HLA transgenic mice, and recall
reactivity of CD8+ and CD4+ T-cells in an IFNγ-ELISPOT assay using HCV
patient samples. Several DNA plasmids containing different sets of selected
epitopes were designed, constructed, and evaluated for immunogenicity in HLA
transgenic mice. Finally, epitopes were included in the candidate HCV
polyepitope therapeutic vaccine based not only on their immunological
properties but also their conservancy within and between HCV genotypes, as well
as their HLA restriction. In addition, the polyepitope construct was expressed
as protein in E. coli, purified using affinity chromatography and tested for
immunogenicity.
Results and discussion:
A plasmid vector was constructed that contains 34 HCV-derived
CTL epitopes, 13 HCV-derived HTL epitopes, and the pan-DR helper T-cell epitope
PADRE®. Theoretical population coverage calculations show that the selected set
of CTL and HTL epitopes can provide recognition of at least four CTL and three
HTL epitopes in any HCV genotype 1-infected subject, irrespective of HLA type.
Vigorous CTL and HTL responses could be induced using the pDNA or protein
formats of the vaccine candidate in HLA-A01, HLA-A02, HLA-A11, and HLA-A24
transgenic mice.
Conclusion:
A set of HCV-derived CTL and HTL epitopes was identified that
showed excellent affinity, immunogenicity, and cross-reactivity, and formed the
basis for the development of a universal T-cell vaccine candidate for treatment
of chronically infected HCV patients. The T-cell vaccine candidate has now been
shown to be immunologically active both in the form of pDNA and protein.
Topic: Experimental Therapies - General
1389.
Efficacy of Interferon β combined cyclosporine A treatment in
the retreatment of chronic hepatitis C - Promising aspect of host factor
targeting therapy.
K. Inoue; T. Watanabe; M. Yamada; M. Yoshiba
Background/Aim
A significant proportion of chronic hepatitis C patients fails to achieve sustained virological response (SVR) even
after the treatment with pegylated interferon (IFN) alpha combined ribavirin.
The effective treatment for patients who previously failed combination standard
IFN plus ribavirin or pegylated IFN plus ribavirin has not been well established.
Management of these patients is the most challenging task and new compounds
targeting NS3 protease or NS5B polymerase are now under evaluation.
Cyclophilins are essential host factors for HCV replication. We have originally
developed IFN combined cyclosporine A treatment and
also reported its favorable anti-HCV effect. We report here the efficacy of
divided administration of IFNβ plus cyclosporine A in the treatment of
chronic hepatitis C patients who failed Peg-IFN or IFN combined ribavirin.
Patients and method
We prospectively included 59 patients (median age, 63) with
1) histologically proven chronic hepatitis C, 2) genotype 1b and 3)
non-responders and relapsers to combination IFN plus ribavirin or combination
pegylated IFN plus ribavirin. We conducted the present study to confirm the
efficacy, safety and tolerability of our protocol. Serum HCV RNA level was 3900
KIU/ml. The treatments consisted of an induction therapy, an intensified
therapy and a maintenance therapy. The induction therapy comprised intravenous
1 MU IFNβ every 4 hours for the first 3 days, 1.5 MU IFNβ every 6
hours for the next 4 days and 2 MU IFNβ every 8 hours for the following 3
weeks, totaling 168 MU of IFNβ. The intensified therapy was induction therapy
shortened to 2 weeks. The maintenance therapy comprised of pegylated
IFNα2b and ribavirin. CsA was given 4 times daily for a total dose of 200
mg during the induction and the intensified therapies. Ribavirin was given
twice daily for a total dose of 800 mg (body weight over 60 kg) or a total dose
of 600 mg (body weight equal to or less than 60 kg) during the maintenance
therapy. The institute review board approved this protocol.
Results
The end treatment response and sustained virological response
rate of the present study were 73%(43/59) and 59%
(35/59), respectively. The relapse rate was 19%(8/43).
SVR in previous combination therapy relapsers was 80% (32/40) and that in
previous combination therapy non-responders was 16%(3/19).
All adverse effects were completely reversible. The treatment protocol was well
tolerable.
Conclusion
·
We
concluded that our protocol should be effective in relapsers to the previous
combination therapies.
·
Host
factor targeting treatment will become a promising treatment option.
Topic: Experimental Therapies - TMC435350
1390. In Vitro
Activity And Preclinical Pharmacokinetics Of The HCV Protease Inhibitor,
TMC435350.
K. Simmen; O. Lenz; T. Lin; G. Fanning; P. Raboisson;
H. de Kock; G. van't Klooster; Å. Rosenquist ; M. Edlund; M. Nilsson; L. Vrang;
B. Samuelsson
Background:
As a class, HCV NS3/4A protease inhibitors have shown promise
in clinical trials for the treatment of chronic hepatitis C virus infection.
TMC435350 is a novel and potent macrocyclic NS3/4A protease inhibitor. To further
assess the potential of TMC435350, we characterized the in vitro activity of
TMC435350 alone or in combination with different classes of HCV inhibitors. The
plasma pharmacokinetics and tissue distribution were also studied in vivo.
Methods:
The effect on HCV RNA level and the emergence of
drug-resistant colonies was analyzed in the replicon model with TMC435350
alone, or in combination with interferon alpha, ribavirin, and different HCV
polymerase inhibitors. Pharmacokinetic profiles were evaluated following single
or repeated dosing in rats. The tissue distribution of TMC435350 was studied in
male rats at time points from 0.5 up to 31 hours after a single oral dose of 40
mg/kg.
Results:
In biochemical HCV NS3/4a protease assays, TMC435350
exhibited Ki values <0.1nM for subtypes 1a (H77) and 1b (con1) enzymes.
TMC435350 was found in the subgenomic genotype1b replicon model to have an EC50
of 8nM and a selectivity index (SI) of > 1000. The combination of TMC435350
with different classes of HCV inhibitors further increases its activity in
reducing HCV RNA in an additive to synergistic manner, and further reduced the
emergence of resistant replicon colonies.
After single oral administration of a PEG400-based solution
of TMC435350 at 40 mg/kg the mean peak plasma concentration (Cmax) was
1430ng/ml and was observed at two hours post-dose (Tmax). The absolute
bioavailability of TMC435350 was calculated at 44% after single oral
administration of a 40 mg/kg dose. TMC435350 was found to be extensively distributed
to the liver, small- and large intestines (tissue/plasma ratios >35).
Concentrations in other organs were similar to plasma. Notably, TMC435350 was
still quantifiable in the liver tissue up to 31 hours post-dosing.
Conclusions:
TMC435350 is a novel potent and specific HCV protease
inhibitor, with good oral bioavailabilty and a favorable liver distribution. In
addition, in vitro studies support the potential use of TMC435350 in
combination with other HCV inhibitors.
Topic: Experimental Therapies - Boceprevir
D. N. Standring; V. Bichko; R. Chase; M. LaColla; L.
Lallos; A. Skelton; M. Soukasakos; M. Tausek; X. Tong; R. Ralston
Background:
Combination of small-molecule antiviral agents directed
against different molecular targets offer an attractive strategy for the
effective therapy of hepatitis C. As monotherapies,
valopicitabine (NM283) (Idenix/Novartis), an investigational nucleoside NS5B
polymerase inhibitor, and boceprevir (SCH 503034) (Schering-Plough), an
investigational NS3 protease inhibitor, have demonstrated antiviral activity
against hepatitis C virus (HCV) in clinical studies. Using cell culture
replicon studies we show that the combination of polymerase and protease
inhibitors leads to greater anti-HCV activity, no cross-resistance and the
suppression of treatment emergent-resistance, compared to monotherapy with each
agent.
Methods:
The combined antiviral effect of the polymerase and protease
inhibitors was evaluated in genotype 1b HCV replicon cells by real time RT-qPCR
or ELISA. Possible cross-resistance of these compounds was evaluated using
replicon variants carrying single protease inhibitor resistance mutations
(T54A, A156S, V170A, A156T), or the polymerase inhibitor resistance mutation
(S282T). The selection of resistant cell colonies was carried out for 3-4 weeks
in the presence of various concentrations of one or both drugs.
Results:
The combination of SCH 503034 and NM107 showed dose-dependent
enhancement of replicon inhibition, compared with the effect of each inhibitor
used alone. No cytotoxicity was observed. In cross-resistance studies, NM107
showed similar antiviral activity (EC50 1.5-2 μM) against wild-type and
SCH 503034-resistant replicons. SCH 503034 showed similar activity (EC50
0.3-0.4 μM) against wild type and NM107-resistant replicons. When tested
against their known resistance mutations, each compound showed a 5- to 125-fold
loss in susceptibility. In selection experiments, the combination of SCH 503034
and NM107 significantly reduced the frequency of resistant colonies in a
dose-dependent manner, compared to each inhibitor used alone.
Conclusions:
In these in vitro studies, the combination of the polymerase
and protease inhibitors showed enhanced anti-replicon activity with no
cross-resistance and a greater genetic barrier to resistance. These results
support clinical evaluation of this combination in patients with chronic
hepatitis C.
Topic: Experimental Therapies - ANA598
L. Kirkovsky; Y. Zhou; D. Norris; E. Okamoto; T. G.
Nolan; D. Bartkowski; J. Khandurina; M. Sergeeva; D. Murphy; B. Ayida; A.
Xiang; D. Ellis; J. Blazel; Z. Sun
Introduction:
Inadequate responses to current HCV therapy
create an urgent unmet need for new antiviral agents to complement
today’s standard of care, particularly for treatment of genotype 1 infections.
Probable future HCV therapies will add multiple direct-acting antiviral agents
taken from differing functional classes to enhance response and suppress the
emergence of resistant HCV variants. The essentiality of the NS5B polymerase
predicts that inhibitors of this enzyme should be attractive additions to
current standard of care. However, first generation development candidates
targeting this essential enzyme suffer notable defects in potency, metabolism,
or pharmacokinetic properties that limit their potential. We describe here the
superior pharmacokinetic properties of ANA598, a novel, orally available and
potent “palm site” inhibitor of HCV genotype 1 NS5B polymerase.
Results:
ANA598 demonstrated high oral bioavailability in all four
species evaluated. ANA598 plasma exposures were lower in the rat than the
monkey; exposure did not differ significantly for solution and suspension
formulations in these species. ANA598 demonstrated a greater than proportional
increase in plasma exposures with increasing dose in monkey and rat; in the
mouse exposures were approximately dose-proportional up to a 1000mg/kg. An oral
dose of 5mg/kg ANA598 to monkeys provided C12 and C24 levels (21,600nM and
7,600nM, respectively) that were substantial multiples of the replicon EC50
(51nM for genotype 1a and 3nM for genotype 1b) even after adjustment for
protein binding. ANA598 accumulated in rat liver and reached a liver-to-plasma
ratio of ~20 at 12 hours after an oral 5mg/kg dose, suggesting significant
additional antiviral coverage in the primary target organ for HCV replication.
Conclusion:
Preclinical studies of ANA598 in four species have demonstrated
high oral bioavailability and plasma and liver trough levels that are
substantial multiples of replicon EC50. Clinical studies of ANA598 in four
species have demonstrated high oral bioavailability and plasma and liver trough
levels that are substantial multiple of replicon EC 50. These favourable antiviral, metabolic,
pharmacokinetic and preliminary toxicologic properties clearly differentiate it
from other molecules of this functional class and strongly support further
evaluation of ANA598 for the treatment of HCV infection.
Plasma PK parameters of ANA598 after a single oral dose of 5mg/kg
|
Species |
Foral, % |
AUCinf, h*μM |
**C12, μM |
**C24, μM |
Cmax, μM |
Tmax, h |
T1/2, h |
|
Cynomolgus Monkey |
65 |
602 |
21.6 |
7.6 |
42 |
5.5 |
8 |
|
Beagle Dog |
85 |
441 |
13.8 |
3.7 |
40 |
2 |
2 |
|
*CD-1 Mouse |
45 |
42 (M) / 114 (F) |
0.10 (M) / 0.74 (F) |
|
11 / 22 |
0.5 / 4 |
3.4 |
|
*Sprague-Dawley rat |
~115 |
94 |
0.3 / 2.0 |
|
24 |
0.4 |
5 |
* - mean
values in rat and mouse are given separately for males and females,
respectively ** - C12 and C24 - plasma levels
at 12 and 24 hours post dose, respectively
Topic: Experimental Therapies - ME3738
1393. ME3738
inhibits hepatitis C virus replication by enhancing interferon-β
Y. Hiasa; Y. Tokumoto; I. Konishi; B. Matsuura; K.
Michitaka; R. T. Chung; M. Onji
Background/Aims:
We previously reported that ME3738, a derivative of
soyasapogenol B, has effects against hepatitis C virus (HCV) in cells derived
from hepatocytes. Our established model of full-length genotype 1a HCV
replication supports replication not only in interferon-β (IFN-β)
induction-deficient Huh7 cells, but also in HepG2 cells. Therefore, we used our
model to examine whether or not ME3738 modifies innate antiviral activity. We
also assessed the effects of ME3738 combined with interferon-α
(IFN-α) on HCV.
Methods:
HepG2 or Huh7 cells were transfected with a full-length HCV
cDNA plasmid (pH77), and infected with a replication-defective adenoviral
vector expressing T7 polymerase (Ad-T7pol). Cells were infected with Ad-T7pol,
then ME3738 (0.1-10 μM) and/or 100 IU/ml of IFN-α was added. Protein
and RNA were harvested from the cells on day 1, 2, 3, 5, 7 and 9
post-infection. To knock down IFN-β expression, 20 nM of siRNA targeting
IFN-β was transfected into the cells 1 day before pH77. We measured HCV
positive and negative strands as well as mRNA levels of innate antiviral
response-related genes using real-time RT-PCR. We assessed HCV core protein
expression by ELISA.
Results:
The anti-HCV effect of ME3738 was more pronounced in HepG2
than in Huh7 cells. ME3738 enhanced mRNA levels of IFN-β in HepG2 cells.
The mRNA levels of 2′-5′ oligoadenylate synthetase and MxA were
stimulated by IFN-β in HepG2 cells. When the IFN-β was knocked-down
by siRNA, the anti-HCV effect of ME3738 was abrogated. In Huh7 cells, the
IFN-β mRNA levels triggered by viral double-stranded RNA were increased slightly,
and neither IFN-β nor IFN-stimulated gene mRNA expression by ME3738 was
enhanced. ME3738 combined with IFN-α elicited synergistic anti-HCV effects
in HepG2 cells (HCV/GAPDH copy ratio (Day 3); 2.585±1.600×10-6
(ME3738+IFN-α) vs. 3.557±1.560×10-5 (ME3738), p<0.05).
Conclusions:
The anti-HCV effect of ME3738 was more potent in HepG2 cells
than in cells deficient in IFN-β induction. The enhancement of endogenous
IFN-β by ME3738 suggests that this agent exerts innate antiviral action
more effectively along the type I IFN pathway. Adding IFN-α
synergistically enhanced the anti-HCV action of ME3738. Thus, ME3738 might be a
useful anti-HCV agent either with or without IFN-α.
Topic: Experimental Therapies -
PF-00868554
S. Shi; K. Herlihy; R. Irvine; S. Binford; C. Lewis;
J. Nonomiya; A. Patick
Introduction:
PF-00868554 is a non-nucleoside inhibitor of the HCV RNA
polymerase, which exerts its inhibitory effect by binding to the thumb-base
domain of the protein. It is a potent and selective inhibitor of the enzyme,
with a mean IC50 of 0.0096 µM against genotype 1 polymerases in biochemical
assays.
Aim:
To determine the in vitro antiviral activity of PF-00868554
against various HCV laboratory and clinical strains, a panel of chimeric
replicons was generated in which polymerase sequences derived from genotype 1a
and 1b clinical isolates were cloned into the genotype 1b (Con1 strain)
subgenomic reporter replicon.
Results:
The antiviral activity of PF-00868554 was evaluated against
this panel of chimeric replicons in the transient replication assay in Huh7.5
cells using the luciferase reporter endpoint. Results indicate that PF-00868554
has potent in vitro antiviral activity against a majority (95.8%) of genotype 1
replicons, with overall mean EC50 and EC90 values of 0.059. PF-00868554 showed
no cytotoxic effect in several human cell lines up to the highest concentration
evaluated (320 µM). Furthermore, the antiviral activity of PF-00868554 was
retained in the presence of human serum proteins. PF-00868554 displayed promising PK
properties in rats and dogs.
Conclusions:
Our results demonstrate that PF-00868554 has potent and
broad-spectrum antiviral activity against genotype 1 HCV strains, supporting
its use as an antiviral agent in HCV-infected patients.
Topic: Experimental Therapies - GS-9190
I. Shih; I. Vliegen; B. Peng; H. Yang; J. Paeshuyse;
G. Purstinger; M. Fenaux; E. Mabery; G. Bahador; L. S. Lehman; S. Bondy; W.
Tse; H. Reiser; W. A. Lee; J. Neyts; W. Zhong
Background and Aims:
GS-9190 is a drug candidate currently being evaluated for
safety, tolerability, pharmacokinetics, and antiviral efficacy in chronically
infected HCV patients. It is a novel imidazopyridine analogue with potent
antiviral activity in HCV replicon cells, especially against genotype 1 HCV.
GS-9190 has lower potency against a genotype 2a (JFH1) subgenomic replicon or
against the JFH1 infectious virus. The aim of this study was to define the
mechanism of action of GS-9190.
Methods:
Chimeric replicons carrying sequences from genotype 1b
(Con-1) and genotype 2a (JFH1) were used to identify viral determinants of
susceptibility to GS-9190. A cell-based, strand-specific qRT-PCR replicase
assay was employed to analyze the inhibitory profile of GS-9190. Drug
resistance selection with GS-9190 was performed in Con-1 replicon cells.
Results:
To investigate the mechanism of action, we utilized the
susceptibility difference between genotype 1b and genotype 2a to GS-9190 and
constructed a chimeric replicon in which all viral genes were derived from
genotype 1b except the NS5B gene, which was derived from genotype 2a. The
antiviral activity of GS-9190 against the chimeric replicon was comparable to
that observed for the genotype 2a replicon, suggesting that NS5B polymerase is
the target of inhibition. Studies with additional 1b/2a chimeric replicons
further indicated that the beta-hairpin in the thumb sub-domain of NS5B was
involved in the interaction. Based on these results, a cell-based replicase
assay utilizing strand-specific qRT-PCR was developed; analysis of positive and
negative strand production indicated that GS-9190 affected viral RNA synthesis
in a manner similar to that of non-nucleoside NS5B inhibitors. Characterization
of replicons resistant to GS-9190 led to identification of multiple mutations
across the viral genome including several inside the beta-hairpin of NS5B.
Subsequent studies showed that only those mutations in NS5B were able to confer
resistance to GS-9190 when introduced into a wild-type replicon, whereby the
total number of mutations correlated with the degree of resistance.
Conclusion:
Collectively, these data demonstrate that GS-9190 represents
a novel non-nucleoside NS5B inhibitor whose binding pocket involves
beta-hairpin and is in close proximity to the catalytic active site of NS5B.
Detailed mechanistic characterization of GS-9190 and its interaction with NS5B
will be presented.
Topic: Experimental Therapies - General
S. P. Galhenage; G. D. Sanders; K. Patel; K. A. Schulman;
J. G. McHutchison
Background:
Current standard of care for chronic hepatitis C (CHC)
infection with peginterferon (PEG-IFN) and ribavirin (RBV) (P+R) is costly, and
effective in only half of all treated cases. Recent data have shown that the
addition of novel Specifically Targeted Antiviral Therapy for HCV (STAT-C) to
standard of care has the potential to advance the treatment of genotype 1 CHC
infection. Thus, we modeled this new strategy to assess the economic impact of
improved viral response on costs and outcomes.
Methods:
A Markov model was developed to compare standard therapy with
4 treatment strategies (a STAT-C agent for 12 weeks combined with P +/- R for
12-48 weeks). The model followed treatment-naïve individuals with mild CHC
infection (Metavir FO-F1) from treatment initiation until death [assuming base
case age 40 years, 60% male, 48 week P + R sustained viral response rate (SVR)
46%]. Costs of PEG-IFN α-2a 180mcg weekly and RBV 1000-1200mg daily were
based on average wholesale prices. Base cost of STAT-C therapy was assumed
equivalent to 48 weeks of P + R. Rates of SVR and adverse effects were
estimated. Natural history of CHC infection, treatment patterns, healthcare
costs and utilities for all disease states were obtained from published data.
Analyses adopted a societal perspective and applied a 3% annual discount rate.
SVR and costs of STAT-C therapy were varied in sensitivity analyses.
Results:
Compared to standard therapy, STAT-C based regimens were associated
with increased survival of 0.14-0.45 years and 0.31-0.90 quality-adjusted life
years (QALYs). These additional health benefits however increased lifetime
costs by $15,641-$39,757. Under base-case assumptions, a strategy of STAT-C +
24 weeks of P + R had an incremental cost-effectiveness ratio of $29,375/QALY
compared with current standard of care for an SVR rate of 70%. Other strategies
were either dominated or prohibitively costly. Results were most sensitive to
treatment efficacy, cost, and patient age. Assuming a threshold of $50,000/QALY
for cost-effectiveness, sensitivity analyses revealed that the STAT-C + 24 week
P + R strategy would remain cost-effective if relative cost increased up to a
factor of 1.44 or with SVR rates as low as 61%. If this regimen was priced to be cost neutral compared to current standard of care,
lifetime costs increased by $4,482 and QALYs improved by 0.78 resulting in an
incremental cost-effectiveness ratio of $5738/QALY.
Conclusions:
Our model suggests that STAT-C therapies that increase
efficacy provide an opportunity to increase life expectancy and may enhance the
value of treatment for patients with genotype 1 CHC infection, depending on the
cost of these agents.
Topic: Experimental Therapies - General
1397. AM3
inhibits HCV replication through activation of peripheral blood mononuclear
cells.
P. L. Majano; S. Martín-Vílchez; Y. Rodriguez-Munoz;
P. Sanz Cameno.; F. Molina-Jimenez; J. L. Alonso; S. Gonzalez; M.
Lopez-Cabrera.; R. Moreno-Otero
Introduction:
Inmunoferon® is a drug whose active principle is a
glycoconjugate of natural origin composed of a glucomannan polysaccharide from
Candida utilis and a storage protein from nongerminated seeds of Ricinus
communis. The glycoconjugate that constitutes the active principle of
Inmunoferon® (hereafter referred as AM3) has been shown to modulate regulatory
and effector functions of the immune system by acting on peripheral blood
mononuclear cells (PBMCs) and modifying the expression of extracellular
mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1
beta. Previously, it has been shown that AM3 has antiviral effect against HBV
due to stimulation of secretion of molecules with antiviral properties by PBMC.
Objective:
To analyze whether AM3 has antiviral
properties against HCV replication in vitro.
Materials and Methods:
Reagents: AM3 was prepared according to the methods described
in patents P9900408 (
Cell culture: We used two clones derived from Huh-7 cell with
genomic bicistronic, full-length HCV genome. PBMCs were purified from
peripheral blood cells from healthy donors by Ficoll density centrifugation and
cultured at 106 cells/ml for 24 h prior to analysis.
PBMC were stimulated or not with AM3 (1 μg/ml) for 48 or 96 h and then
cell supernatants were collected. Huh7/HCV clones were treated for 24 or 48 h
with the PBMC supernatant (conditioned medium; 1:2 proportion,
with normal culture medium). To analyse whether AM3 has a direct antiviral
effect on HCV replication, Huh7/HCV clones were incubated with various doses of
AM3 for 48h.
Methods: Total RNA Huh/HCV clones were isolated and HCV RNA
was analyzed by real-time RT-PCR. Additionally, core and non-structural protein
NS5a levels were determined by western blot.
Results:
HCV replicons cells treated with supernatant derived from AM3
stimulated PBMC exhibit lower HCV RNA and protein accumulation when compared to
untreated controls. However, AM3 did not affect directly the expression of RNA
or protein in any of the cell clones tested.
Conclusion:
In this report, we found that AM3 inhibited HCV RNA and
protein expression by an indirect mechanism. We found that AM3 lacked intrinsic
antiviral properties, and that the antiviral effect of the glycoconjugate was
due to stimulation of secretion of molecules with antiviral properties by PBMC.
Our data suggest that the employment of AM3 as an adjuvant administered
simultaneously with conventional antiviral drugs may potentiate the endogenous
response against viral infection.
Topic: Experimental Therapies - GS-9190
C. Yang; Y. Wang; L. Wieman; E. Eisenberg; M. Lee; B.
Murray; L. Tong; A. Ray; S. Bondy; W. Tse; A. Coluci; M. Wright; L. S. Lehman;
W. A. Lee; G. Rhodes
Background and Aims:
GS-9190 is a novel non-nucleoside HCV RNA polymerase
inhibitor with potent in-vitro antiviral activity and a high selectivity index.
GS-9190 is currently being evaluated for safety/tolerability, pharmacokinetics
and antiviral efficacy in chronically infected HCV patients. It is a novel
imidazopyridine analogue with potent antiviral activity against genotype 1 HCV
replicon cells. The aim of these studies was to characterize the
pharmacokinetic profile of GS-9190 in relevant preclinical models prior to
administration in humans.
Methods:
Single dose pharmacokinetic studies were conducted following
intravenous and oral administration of GS-9190 in rats, dogs and cynomolgus
monkeys. The distribution and routes of excretion were determined in rats
following oral administration of 14C-GS-9190. The absorption, metabolic
stability, protein binding and the CYP450 inhibition and induction profile of
GS-9190 were evaluated in vitro in systems derived from human and, where
appropriate, preclinical species.
Results:
GS-9190 was stable to in vitro metabolism in microsomal and
S9 fractions derived from all species studied. Reaction phenotyping studies
also suggested slow turnover by human CYP1A, CYP3A and CYP2C19. In all species,
protein binding was extensive (> 98 %). GS-9190 demonstrated limited
potential to alter human CYP function through either inhibition or induction.
The absorption potential of GS-9190 was shown to be high based on its extensive
Caco-2 cell monolayer permeation and lack of recognition by intestinal efflux
proteins.
In vivo preclinical data are consistent with the in vitro
profile of GS-9190. In all preclinical species GS 9190 displays low total body
clearance and a volume of distribution comparable to total body water. Oral
bioavailability was greater than 30 % in all preclinical species and was not
limited by hepatic first pass extraction. In the rat, the majority of the
14C-radiolabelled dose was excreted slowly into the bile with only minor
excretion in the urine. Recovery of radioactivity was essentially complete 48
hr after administration of 14C-GS-9190.
Conclusion:
The available human in vitro data project a favorable
clinical pharmacokinetic profile, with high oral bioavailability for GS-9190 in
human subjects. As a result it is predicted that plasma concentrations of
GS-9190 sufficient to drive pharmacological effect can be achieved with
relatively modest doses in humans.
Topic: Experimental Therapies - VCH-759
LB11.
Antiviral activity of the non-nucleoside polymerase inhibitor, VCH-759, in
chronic Hepatitis C patients:Results from a
randomized, double-blind, placebo -controlled, ascending multiple dose study.
C. Cooper; E. J. Lawitz; P. Ghali; M.
Rodriguez-Torres; F. H. Anderson; S. S. Lee; L. Proulx
Background:
VCH-759 is a novel, orally bioavailable non-nucleoside
inhibitor of hepatitis C virus RNA-dependent RNA polymerase. It has
demonstrated sub-micromolar IC50s against the HCV replicons of
genotype 1a and 1b.
Methods:
This multiple ascending dose study was designed to assess the
effect on viral kinetics, viral resistance, pharmacokinetics, safety and
tolerability of VCH-759 given as monotherapy for 10 days with a 14-day
follow-up period. Three cohorts of treatment-naive chronic hepatitis C patients
infected with HCV genotype 1 received either placebo,
400 mg tid, 800 mg tid or 800 mg bid. Viral loads were determined using the
Roche Amplicor assay (lower limit of quantification=600 IU/ml).
VCH-759 plasma levels were assessed over 6 hours for the tid
regimen and over 12 hours for the bid regimen on Days 1 and 10 and daily, prior
to the morning dose, on Days 1 to 11.
Results:
Thirty-two (32) subjects were enrolled and completed the
study (9: placebo, 9: 400mg tid, 9: 800 mg tid, 5: 800 mg bid). VCH-759 was
rapidly absorbed with peak plasma levels Day 1: 1857 ± 773 ng/ml, 4857.2 ±
4106.6 ng/ml and 4,627 ± 1688 ng/ml and Day 10: 71814.4 ± 3798.6, 22706.3 ± 26035.3, 21806.1 ±
19925.5 for the 400 mg tid, 800 mg tid and 800 mg bid doses respectively.
No serious adverse events or dose-limiting toxicities were
reported. All adverse events were mild
to moderate. The most frequently
reported treatment-related AEs wer diarrheas, headache, flatulence, dyspepsia
and fatigue. The incidence of
gastrointestinal AEs in the placebo group was comparable to that in the active
treatment grups suggesting that the formulation vehicle (an aqueous mixture of
Solutol HS 15 and Polyethylene glycol 400 which is known to affect the GIT). Clincial laborator evaluations revealed no
clinically significant effects of VCH-759 on blood chemistry, urialysis, vital
signs and ECG measurement.
Conclusions:
·
VCH-759
demonstrated a rapid and significant antiviral response ewithin the first few
days of treatment. All subjects had more
than one log 10 decrease in plasma HCV RNA with mean maximal decrease of 1.9,
2.3, 2.5 log 10 at 400 mg tid, 800 bid, and 800 tid, respectively.
·
The
viral load response was similar for both HCV genotype 1a and 1b
·
Multiple
administration of VCH-759 at difference dosing regimens for 10 days was well
tolerated in treatment-naïve subjects with HCV
·
The
pharmacokinetic results demonstrated no accumulation of VCH-759 after 10 days
of treatment
·
VCH-759
plasma tough concentrations were at or above the replicon IC90 for the duration
of treatment for the three different dosing regimens
·
Genotypic
sequencing of the NS5B polymerase is ongoing to determine if mutations are
associated with virologic rebound observed in some subjects prior to the final
dosing day.
Topic: Experimental Therapies - Locteron
I. Dzyublyk; T. Yegorova; L. Moroz; O. Popovych; I.
Zaytsev; V. Miroshnichenko; E. Herrmann; S. Zeuzem; E. J. van Hoogdalem; J. E.
Humphries
Background:
Controlled-release recombinant interferon-alfa 2b (Locteron)
is a novel approach to delivery of interferon (IFN) given every 2 weeks with
improved tolerability combined with a high level of hepatitis C virus (HCV)RNA
reduction.
Methods:
A phase 2a, open-label, dose-ranging study was conducted in
treatment-naïve patients with genotype 1 chronic HCV infection to evaluate the
safety, tolerability and anti-viral effect of Locteron. 32 patients were
randomized to receive subcutaneous injections of Locteron 14 days apart over 12
weeks in 4 dose cohorts (8 per cohort) of 160, 320, 480 and 640 µg, with the
640 µg group starting after safety evaluation of the other cohorts. All
subjects received weight-based ribavirin. HCV RNA reduction modeling was
performed.
Results:
The mean HCV RNA reduction at week 4 for the 160, 320, 480
and 640 µg groups were 1.1, 3.1, 2.9 and 3.1 logs, respectively. Percent of HCV
negative subjects at week 4 were 0, 25, 38 and 25, respectively. Average viral
reduction after 12 weeks for the 3 lower doses of Locteron (160, 320 and 480
µg) was 1.8, 4.5 and 4.2 logs, respectively. 63% of subjects at the 2 middle
doses (320 & 480 µg) were HCV negative (LLOQ < 28 IU/mL) at 12 weeks.
Early viral response (EVR: 12-week ≥ 2-log drop in HCV RNA) was achieved
in 88% and 100% of subjects in the 320 and 480 µg Locteron dose cohorts,
respectively. Modeling of HCV kinetics demonstrated dose-dependent biphasic
kinetics reflected by mean and maximum efficiency in blocking viral production
from day 1 to day 28 of treatment. Mean and maximum efficiency were 41%±23% and
54%±27%, respectively, in the 160 µg cohort, 58%±19% and 71%±21% in the 320 µg
cohort, 72%±20% and 84%±11% in the 480 µg cohort, and 73%±24% and 80%±22% in
the 640 µg cohort. The median T1/2 of free HCV RNA was 2 hours and the median
T1/2 of infected cells was 2.8 days. Clinical adverse events were almost
exclusively mild in intensity with only 1 severe adverse event in the 3 lower
dose cohorts. The most common adverse events were arthralgia (50%), weakness
(50%), myalgia (38%) and headache (33%), with chills, nausea and diarrhea each
reported in fewer than 5% of subjects. Fever (Temp ≥ 38.0°C) occurred in
only 1 subject in these first 3 cohorts. Full data on all 4 cohorts for all 12
weeks will be available by the AASLD meeting.
Conclusions:
In this study, Locteron, a controlled-release formulation of
unmodified IFN-alfa 2b, administered every 2 weeks to treatment-naïve patients
with chronic hepatitis C (genotype 1) demonstrated strong anti-viral activity
combined with an improved safety and tolerability profile compared to currently
marketed IFNs and those in development.
Topic: Experimental Therapies - R7128
R. Reddy; M. Rodriguez-Torres; E. Gane; R. Robson; J.
Lalezari; G. T. Everson; E. DeJesus; J. G. McHutchison; H. E. Vargas; A. Beard;
C. A. Rodriguez; G. Z. Hill; W. Symonds; M. Berrey
Background:
R7128 is a prodrug of PSI-6130, an oral cytidine nucleoside
analog polymerase inhibitor, currently in development for the treatment of HCV.
This multiple ascending dose study assessed safety, tolerability,
pharmacokinetics, and preliminary antiviral activity of R7128 in subjects with
HCV genotype 1 infection.
Methods:
Multiple oral doses of R7128 monotherapy were administered
for 14 days to 40 HCV-infected patients (n=10 per cohort with 8 active + 2
placebo) of 750mg QD, 1500mg QD, 750mg BID & 1500mg BID. PK, safety and
virology assessments were conducted throughout the study period. Data are
available for the 750mg QD, 1500mg QD and 750mg BID cohorts. The 1500mg BID
cohort is fully enrolled.
Results:
Demographics and Clinical Safety
·
Baseline
demographics were similar across groups:
All subjects had HCV genotype 1 (29 – 1a; 11 – 1b), had previously
failed alpha-interferon and were non-cirrhotic.
·
No
serious adverse events were reported. No subjects discontinued R7128 due to an
AE.
·
There
was no trend of drug or exposure-related AEs.
·
The
placebo group reported the highest number of AEs with 34 events in 7 of 8
subjects.
·
The
most commonly reported AEs were headache, diarrhea, dry mouth, nausea. The majority were mild in grade.
·
There
were no clinically significant changes noted in the vital sign parameters
across the treatment groups.
·
No
trends in laboratory abnormalities were noted, and no treatment emergent grade
2 or higher labs were reported.
·
Of
those receiving R7128 with abnormal ALT at baseline, 78% normalized by Day 14.
·
No
clinically significant changes were reported for serial ECGs, including no QTc
prolongation beyond 500ms.
Antiviral Activity
·
R7128
demonstrated dose-dependent HCV RNA decreases through 14 days of monotherapy in
all dose groups
·
Viral
nadir occurred at Day 15 with no evidence of clinically relevant rebound during
therapy.
·
HCV
RNA values in the placebo group remained at baseline.
·
The
range at Day 15 in HCV RNA decrease from baseline in the 1500mg BID cohort was
-1.2 to -4.2 log10 IU/mL with this subject having HCV RNA below the limit of
detection.
·
Two
subjects with ~1.2 log10 IU/mL decline included a prior null responder and
Pharmacokinetics
·
Oral
dosing with R7128 resulted in dose-dependent but not dose proportional exposure
to PSI-6130, the active moiety.
·
Plasma
concentrations of the pro-drug, R7128, were below the limit of detection for
all subjects
·
The
monoester intermediate form was detected only at higher doses at tmax in a
subset of subjects indicating efficient conversion of pro-drug to parent.
·
The
terminal plasma elimination half-life (t1/2) of PSI-6130 was ~5 hrs, while
Summary
·
A
mean 2.7 log10 decline and maximum 4.2 log10 decline was demonstrated following
14 days of monotherapy
·
R7128
was generally well-tolerated and demonstrated no evidence of acute target organ
toxicity
·
78%
of subjects receiving R7128 with abnormal ALT at baseline normalized
·
R7128
was effective as a pro-drug delivery of PSI-6130
·
Terminal
plasma half-life of the parent compound, PSI-6130, was ~5 hrs; terminal plasma
half-life of the metabolite, PSI-6206, was ~20 hrs
·
A
maximum tolerated dose of R7128 has not been identified
Conclusions:
·
R7128
has provided positive proof-of-concept that a direct acting antiviral can
deliver sufficient antiviral potency via monotherapy to suppress below the
level of detection (<15 IU/mL) in a prior IFN non-responder population
·
BID
dosing of R7128 was superior to QD dosing in this monotherapy trial
·
Lack
of clinical rebound provides early evidence of high genetic barrier for
nucleoside inhibitors of NS5b polymerase
·
The
safety and efficacy of this monotherapy study support further development of
R7128 in combination with the standard of care (pegylated interferon and
ribavirin)
|
Dose |
750mg QD (n=8) |
1500mg QD (n=8) |
750mg BID (n=8) |
1500mg BID(n=10) |
|
Mean baseline HCV RNA concentration (log10 IU/mL) |
-0.90 |
-1.48 |
-2.11 |
-2.72 |
|
Mean(range) change from baseline on Day 15 (log10 IU/mL) |
-0.67 To -1.10 |
-0.90 To -2.50 |
-1.80 To -3.00 |
-1.2 To -4.21 |
|
Proportion with ≥1 log decline by Day 15 |
3 of 8 37.5% |
7 of 8 87.5% |
8 of 8 100% |
8 of 8 100% |
Topic: Diagnostic tools
1335.
European Liver Fibrosis (ELF) panel of serum markers can predict clinical
outcome in a cohort of patients from
J. Parkes; P. Roderick; S. Harris; C. Gough; M.
Wheatley; G. J. Alexander; J. D. Collier; C. P. Day; D. J. Mutimer; J. Ramage;
A. Burt; W. M. Rosenberg
Introduction
The performance of non-invasive tests has been evaluated
against fibrosis on biopsy but use of clinical outcomes as the reference
standard would be ideal. The ELF panel of markers (TIMP1, HA, PIIINP) has been
shown to have excellent ability to identify significant fibrosis on biopsy. To
evaluate ELF performance in predicting clinical outcomes, the original ELF
cohort was followed-up at 8-9 years.
Methods
Patients recruited to the ELF study at 6 centres were
followed up for liver morbidity and mortality by examination of clinical data.
Those lost to follow up were followed up for morbidity by questionnaires to the
family practitioner. Primary outcome measure was liver related morbidity or
death; secondary outcome was all-cause mortality.
Results
448 patients were followed up after a median of 7.7 years
representing 99% of those recruited at 6 sites. Median age=43 years, 67% male,
44% CHC and 17% ALD. 28% were lost to follow up and 13% were discharged. 85% of
family practitioner questionnaires were returned reporting no liver outcomes.
There were 57 liver outcomes (34 liver related deaths) and 61 deaths in total.
Crude unadjusted analyses by Kaplan Meier plots showed that tertiles of
baseline ELF score can predict liver outcomes and all-cause mortality (log rank
test p= <0.001) (Figure 1). Histology was also predictive of outcome when
classed as mild, moderate or severe fibrosis. Cox Proportional Hazards model
analyses show that ELF remains predictive when adjusted for age, gender and
disease aetiology (p=<0.0001); adjusted hazard ratio for the middle tertile
ELF score versus lowest tertile ELF score= 4.06 (95% CI 1.55-10.624), and for
highest tertile ELF score versus lowest tertile, HR=29.87 (95% CI 8.55-104.42)
Conclusions
ELF score can predict clinical outcomes in patients with
chronic liver disease at least as well as liver biopsy, and is likely to be a
useful prognostic tool in clinical practice.
Figure
1
Kaplan-Meier
plot for liver related outcome ELF tertiles
Topic Disease Progression
1336.
Tracking the Course of Hepatitis C with Paired Biopsies - A Critical Analysis
M. Rajablou; A. S. Mugglin; K. P. Batts; C. I.
Smith
Purpose:
To determine if paired liver biopsies in following the course
of patients with hepatitis C is of value.
Methods:
Blinded histologic re-examination of liver biopsy samples was
undertaken from a cohort of 161 chronic hepatitis C patients who had undergone
at least two (non-protocol) liver biopsies. Fibrosis was assessed using the
Batts/Ludwig 0-4 staging system, with intermediate stages (e.g. 1.5) being used
in an attempt to maximize the sensitivity. Grade and other co-morbid conditions
were also recorded. The rate of fibrosis (stage/year) was determined both from
the paired samples ("short-term rate") and from the estimated time of
infection by hepatitis C (per history) to the first liver biopsy
("long-term rate"). Linear regression was used to assess the
relationship of demographic variables to fibrosis rate. Linearity of long-term
fibrosis change over time was assessed via polynomial regression.
Results:
Of the 161 paired biopsy patients, 136 had historical
information allowing estimation of a long term rate of fibrosis prior to
therapy: mean time interval to first biopsy 23.6 years; stages: <1 (17.6%,
mean 21.4 yrs), 1-2 (71.3%, mean 24.0 yrs), >2 (11.0%, mean 24.8 yrs);
overall fibrosis rate .06545 stages/year with "best fit" statistical
analysis revealing non-linearity of the stages (p < 0.001). Body mass index
(BMI) (p= 0.018) and increased age at infection (p<0.0001) were associated
with accelerated rates of fibrosis. The mean interval between biopsy samples
was 4.1 years; overall stage increased by just 0.168 stages (8.7% decreased,
67.1% stable, 10.6% increased by 0.5 stage and 13.7% by one stage or more),
resulting in an overall short term fibrosis rate of 0.03995 stages/year; BMI
(p=0.0032) was associated with more rapid fibrosis. No association between
long-term and short-term fibrosis rates was detected (correlation = -0.018, p =
0.83).
Conclusions:
Short-term (~4 years) follow up biopsy in hepatitis C
patients uncommonly (13.7%) demonstrates a significant (one or more stage)
increase in stage. Increased BMI is associated with more rapid progression.
Short-term fibrosis rate cannot be used to predict long term fibrosis rate,
perhaps in part because the individual 0-4 stages are likely not of equal time
duration (non-linear), making comparison of long-term and short-term fibrosis
rates problematic.
Topic: Disease Progression
1337.
Long-term Morbidity and Mortality of HCV Infection: A 25 years Follow-up
S. Kamal; I. Nasser; S. El Kamary; M. Shardell; M. Hashem;
A. Ibrahim; A. Moustafa; I. Fathy; M. Sobhi; A. Abdel Baky; H. Mansour
Background/Aims:
The natural history of HCV is highly variable and not well
characterized. Most cohort studies have not been well controlled with serial
liver biopsies to estimate true disease progression. The aim of this study was
to investigate the long-term clinical and histological outcome of a cohort of
untreated and treated subjects followed for 25 years with a known onset of
acute HCV.
Study design/methods:
In this retrospective-prospective longitudinal cohort study,
archived serial serum samples from 420 subjects with non A-non B acute
hepatitis between 1981-1982 were re-screened for HCV (ELISA, PCR). Of the 385
subjects with proven acute HCV, 36 subjects refused ebrollment, 45 had
coinfections and were excluded, and 214 were enrolled and prospectively
followed. Clinical, virological and HRQL evaluations were performed. Liver
biopsies were either available at entry (n=49) or were performed at enrollment
(n=96), Liver biopsies were repeated6-17 years after the initial biopsies in
patients considered for treatment,. Ishak score and
fibrosis progression rates were determined. The clinical end-points were
end-stage disease, hepatocellular carcinoma (HCC), liver transplantation or
death.
Results:
The disease duration ranged between 22-25 years. .Of the 385
patients with acute hepatitis C, 127 subjects (33%) had spontaneous persistant
resolution. At baseline, none of the 214 patients with chronic hepatitis had
clinical decompensation, HCC or significant impairment of HRQOL. Eighty-two
patients (38%) had history of interferon therapy or were treated during the
study. \ The baseline mean necroinflammatory and
fibrosis scores were 2.8±3.9 and 0.5±0.02 respectively. Progression of fibrosis
was detected in 123 untreated patients (57.4%), and 18 patients with no
response to treatment. . The mean rate of fibrosis
progression in untreated patients was 0.19± 0.08 in men and 0.08± 0.01 in women
(p<0.05). Improvement in fibrosis scores was detected in all treated
patients with sustained virologic response. The rate of progression was non
linear and higher in older patients. During follow-up significant impairment of
HRQOL was reported in 63 subjects (29.4%), end-stage disease in 41 (19%), liver
transplantation in 23 (10.7%), HCC in 23 (10.7%). Death due to liver-related
causes was reported in 23 patients (11%).
Conclusion:
Disease progression is non-linear in HCV with accelerated
disease over time in untreated patients resulting in complications of chronic
liver disease, hepatocellular carcinoma and death. Cohort studies and clinical
decisions based on single biopsy estimates of disease progression may
underestimate the risk of fibrosis progression.
Topic: Diagnostic Tools
A. Shaheen; R. P. Myers
Background:
The development of noninvasive markers of liver fibrosis is a
clinical and research priority. The aspartate aminotransferase to platelet
ratio index (APRI) is a promising tool with limited expense and widespread
availability. Our objective was to systematically review the performance of the
APRI in hepatitis C virus (HCV)-infected patients.
Methods:
An electronic search on Medline, EMBASE, and the Cochrane
Library (01/1997-12/2006), supplemented with a manual search, identified
studies comparing the APRI with liver biopsy for the assessment of HCV-related
fibrosis. Random effects meta-analyses and areas under
summary receiver operating characteristic curves (AUC) were examined to
characterize APRI accuracy for significant fibrosis (stages 2-4) and cirrhosis.
Random effects meta-regression was used to determine the impact of study and
patient-related factors on APRI performance.
Results:
In 22 studies including 4,266 patients (median age, 44 years;
61% male), the prevalence of significant fibrosis and cirrhosis were 47% (range
9-72%) and 15% (range 7-33%), respectively. The summary AUCs of the APRI for these
outcomes were 0.76 (95% CI 0.74-0.79) and 0.82 (95% CI 0.79-0.86),
respectively. For significant fibrosis, an APRI threshold of 0.5 was 81%
sensitive and 50% specific. At a 40% prevalence of significant fibrosis, this
threshold had a negative predictive value (NPV) of 80%, but could reduce the
necessity of liver biopsy by only 35%. For cirrhosis, a threshold of 1.0 was
76% sensitive and 71% specific. At a 15% cirrhosis
prevalence, the NPV of this threshold was 91%. Higher APRI thresholds had
sub-optimal positive predictive values except in settings with a high
prevalence of cirrhosis. APRI accuracy for significant fibrosis was not
affected by the prevalence of advanced fibrosis, or study and biopsy quality.
However, the accuracy for cirrhosis was greater in studies including
HIV/HCV-coinfected patients.
Conclusions:
The major strength of the APRI is the exclusion of
significant HCV-related fibrosis. Future studies of novel markers should
demonstrate improved accuracy and cost-effectiveness compared to this
economical and widely available index.
Topic: Diagnostic tools
1339.
Comparison of reproducibility of histology, blood tests and Fibroscan for liver
fibrosis
P. Cales; J. Boursier; M. Rousselet; S. Michalak; F.
Oberti; Y. Gallois; V. De Ledinghen; F. Lunel
Aim:
Our aim was to compare the reproducibility of histology,
blood tests and Fibroscan for liver fibrosis by comparing the intra-method and
the inter-method agreements by taking as histological reference the reading by
a senior expert pathologist.
Methods:
Several studies were used. All patients had chronic liver
disease. Agreements were evaluated with kappa index (κ) and intraclas
correlation coefficient (Ric).
Results:
1/ Intra method agreement. Blood tests.
In study 1, 33 patients and 12 laboratories were included; Ric was: APRI:
0.897, FibroMeter: 0.942. In study 2, 20 patients and 10 laboratories were
included; Ric was: APRI: 0.949, Fibrotest: 0.984, FibroMeter: 0.963. In study
3, 33 patients and 2 laboratories were included; Ric for FibroMeters was:
virus: 0.991, alcohol: 0.976, NAFLD: 0.990. Liver biopsy.
Intra center agreement. In study 4, the Metavir
staging was evaluated in 44 patients by 4 pathologists from an academic
hospital: κ=0.59. In study 5, agreement was evaluated between one senior
and one junior expert in 157 patients: κ=0.48. Inter center agreement. In
1998 (study 6), agreement was evaluated in 26 patients between an academic
senior expert and 10 non-expert out-pathologists: κ=0.13 and Ric=0.69. In
2003 (study 7), 33 patients were evaluated by 8 out-pathologists: κ=0.18
and Ric=0.69. In 2004, the agreement was between one expert from the Metavir
group and 6 out-pathologists in 205 chronic hepatitis C
(study 8): κ=0.336 and Ric=0.649. Fibroscan. 46
patients and 4 observers were enrolled into the study 9: Ric=0.93. 2/ Comparison between methods. Non invasive tests translated
into Metavir F stages. The agreement of FibroMeters was: Ric=0.965,
κ=0.874 (study 3). Agreement of Fibroscan was: Ric=0.84-0.89,
κ=0.63-0.65 (study 9). Misclassification rates.
The misclassification rates for significant fibrosis were: blood tests:
FibroMeter: 23.3%, Fibrotest: 27.9%, Hepascore: 27.8% in 825 patients (study
10); liver biopsy: 22.9% against senior expert (study 8), 9.6% against consensus
reading (study 5); Fibroscan: 16.5% in 194 patients (study 11), 20% in 65
patients (study 11) and 24.1% in 461 patients (study 13).
Conclusions:
Intra method reproducibility is as follows: blood test >
Fibroscan > histology. Considering the liver interpretation by a senior
expert or consensus reading as the reference, the agreement between
measurements is as follows: blood test > Fibroscan > histology. In
routine practice, the observed misclassification rate of non invasive tests is
similar to that of liver biopsy. Finally, liver biopsy should be considered as
a specialized tool read by experts whereas non invasive tests are more
reproducible in clinical practice.
Topic: Disease Progression
S. Barrett; J. A. Browne; C. O' Keane; R. A. Levine;
J. P. Crowe
Background and Aims:
The cohort of Irish women infected with Hepatitis C virus (HCV)
genotype 1b in 1977, represent a unique homogenous group to investigate the
natural course of HCV infection. We have previously demonstrated strong genetic
associations with viral clearance in this cohort. More recently, we have
demonstrated minimally progressive disease and histological improvement (after
27 years) in serial liver biopsies. To date we have not investigated whether
genetic factors are responsible for the favourable histological outcomes
observed in serial liver biopsies. In the current study we aim to describe the
natural history of infection after 30 years and to investigate whether genetic
factors including HLA Class I and Class II (DRB1 and DQB1) alleles or
polymorphisms of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma genes could
predict biochemical or histological outcomes.
Methods:
The study cohort comprised of 56 untreated women with
persistent viremia who had paired or multiple liver biopsies. All were infected
with HCV genotype 1b in 1977. Biochemical (alanine aminotransferase [ALT]) and
histological assessments in serial liver biopsies were performed. Baseline and
sequential biopsy specimens were assessed for grade (increase/decrease of 2
points) and stage change (increase/decrease of 1 point). Genotyping for the
various genetic markers was carried out on genomic DNA using polymerase chain
reaction sequence-specific primers.
Results:
The mean age of the 56 women at the time of baseline biopsy
was 44.3 [range 23-57]. The mean baseline grade and stage scores were 3.89 [range
2-9] and 0.72 [range 0-3] respectively. Mean number of biopsies was 2.73±0.7
and mean interval to last biopsy was 7.5 years [range 1-13]. Over this time
period, grade scores remained unchanged in 51.8%, increased in 28.6% and
improved in 19.6% patients; stage scores remained unchanged in 55.4%, increased
in 17.9% and improved in 17.9% patients. The mean baseline ALT was 45.5 [range
11-110]. There were positive correlations between baseline ALT, grade and stage
and between sequential grade and stage scores. Only DQB1 0203 was associated
with increased ALT values (p<0.024). There were no significant associations
between genetic factors and histological outcomes.
Conclusion:
A benign course of HCV genotype 1b infection with 17.9%
disease regression was observed in untreated women with paired or multiple
liver biopsies 30 years after infection. Genetic factors including HLA Class I
and Class II (DRB1 and DQB1) alleles or polymorphisms of TNF-alpha, TGF-beta,
IL-10, IL-6, and IFN-gamma genes do not account for this favourable
histological outcome.
Topic: Disease Progression
A. A. Modi; J. J. Feld; Y. Park; J. Everhart; T.
Liang; J. H. Hoofnagle
Introduction:
Two recent population-based surveys (NHANES I and III) have
reported that higher caffeine consumption was associated with lower risk of
elevated ALT levels and lower risk of chronic liver disease (CLD).
Aim:
To develop an instrument to assess
caffeine consumption and evaluate the association of caffeine intake with
severity of fibrosis in pts with CLD.
Methods:
A questionnaire aimed at measuring caffeine consumption over
the previous month was developed and administered to all pts undergoing liver
biopsy. Modified from a Nurses Health study questionnaire, it asked the
frequency of consumption of caffeine-containing foods and beverages, including
soft drinks, coffee, tea, cocoa as well as caffeine-fortified drinks, chocolate
bars, caffeine-containing medications and alcohol intake. Caffeine consumption
was quantified as the average mg of caffeine per day in which one 8 oz cup of
coffee = 136 mg. Routine liver tests were obtained at the time of questionnaire
completion, and liver histology was scored using a modified Ishak scoring
system for activity and fibrosis. Logistic regression was performed to evaluate
the association of caffeine with advanced liver fibrosis (Ishak score≥3).
Results:
Among the 182 pts (60% male, 58% Caucasian, mean age 48
years), 112 had HCV, 38 HBV, 3 HDV, 21 NASH, 4 PBC and 4 AIH. 137 pts underwent
liver biopsy and 30% had advanced fibrosis. The average caffeine intake was 193
mg/day (~ 1.5 cups of coffee/day). No patient reported more than minimal
alcohol intake. Repeat administration of the questionnaire (> 2 weeks after
initial) demonstrated consistency in reporting of caffeine intake (Cronbach
coefficient alpha = 0.97). Among the entire cohort, after adjusting for other
factors known to be associated with fibrosis (age, sex and baseline ALT),
caffeine intake ≥ 300 mg/day (~2.2 cups of coffee daily) was associated
with reduced fibrosis compared to lesser amounts or no caffeine intake
(OR=0.39, 95% CI 0.15-1.03, p=0.057). The effect of caffeine was even more
pronounced in pts with HCV. HCV pts with caffeine intake ≥ 300 mg/d were
88% less likely to have advanced fibrosis than pts with lower consumption both
by univariate and multivariate regression (adjusted OR=0.22, 95% CI 0.06-0.89,
p= 0.03). Higher caffeine consumption was also independently associated with
ALT values below the median (58 IU/l) for the HCV cohort (OR=0.37 95% CI
0.15-0.92, p=0.03).
Conclusions:
Higher caffeine consumption is associated with milder
fibrosis in pts with CLD, particularly those with HCV infection.
Topic: Diagnostic Tools
G. Sebastiani; P. Halfon; L. Castera; S. Pol; D. L.
Thomas; A. Mangia; V. Di Marco; M. Pirisi; M. Voiculescu; M. Bourliere; A.
Alberti
Background:
Noninvasive methods have been proposed in hepatitis C as
surrogates of liver fibrosis but their diagnostic performance is not such to
completely substitute liver biopsy. Moreover, large validation studies are
still pending. We have recently proposed sequential algorithms that combine
AST/Platelets Ratio Index (APRI) and Fibrotest (FT) with liver biopsy, with
excellent performance and >50% reduction in liver biopsy needed (J Hepatol
2006;44:686-93). These algorithms (SAFE biopsy) are
based on sequential use of APRI and FT,restricting
liver biopsy to cases in which these noninvasive markers show insufficient
accuracy.
Aim:
Large-scale validation of the SAFE
biopsy to identify significant fibrosis (≥F2 by METAVIR) and cirrhosis
(F4) in hepatitis C.
Methods:
International, multicenter study of 1978 HCV monoinfected
cases (1112 males, 866 females; mean age: 46.9+11.9yrs). FT and APRI were
measured at the time of liver biopsy,taken as gold
standard. Subgroup analysis was conducted to determine whether age, gender, HCV
genotype and BMI modify the performance of SAFE biopsy.
Results:
Performance of the SAFE biopsy using the cutoff for APRI and
FT of the original studies is shown in table. Overall, SAFE biopsy for
significant fibrosis saved 47.1% of liver biopsies with >95% accuracy. SAFE
biopsy for cirrhosis also had excellent performance and saved 82% of liver
biopsies. The performance of SAFE biopsy was excellent across all major HCV
genotypes while it was somehow reduced for ≥F2 with age >50yrs
(AUC=0.83, p=0.001 vs. overall AUC) and for F4 with BMI>30 (AUC=0.84,
p=0.01). Therefore, specific cutoff for FT (0.57 for ≥F2 with >50yrs;
0.84 for F4 with BMI>30) were identified, allowing to optimise the
performance of SAFE biopsy (AUC=0.87 for ≥F2 with >50yrs; AUC=0.90 for
F4 with BMI>30). SAFE biopsy applied to HCV patients with normal ALT showed
excellent performance (AUC=0.94 for ≥F2; AUC=0.89 for F4).
Ideal target populations for screening:
·
HCV
patients aged > 60 years (5-15% Mediterranean population)
·
HCV
carriers with normal ALT (20-25% have significant fibrosis)
·
Candidates
to antiviral therapy with relative contraindications
·
HCV-1
patients with high virus loads.
Conclusions:
This large-scale, multicenter validation study confirms that
SAFE biopsy is a rational way of combining noninvasive markers with marked
reduction in liver biopsies needed to correctly classify liver fibrosis in
hepatitis C. This approach can be useful for large scale screening of HCV
patients.
|
|
Overall |
<50 yrs |
>50 yrs |
BMI<30 |
BMI>30 |
|||||
|
SAFE biopsy |
≥F2 |
F4 |
≥F2 |
F4 |
≥F2 |
F4 |
≥F2 |
F4 |
≥F2 |
F4 |
|
Sens (%) |
100 |
89.3 |
100 |
92.3 |
100 |
98.5 |
100 |
91.5 |
100 |
80 |
|
Spec (%) |
88 |
94.6 |
86.3 |
97.6 |
66.4 |
92.6 |
83.2 |
95.5 |
69.2 |
89.4 |
|
PPV (%) |
92.3 |
64.9 |
83.9 |
63.2 |
84.1 |
59.8 |
89.1 |
72 |
91.8 |
61.5 |
|
NPV (%) |
100 |
98.8 |
100 |
99.7 |
100 |
99.8 |
100 |
99.1 |
100 |
95.4 |
|
Accuracy(%) |
95.1 |
93.5 |
92 |
97.4 |
87.9 |
93.2 |
92.6 |
95 |
93.1 |
37.7 |
|
AUC |
0.89 |
0.92 |
0.93 |
0.94 |
0.83 |
0.89 |
0.92 |
0.94 |
0.86 |
0.84 |
|
Saved biopsies (%) |
47.1 |
82 |
31.8 |
89 |
58.9 |
73.8 |
41.4 |
72.5 |
45.2 |
71.9 |
Topic: Diagnostic Tools
D. Lucidarme; G. Forzy; V. Gremaux; B. Filoche
Background:
The results of transient elastography using FibroScan
(Echosens,
Patients and methods:
LSM was performed by 2 different operators who were blinded
to the other’s result in 399 patients (mean age: 48 y; males: 63%, BMI: 24.0
Kg/m2) with chronic liver diseases of various causes (VHC: n = 167; VHB: n =
41; NASH: n = 85; alcohol: n = 39; other: n = 67). Thirty patients in whom one
operator failed to obtain 10 successful acquisitions were excluded from the
analysis. Results of 369 patients were analyzed. Variability between the 2
operators was evaluated by the inter-observer gap between LSM [(LSM operator 1
– LSM operator 2)/ (average LSM operators 1 and 2)]. Inter-observer agreement
was analyzed using the intra-class correlation coefficient (ICC) and kappa
index for the diagnosis of cirrhosis using a threshold of 14,6 KPa (1). The
effect on agreement of age, gender, BMI, etiology of liver disease, rate of
success, median value of LSM, interquartile range (IQR) and the ratio between
IQR on the median value of LSM (IQR/LSM) was assessed by comparing 2 groups
according to the median inter-observer gap.
Results:
The median inter-observer gap was 0.21. The overall
inter-observer ICC was 0.87, and kappa index was 0.73. By univariate analysis,
median value of LSM and IQR/LSM were associated with agreement (P < 0.10).
In multivariate analysis, IQR/LSM was the only factor independently associated
with the median inter-observer gap (P < 0,001). Four groups (Gr) were
defined according to IQR/LSM. Gr1: Both operators found an IQR/LSM < 0,2 (n
= 119): median inter-observer gap = 0,15; ICC = 0.99, and kappa index = 0,95;
Gr2: At least one of the two operators found an IQR/LSM > 0,2 and < 0,3
(n = 124): median inter-observer gap = 0,19, ICC = 0.86, and kappa index =
0,64; Gr3: At least one of the two operators found an IQR/LSM > 0,3 and <
0,5 (n = 84): median inter-observer gap = 0,23; ICC = 0.84 and Kappa index =
0,60; Gr4: At least one of the two operators found an IQR/LSM > 0,5 (n =
42): median inter-observer gap = 0,41 ; ICC = 0.41, and kappa index = 0,58. The
ICC and kappa index of Gr1 were different from those of the 3 other groups (P
< 0.05).
Conclusion:
The reproducibility of transient elastography is excellent.
However, IQR/LSM is a key factor of inter-observer agreement. The
reproducibility of transient elastography is significantly reduced in patients
with IQR/LSM > 0,2.
1)
Ganne-Carrié et al. Hepatology 2006;44:1511-7.
Topic: Diagnostic Tools
1346. The
result of liver stiffness measurement is influenced by the serum bilirubin
level
Y. Seo; S. Suh; Y. Kwon; S. Park; B. Keum; B. Park; Y.
Kim; Y. Jeen; H. Chun; C. Kim; H. Ryu; S. Um
Background/Aim:
Although liver stiffness measurement (LSM) using FibroScan is
usually well correlated with the fibrosis score on liver biopsy, discrepancies
between the results of LSM and fibrosis score could appear in some patients.
Until now, except fibrosis score, any factors which could influence the result
of LSM were not identified. This study was performed to evaluate whether acute
liver injury could affect the result of LSM.
Methods:
All consecutive patients with acute hepatitis who admitted to
our hospital during 6 months were included. Patients with previous or family
history of liver disease were excluded. These patients were subjected to
FibroScan during admission and followed 1-6 months later. At the time of LSM,
serum AST, ALT, ALP, GGT and bilirubin levels were examined. For validation,
correlation between the LSM and fibrosis score were compared according to the
results of biochemical tests in patients who undergone liver biopsy and LSM.
Results:
Seventy-five patients with acute hepatitis were enrolled
(median age, 30 years; M:F, 40:35). The causes of acute
hepatitis were acute hepatitis A in 61 patients, acute hepatitis B in 3, toxic hepatitis in 8, and others in 3. Baseline LSM was
10.6±6.9 kPa (median, 8.8). There was no difference in the results of AST, ALT,
ALP and GGT between patients with higher LSM and lower LSM, but bilirubin level
was significantly higher in patients with high LSM (P=0.024). Bilirubin level
was the only significant correlated factor with LSM in bivariate correlation
analysis (
Conclusion:
Serum bilirubin level seems to affect the result of LSM.
Caution is required when interpret the result of LSM in patients with jaundice.
Topic: Disease Progression
A. A. Pillai; L. M. Yerian; R. Lopez; I. A. Hanouneh;
N. N. Zein
Introduction:
Obesity is a contributing factor to the development of
steatosis and in treatment failure in chronic HCV.
Aims:
Evaluate the interaction between obesity and fibrosis progression
in a cohort of HCV patients with paired liver biopsies.
Methods:
We identified all HCV patients with at least two liver
biopsies (1997-2006). Patients with insufficient tissue (<10 portal tracts)
or lack of body mass index (BMI) were excluded. A hepatopathologist scored 215
biopsies from 102 patients for necroinflammation (modified histologic activity
index (HAI)) and fibrosis (Ishak, stage 0-6). A change by at least one
histologic stage was used to define progression or regression. Univariable and
multivariable logistic regression analysis was performed to assess the
association of baseline factors with advanced fibrosis on each of the paired
biopsies separately. To assess factors associated with progression between the
two biopsies, a Cox regression model was used. Backward elimination method was
used to select factors included in the final model.
Results:
Time between 1st and 2nd biopsy was 1-13.5 years in which 43%
of subjects had progression, 29% had no change and 27% had regression. Rate of
change between 1st and 2nd biopsy was -0.16 to 0.49 units annually. Older age,
higher HAI score and diabetes were independently associated with advanced
fibrosis in 1st and 2nd biopsy. Obesity (BMI >30) was the only factor found
to be significantly associated with fibrosis progression between 1st and 2nd
biopsy by univariable (P=0.023) and multivariable (P=0.006) analysis,
independent of antiviral therapy. A Kaplan-Meier plot was constructed (Figure)
to outline the association between obesity and fibrosis progression.
Conclusions:
1)Older age, higher HAI score and diabetes
in chronic HCV patients are independently associated with advanced fibrosis in
a cross-sectional single time point biopsy. 2)Using
paired biopsy specimens, obesity is a strong predictor of fibrosis progression
over a defined time interval between biopsies.
Topic: Diagnostic Tools
G. Lalazar; O. Pappo; Y. Ilan
Introduction:
Current treatment of chronic HCV infection is based on the
degree of hepatic fibrosis. Liver biopsy has been the gold standard for this
assessment. The point-of-care non-invasive BreathID® continuous online 13C
methacetin breath test (MBT) reflects hepatic microsomal function (CYP1A2) and
was shown to correlate accurately with the degree of hepatic fibrosis.
Aim:
To develop a treatment algorithm for patients with chronic
HCV infection based on detection of the degree of liver fibrosis using MBT.
Methods:
100 patients with chronic HCV infection and 100 healthy, age
and sex-matched controls underwent 13C MBT following ingestion of 75 mg
methacetin. All HCV patients had undergone a liver biopsy within 6 months of
performing the MBT. Breath test parameters tested included
Results:
MBT parameters were significantly correlated with the stage
of fibrosis (p<0.0001). By using an algorithm that includes age,
Conclusions:
The BreathID® continuous online 13C MBT accurately detects
liver fibrosis in patients with chronic HCV infection enabling a non-invasive
alternative to liver biopsy. Using the above algorithm, liver biopsy could have
been avoided in two thirds of this patient population. MBT is a practical
non-invasive tool for decision-making in the evaluation of patients with
chronic HCV infection.
Topic: Diagnostic Tools
1349. Iron overload
does not effect the quantification of fibrosis by Liver Stiffness Measurement
V. Di Marco; F. Bronte; D. Cabibi; F. Barbaria; Z.
Borsellino; G. Alaimo; V. Calvaruso; S. Ciminnisi; M. Capra; A. Maggio; P.
Almasio; A. Craxì
Background and aims:
Several studies report a close relation between liver
stiffness measured by FibroScan (
Methods:
52 patients with HβT (mean age 27 years; 18 HCV-RNA positive
and 34 HCV-RNA negative) and 104 non-thalassemic adults with chronic hepatitis
C (mean age 55±10.6 years, mean BMI 27.3±4.7 Kg/m2) underwent LB (mean length
of biopsy 17 mm) and simultaneous LSM. Liver inflammation and fibrosis were
scored according to METAVIR, steatosis according to Brunt’s score and LIC was
measured on fresh tissue cores by atomic absorption spectrometry and was
expressed as mg/gr of liver dry weight (normal values < 1.6 mg/gr).
Results:
The degree of liver fibrosis, the LSM expressed as KPa, and the LIC in patients with HBT and in patients with
chronic hepatitis C are reported in the table 1.
LSM increased proportionally to the METAVIR stage, with a
highly significant relation to fibrosis (rho= 0.70; p >0.001 by Spearman’s
test) independently of LIC values (r= 0.16; p= 0.07 by Spearman’s test), both
for thalassemics and non-thalassemics patients. At univariate analysis, LSM
correlated with histological grading (95% CI: 3,0–37,5;
p < 0.0001), presence of steatosis (p< 0.0001) and degree of fibrosis
(95% CI: 2,8–37,5; p < 0.0001). At multivariate analysis, presence of
steatosis (r= 0.362; p < 0.0007 and fibrosis (r= 0.684; p < 0.0001)
remained factors associated with LSM. LSM had excellent value in discriminating
patients with F4 fibrosis (i.e. cirrhosis), but was less performing at lower
stages of fibrosis.
Conclusion:
LSM by FibroScan is an adequate and reliable non-invasive
tool to diagnose advanced liver fibrosis even in subjects with severe liver
iron overload.
Liver fibrosis, LSM (expressed as KPa) and the LIC (expressed as mg/gr of liver dry weight) in patients with HβT and in patients with chronic hepatitis C
|
Liver Fibrosis (METAVIR) |
HβT patients (52) |
LSM (median, range) |
LIC (median, range) |
Chronic Hepatitis C patients (104) |
LSM (median, range) |
LIC (median, range) |
|
F0/F1 |
23 |
4.9 (3.2-10.1) |
3.51 (0.50-10.71) |
18 |
6.0 (3.1-10.3) |
0.46 (0.10-3.66) |
|
F2 |
14 |
5.1 (2.8-6.8) |
2.86 (0.77-22.03) |
48 |
6.7 (3.8-16.9) |
0.48 (0.12-2.69) |
|
F3 |
8 |
7.1 (4.7-10.4) |
2.73 (0.23-6.96) |
21 |
13.6 (6.6-25.8) |
0.36 (0.05-4.04) |
|
F4 |
7 |
15.9 (13.1-21.3) |
6.66 (0.66-11.73) |
16 |
17.6 (8.0-37.7) |
0.52 (0.16- 6.78) |
Topic: Diagnostic Tools
E. Veselkin; M. Kondratyev; E. Ron; M. Santo; S. Reif;
I. Elashvili; L. Bar; Y. Lurie; R. Oren; G. Z. Lederkremer
Purpose:
We have evaluated the possible use of a soluble secreted form
of the human asialoglycoprotein receptor (ASGPR sH2a) as a new non-invasive
marker for the sensitive assessment of liver function. The current markers
(prothrombin time, albumin and others) can only detect liver dysfunction in
advanced disease. On the other hand, blood levels of enzymes such as alanine
and aspartate aminotransferases (ALT and AST) indicate liver damage and not
function and can appear normal in many cases of liver disease or abnormal in a
wide range of non-hepatic diseases. sH2a is
liver-specific as it is secreted to the serum exclusively by hepatocytes.
Methods:
We have measured sH2a levels in serum using a monoclonal
antibody and an ELISA assay that we developed, comparing with routine liver
function tests.
Results:
We determined in a series of double blind studies that sH2a
was present at very constant levels in serum from 57 out of 63 healthy control
individuals. The <10% of controls that showed abnormal levels of sH2a also
revealed borderline levels for one or more of the established liver function
markers. A study of 43 HCV patients showed abnormal sH2a values in 25% of those
at fibrosis stage 0, 37% of those at stage 1, 57% at stages 2-3 and 100% at
stage 4 (cirrhosis). The combined analysis of sH2a levels and those of ALT and
AST allows prediction of fibrosis stage.
Conclusions:
sH2a appears to be a uniquely sensitive
marker of liver function with potential widespread use. In combination with
routine markers it could also be used for non-invasive determination of
fibrosis stage.
Topic: HIV/HCV Coinfection
H. Thein; Q. Yi; G. J. Dore; M. D. Krahn
Objectives:
Our objectives were to estimate stage-specific hepatic
fibrosis progression rates in HIV/hepatitis C virus (HCV) coinfected
individuals and to determine factors associated with fibrosis progression in
this population, including the impact of HIV on HCV disease progression.
Methods:
A systematic review of published prognostic studies was
undertaken. Study inclusion criteria were: i) HIV and HCV infections determined
by serological assays; ii) information about age at assessment of liver disease
or HCV acquisition; iii) duration of HCV infection; and iv) histological
fibrosis staging (F0-F4) and/or clinical diagnosis of cirrhosis. Annual
stage-specific transition probabilities (F0→F1, F3→F4) were derived
using the Markov maximum likelihood estimation method and a meta-analysis was
performed using both fixed and random effects models. The impact of covariates
– study design (cross-sectional/retrospective, prospective, retrospective-prospective),
study setting (clinical-/community-based), age at/duration and mode of HCV
infection, gender, alcohol consumption, HCV genotype and RNA, CD4 cell count,
and highly active antiretroviral therapy (HAART)) on fibrosis progression was evaluated
using meta-regression models. Pre-HAART and HAART era cirrhosis rates were
compared in studies reporting both HCV groups. Sixteen of 65 studies reviewed
fulfilled the inclusion criteria. Mean (95% CI) fixed effects annual transition
rates of the HIV/HCV coinfected individuals (82% injection drug users) were: F0→F1
0.119 (0.114, 0.125); F1→F2 0.118 (0.112, 0.125); F2→F3 0.156
(0.145, 0.169); and F3→F4 0.122 (0.109, 0.137). Random effects estimates
showed comparable results.
Results:
The mean (95% CI) probability of cirrhosis after 20 and 40
years was 25% (22%, 27%) and 77% (74%, 79%), respectively. All covariates of
interest were significantly associated with fibrosis progression from F0→F1,
while study setting and HCV RNA positivity were associated with progression
from F3→F4. Overall, the rate ratio (95% CI) of cirrhosis between HIV/HCV
coinfected and HCV monoinfected individuals was 2.1 (1.8, 2.5): 1.7 (1.1, 2.7)
in the pre-HAART era (n=6); and 2.2 (1.9, 2.6) in the HAART era (n=10).
Conclusion:
In conclusion, our predicted estimates for cirrhosis in
HIV/HCV coinfected individuals appear to be higher than published estimates for
HCV monoinfection. This study improves on previous studies by using a method
that does not require the assumption of constant transition rates between
stages and taking into account the effects of study design and setting,
clinical factors, and HAART on disease progression.
Topic: HIV/HCV Coinfection
L. Castera; M. Loko; F. Dabis; B. Le Bail; M. Winnock;
G. Coureau; D. Neau
Background:
Several non-invasive indexes using routinely available
parameters have been proposed recently for the prediction of liver fibrosis in
patients with chronic hepatitis C. However, little information regarding the
validity of these indexes in human immunodeficiency virus (HIV)-HCV coinfected
patients is available.
Aim:
To determine the diagnostic performance of FIB4, APRI, Forns
index and platelet count for the prediction of liver fibrosis in HIV/HCV
coinfected patients.
Methods:
200 HIV/HCV co-infected patients (male 66%, age 40±6 yrs) of
the ANRS CO3 Aquitaine Cohort who underwent liver
biopsy between 1999 and 2005 and had complete data to validate all the
considered tests, were studied. Liver fibrosis was assessed using METAVIR
scoring system and diagnostic performance by measuring areas under the ROC
curve (AUROC).
Results: Significant fibrosis (F2-F3-F4) was present in 157
patients (78.5%) and cirrhosis (F4) in 19.5%. Performance of the different
methods using the published cut-offs are shown in the table.
Conclusion:
Overall, the diagnostic accuracy of these indexes was lower
in HIV-HCV coinfected patients than in HCV monoinfected patients, particularly
for the diagnosis of significant fibrosis. However, the use of FIB-4, APRI or
platelet count may obviate the need for liver biopsy for the diagnosis of
severe fibrosis-cirrhosis in up to 55% to 85 % of cases in HIV-HCV coinfected
patients.
|
End-point |
Significant fibrosis F2-F3-F4 |
Severe fibrosis F3-F4 |
Cirrhosis F4 |
||||||
|
Indexes |
Forns |
APRI |
Fib-4 |
APRI |
Platelet |
||||
|
Cut-offs |
<4.2 |
>6.9 |
<0.5 |
>1.5 |
<1.45 |
>3.25 |
<1.0 |
>2.0 |
<130 |
|
Se(%) |
83 |
23 |
78 |
28 |
73 |
31 |
77 |
41 |
59 |
|
Sp(%) |
35 |
100 |
65 |
98 |
70 |
93 |
71 |
91 |
91 |
|
PPV(%) |
86 |
100 |
89 |
98 |
57 |
71 |
39 |
53 |
62 |
|
NPV(%) |
30 |
21 |
44 |
27 |
83 |
72 |
92 |
86 |
90 |
|
AUROC |
0.75 |
0.77 |
0.77 |
0.80 |
0.78 |
||||
|
Saved biopsies(%) |
25 |
35 |
56 |
65 |
85 |
||||
Topic: Diagnostic Tools
1355. Can
platelet count or APRI be the poor man’s Transient Elastography in HCV
patients?
V. Calvaruso; S. Maimone; F. Bronte; L. Marelli; V. Di
Marco; P. Manousou; A. Corbani; E. Xirouchakis; A. Sigalas; G. M. Dusheiko; A.
Craxi'; A. K. Burroughs
Background:
Non invasive tests for fibrosis are being evaluated
extensively in many clinical settings, to substitute for liver biopsy,
particularly in HCV disease. Transient elastography (TE) is the major indirect
test for fibrosis with good accuracy to identify cirrhosis.
Aim:
To assess TE measurements (Fibroscan) in relation to platelet
count and APRI score (AST(/ULN)/PLATELET(109/L) x 100)
in two independent cohorts of HCV patients.
Patients and methods:
333 HCV-RNA PCR positive patients (having excluded 16
patients due to TE technical failure), not receiving antiviral therapy, nor
co-infected, nor alcohol abusers (198 in Palermo, 135 in London) had TE, liver
function tests and platelet count assessed contemporaneously. Main patient
characteristics are shown in the table. Correlations were evaluated by linear
regression analysis.
Results:
There was a similar and significant correlation between
platelet count and stiffness measurement: r = 0.69(
AUROC curve for platelets was 0.82 for Stiffness ≥
8.3KPa (Metavir ≥ F2) and 0.88 for Stiffness ≥ 14KPa (Metavir =
F4). The best platelet cut off values were 195.000 for Stiffness ≥ 8,3
and 160.000 for Stiffness ≥ 14 with sensitivity 77% and 80%; specificity
73% and 83%; PPV 74% and 67%; NPV 75% and 91%; diagnostic accuracies 75% and
82% respectively.
AUROC curve for APRI was 0.88 for both cut off stiffness
values. APRI cut off values were 0.6 for Stiffness ≥ 8.3 and 1.0 for
Stiffness ≥ 14 with sensitivity 84% and 83%; specificity were 74% and
78%; PPV 76% and 62%; NPV 82% and 91% respectively; Diagnostic accuracies 79%
for both cut offs.
Conclusion:
Easily available serum markers of platelet count and AST have
good correlation with liver stiffness measurements across the spectrum of HCV
liver disease including cirrhosis. The AUROC values for platelet count are
similar to those for indirect fibrosis markers for F2 or more or F4(Coco J Viral Hep 2007;14:360). The use of APRI is better
than platelet count for non cirrhotic fibrosis, but has the same AUROC as
platelet count in cirrhosis.
Characteristics of Patients
|
|
All patients (333) |
|
|
p |
|
Males |
187(56%) |
109(55%) |
78(58%) |
n.s. |
|
Age Mean(range) |
55 (9-84) |
56 (9-77) |
54 (24-84) |
n.s. |
|
AST(U/l) Mean(range) |
71 (11-262) |
74 (11-262) |
67 (15-261) |
n.s. |
|
ALT (U/l) Mean(range) |
92 (11-373) |
96 (11-375) |
86 (12-373) |
n.s. |
|
Platelet
count Mean(mm3/L) (range) |
189 (20-457) |
168 (20-345) |
218 (48-457) |
< 0.001 |
|
APRI |
1.3 |
1.5 |
1.0 |
0.001 |
|
Stiffness
(Kpa) Mean(range) |
13.0 (3-75) |
14.6 (3-75) |
10.8(3.2-53) |
0.001 |
|
Cirrhosis |
106(32%) |
74(37%) |
32(24%) |
0.009 |
Topic: Epidemiology
1358.
Evolution of hepatitis C virus (HCV) viremia in prospectively followed
intravenous drug users (IVDU:s) with
documented anti-HCV antibody seroconversion participating in a Swedish
needle-exchange program
M. Alanko; P. Björkman; V. Molnegren; L. Flamholc; A.
Widell
Background:
The dynamics of HCV viremia following acute HCV infection
have mostly been studied in cases of symptomatic acute hepatitis C, which
represent a minor proportion of incident HCV infections. We used sera drawn
approximately every 3-6 months for surveillance of blood-borne viruses among
participants in a needle-exchange program (NEP) to assess the longitudinal
evolution of HCV viremia in incident HCV infection.
Methods:
Out of 1150 newly registered participants in a NEP in
Results:
HCV RNA was detected in 81 (41%) of anti-HCV negative
pre-seroconversion sera. HCV viremia was detected in the 1 year sample in 145
cases (73%), indicating probable establishment of chronic infection.
Eight patterns of longitudinal HCV viremia were observed
(Median viral load, see Table):
1) undetectable HCV RNA in all samples (17;
8.6%)
2) undetectable HCV RNA pre-seroconversion and at
one year, detectable HCV RNA in seroconversion sample (16; 8.1%)
3) undetectable HCV RNA in first two samples,
detectable HCV RNA at one year (19; 9.6%)
4) undetectable HCV RNA pre-seroconversion,
detectable HCV RNA in both later samples (65; 33%)
5) detectable HCV RNA pre-seroconversion, both
later samples undetectable HCV RNA (7; 3.5%)
6) detectable HCV RNA in first two samples,
undetectable HCV RNA one year later (13; 6.6%)
7) detectable HCV RNA pre-seroconversion and at
one year, undetectable HCV RNA in first post-seroconversion sample (17, 8.6%)
8) detectable HCV RNA in all samples (44; 22%).
Conclusions:
Several different patterns of HCV viremia were observed in
acute hepatitis C in this cohort of IVDU:s, most of
whom had subclinical acute HCV infection. Chronic infection developed in 73% of
cases and HCV viremia was detected in 41% of the last anti-HCV negative
pre-seroconversion samples.
Median viral HCV RNA load*(IU/mL) during follow-up in IVDU:s with anti-HCV antibody seroconversion.
|
|
No |
Last anti-HCV neg |
First anti-HCV pos |
One year later |
|
A |
17 |
- |
- |
- |
|
B |
16 |
- |
810 |
- |
|
C |
19 |
- |
- |
24 700 |
|
D |
65 |
|