Sunday Poster
Sessions,
Topic:
Current Treatment - Pegasys
M. R. Charlton; N. Bzowej; S. Rossi; D. R. Nelson
Introduction:
Recurrent HCV infection after OLT can cause graft
failure and death, but safety concerns have limited prophylactic/early
treatment with pegylated interferon/ribavirin.
Aim:
The
Methods:
Patients were randomized 10-26 wks after OLT. Patients
in the Prophylaxis arm received 135 μg peginterferon alfa-2a/wk for 4 wks
and 180 μg/wk for 44 wks; plus 400 mg/d ribavirin (initial dose),
escalating over 12 weeks to 1000 or 1200 mg/day for 36 weeks. Patients in the
Observation arm were treated with the same regimen only upon histologic
recurrence of HCV (HAI >3 and/or FS >2), followed by 24-72 weeks of
treatment free follow-up. The primary efficacy assessment is the proportion of
patients in each group who experienced histological evidence of HCV recurrence
at 120-weeks post-randomization. Here we report 24-wk interim data.
Results:
To date 115 patients have been enrolled and the first
24 week data is presented here. The
patient characteristics in the prophylaxis arm and the observational arm were
well matched. The virologic response at
week 24 was 38% in the prophylaxis group compared to the control arm. Of patients in the Prophylaxis and
Observation arms, 100% and 93%) respectively, have experienced at least 1
adverse event (AE); and 44% and 23%, respectively, have experienced at least 1
serious AE. In the Prophylaxis are 30% of the patients discontinued treatment due a adverse
event compared to 25% in the Observational group. 75% of the patients in the prophylaxis group
experienced at least one adverse event that led to treatment
modification/interruption compared to 25% in the Observational group.
Conclusion:
o On-treatment virologic
response is achievable in OLT recipients with prophylactic or delayed treatment
SVR data are not yet available
o Although AEs were common
during prophylaxis with peginterferon alfa-2a and ribavirin for post-OLT HCV
recurrence, the incidence of clinically significant ACR was not increased by
prophylaxis
o ACR rates observed during
prophylaxis were low
o Rates of anemia and grade 3/4
neutropenia, secondary to HCV antiviral drug toxicity, were higher in the
prophylaxis arm than in untreated patients in the observation arm
o The incidence of
clinically significant infections was low in both arms, and depression was not
observed in any patient
o Relative impact of
prophylaxis versus no prophylaxis strategy on allograft histology remains to be
determined
Topic: Liver Transplantation
A. Regev; A. L. Mindikoglu; L. S. Magder
Background:
The outcome of liver transplantation (LT) in patients
infected with Human Immunodeficiency Virus (HIV) has been a matter of
controversy. Patients coinfected with HIV and hepatitis C virus (HCV) appeared
in several small studies to have poorer outcome after LT compared to patients
with HCV monoinfection.
Methods:
A retrospective cohort study was performed to assess
the impact of HIV on LT survival by using UNOS Standard Transplant Analysis and
Research (STAR) files.
Results:
A total of 138 HIV(+) and
30,520 HIV(-) patients who were ≥ 18 years old and underwent LT during
the HAART era (starting from
Conclusion:
Patients who had HIV/HCV coinfection had lower
survival rates after LT compared to HCV patients without HIV coinfection. Such
difference was not observed in HIV/HBV coinfected patients compared to HBV
monoinfected patients undergoing LT.
Topic: Experimental Therapies - GS-9190
49. Antiviral, Pharmacokinetic and Safety Data for
GS-9190, a Non-nucleoside HCV NS5b Polymerase Inhibitor, in a Phase-1 Trial in
HCV Genotype 1 Infected Subjects.
L. Bavisotto, . C. Wang; I. M.
Jacobson; P. Marcellin; S. Zeuzem; E. J. Lawitz; M. Lunde; P. Sereni; C.
O'Brien; D. W. Oldach; G. Rhodes
Background
& Aims:
GS-9190 is a novel non-nucleoside HCV NS5b polymerase
inhibitor with potent in vitro antiviral activity (0.6 nM EC50 in Genotype 1b
replicon) and a high selectivity index in vitro. Initial results from an
ongoing single-dose/multiple-dose escalation clinical trial of GS-9190 in
HCV-infected volunteers are reported here.
Methods:
Study GS 196-0101 is a randomized, double-blind,
placebo controlled trial designed to evaluate the safety/tolerability,
phamacokinetics and antiviral activity of single (in Part A) and multiple (in
Part B) doses of GS-9190 in subjects chronically infected with HCV genotype 1
(GT-1) without cirrhosis. Prospective subjects are 18-60 years of age and are
HCV treatment naïve.
In an already completed Part A, five successive
cohorts of 6 subjects were randomized (5:1) to receive single ascending doses
of GS-9190 (40, 120, 240, 240-with food, or 480 mg) or placebo. In ongoing Part
B, four successive cohorts of 12 subjects are randomized (10:2) to receive
multiple ascending doses of GS-9190 (40 mg BID, 120 mg BID, 240 mg QD, 240 mg
BID) or placebo, over 8 days.
Results:
Thirty-one subjects enrolled in Part A were of mean
age 43.6 years, predominantly male (20/31), Caucasian (25/31), and infected
with either HCV Genotype-1a (24) or 1b (6). Median (range) baseline HCV viral
load was 6.6 log10 RNA IU/mL (5.2-7.3). Single doses of GS-9190 were well
tolerated, with no serious or treatment-limiting adverse events (AEs) reported.
All AEs (except one moderate) were mild in severity, with the most common being
headache. There were no Grade 3 or 4 treatment
emergent laboratory abnormalities.
Median GS-9190 plasma half-life ranged from
Conclusions:
This study demonstrates potent dose-dependent
antiviral activity of GS-9190, a novel non-nucleoside HCV polymerase inhibitor
in HCV infected volunteers. Single dose exposure to GS-9190 was well tolerated
and demonstrated favorable PK properties that may support QD or BID dosing. The
multiple dose phase of this trial is ongoing, and updated results will be
provided.
Topic: Experimental Therapies - Telaprevir
N. Forestier,
S. Susser, M. W. Welker, C. J. Weegink, H. W. Reesink, S. Zeuzem1,; C.
Sarrazin
Introduction:
Telaprevir (TVR) is a highly selective inhibitor of
the hepatitis C virus (HCV) NS3/4A protease with highly effective blocking of
HCV replication in patients with hepatitis C. Mutations have been identified in
the NS3 protease gene at positions 36, 54, 155 and 156 conferring resistance to
TVR in vitro and in vivo. For single resistance mutations an inverse
correlation of resistance level and viral fitness has been described while
combined mutations (i.e. V36/R155) display relative high resistance with
compensatory effects on replication efficiency. Little is known about
persistence of TVR resistance mutations in patients treated sequentially with
TVR, peg-interferon and ribavirin (RBV).
Methods:
Fifteen patients received either TVR
monotherapy or TVR peg-interferon alfa 2a combination therapy for 2 weeks
followed by peginterferon alfa 2a plus RBV standard combination therapy for 24
or 48 weeks. In the present study, we performed amplification and clonal
sequencing (approx. 50 clones per patient and time point) of the HCV NS3
protease gene in 5 patients who relapsed so far. All 5 patients were tested HCV
RNA negative during therapy but relapse with increasing HCV RNA concentration
was observed after the end of standard combination treatment for 24 or 48
weeks.
Results:
While in 2 patients no mutations conferring resistance
to TVR were detected during different time points after relapse, in 3 patients
known TVR resistance mutations within the NS3 protease gene were detected. Patient
1 with initial TVR monotherapy, 48 weeks of standard therapy, and relapse at
week 4 after treatment discontinuation (433.000 IU/ml) showed mutations at
positions V36 (100% of clones) and R155 (100% of clones). In patient 2 with
initial TVR monotherapy, 24 weeks of standard treatment and relapse at week 4
(viral load pending) only single isolates with resistance mutations were
observed at position V36 (2%) and A156 (2%). Finally, patient 3 received
initially combination therapy followed by 48 weeks of standard treatment. In
this patient relapse was detected at follow up week 8 (1.400 IU/ml) and
resistance mutations were detected at position V36 (84% of clones) only. In
both patients who received TVR monotherapy mutations at positions V36, T54,
R155 and A156 were observed during the initial 2 weeks of treatment.
Conclusion:
In patients treated with TVR with and without
peginterferon alfa 2a for 2 weeks followed by standard therapy with
peginterferon and RBV for 24 or 48 weeks mutations conferring resistance to TVR
can be detected after relapse. The significance of TVR resistance mutations for
the probability of relapse has to be investigated in future studies.
Topic:
Current Treatment - PegIntron
51. Sustained Virologic Response with
albinterferon alfa-2b/ribavirin treatment in prior interferon therapy
non-responders
D. R. Nelson; V. K. Rustgi; V. Balan; M. Sulkowski; G.
L. Davis; A. Muir; L. Lambiase; R. C. Dickson; R. H. Wiesner; J. G.
McHutchison1; E. Pulkstenis; P. Cronin; G. M. Subramanian
Background/Aim
Albinterferon alfa (alb-IFN) is a novel recombinant
protein consisting of IFNa-2b genetically fused to human albumin. This
randomized Phase 2 study evaluates the efficacy and safety of alb-IFN/ribavirin
treatment in chronic Hepatitis C (CHC) patients who were non-responders (NR) to
previous IFNa-based regimens.
Methods
Subjects were randomized into 3 alb-IFN treatment
cohorts (900mcg Q2w, 1200mcg Q2w or 1200mcg Q4w) in combination with
weight-based oral ribavirin (RBV) 1000-1200 mg/day. After evaluating safety
data, 2 further cohorts were treated with higher doses of alb-IFN 1500mcg Q2w
and 1800mcg Q2w. The treatment duration is 48 weeks and the primary efficacy
end-point is sustained virologic response (SVR) at 24 weeks post-treatment. The
protocol was amended to allow extended treatment (a total of 72weeks) for slow
responders, ie, subjects who became RNA negative after w24.
Results
The demographics and antiviral response for the 115
patients enrolled are summarized in the table. The 1500 and 1800mcg treatment
groups had more patients with baseline characteristics associated with poor
response (eg, pre-treatment HCV RNA, PEG-IFN+RBV NR, % African-Americans). All
doses were well tolerated and the safety profile in the 1500 mcg and 1800 mcg cohorts
was comparable to the 900-1200mcg cohorts in incidence and types of adverse
events. The overall SVR rate for the first 4 treatment groups was 19% (18/93),
though lower in the genotype 1, PEG-IFN+RBV NR group 12% (7/57). Importantly,
the 1800mcg group showed robust antiviral response (50% [6/12] achieved EVR12)
in genotype 1 “null-responders” to prior PEG+RBV therapy.
Conclusions
Alb-IFN in combination with oral RBV is safe and
effective. Treatment with 1800mcg Q2w demonstrates significant antiviral
activity in prior IFNa non-responder patients.
Topic:
Experimental Therapies - Bavituximab
53.
Multiple dose safety and pharmacokinetic study of bavituximab in
patients with chronic hepatitis C virus (HCV) infection
E. J. Lawitz; E. W. Godofsky; J. S. Shan
Background:
Bavituximab, an investigational monoclonal antibody
targeting phosphatidylserine (PS) located on the surface of virus infected
cells and enveloped viruses, is being developed as an anti-HCV agent. It has
immunostimulatory effects in preclinical viral models. Single intravenous (IV)
infusions of bavituximab up to 6 mg/kg were well-tolerated and showed transient
antiviral activity in chronic HCV patients.
Methods:
To determine the safety, tolerability and
pharmacokinetics of multiple IV infusions of bavituximab, sequential cohorts of
6 patients were given twice weekly 90 min IV infusions for two weeks at 0.3, 1,
3 or 6 mg/kg and followed until week 12. Vital signs, physical exams, safety
laboratory parameters, serum bavituximab levels and serum HCV RNA levels were
measured.
Results:
Twenty-four patients (15 male, mean age
49) were enrolled. Eleven were non-responders, 8 were relapsers and 5 were
treatment-naïve. Mean baseline viral load was 5,000,000 copies/mL and 15 were
infected with genotype 1, 8 with genotype 3 and 1 with genotype 2. The
infusions were well-tolerated. No serious adverse events (SAEs) or early
discontinuations were reported. There was no dose-related increase in incidence
or severity of adverse events (AEs). All AEs were mild or moderate and
transient, except for grade 3 neck pain and arthralgia (drug-related) in a
patient with a history of joint pain at 3 mg/kg bavituximab and grade 3
elevated blood glucose (unrelated) in another patient with diabetes at 0.3
mg/kg bavituximab. All other drug-related AEs were mild: hypertension in 1
patient at 0.3 mg/kg, headache in 1 patient and headache and pruritis in 1
patient at 1 mg/kg and flu-like illness/symptoms in 2 patients at 6 mg/kg after
the first infusion. Bavituximab reaches Cmax at 2-3 h postdose with a mean
elimination half-life of ~34 h. Bavituximab exhibited dose-proportional
increases in Cmax and AUC in single and multiple dosing and did not lead to
significant accumulation. All dose levels exhibited on therapy antiviral
activity (decline of >0.5 log10 reduction in HCV RNA). The 3mg/kg cohort had
the largest number of patients showing antiviral activity, as 5 of 6 subjects
achieved >0.5 log decline in HCV RNA.
Conclusions:
Twice weekly IV doses of bavituximab up to 6 mg/kg
were safe and well-tolerated. Single-dose and multiple dose pharmacokinetics of
bavituximab are linear, predictable and no accumulation appears to occur over
time. Two weeks of dosing is indicative of antiviral effect in a proportion of
patients. Future studies designed to optimize the dosing schedule and
investigate combining bavituximab with current standard therapy are planned.
Topic:
Current Treatment - Pegasys
S. Roberts; M. D. Weltman; D. Crawford; W. Cheng; W.
Sievert; G. W. McCaughan; P. V. Desmond; M. Yoshihara; J. E. Miller; J.
Depamphilis; P. Marks; G. J. Dore; C.
Background:
The CHARIOT study evaluates the efficacy & safety
of a 360 µg/wk dose peginterferon alfa-2a (Peg-IFNα-2a) induction regimen
compared to standard 180 µg/wk Peg-IFNα-2a, in
combination with standard ribavirin (RBV) in treatment-naive patients with
chronic hepatitis C genotype 1. We report results of the planned interim
analysis of on-treatment virological responses over the first 12 wks of
therapy.
Methods:
In this international, multi-centre, open label study
patients were stratified by baseline HCV RNA and randomised 1:1 to 180 µg or
360 µg Peg-IFNα-2a qw for 12 wks followed by 36 wks of 180 µg
Peg-IFNα-2a plus RBV 1000–1200 mg/d for 48 wks. Endpoints include
virologic response at wks 4, 8 and 12.
Results:
845 patients were evaluable for efficacy & safety
analysis. Age, gender, weight, BMI, ethnicity, viral load and fibrosis scores
were similar in the two groups. At wks 4, 8 and 12, virological response rates
were greater (p<0.001) in the 360 µg/wk arm (Table). Significantly higher
response rates (p<0.001) at wk 12 occurred in patients receiving 360 µg dose
in all subgroups including baseline HCV RNA ≥800,000 IU/mL (71% vs 55%)
and <800,000 IU/mL (84% vs 71%), weight ≥85 kg (74% vs 56%) and
<85kg (74% vs 62%), and age >40yrs (70% vs 54%) and ≤40yrs (84% vs
73%). Induction therapy was associated with higher rates of diarrhoea (17% vs
12%), pyrexia (14% vs 8%), chills (14% vs 7%) and weight loss (10% vs 3%).
Depression and fatigue reports were similar. Discontinuations were similar in
both groups, however induction therapy led to more
dose modifications (Table). Use of haematopoetic growth factors was the same in
both groups (4 patients [<1%]).
Conclusion:
Induction dosing with 360 µg/wk
Peg-IFNα-2a is more effective than standard 180 µg/wk dosing in
achieving early and rapid virological responses and is safe and well tolerated.
The effect was independent of baseline viral load, weight, BMI and age.
|
|
Peg-IFN
α-2a |
Peg-IFN
α-2a |
|
Efficacy (HCV RNA <15IU/mL) |
|
|
|
Wk 4 RVR |
108 (26) |
149 (35)* |
|
Wk 8 |
209 (49) |
256 (61)* |
|
Wk 12 |
255 (60) |
313 (74)* |
|
Wk 12 EVR (HCV RNA <15IU/mL or ≥2log10 drop) |
333 (79) |
374 (89)* |
|
Safety |
|
|
|
Overall Tx discontinuations (d/c) |
19 (4) |
21 (5) |
|
Tx d/c due to AEs or lab abnormalities |
10 (2) |
11 (3) |
|
SAEs |
13 (3) |
18 (4) |
|
Dose modifications (PEG-IFN α-2a) |
60 (14) |
93 (22) |
|
Neutropenia (<0.5 x 109/L) |
9 (2) |
23 (5) |
|
Thrombocytopenia (<50 x 109/L) |
4 (<1) |
15 (4) |
|
Anemia (<10g/dL) |
29 (7) |
44 (10) |
*Cochran-Mantel-Haenszel test p<0.001