Monday – Complications of Liver Disease, Epi, etc.
Time of
Presentation:
May 22 3:30 PM - 3:45 PM
Location:
409 A/B (LA Convention Center)
338 - Efficacy and Safety of Eltrombopag, an Oral Platelet Growth Factor, in
Subjects with HCV Associated Thrombocytopenia: Preliminary Results from a Phase
II Multicenter, Randomised,
Placebo Controlled, Double-Blind, Dose-Ranging Study
J. G. McHutchison; N. Afdhal; M. L. Shiffman; S.
Gordon; P. Mills; S. Sigal; D. Midwinter; F. M.
Campbell; S. Mangum; J. Jenkins; D. Theodore
INTRODUCTION
Eltrombopag olamine
(SB-497115) is an orally bioavailable small molecule thrombopoeitin receptor agonist that may be beneficial in
patients with thrombocytopenia secondary to advanced liver disease. This
ongoing study is designed to assess the safety and tolerability, efficacy and
pharmacokinetics of repeat oral doses of eltrombopag
in subjects with chronic hepatitis C (HCV) associated thrombocytopenia that
precludes treatment with peginterferon and ribavirin according to recommended
regulatory guidelines.
METHODS
Subjects with HCV infection, cirrhosis, compensated liver
disease and platelet counts between 20-70,000/ul were randomly allocated
equally to 1 of 4 treatment groups (30, 50, 75mg eltrombopag
or placebo). Eltrombopag was administered once daily
for 4 weeks. Subjects who achieved platelet counts of > 70,000/ul after the
28 days of treatment were then eligible to start antiviral therapy with
peginterferon and ribavirin, while eltrombopag was
continued. Response was defined as an increase in platelet count to ≥
100,000/ul at Day 28.
RESULTS
The proportion of responders was higher in all active
treatment groups compared to placebo. The highest response rate was observed in
the 75mg eltrombopag group where 9/10 (90%)subjects
were responders. No responders were observed in the placebo group. After 28
days of treatment median platelet counts were higher in the active treatment
groups than in the placebo group. No serious adverse events were reported in
any group after 28 days of treatment. The most common adverse events were
pyrexia, chills, flu-like symptoms, and headaches. There were no
discontinuations for adverse events.
CONCLUSION
An increase in platelet count was observed in all 3
treatment groups. To date, no safety issues have been identified in this
population. The limited interim data from this ongoing study show the potential
for eltrombopag to increase platelet counts and
enable the initiation of peginterferon treatment in subjects with HCV cirrhosis
and associated thrombocytopenia.
|
|
Placebo
|
30mg
|
50mg
|
75mg
|
|
Age |
54 |
49 |
56 |
51 |
|
Gender, male |
3/5 |
7/8 |
6/9 |
8/11 |
|
Responders at Day 28* |
0/5 |
4/6 |
7/9 |
9/10 |
|
Platelet count at baseline, x103/ul |
47 |
61 |
45 |
56 |
|
Platelet count at Day 28, x103/ul |
38 |
119 |
174 |
246 |
|
Subjects who experienced an AE |
3/5 |
7/8 |
7/9 |
9/11 |
J. Garcia-Leiva; A. Meixueiro-Daza; A. Montano-Loza;
M. Sanchez-Osorio; M. Weimersheimer-Sandoval; A. Loaeza-del Castillo; G. Castro-Narro;
J. F. Gallegos-Orozco; F. Vargas-Vorackova; F.
Sanchez-Avila; M. Uribe
Background:
Several autoimmune disorders have been described in
patients with chronic hepatitis C (CHC) including the presence of auto-antibodies.
The most frequent auto-antibodies are antinuclear antibodies (ANA), followed by
anti-smooth muscle antibodies (SMA). However the prevalence and clinical
relevance of these auto-antibodies remains uncertain.
Aim:
To determine the frequency of ANA and SMA in Mexican
patients with CHC and its association with their demographic characteristics,
genotype, viral load, aminotransferase levels, pathological findings and
autoimmune clinical disease.
Material
& Methods:
One hundred and twenty five patients with CHC naive to
antiviral treatment were included. Eighty one were females (64.8%). The mean
age was 48.5 ± 12.4 years. HCV Genotype 1 was found in 92 patients (73.6%). ANA
and SMA were performed by indirect immunofluorescence.
Serum dilutions of ANA ≥ 1:160 and SMA ≥ 1:40 were considered
positive. Liver biopsies were evaluated according to METAVIR. Activity and/or
fibrosis score ≥ 2 were considered significant. All patients with
positive auto-antibodies were evaluated by one rheumatologist.
Results:
Seventy seven patients (61.6%, 95% CI=52-70%) had at
least one positive auto-antibody:
·
ANA were positive in 60 patients (48%)
·
SMA in 29 patients (23.2%).
·
12 patients (16%) were ANA and SMA postive
·
There were no significant differences regarding clinical and
viral characteristics between patients with and without auto-antibodies
(Table).
·
No patient had evidence of associated rheumatologic disease.
Conclusions:
We found a high prevalence of positive auto-antibodies
in patients with CHC. We did not find any differences in clinical, biochemical
and histological characteristics between CHC patients with and without
auto-antibodies. This may suggest that auto-antibody occurrence in patients
with CHC is frequent and does not appear to have significant clinical impact.
Future studies are needed to address the out come of
antiviral treatment in these patients.
|
|
Auto-antibodies+
|
Auto-antibodies
– |
P value |
|
Female gender (%) |
53 (69) |
28 (58) |
0.2 |
|
Age (mean ± SD) |
49.1 ± 12.2 |
47.6 ± 12.6 |
0.5 |
|
ALT (mean ± SD) IU/L |
82.6 ± 46.6 |
76.3 ± 55.9 |
0.5 |
|
AST (mean ± SD) IU/L |
73.1 ± 37.7 |
59.8 ± 37.7 |
0.06 |
|
Genotype 1 (%) |
61 (79) |
31 (65) |
0.2 |
|
Viral load (mean ± SD) IU/mL |
1.1 ± 1.9 x 106 |
1.7 ± 2.2 x 106 |
0.1 |
|
Activity score ≥ 2 (%) |
31 (40) |
13 (27) |
0.3 |
|
Fibrosis score ≥ 2 (%) |
42 (55) |
19 (40) |
0.1 |
M1032 - The occurrence of malignancy in patients
with liver cirrhosis-more than HCC
S. A. Gunnarsdottir; E. Kalaitzakis; E. Bjornsso
Background:
The impact of etiology for the development of HCC in
liver cirrhosis (LC) is somewhat unclear as most studies of the incidence of HCC
date before the identification of hepatitis C (HCV). Data on the occurrence of
other malignancies than HCCs in cirrhotics
are scarce. The importance of the diagnosis of a cancer in LC for the natural
history of LC patients is unclear.
Methods:
Al consecutive patients diagnosed with liver cirrhosis
for the first time in Gothenburg, Sweden (inhabitants 600.000) 1994-2005 were
included. Cumulative incidence of malignancies were compared with the incidence
rates in the Swedish population.
Results:
A total of 1016 were diagnosed with LC during the
study period (mean age 60±12 years, 69% men). Alcoholic liver disease (ALD) was
the cause in 452 (45%), HCV in 102 (10%), ALD+HCV in 115 (11%), cryptogenic in
161 (16%) and others 186 (19%). The median follow-up was 19 (range 0-118)
months. A total of 86 (8.5%) developed HCC during the study period, 27/452 (6%)
of those with ALD, 17/102 (17%) with HCV, 16/115 (14%) with ALD and HCV and
26/347 (7%) in other patients. Of the HCV patients, 17% developed HCC vs 7% of those with other etiologies (p<0.001).
Altogether 45 (4.4%) patients developed other cancer (OC) than HCC during the
follow-up most commonly colon cancer 11/45 (24%), lung cancer 4 (9%),
pancreatic cancer 4 (9%), prostate cancer 3 (7%), uterus cancer 3 (7%), others
20 (44%). The total number of malignancies 131/1016 (13%) was higher than the
cancer incidence in the general population (10.7%; p=0.017). Of other
malignancies, the incidence of colon cancer was higher 11/1016 (1.1%) than in
the general population (0.4%;p=0.002). No significant difference was observed
in the incidence of the total number of cancers and colon cancer among patients
with different etiologies. The median transplantation free survival time for
patients with HCC was 8 (2-24 IQR) months and in those with OC 12 (2-36)
months. The transplantation free 5-year survival was 4% for the patients with
HCC (9% were transplanted) and 5% for the patients with OC. A total of 42/45
(93%) with OC died during follow-up and 74/86 (86%) of the patients with HCC.
Among those who had OC the cause of death was cancer in 33/45 (79%) and in
73/86 (85%) among those with HCC.
Conclusion:
·
HCC in cirrhotics was most commonly
associated with hepatitis C.
·
The total number of cancers and colon cancer were higher than
the incidence in the general population.
·
The etiology of cirrhosis does not seem to have major impact
on the risk of other cancers than HCC in cirrhotic.
·
Cancer in cirrhotics carries a very
poor prognosis.
M1043 - The incidence, etiology and the natural
history of liver cirrhosis in Iceland and Sweden
S. A. Gunnarsdottir; N. Craglia; S. Olafsson; B. Thodleifsson; E. Bjornsson
Background:
Incidence of liver cirrhosis (LC) in Iceland has
previously been reported to be the lowest in the Western world, with 2.4
patients per 100.000/year between 1950-1990 (Ludviksdottir
et al Eur J Gast &
Hepatol 1997). Data on the etiology and natural history of LC after the
discovery of hepatitis C is limited and comparison with other Nordic countries
is lacking.
Aim:
We aimed to investigate the incidence, etiology and
prognosis of liver cirrhosis in Iceland in comparison with that in Sweden.
Methods:
All consecutive patients diagnosed with liver
cirrhosis for the first time in the whole population of Iceland (inhabitants
280.000) from 1994-2003 were included and compared with patients diagnosed with
liver cirrhosis in the same time period in Gothenburg, Sweden (inhabitants
600.000).
Results:
A total of 1016 patients (97 patients in Iceland (IC) and
918 in Gothenburg (GO)) during the 10-year period. Comparison of the etiology
in IC and GO revealed that alcoholic liver disease (ALD) was the most common
cause in both countries (Table 1), Hepatitis C (HCV) in 5 % vs. 9%, ALD+HCV 3 %
vs. 12%, cryptogenic cirrhosis 21 % vs. 16%, PBC 14 % vs. 4%, AIH 9 % vs. 2%, haemochromatosis 7 % vs. 1% and others 12 % vs. 6%, in IC
and GO, respectively. The total proportion of patients with HCV was 8% in IC vs 21% in GO (p<0.01). Causes of death were: liver
failure in IC 18 % vs 39% in GO, variceal bleeding 4
% vs 11 %, GI-bleeding 3 % vs
2 %, HCC 11 % vs
13 %, non-liver related 31% vs 26 %, other causes 15%
vs. 9%.
Conclusion:
The incidence of liver cirrhosis is still low in
Iceland and is only one fourth of the incidence in Sweden mostly due to lower
prevalence of alcoholic liver disease in spite of similar alcohol consumption.
This raises the question of environmental or genetic influences. Hepatitis C is
also a more common cause of cirrhosis in Sweden.
|
|
Annual
incidence per 105 |
% |
Mean age
±SD |
ALD % |
Alcohol
liters per inhabitant>15 years |
|
|
|
Gothenburg |
15*** |
68** |
60±12* |
50*** |
6.7 |
|
|
|
Iceland |
3.5 |
54 |
64±14 |
26 |
5.5 |
|
|
*p=<0.01
** p<0.0001
***p<0.0001
W. Chen; S. Cope; J. Watkins; J. Heathcote;
M. Krahn
Background:
Complications of portal hypertension are a major
source of morbidity and mortality among cirrhotic patients infected with the
hepatitis C virus (HCV). Treatment with non-selective beta-blockers and
esophageal variceal ligation are current options to prevent the first esophageal
variceal bleed in cirrhotics with grade 2 to 3
varices.
Objective:
To compare current primary prevention options using a
decision analytic model that projects health and economic outcomes. Methods: A
Markov model was developed for three strategies which included beta-blockers,
esophageal variceal ligation, and no intervention. The model included the
relevant clinical outcomes related to cirrhosis with HCV (esophageal variceal
bleeding, esophageal variceal rebleeding, hepatic decompensation, hepatocellular
carcinoma, liver transplant, and death). We performed a systematic review of
MEDLINE and EMBASE to identify cohort studies describing the natural history of
cirrhotics with HCV, randomized clinical trials of
the effectiveness of beta-blockers and esophageal variceal ligation in
preventing the first variceal bleed in cirrhotics,
and utility studies characterizing the utility of relevant health states. We
used linear regression to project the annual incidence of clinical outcomes in
the model. Costs of managing cirrhotic patients with HCV were collected from
the University Health Network, Toronto, Canada.
Results:
Primary prevention with beta-blockers was associated
with a longer life expectancy than variceal ligation (13.35 life years vs. 12.36
life years), and was also less costly. Beta-blocker therapy was also associated
with a greater quality adjusted life expectancy (9.33 QALYs
vs. 8.64 QALYs). One-way sensitivity analysis was
conducted for important variables that might be affecting optimal strategy.
Variations in these parameters within the range of clinical plausibility did
not change the analytic results. The beta-blocker strategy remained dominant.
Conclusions:
Our decision analytic model suggests that
non-selective beta-blocker therapy is associated with longer life years and QALYs and lower cost than esophageal variceal ligation in
preventing the first esophageal variceal bleed among cirrhotics
with HCV and grade 2 to 3 varices.
J. A. Talreja;
A. A. MIHAS; D. M. Heuma
Background:
Current AASLD practice guidelines recommend screening
for esophageal varices every 1-2 years in all patients of liver cirrhosis
irrespective of its etiology. Consequently, these directives exclude all
patients with chronic liver disease and no evidence of cirrhosis. However,
previous studies have shown that portal hypertension develops in patients with
chronic hepatitis C and advanced fibrosis even in the absence of frank
cirrhosis. This is further compounded by the large margin of error due to the
liver biopsy “sampling error”, which may be as high as 30%.
Aims:
To assess the prevalence of esophageal varices (EV)
and portal hypertensive gastropathy (PHG) in patients
with chronic hepatitis C and bridging fibrosis (BF, Ishak stages 3 and 4) and
compare it to that of compensated cirrhosis (CC, Ishak stages 5 and 6).
Patients and
Methods:
Eighty patients with chronic hepatitis C and advanced
fibrosis (Ishak stages 3-6) and fully compensated liver disease were included
in this study. There was no prior history of variceal bleeding in any of these
patients. All patients had routine hematologic
(including platelet count) and biochemical labs, liver imaging by US or CT scan
and a liver biopsy. The presence of varices and/or PHG was assessed by EGD. A
platelet count lower than 130 k was considered thrombocytopenic.
Results:
Presence
of Esophageal Varices or Portal Hypertensive Gastropathy in Patients with Bridging Fibrosis vs.
Compensated Cirrhosis:
o
Esophageal varices were present in 24 of 80 patients (30%), including 8 of 40
patients with compensated cirrhosis (40%).
o
Portal hypertensive gastropathy was present in 31 of 80 patients (38.5%),
specifically 11 of 40 patients with bridging fibrosis (27.5%) and 20 of 40
patients with compensated cirrhosis (50%)
o
No patient with bridging
fibrosis was found to have large varices.
Evaluation
of Thrombocytopenia as a Marker for Esophageal
Varices
o
Thrombocytopenia (Plt <130k) was present in 4 of 8 patients with bridging
fibrosis and no varices (50%), and in 6 of 32 patients with bridging fibrosis
and no varices (17%)
o
Thrombocytopenia was
present in 10 of 16 patients with compensated cirrhosis and no varices (38%).
o
Thrombocytopenia is more
common in patients with varices (14/24, 58%), but a substantial proportion of
varices occur in patients with normal platelet counts
Summary
o
The prevalence of varices
and portal hypertensive gastropathy increase with the
severity of fibrosis
o
Varices and/or portal
hypertensive gastropathy were found in more than ¼ of
patients with pre-cirrhotic fibrosis on biopsy (Ishak Stages 3-4)
o
Thrombocytopenia is more
common in patients with varices, but a substantial proportion of varices occur
in patients with normal platelet counts.
Conclusion
o
About one if four patients
with pre-cirrhotic hepatic bridging fibrosis (Ishak Stages 3-4) has esophageal varices and/or portal hypertensive gastropathy.
o
Endoscopy may be useful in
patients with pre-cirrhotic fibrosis on liver biopsy to identify early vascular
changes of portal hypertension.
M1921 Persistently High Mortality Rate of
Alcoholic Liver Disease Despite The Hepatitis C Epidemic
W. Kim; V. H. Shah; J. T. Benson
Background/Aim:
Although some have suggested that the prevalence of
alcoholism may be decreasing, alcoholic liver disease (ALD) continues to be an important
cause of liver-related morbidity and mortality. The prevalence of hepatitis C
(HCV) infection among patients with alcohol dependence is high. The aim of the
study was to evaluate the impact of these epidemiological trends on mortality
related to ALD.
Methods:
Multiple Cause of Death files, which compile all death
certificates issued in the US, were analyzed between 1980 and 1998. Predetermined inclusion criteria were used to
identify decedents from ALD and HCV. Alcoholic hepatitis (AH) was separately
accounted for. Age-, and sex-specific mortality was calculated using 2000 US
Census as the standard population.
Results:
Between 1980 and 1998, 186,081 decedents met the
criteria for ALD, 19,127 for AH and 18,951 for HCV (Table). There were 1,721
decedents with ALD and 195 with AH that also had a HCV diagnosis. In the
Figure, there was a mild, but significant downward trend in the age- and
sex-adjusted mortality from ALD (p<0.01, Poisson regression). The mortality
rate from AH was on the order of 1/10 of that from ALD and also showed a slight
decrease over time (p=0.01). In the late 1990s, there was a rapid rise in HCV
mortality, which likely represents increasing ascertainment as well as true
increase in mortality from HCV.
Conclusions:
While mortality from HCV increases rapidly, ALD
continues to be a greater cause of death from liver disease. Furthermore,
despite the changes in US alcohol consumption, the incidence of AH has remained
nearly unchanged during the 1980s and 1990s. Although its impact is slowly
decreasing, alcohol remains the most important cause of death from liver
disease in the U.S.
|
|
ALD |
AH |
HCV |
|
n |
186,081 |
19,127 |
18,951 |
|
Age at death |
54.7±12.6 |
56.9±15.8 |
50.1±12.8 |
|
Male (%) |
73.0 |
68.5 |
60.5 |
|
HCC(%) |
1.4 |
0.4 |
10.7 |
