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 HEPATOLOGY WATCH®
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Editorial Board:
Emmet B. Keeffe, MD (Chair); M.
Eric Gershwin, MD; Ira
S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD; Paul Martin,
MD; Marion G. Peters, MD
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JUNE 2004
CHRONIC HEPATITIS C VIRUS (HCV)
INFECTION
Peginterferon alfa-2a and ribavirin
treatment of nonresponders. Mitchell
Shiffman and colleagues report results from the first
604 patients enrolled into the Hepatitis C Antiviral Long-Term Treatment against
Cirrhosis (HALT-C) trial. At entry
patients were HCV RNA positive, had not responded to interferon-based therapy,
and had bridging fibrosis or cirrhosis on liver biopsy. Patients were treated with peginterferon
alfa-2a 180 ug/wk plus ribavirin 1,000-1,200 mg/d. At wk 20, 35% of patients did not have
detectable serum HCV RNA and thus continued treatment for a total of 48
wk. Eighteen percent of patients had a
sustained virological response (SVR) 24 wk after the completion of 48 wk of
therapy. Factors associated with an SVR
were: 1) previous treatment with interferon monotherapy; 2) infection with
genotypes 2 or 3; 3) lower AST/ALT ratio; and 4) absence of cirrhosis. Reducing the dose of ribavirin to £60% of the
starting dose during the first 20 wk of therapy was associated with a reduced
SVR (21% vs. 11%). This study
demonstrated that therapy with peginterferon alfa-2a plus ribavirin can induce SVR
in 18% of patients who did not respond to previous interferon-based
therapies. (Shiffman ML, et al. Gastroenterology 2004;126:1015-1023)
DRUG-INDUCED LIVER INJURY
Risk of statin hepatotoxicity in
patients with elevated liver enzymes. Rare
instances of marked hepatotoxicity from statins have been reported. Although data are lacking, the third report
of the National Cholesterol Education Program (NCEP) stated that the use of
statins are contraindicated in patients with active liver disease. In order to test the hypothesis that patients
with elevated baseline liver enzymes have a higher risk of statin-induced
hepatotoxicity, Naga Chalasani and colleagues analyzed demographic, clinical,
laboratory, and prescription data on patients from 3 hospitals and 30 clinics
in the Indianapolis area. Three cohorts
of patients seen between January 1998 and June 2002 were studied: Cohort 1 =
342 hyperlipidemic patients with elevated baseline serum aminotransferase
levels who were prescribed a statin; Cohort 2 = 1,437 hyperlipidemic patients
with normal baseline aminotransferase levels who were prescribed a statin; and
Cohort 3 = 2,245 patients with elevated aminotransferase levels who did not
receive a statin. Cohort 2 subjects had
a lower incidence of mild-moderate elevation of aminotransferase levels from
baseline compared to Cohort 1 subjects (1.9% vs. 4.7%), while the incidence of
severe elevations was similar in both groups.
However, between Cohorts 1 and 3, there were no differences in the
incidence of mild-moderate or severe elevation of aminotransferase levels. The incidence of statin discontinuation was similar
between Cohorts 1 and 2. These findings
indicate that patients with elevated baseline liver enzyme levels are not at an
increased risk for hepatotoxicity from statins.
An accompanying editorial by Mark Russo and Paul Watkins stressed the
importance of the inclusion of Cohort 3 as a control group and note the
establishment of a Drug Induced Liver Injury Network to facilitate progress in
drug-induced hepatotoxicity research.
(Chalsani N, et al. Gastroenterology
2004;126:1287-1292; and Russo M, Watkins PB. Gastroenterology 2004;126:1477-1479)
PRIMARY BILIARY CIRRHOSIS (PBC)
Treatment with ursodeoxycholic acid
(UDCA). UDCA
therapy was not found to significantly impact clinical outcomes in recently
reported studies of PBC therapy. In the
first study, Burton Combes and coworkers analyzed data from an extended
follow-up of patients from a US
multicenter, double-blind study of UDCA therapy. Originally 151 patients with PBC had been
randomized to receive UDCA or placebo, and the proportions of patients who
progressed to liver transplantation or death without liver transplantation were
similar in both treatment groups. All
patients remaining on study were then offered open-label UDCA. Among 61 original UDCA-treated patients and
56 original placebo-treated patients who crossed over to UDCA therapy, no
differences were seen after a follow-up of up to 6 years in the number of
patients who underwent liver transplantation or died without liver
transplantation. In a second report, J.
Talwalkar et al. evaluated outcomes of pruritus from 2 clinical trials of UDCA
therapy in PBC patients. In one trial a
55% prevalence rate for pruritus was observed, and in the second study more
than a third of the PBC patients developed pruritus. In both studies serum alkaline phosphatase
level and Mayo risk score were identified as independent risk factors for
pruritus. No significant risk reduction
in developing pruritus with UDCA therapy was observed compared to
placebo-treated patients in either trial.
Additionally, Marshall Kaplan and colleagues randomized 85 PBC patients
who were not yet candidates for liver transplantation to receive colchicine or
methotrexate in a double-blind study.
UDCA was administered to all patients after 2 years. Patients were followed for up to 10 years or
until treatment failure. Transplant-free
survival was not improved beyond that predicted by the Mayo prognostic model in
either treatment group. However,
improvements in liver biochemical tests and histology were seen in patients in
both treatment arms who remained in the study for all 10 years. These findings suggest that UDCA therapy does
not affect clinical outcomes in patients with PBC. In an editorial, Raoul Poupon emphasized that
while the study by Kaplan et al showed a negative result, there were 29
patients that remained on study for 10 years and had baseline and 10-year liver
biopsies. No patient with a baseline
histological stage of I to III progressed to cirrhosis and there was an
improvement in serum bilirubin levels in these patients. Dr. Poupon argued that this result was
unlikely to have occurred by chance and argued that methotrexate may provide
benefit in a subset of selected patients with early-stage disease. He concluded that UDCA should be given early
in the natural history of PBC and that well-designed studies with appropriate
sample sizes are needed for future investigations. (Combes B, et al. Am J Gastroenterol 2004;99:264-268; Talwalkar JA, et al. Clin Gastroenterol Hepatol
2003;1:297-302; Kaplan MM, et al. Hepatology
2004;39:915-923)
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