May 17, 2005
Abstract ID:
T1096
A. Samanta, A. Mandalapu, A. Fisher, D. Wilson, A. de la Torre, K.M.
Klein, B. Koneru
Introduction
Hepatitis C recurs in virtually all liver transplant
recipients, runs an aggressive course and causes graft dysfunction and loss.
Treatment with interferon and ribavirin has not impacted the disease
progression. Outcome data on pegylated interferon plus ribavirin treatment of
nonresponders to interferon plus ribavirin for post transplant hepatitis C is scarce
and end point of treatment not well defined.
Aim
To study treatment efficacy of peginterferon alfa-2b
plus ribavirin for post-transplant recurrent hepatitis C nonresponsive to
interferon alfa-2b plus ribavirin.
Methods
Twenty-six patients with post transplant hepatitis C
recurrence, unresponsive to interferon alfa 2b and ribavirin were treated with
peginterferon alfa-2bplus ribavirin. Criteria for hepatitis C recurrence
included elevated ALT and AST, circulating HCV-RNA, histologic
features of hepatitis and absence of rejection.
Patients were treated with weekly pegylated interferon alfa 2b 1.5
mcg/kg and daily ribavirin starting at 400 mg (increased to 1000 mg).
Erythropoietin and G-CSF were given when required.
Results
Mean age was 52.4 + 7.5 years; 85% were
male. Twenty-three patients (88.5%)
completed treatment for 24 to 60 weeks and three (11.5%) stopped medication for
drug intolerance. Tolerated dose for peginterferon was 88+42 mcg/week
(range 32-240 mcg/week) and for ribavirin was 600+200 mg/day (range
400-1000 mg/day). Dose interruption for peginterferon occurred in 12 (46%) and
15 (57%) required erythropoietin and/or G-CSF.
At end of treatment, ALT, AST and HCV-RNA (57+28 IU, 60+40
IU and 500,000+200,000 copies/ml respectively) decreased significantly
(p<0.05) from pretreatment values (109+82 IU, 90+70 IU, and
4,000,000+6,000,000 copies/ml respectively). Intent-to-treat analysis
showed end of treatment biochemical response (normalization of transaminases) in 10 patients (38%) and HCV-RNA clearance
in 5 (19%). Sustained response (undetectable HCV-RNA at six months after
treatment) occurred in one (4%).
Conclusions
Treatment of post transplant hepatitis C recurrence
with peginterferon alfa-2b plus ribavirin for 24-60 weeks in nonresponders to
interferon alfa 2b plus ribavirin achieves viral decrease in many patients with
improvement in transaminases at the end of treatment.
However, sustained viral clearance is achieved in a few (4%). Dose reduction or
interruption for drug intolerance limits therapy in post transplant population.
Longer duration of therapy may prove beneficial.
Abstract ID: T1415
H.T. El-Zimaity,
B. Yoffe, T. Tabassi, B.
Hollinger, S.A. Abudayyeh, Z.Z. Nurgalieva,
F. Hammoud, B.S. Anand
Background
Hepatitis C virus (HCV) is a
major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma
(HCC). It has been observed that African
Americans (AA) have a higher infection rate, an inferior response to anti-viral
treatment, and are more likely to develop HCC compared to Whites. It is unclear why these ethnic differences
occur. A possible explanation is the confounding effect of concurrent infections
such as H. pylori (HP) is more prevalent in AA.
HP might influences HCV infection by altering the host immune response.
Aim: To compare HCV viral load and treatment response in HP positive vs. HP
negative patients.
Methods
HCV was confirmed by
positive HCV-RNA by PCR. HCV viral load
was determined at baseline (prior to treatment), after 24 and 48 weeks of
treatment, and at 6 month after stopping anti-viral therapy. Sustained virology
response (SVR) was defined as negative HCV-PCR 6 months post therapy. Patients
were treated with interferon alone or interferon and ribavirin combination
therapy. HP status was assessed by
serology (HM-CAP; Enteric Products Inc, Stony Brook, NY).
Results
107 patients with HCV
infection were included (42 received monotherapy and 65 combination therapy).
42 (39%) were HP antibody positive. The
SVR rate was lower among HP positive patients compared to HP negative patients
(19% vs. 43%) (p = 0.01). By ordered
logistic regression analysis, other factors associated with a lower SVR rate
were genotype 1 and being African American. The baseline viral load was also
lower in HP negative patients compared to HP positive patients
(p<0.001). After treatment, the mean
viral load in the non-responder patients (27 HP negative and 32 HP positive)
was higher in HP positive patients (2.32 x 106 + 3.2 vs. 1.51 x 106 + 4.8
copies) (p = 0.056).
Conclusion
HP infection is associated
with significantly lower sustained virologic response
rate and a higher HCV viral load compared to patients without HP
infection. The lower SVR rate in AA may
be explained by the higher prevalence of H. pylori infection. Eradication of H. pylori infection might
result in a significant improvement in the outcome of HCV treatment.
Abstract ID: 436
Y.H. Shaib,
H.B. El-Serag, M. Hassan
Background
Risk factors of cholangiocarcinoma are not well defined. This study
evaluates viral hepatitis (HCV, HBV) and liver cirrhosis as risk factors for
intrahepatic (ICC) and extrahepatic cholangiocarcinoma
(ECC).
Methods
A hospital-based prospective
case-control study. Cases were patients
with histologically confirmed cholangiocarcinoma
referred to M.D. Anderson cancer center between 1992-2002 and were matched (1:2
for ICC and 1:1 for ECC) by age and gender to controls obtained from the
companions of patients with a diagnosis of cancer, other than hepatobiliary cancers. Data were collected using a
structured questionnaire about liver disease, family history, diabetes,
smoking, and alcohol. Blood samples from all participants were tested for HBs Ag, HBc and anti-HCV
antibodies. Comparisons were conduced in bivariate
and multivariable logistic regression analyses.
Results
We identified 246 cases (83
cases with ICC and 163 with ECC) and 156 controls (Table). There were no
significant differences between cases and controls in age, gender, and race.
|
|
ICC Cases (N=83) |
ECC Cases (N=163) |
Controls (N=156) |
Mean Age (SD)
|
59.8 (11.4) |
61.1 (10.2) |
59.8(11.8) |
|
Gender |
|
|
|
|
Women |
37 (44.6%) |
67 (41.1%) |
58(37.2%) |
Race
|
|
|
|
|
White |
67 (80.7 %) |
126 (77.3%) |
123 (78.8%) |
|
Other |
16 (19.3%) |
37 (22.7%) |
33 (21.2%) |
Compared with controls, ICC
cases had higher prevalence of anti-HCV antibodies (6.0 % vs. 1.3 %, p=0.04)
and Anti HBc antibodies (10.8% vs. 0.65 %, p=0.0002)
but not HBs Ag (1.2% vs. 0.7%, p=0.7). The race-adjusted odds ratio for HCV was 4.5
(1.1-34.5) and for Anti HBc antibodies was18.3 (3.3-340.0). The prevalence of diabetes (14.5 % vs.9.2 %,
p=0.2), smoking (44.6 % vs. 47.4 %, p=0.7) and alcohol (55.4 % vs.57.9 %,
p=0.7) were not significantly different between ICC cases and controls. Most of
the ICC patients with HCV (80%) had liver cirrhosis. Only 2 ICC cases (2.4 %)
had ulcerative colitis or sclerosing cholangitis. The
prevalence of most of the risk factors was not different between ECC cases and
controls: anti HCV (3.7% vs. 1.3%, p=0.2), HBs Ag (0
vs. 0.6 %, p=0.3), diabetes (11.6 vs. 9.2 %, p=0.5), and smoking (47.2 % vs.
47.4 %, p=0.9). The prevalence of
cirrhosis was significantly higher among patients with ICC than those with ECC
(24.1% vs. 4.9 %, p<0.0001).
Conclusion
Chronic HCV and possibly HBV
are risk factors for ICC but not ECC. Liver cirrhosis is a common and strong
risk factor for ICC and less so for ECC.
Abstract ID: 535
L. Kapelusznik,
E.J. Bini
BACKGROUND
The association between
chronic hepatitis C virus (HCV) infection and gallbladder disease (GBD) is
controversial. The aims of this prospective study were to determine the
prevalence of GBD among men with chronic HCV infection and to evaluate racial
differences in the prevalence of GBD in this population.
METHODS
727 men with a positive HCV
antibody test were interviewed by research coordinators who obtained detailed
demographic and clinical data, and all patients had routine laboratory testing,
HCV PCR testing, and abdominal ultrasonography. GBD
was defined as the presence of one or more gallstones or evidence of prior cholecystectomy on ultrasonography.
RESULTS
Among the 727 men, 564
(77.6%) were HCV RNA(+); the remaining 163 HCV RNA(-) patients served as
controls. Overall, the mean age was 51.9 +/- 8.5 years and there were 32.3%
non-Hispanic whites, 42.1% non-Hispanic blacks, 24.6% Hispanics, and 1.0% other
racial groups. The age and race distribution were similar in the HCV positive
and control groups. The prevalence of gallstones (20.6% vs. 7.4%, p <0.001),
cholecystectomy (8.2% vs. 1.8%, p = 0.002), and the
combined endpoint of GBD (28.7% vs. 9.2%, p <0.001) were all significantly
higher in HCV positive patients compared with controls. The prevalence of GBD
among our controls was no different from U.S. men of similar age
(Gastroenterology 1999;117:632-639). After adjusting for age and race, the odds
of GBD (OR = 4.31; 95% CI, 2.39 - 7.76; p <0.001) was significantly higher
among HCV positive patients compared to controls. These findings remained
highly significant after adjusting for education, income, alcohol use, smoking,
diabetes, cholesterol, body mass index, and recent weight loss. Among HCV
positive patients, the prevalence of GBD increased with age and was 20.4% in
men <50 years old, 30.5% in those 50 - 59 years old, and 45.2% in those
>=60 years old (p <0.001). The prevalence of GBD in HCV positive men was
47.2% in Hispanics, 30.2% in non-Hispanic whites, 16.7% in other racial groups,
and 16.3% in non-Hispanic blacks (p <0.001). Patients with genotype 3 had
the highest prevalence of GBD (49.0%) as compared with 26.3% in genotype 1,
32.1% in genotype 2, and 23.1% in those with other genotypes (p = 0.009).
CONCLUSIONS
The prevalence of GBD was
significantly higher in HCV positive men compared to men without HCV infection.
Among HCV positive men, there were marked racial and HCV genotype differences
in the prevalence of GBD.
Abstract ID: 524
N.
Dharel, N. Kato, H. Taniguchi, M. Otsuka,
M. Moriyama, R. Muroyama, Y. Wang, R. Shao, T. Kawabe, M. Omata
Background & Aims
Chronic hepatitis C virus
(HCV) infection is a major cause of liver cirrhosis and hepatocellular
carcinoma worldwide. Host cellular factors regulating HCV replication are still
to be elucidated.
Methods
1)
Naive Huh7 cells and
Huh7-168 (high replication permissive Huh7 cells), were transfected
with subgenomic HCV replicon
and their replication permissiveness was compared.
2)
p53 expression among high or
low-replication permissive cells was examined by Western blot.
3)
p53 expression in Huh7 cells
non-permissive to HCV replicon was silenced by siRNA, and the p53 knocked down cells were transfected with HCV replicon.
4)
p53 overexpressing
plasmid or p53 silencing plasmid were co-transfected
with HCV replicon into Huh7-168, and colony formation
assay was performed.
5)
p53 overexpressing
plasmid was transfected into replicon
harboring cells, and immunofluorescence staining of
p53 and HCV NS5A was performed.
6)
p53 mutant with point
mutation at cell cycle regulating or apoptosis regulating residue was constructed,
and their effect on HCV replication was compared to that of the wild type p53.
Results
1)
Numerous neomycin resistant
colonies were obtained from Huh7-168 but no colony was obtained from naïve Huh7
cells.
2)
Higher-replication
supporting cells (confirmed by Western blotting for NS5B and real time RT-PCR)
had a tendency of lower p53 expression.
3)
Following p53 silencing,
replication non-permissive naïve Huh7 cells supported a high level replication
of HCV replicon.
4)
p53 overexpression
reduced the number of colonies, whereas p53 silencing increased.
5)
HCV NS5A expression was low
in cells overexpressing p53, whereas high expression
of HCV NS5A was seen in p53 knocked down cells.
6)
Mutant p53 with point
mutation at cell cycle regulating or apoptosis regulating residue suppressed
HCV replication as well as the wild type.
Conclusions
p53 inhibits HCV replication
independent of cell cycle arrest and apoptotic function. Exploration of the
mechanism of this hitherto unrecognized link between p53 and HCV could enhance
the understanding of HCV replication, and could lead to the development of
better therapeutic options.
Abstract ID: 538
P. THIERRY, V. GEOFFROY, C.
FAREDJ, A. ZEINA, R. CHRISTOPHE, H. PIERRE MICHEL, T. ALBERT
Background & aims
There is a lack of available
effective therapy for fatigue associated with chronic hepatitis C (CHC). The
serotonin antagonist ondansetron has shown its
efficacy in the chronic fatigue syndrome. The present randomized,
placebo-controlled double blind trial investigated the effect of orally
administered ondansetron on fatigue in CHC.
Methods
Thirty six patients with CHC
were included if fatigue was their predominant symptom and they scored more
than 4 on a visual analog scale (0-10). During the study, fatigue and
depression were measured at day 0, 15, 30 and 60 using validated self report
questionnaire (Fatigue Impact Scale and Beck Depression Inventory). The
patients were randomized to receive ondansetron
tablets 4 mg bid or placebo for one month followed by an additional four weeks
observation.
Results
The fatigue score was
85.4±28.2 and 98.2±26.9 in the ondansetron and placebo
group respectively (NS). Ondansetron significantly
reduced the fatigue score with more than 30% improvement at day 15 (57.1±38.9,
p<0.01), day 30 (54.5±37.6, p<0.01) and day 60 (60.8±37.3, p<0.01)
whereas placebo did not. Overall, the reduction of fatigue was significantly
higher with ondansetron as compared with placebo
(ANOVA for repeated measurements), either for the whole follow-up (p=0.03) or
restricted to the treatment period only (p=0.04). Ondansetron
also significantly reduced the depression scores.
Conclusions
The 5-hydroxytryptamine
receptor type 3 antagonist ondansetron has a
significant positive effect on fatigue in CHC. These observations support the
concept that fatigue involves serotoninergic pathways
and may encourage the further evaluation of the efficacy of ondansetron
on fatigue in chronic liver diseases.
Abstract ID: 527
H.W.
Reesink, S. Zeuzem, A. van Vliet, L. McNair, S. Purdy, H. Chu,
P.L. Jansen
Background
VX-950
is an orally administered, highly selective peptidomimetic
inhibitor of the Hepatitis C virus (HCV)
NS3·4A protease that is designed to block HCV replication. VX-950 is among the most advanced direct
antivirals in clinical development for the treatment of HCV infection. A single-dose Phase 1 study conducted in
healthy subjects demonstrated that VX-950 was well tolerated at all dose levels
up to 1250 mg, with good bioavailability.
A multiple-dose study is now underway that includes healthy subjects and
subjects with chronic Hepatitis C. This
abstract reports on the initial results in the healthy subject component of the
study.
Methods
The
VX04-950-101 clinical study includes three panels of eight healthy subjects
(Part A) and three panels of twelve subjects with Hepatitis C (Part B). In Part A, subjects are dosed for 5 days at
doses of 450 mg, 750 mg, and 1250 mg, or placebo. In Part B, subjects will be dosed for 14 days
at doses of 450 mg, 750 mg and 1250 mg, or placebo. The primary objective of the study is to
assess safety and tolerability; the secondary objective is to assess antiviral
activity in subjects with Hepatitis C.
Results
At
this time, dosing of the first two panels of healthy subjects in Part A of the
clinical study has been completed, and dosing of the third panel is
ongoing. VX-950 has been well tolerated,
with no serious adverse events. All
adverse events possibly related to VX-950 were mild, and no subject has
discontinued from the study. Pharmacokinetic (PK) assessment showed that
VX-950 is orally bioavailable, and steady state was
attained within 24 to 48 hours of dosing initiation. The minimum average trough concentration is
about 400 ng/mL, exceeding 50% of the inhibitory
concentration in the VX-950 replicon assay (IC50 =
240 ng/mL) and infectious virus assay (IC50 = 196 ng/mL).
Discussion
VX-950
has been well tolerated for 5 days in healthy subjects. The PK behavior of the drug is consistent
with the prior single dose PK results.
At steady state, trough concentrations in the blood were significantly
higher than the IC50 for the drug.
Based on these data and extensive pre-clinical data on plasma-to-liver
drug concentration ratios, the doses are also expected to yield liver exposures
that exceed 90% of the inhibitory concentration (replicon
IC90 = 476 ng/mL). Part B of the study, in subjects
with chronic Hepatitis C, is currently underway.
Presentation
Number: S929
S.L. Currie, T.L. Wright,
E.J. Bini, H. Shen, H.S.
Yee, F. VA-HCV-001 Research Group
Background
Many patients chronically infected with the hepatitis
C virus (HCV) are not considered treatment (Tx)
candidates and for those whom Tx is recommended, many
decline. However, there are also many patients that do agree to Tx, but do not initiate Tx.
Little is known about this group.
Objective
To examine whether there are site variations in the
number of persons who are HCV Tx candidates who agree
to Tx, but who do not initiate Tx.
Methods
Data were prospectively collected in 4,084 HCV RNA
positive, Tx naive patients at 24 VAMCs
undergoing evaluation for interferon and ribavirin therapy between December
1999 and December 2000. All sites had a
trained hepatologist as well as dedicated staff for the study and Tx candidacy was determined according to standardized inclusion/exclusion
criteria. Persons considered candidates who agreed to Tx
were assessed on whether Tx was actually initiated,
by site. Enrollment variations were recorded, using one of the sites as a
reference.
Patient
Characteristics
o Age, years
(IQR) =46.0 (46.0—53.0)
o Male gender
= 97.2%
o Caucasian =
56.6%
o African
American = 29.4%
o Hispanic =
9.5%
o Service
during
o Less than or
equal to 12 years of education = 47.1%
o Income less
than $10,000 or less = 39.0%
o Consumed 3
or more drinks/day = 73.6%
o Injection
drug use = 60.0%
Results
o Overall,
32.2% (95% CI, 30.8% – 33.7%) were candidates for HCV treatment according to
the standardized criteria, and
o 40.7% (95%
CI, 39.2% – 42.3%) were candidates in the opinion of the treating clinician.
o Of the 1,624
patients who were offered treatment, 377 (23%) declined and 1247 (77%) agreed
to be treated.
o In those
patients who agreed to be treated, 721 (58%) enrolled in treatment.
o Among the 17
sites, there was significant variation in the percentage of persons who were
offered and agreed to be treated and those who actually initiated treatment,
ranging from 30% to 94% across the sites.
o Using one
site as a reference, univariate analysis showed that
9 of the 16 sites had statistically significant variations, with one site over
12.5 times less likely to have their patients initiate Tx
(OR 12.54, 95% CI, 4.77 - 32.99).
Conclusion
Known barriers to HCV treatment
include: relative and absolute
contraindications to treatment, local resources available to support patients
on therapy and patient unwillingness to be treated. In the current study, all of these potential
barriers were removed.
Despite the availability of therapy,
our data show significant variation in treatment initiation rates, which may
suggest yet another barrier to HCV treatment.
Further study is needed to identify
the factors that reduce initiation of HCV treatment, once patients have met
criteria and have agreed to be treated.
Strategies should be developed to
improve initiation rates and reduce such significant variations in care.
Despite standardized candidacy
selection, staff and HCV treatment resources being available, our data suggest
that there are significant variations in the number of treatment candidates who
agreed to be treated and who were actually enrolled. The gap between acceptance
and enrollment needs to be further investigated and include factors such as
geography, provider experience and patient follow-up