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
n=5

30mg
n=8

50mg
n=9

75mg
n=11

Age
(median, years)

54

49

56

51

Gender, male
(n, %)

3/5
(60%)

7/8
(88%)

6/9
(67%)

8/11
(73%)

Responders at Day 28*
(n, %)

0/5

4/6
(67%)

7/9
(78%)

9/10
(90%)

Platelet count at baseline, x103/ul
(median, min/max)

47
(38,62)

61
(42,94)

45
(26,66)

56
(28,75)

Platelet count at Day 28, x103/ul
(median, min/max)

38
(34,55)

119
(58,214)

174
(47,252)

246
(78,478)

Subjects who experienced an AE
(n, %)

3/5
(60%)

7/8
(88%)

7/9
(78%)

9/11
(82%)

 


M1009 - HIGH PREVALENCE AND LACK OF CLINICAL RELEVANCE OF AUTO-ANTIBODIES IN CHRONIC HEPATITIS C PATIENTS

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+
(n =77)

Auto-antibodies –
(n= 48)

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

%
males

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

 


M1051 - Primary prevention of esophageal variceal bleeding among cirrhotic patients with hepatitis C and grade 2 to 3 esophageal varices: a cost-utility analysis.

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.

 


M1063 - Screening for esophageal varices in US veterans with chronic hepatitis C and advanced fibrosis : A pilot study

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