HEPATOLOGY WATCH®
Timely
Information for Practicing Physicians
highlights of the 52nd
annual meeting of
the american association for the
study of liver diseases
November 9-13, 2001
HEPATOLOGY, VOLUME
34, 2001
Treatment of Chronic Hepatitis C (CHC) WITH
INTERFERON (IFN)-BASED THERAPY
Tarek Hassanein and
colleagues assessed quality of life (QOL) using two validated instruments, the
SF-36 Health Survey and the Fatigue Severity Scale (FSS), in patients with CHC
receiving antiviral therapy in a large international trial. During 48 weeks of therapy, patients treated
with peginterferon alfa-2a, with or without ribavirin, reported better QOL and
less fatigue on all domains of the SF-36 and FSS compared to those patients
treated with IFN alfa-2b plus ribavirin.
These findings indicate that the lower rates of side effects associated
with peginterferon alfa-2a and ribavirin combination therapy result in less
health-related interference of normal activities (Abstract 280). CHC patients who achieved a sustained
virological response after treatment with IFN alfa-2b plus ribavirin or IFN
alfa-2b alone in 4 large multicenter trials have been followed for 4 years, and
John McHutchison and coworkers report that relapse was rare, i.e., only 10 of
395 patients who had remained HCV RNA negative 6 months after the end of
therapy (Abstract 281). Thierry Poynard
and associates pooled data from 4 randomized trials to assess the histological
impact of various IFN and peginterferon alfa-2b plus ribavirin treatment
regimens. In general, the fibrosis
progression rate was reduced by all treatment regimens, and reversal of
cirrhosis was found in 75 of 153 patients (49%). Compared with IFN alone, peginterferon alfa-2b and ribavirin was
associated with greater improvement of the necrosis and inflammatory score and
less frequent worsening of the fibrosis score (Abstract 282).
TREATMENT OF CHRONIC HEPATITIS B
(CHB)
Lamivudine. Nancy Leung
and colleagues studied the durability of HBeAg seroconversion induced by
lamivudine treatment during the Asian Lamivudine Study. After a median follow-up of 19.6 months, the
HBeAg response was maintained in 83% (30/36) of patients (including 5 patients
with YMDD variant HBV). These data
suggest that lamivudine-induced HBeAg seroconversion is generally stable and
that HBeAg seroconversion is an appropriate stopping point for therapy
(Abstract 705). Nancy Leung and
colleagues also reviewed liver biopsy results obtained from the same
study. Of 62 patients with evaluable
liver biopsies at 3 yearly time points, 27 had no lamivudine-resistant
mutations (YMDDm), 16 had YMDDm for <1 year, 14 had YMDDm for 1-2 years, and
5 had YMDDm for 2-3 years. Knodell
necroinflammatory scores and Ishak fibrosis scores were found to worsen over
the 3 years in biopsies from patients with YMDDm. These data show that, despite continued lamivudine therapy, the
liver histology of Chinese patients harboring YMDDm deteriorated (Abstract
706). A 12-month double-blind study
(n=286) showed that children (aged 2-17 years) with CHB treated with lamivudine,
compared to those given placebo, had higher rates of complete viral response
(loss of HBeAg and undetectable HBV DNA).
Maureen Jonas et al report a 6-month interim analysis of a planned
24-month follow-on study, which reveals that an additional 10% of
HBeAg-positive patients treated previously with lamivudine have achieved a
complete viral response and that 83% of lamivudine-induced HBeAg-negative
children have maintained a complete viral responses. The cumulative incidence of YMDD variant HBV has increased from
19% at 12 months to 33% at 18 months.
These interim results demonstrate that further viral responses were
attained with additional lamivudine therapy and that lamivudine-induced
complete viral responses were durable (Abstract 707).
Adefovir dipivoxil
(ADV). ADV is a nucleotide analogue with potent activity against
wild-type and lamivudine-resistant HBV.
Patrick Marcellin and coworkers conducted a double-blind study in which
515 HBeAg-positive patients were randomized to receive ADV 10 mg daily, ADV 30
mg daily, or placebo for 48 weeks.
Forty-seven (9%) patients discontinued therapy prior to 48 weeks, and
the most frequently reported adverse events were pharyngitis (32%), headache
(25%), asthenia (25%), abdominal pain (21%), and flu syndrome (19%). Safety was excellent with the 10 mg
dose. HBeAg seroconversion rates were
12% in the ADV treatment groups vs 6% in the placebo group. Histological analysis showed that 53% in the
ADV groups had more than 2-point improvement in inflammation vs 25% with
placebo, and fibrosis improved in 41% vs 25% (Abstract 674). Robert Perrillo and associates performed a
phase II study in which ADV 10 mg/day was added to ongoing lamivudine therapy
in 40 CHB patients with hepatic decompensation and YMDD variant HBV. Serum HBV DNA was significantly reduced, and
serum ALT, bilirubin and albumin normalization occurred in 41%, 62%, and 40% of
patients, respectively (Abstract 708).
Entecavir. Entecavir is
a guanosine nucleoside analogue that demonstrates in vitro activity against lamivudine-resistant HBV. Nikolas Tassopoulos et al conducted a study
in which 181 CHB patients who remained viremic after 24 weeks of lamivudine
therapy were randomized to receive one of 3 doses of entecavir (0.1, 0.5, or 1
mg daily) or to continue lamivudine 100 mg daily for up to 52 weeks. The YMDD mutation was present in 87% of
these patients. At week 24, the
percentage of patients with undetectable HBV DNA was 19%, 53%, 79%, and 13% in
the entecavir 0.1, 0.5, 1 mg, and lamivudine treatment groups,
respectively. The mean log decrease in
HBV DNA with all 3 doses of entecavir was greater than that with lamivudine,
and the safety profile of entecavir was similar to that of lamivudine (Abstract
673).
Emtricitabine (FTC). FTC is a
cytosine nucleoside analogue with potent antiviral activity against HBV and
HIV. Nancy Leung and colleagues
performed a dose-ranging double-blind study in which 98 CHB patients with
detectable HBV DNA were randomized to one of 3 daily doses of FTC (25, 100, and
200 mg) for 48 weeks of therapy. At 1
year, the proportion of patients with undetectable HBV DNA was 38%, 42%, and
61% for the 25, 100, and 200 mg FTC dose groups. Patients in the 200 mg dose group also had the lowest percentage
of patients with evidence of genotype changes associated with resistance. All 3 FTC doses were well tolerated
(Abstract 709). The most common variant
form of CHB is HBeAg-negative/HBV DNA-positive hepatitis. Chia Wang and associates analyzed the
effectiveness of FTC treatment in a subpopulation of HBeAg-negative CHB patients
accrued to the FTC dose-ranging study.
Sixteen of 21 (76%) HBeAg-negative patients achieved undetectable HBV
DNA levels at 1 year, and all patients treated with 200 mg/day of FTC had
undetectable viremia. These findings
suggest that FTC is a potentially efficacious agent for patients with
HBeAg-negative CHB (Abstract 604).
PBC/PSC
S.A.
Long et al discuss an etiologic model whereby environmental organic compounds
(xenobiotics) may cause primary biliary cirrhosis (PBC) by altering native
self-proteins sufficiently to induce an immune response. To support their hypothesis they altered the
inner lipoyl domain of PDC-E2 with 18 different synthetic structures and
identified 3 organic modified epitopes that exhibited strong reactivity to
purified antisera to PDC-E2. This
reactivity was found only in patients with PBC, and structural analyses
determined that many chemicals in common usage have the potential to cause
these changes to PDC-E2. These
observations support a possible environmental cause for PBC (Abstract
677). Claudia Zein and colleagues
evaluated data from 131 patients with a positive antimitochondrial antibody
(AMA) and a histological diagnosis compatible with PBC. They concluded that liver biopsy is not
necessary to establish the diagnosis of PBC in patients with positive AMA,
cholestatic biochemical profile, and no other features suggestive of other
liver diseases (Abstract 686). Primary
sclerosing cholangitis (PSC) is commonly associated with ulcerative colitits
(UC). Because UDP-glucuronosyltransferases
(UGT) detoxify a broad range of xenobiotics that induce mucosal inflammation
and polymorphisms of the UGT1A7 gene have been shown to express products with
reduced activity, Arndt Vogel and coworkers analyzed the presence of UGT1A7
polymorphisms in 70 controls, 56 PSC patients with (n=27) and without (n=29)
UC, and 31 UC patients. These results
indicate that PSC with UC and UC without PSC are distinguishable by UGT1A7
polymorphism analysis and suggest a possible etiologic role for UGT1A7 in PSC
(Abstract 270). Kirsten Boberg et al
reviewed data from 394 PSC patients with a median follow-up of 4.7 years. Forty-eight (12.2%) of these patients
had developed cholangiocarcinoma (CC), which was diagnosed within a year of the
diagnosis of PSC in 24 (50%) patients and during an intended liver
transplantation procedure in 13 (27%) patients. The prevalence of inflammatory bowel disease (IBD) was similar in
patients with or without CC. However,
the duration of IBD until the diagnosis of PSC was longer in patients who
developed CC (median of 17.4 versus 9.0 years). This clinical data review indicates that the duration of IBD is a
risk factor for the development of CC in patients with PSC (Abstract 733).
Liver Transplantation
Robert Brown and coworkers sent questionnaires to the
directors of all 122 UNOS-approved liver transplant programs in the US, and
questionnaires were returned by 83 programs. Adult-to-adult living donor liver
transplantation (LDLT) was being performed in 42 programs, and another 32
programs were planning to begin LDLTs within 12 months. Centers that performed LDLT procedures were
likely to also perform pediatric cadaveric or living donor transplants. Thirteen centers accounted for 80% of all
the LDLTs performed by the 42 programs and these centers were the only programs
that had performed more than 10 procedures. The number of procedures performed
by each of the 42 programs ranged from 1 to 71. Donor adverse events included biliary complications that resulted
in medical intervention (6%), reoperation (5%), and a single death (0.2%). These data indicate that LDLTs are performed
in approximately half of the liver transplant centers in the US but that most
programs have done only a few procedures. Biliary complications are common and
donor mortality is low (Abstract 245). Kris Kowdley and colleagues reviewed data collected from 15
liver transplant centers participating in the National Hemochromatosis
Transplant Registry (NHTR). Survival
data was available for 213 patients who underwent liver transplantation and
were found to have iron overload in the explant liver. One- and 3-year survival rates were
decreased among C282Y+/+ and compound heterozygous (C282Y and H63D mutations)
patients compared to patients having iron overload with other HFE
genotypes. There was also a trend
towards decreased survival for patients with a hepatic iron index >1.9
(Abstract 250). Humberto Soriano et al
conducted a multicenter pediatric study in which 7 children with liver failure
received 30 hepatocyte transplantations (HTX).
Few hepatocyte infusion-related complications occurred. Engraftment was detected in 4 of 5 patients
receiving immunosuppressive therapy.
Four of the last 5 children treated with HTX recovered spontaneously or
were bridged to transplantation. The
earliest effect of HTX in these 4 children was improvement of
encephalopathy. This trial has
demonstrated the safety and feasibility of HTX for children with liver failure
(Abstract 306).
LIVER
BIOPSY MONITORING DURING METHOTREXATE THERAPY
Guruprasad Aithal and associates reviewed 121 liver
biopsies performed during 1970-2000 in 69 patients who were being treated with
low-dose methotrexate for psoriasis. The mean cumulative dose was 3,768 ± 452 mg and the mean follow-up period was 340 ± 38 weeks.
Overall 11% of biopsies showed progression of fibrosis and the
cumulative probability of finding advanced fibrosis was 0%, 1.5%, 1.5%, 5.2%,
and 11% at cumulative doses of 1,500, 3,000, 4,500, 5,000, and 6,000 mg,
respectively. No patient developed
cirrhosis, and methotrexate was not discontinued due to liver biopsy findings
in any patient. This study shows that
the frequency of advanced fibrosis associated with low-dose methotrexate
therapy was less than previously reported and monitoring liver biopsies had
little impact on the management of these patients. (Abstract 682)
Correction
Abdelmalek et al, November issue: the correct dose
of betaine (Cystadane) is 10 gm bid (not
10 mg as printed).
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