HEPATOLOGY WATCH®
HIGHLIGHTS OF THE
ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
CHRONIC HEPATITIS C
VIRUS (HCV) INFECTION
BILN 2061.
BILN 2061 is a potent and specific inhibitor of HCV serine
protease. Holger Hinrichsen and
associates treated 31 patients with HCV genotype 1 and minimal hepatic fibrosis
in a sequential group comparison with 2 days of oral BILN 2061 25, 200, or 500
mg b.i.d. In each group, patients were
randomized to placebo in a 2:8 ratio.
Viral load was decreased by ³ 1 LOG10 unit in 7 of 9, 8 of 8, and
8 of 8 patients treated with 25, 200, and 500 mg of BILN 2061, respectively,
while no responses were seen in placebo-treated patients. In a second study, Yves Benhamou et al. randomized
10 patients with HCV genotype 1 and advanced hepatic fibrosis to receive 200 mg
b.i.d. of BILN 2061 or placebo for 2 days.
All 8 patients randomized to oral BILN 2061 achieved a decrease in virus
load of ³ 1 LOG10 unit. BILN
2061 was well tolerated in both studies.
These preliminary studies demonstrate that BILN 2061 is active against
HCV. (Abstracts 866 and 563)
Impact of psychiatric
illness, drug use, and alcohol use in recovering injection drug users.
Diane Sylvestre and Barry Clements administered standard interferon/ribavirin
therapy to 66 recovering heroin users (stabilized on methadone maintenance)
with active HCV infection. Neither
psychiatric illness, occasional drug use, nor alcohol use was found to
adversely affect the sustained virological response (SVR) rate. However, none of 7 patients who used drugs
regularly and none of 4 patients with psychiatric illness who also used drugs
and/or alcohol had a virological response.
Multiple logistic regression analysis revealed only psychiatric illness
to be an independent predictor of poor outcome.
These data suggest that reasonably successful outcomes can be expected
with anti-HCV treatments in a recovering injection-drug-use population. (Abstract 225)
Low-accelerating-dose
regimen (LADR) protocol for decompensated liver disease.
Existing studies have not examined treatment outcomes in HCV patients
with decompensated liver disease.
Gregory Everson and associates initiated interferon alfa-2b plus ribavirin
therapy according to the LADR protocol in 102 HCV patients with decompensated
liver disease. Preliminary data for 91
patients shows that the end-of-treatment rate of virological clearance was 38%
and the SVR rate was 22%. SVR was correlated
with non-1 genotype and achievement of full dose therapy. These findings indicate that LADR protocol
therapy can result in virological remission in HCV patients with decompensated
liver disease. (Abstract 536)
Retreatment with
peginterferon (PegIFN) and ribavirin (RVN). Mitchell
Shiffman and colleagues report that SVR is evaluable in 212 of 863 patients
enrolled in the HALT-C Trial. In this
study, HCV patients who have failed to respond to treatment with either IFN or
IFN plus RVN are retreated with PegIFN plus RVN. Dose reductions of PegIFN and/or RVN have
been required in 60% of patients, but only 5% of patients have been unable to
complete 24 weeks of treatment. The
end-of-treatment response rate was 53%, but the SVR rate was only 20%. The SVR rate was greater in patients who: 1)
had failed prior IFN monotherapy compared to IFN plus RVN (34% vs. 11%); 2)
were non-African Americans (22% vs. 0%); 3) had non-1 genotype infection (60%
vs. 15%); 4) were <50 years of age (25% vs. 13%); or 5) had a ³ 2 log
decline in HCV RNA by week 12 (41% vs. 7%). PegIFN maintenance therapy is being
evaluated. (Abstract 527)
CHRONIC HEPATITIS B
VIRUS (HBV) INFECTION
Rising health burden of
HBV in the US. W. Ray Kim and associates at the Mayo Clinic
(Rochester, MN) utilized 2 nationwide databases (the Death Registry and
Healthcare Utilization Project) to investigate if the recent influx of
immigrants from HBV endemic areas has increased the health burden of HBV in the
US. The age-adjusted death rate for HBV
increased 4-fold from 1979 to 1998; it was most pronounced in non-white,
non-black men. From 1989 to 1998 there
was a 4.9-fold increase in hospitalizations for HBV liver disease, a 3.8-fold
increase in hospitalizations for hepatocellular carcinoma, a 2.2-fold increase
in hospital deaths, and a 2.2-fold increase in hospital charges. These data show that HBV-related mortality
and hospitalizations have increased in the
Entecavir (ETV)
treatment of lamivudine (LAM) failures. Ting-Tsung Chang et
al. conducted an international study in which 181 HBV patients who had failed
to respond to ³ 24 weeks of LAM therapy or had
evidence of YMDD mutation were randomized to receive one of 3 doses of daily
ETV (0.1, 0.5, or 1.0 mg) or to continue LAM 100 mg daily. The mean decrease in HBV DNA at 48 weeks for
all 3 ETV treatment groups was superior to that for patients treated with LAM
(p£0.01). No patient in
the ETV 1.0 mg group had breakthrough viremia within 48 weeks and no mutations
conferring resistance to ETV were identified in any ETV treatment group. These data demonstrate that ETV is
potentially effective therapy for LAM-resistant HBV. (Abstract 550)
PRIMARY BILIARY
CIRRHOSIS
Occurrence in
monozygotic twins. Carlo Selmi et al., through an international
effort, have identified 8 sets of identical twins within 1,400 families in
which a member had PBC. The identical
twins were all female and 6 of the sets of twins were concordant for PBC. The high concordance for PBC suggests that
genetic factors play a major role and highlight the need for genetic studies in
PBC patients. (Abstract 897)
Possible role of
xenobiotics for induction of antimitochondrial antibodies (AMA).
Patrick Leung and coworkers performed detailed experiments in which rabbits
were immunized with BSA-conjugated halogenated hydrocarbons. Within 4 weeks after immunization, the
rabbits developed antibodies to PDC-E2, BCOADC-E2, and OGDC-E2. Furthermore, these antibodies were found to
recognize rabbit mitochondrial proteins by immunoblotting. These experiments provide the first evidence
that AMA may be induced by exposure to a chemical xenobiotic, leading to the
postulate that PBC may occur from chemical exposure. (Abstract 528)
Ondansetron ameliorates
fatigue. Fatigue is
commonly associated with PBC and may be related to altered serotonergic
neurotransmission. Jeremy Theal and
colleagues conducted a multicenter, double-blind, placebo-controlled study in
which 56 patients were randomized to receive either ondansetron (a selective
HT5-HT3 receptor antagonist) 4 mg t.i.d. or placebo for 4 weeks and then
crossed over for another 4 weeks of treatment.
Fatigue was assessed by the Fisk Fatigue Severity Score (FFSS). The ondansetron-treated patients had a
greater reduction of fatigue compared to patients in the placebo group (P
<0.03). No serious adverse events
were reported, and the most common side effects were headaches and
constipation. These findings suggest
ondansetron may effectively treat PBC-related fatigue. (Abstract 533)
NONALCOHOLIC
STEATOHEPATITIS (NASH)
Leptin is a marker of
liver fibrosis. High levels of leptin have been reported in
obese and diabetic subjects and in patients with alcoholic or hepatitis C
cirrhosis. Laura Alba and colleagues
assessed fasting serum levels of leptin, glucose, insulin, and c-peptide in 88
patients with NAFLD. Multivariate
analysis identified serum leptin levels >19.7 ng/mL, serum glucose levels
>13.5 uU/mL, age >45 years, diabetes mellitus, and AST/ALT ratio >1 to
be independent predictors of advanced fibrosis (stage 3-4). (Abstract 531)
Rosiglitazone therapy.
Brent Neuschwander-Tetri and associates treated 30 NASH patients with
rosiglitazone (a PPARg agonist that improves insulin
sensitivity) 4 mg b.i.d. for 48 weeks.
Insulin sensitivity was increased with rosiglitazone therapy and serial
liver biopsies revealed improvements in the grade and stage of NASH. Furthermore, hepatic steatosis was improved
as measured by CT imaging. These
preliminary results warrant further investigations of rosiglitazone treatment
for NASH. (Abstract 863)
ALCOHOL-INDUCED LIVER
INJURY
Effect of
polyenylphosphatidylcholine (PPC). PPC is a 95% pure mixture of polyunsaturated
phosphatidylcholine extracted from soybeans that has been shown to prevent the
progression of alcohol-induced liver fibrosis in non-human primates. Charles Lieber and colleagues in the VA
Cooperative Studies Program randomized 789 patients with alcoholic liver
disease in a multicenter study to receive either daily PPC (1.5 gm) or placebo
for 4-6 years. Counseling successfully
caused most patients to markedly reduce their alcohol intake, resulting in a
slowing of the progression of liver fibrosis.
PPC had little effect in this population; however, in the subgroup of
patients that continued to consume ³ 6 drinks/day, there was a trend in
favor PPC therapy in terms of progression of fibrosis as assessed by the
semi-quantitative scoring system, change from baseline for ALT, AST, and
bilirubin (p<0.05), and the occurrence of ascites. This study demonstrates that a sustained
marked decrease of alcohol intake slows the progression of liver fibrosis and
that PPC may alleviate some manifestations of liver disease. (Abstract 874)
LIVER FAILURE
Molecular adsorbents
recirculating system (MARS) therapy. Christian Steiner
and Steffen Mitzner (University of Rostock) reported the results of a
retrospective analysis of extracorporeal liver support using MARS therapy for
202 patients with liver failure (acute-on-chronic liver failure [AoCLF]; acute
liver failure [ALF]; primary graft dysfunction [PGD]; liver failure post liver
surgery; and misc.). AoCLF patients were
observed to have a decrease of hepatic encephalopathy grade, an increase in
mean arterial pressure, and improved biochemical parameters. The hospital survival of ALF patients was
61%, and 56% of PGD patients recovered without retransplantation. These findings indicate that MARS therapy is
effective treatment for patients with liver failure. (Abstract 16)
Prognostic factors for progression to deep hepatic
encephalopathy (HE). An analysis of 170 ALF patients with grade
1,2 HE at baseline by Javier Vaquero and colleagues of the ALF Study Group
showed that survival was poorer for patients who progressed to grade 3,4 HE
(69.7% vs. 26.8%). Multivariate analysis determined that baseline AST in the
non-acetaminophen group and early infection in the acetaminophen group were the
most important variables to predict progression of HE. (Abstract 221)
HEREDITARY
HEMOCHROMATOSIS (HH)
C282Y homozygous
relatives. Lawrie Powell and colleagues analyzed the
expression of HH in 371 C282Y homozygous first or second degree relatives of
patients with classical HFE-associated HH.
All subjects were of European descent, the most common symptom was arthralgia
(14.5%), and abnormal LFTs were present in 17.7% of patients. Of 183 evaluable
patients, 84 males (43%) and 44 females (25%) were found to have grade 3 or 4
iron stores at liver biopsy. Hepatic
fibrosis was identified in 52 (14%) patients and cirrhosis in 11 (3%)
patients. These data demonstrate that
the screening of relatives of patients with HFE-associated HH remains an
important strategy. (Abstract 577)
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