HEPATOLOGY WATCH®
Timely
Information for Practicing Physicians
highlights from the 51st annual meeting of
the American association for the study of liver
diseases
October 27-31, 2000
HEPATOLOGY, VOLUME 32, 2000
Primary
Biliary cirrhosis (PBC)
New Clinical Observations. Investigations by Angela Cheung et al.
(abstract 41) and Enrico Souto et al. (abstract 42) report data concerning
clinical complications associated with PBC that have not previously been well
defined. Cheung et al. found that
>80% of patients with PBC (n=162) have evidence of either osteopenia or osteoporosis
and that no therapy (including calcium plus vitamin D supplements,
bisphosphonates, or hormone replacement therapy) improved bone mineral density
measurements. Souto et al. found that
the majority (55%) of patients with PBC (n=180) are symptomatic with
pruritus. Treatments beneficial for
pruritus control were ursodeoxycholic acid, antihistamines, cholestyramine, and
rifampin.
Is PBC an Infectious Disease? Several abstracts provide data that are
supportive of the notion that an infectious agent may have an etiologic role in
the development of PBC. Two abstracts
discuss findings that peptides derived from microbial proteins containing an
ExDK motif can cross-react with T cell epitopes in patients with PBC, i.e.,
PDC-E2 163-176 or OGDC-E2 100-113 (abstracts 25 and 38). Data indicating that cross-reactivity
between the lactase of Lactobacillus delbrueckii and human PDC-E2 is specific
for PBC was also presented (abstract 561).
One group of investigators (abstract 550) isolated an agent from patients
with PBC that has genomic and morphologic properties suggestive of an enveloped
virus. Finally, other studies provided
evidence that PBC is a generalized mucosal disease (abstract 28) and that a
similar pattern of gene expression (increased WNT pathway gene expression) is
observed in PBC-associated cirrhosis as has been seen in HCV-associated
cirrhosis (abstract 562).
Hepatocellular Carcinoma (HCC)
Screening with annual
ultrasonography was reported to result in a yearly HCC detection rate of 1.6%
in high-risk patients (cirrhosis, chronic hepatitis, chronic HCV or HBV
infection, or age >40 years) from a hepatitis endemic area (Kwang-Hyub Han
et al., abstract 178). Data was also
provided suggesting that thrombocytopenia (platelet count <60,000/mm3)
in patients with chronic hepatitis or cirrhosis is predictive of an increased
incidence of HCC (S. Obi and Y. Shiratori, abstract 297). In addition, Shiratori et al. (abstract 174)
provided data on a specific population (n=74) of patients with low tumor burden
(<3 HCC liver lesions) and low HCV RNA load (<2 x 106
copies/ml) who had previously received interferon (IFN) therapy for chronic HCV
infection. Tumor ablation was
accomplished in these patients by percutaneous ethanol injection. The results among sustained responders to
IFN plus ablation (83% 5 yr-survival rate) were comparable to that of liver
transplantation.
chronic hepatitis
Histology Can Improve. Data was presented showing that histological
improvement occurs in chronic hepatitis after various treatment responses. In patients with chronic HCV infection,
treatment with pegylated interferon alfa-2a was associated with histological
responses in a greater proportion than patients receiving standard IFN alfa-2a
(P=0.001) (abstract 246). In addition,
improvement of fibrosis occurs even in patients who had relapsed after, or had
not responded to, pegylated IFN alfa-2b (13% and 16%, respectively) (abstract
804). Nonresponders were also seen to
benefit from antiviral therapy in another study (abstract 205) that analyzed
long-term follow-up of asymptomatic HCV patients and showed that disease
progression was slowed. In this study,
age and ALT level at baseline were prognostic indicators. A retrospective analysis of HCV patients
(n=109) also revealed that therapy with IFN might allow complete regression of
cirrhosis in a small percentage (8.2%) of patients (abstract 805). In another study (n=255) of histological
findings in chronic HCV patients (abstract 421), the presence of steatosis was
shown to be associated with increased histological activity and fibrosis. In patients with chronic HBV infection,
lamivudine therapy was found to result in histological improvements in
cirrhosis (64%) and bridging fibrosis (51%) (abstract 546) and to result in a
decrease in markers of fibrogenesis (abstract 870).
Posttransplant HCV Reinfection.
HCV reinfection following liver
transplantation is frequent, and therapy with IFN alone is ineffective. Two pilot studies of combination IFN plus
ribavirin therapy in liver transplant recipients with recurrent hepatitis C
were reported. In the first trial, IFN
plus ribavirin treatment (n=49) resulted in a loss of serum HCV RNA in 25% of
patients (abstract 221). In the second
trial, 28 of 52 patients were randomized to receive IFN plus ribavirin, and 21%
achieved a sustained virological response (compared to no responses in the 24
patients in the untreated control group; p=0.019) (abstract 542). However, adverse events (primarily anemia)
caused 43% of patients to stop treatment.
HCV and diabetes mellitus. Charles Beymer and coworkers reviewed the
anti-HCV status of 16,529 persons utilizing the NHANES III database. Diabetic and non-diabetic subjects were
similar with regard to anti-HCV prevalence.
In addition, no association was seen between measurements of glycemia
and anti-HCV status. In contrast to the
results of some prior studies, no association between HCV infection and the
development of type 2 diabetes mellitus was found (abstract 616).
HCV and pregnancy. Helene Fontaine
and colleagues analyzed histological samples from 12 women who were anti-HCV
positive, untreated, and had a pregnancy between 2 sequential liver
biopsies. Increases in the
necroinflammatory score and the yearly activity progression rate were greater
in these women compared to 12 age-matched controls without pregnancy (P = 0.007
and 0.001, respectively). These
findings suggest that pregnancy may worsen HCV-related hepatitis (abstract
467).
HCV and weight reduction.
Andrew Clouston and associates treated 7 patients with chronic HCV
infection with a calorie-controlled diet and daily exercise for 12 weeks. This
regimen resulted in a mean weight loss of 8.8 kg. Steatosis, necro-inflammatory activity, and fibrosis were all
found to improve histologically, and a progressive reduction in ALT occurred in
6 of 7 patients. These results
demonstrate the need for further studies to assess weight loss as an ancillary
approach to the management of patients with chronic hepatitis C (abstract 593).
Satellite Symposium on Pegylated interferons
An update was provided on the
current status of clinical studies of pegylated interferons for the treatment
of chronic hepatitis C as well as background data on pharmacokinetics of these
products and the viral kinetics of HCV.
Two pegylated interferons are currently in clinical trials: pegylated
IFN a-2b
(PEG-Intron; Schering) is characterized by the attachment of a 12-kilodalton
(kDa) linear polyethylene glycol (PEG) molecule to IFN a-2b;
pegylated IFN a-2a
(Pegasys; Roche) is formed by covalent attachment of a branched 40-kDa PEG
moiety to IFN a-2a. With improved insight into HCV kinetics, it
is possible to further define categories of virologic response to antiviral
therapy: nonresponders and relapsers, flat partial responders, slow partial
responders, and rapid virologic responders.
The rapidity of decline of serum HCV RNA during the first 4 weeks of
therapy may be a better predictor of response to therapy than baseline viral load. As reviewed by Dr. Paul Pockros (Scripps
Clinic), a sustained virologic response rate of 39% was reported in
treatment-naïve patients by Zeuzem et al. with Pegasys compared to 19% with
interferon alfa-2a monotherapy (J
Hepatol 2000;32[suppl 2]:29).
The adverse events and laboratory abnormalities associated with
pegylated IFN were similar to those seen with standard IFN therapy and less
than those seen with combination therapy (IFN plus ribavirin) (Reddy et al.,
2000). In a trial comparing PEG-Intron
1.0 mg/kg
compared to standard IFN a-2b,
sustained viral response rates were 25% and 12%, respectively, as reported by
Trepo et al. (J Hepatol
2000;32[suppl 2]:29).
Treatment of chronic hepatitis C
with combination pegylated interferon and ribavirin is under study. In an open-label pilot study of 20 patients
receiving 48 weeks of treatment with Pegasys 180 mg weekly plus ribavirin 1,000 mg to 1,200 mg daily,
sustained virological rates were 65% overall, and 38% for genotype 1 and 100%
for genotype non-1 (Sulkowski M et al. Hepatology
1999;30:197A). Manns and colleagues in
a large multicenter study reported a sustained response rate of 54% in patients
receiving combination PEG-Intron and ribavirin, with a sustained response rate
of 42% for genotype 1 patients. The
control group treated with standard Rebetron® has a sustained response rate of
47%, with 33% for genotype 1. Analysis
of the Pegasys database by Lee (reported at this year’s AASLD) identified
additional predictors of sustained response other than non-1 genotype, lower
viral load, absence of cirrhosis and lower body weight: ALT elevated more than
3 times the upper limit of normal, hepatic activity index more than 10 and or a
2 log10 decrease of HCV RNA from baseline at week 12 of therapy.
The impact of therapy on quality of life (QOL) was reviewed by Dr. David
Bernstein. As reported by Perrillo at
this year’s AASLD meeting, work productivity was less impaired by Pegasys
therapy, with only 3.3% of time missed from work compared to 19.1% with Rebetron
therapy. Rasenack reported that QOL was
also less impaired in patients receiving Pegasys during therapy compared to
interferon monotherapy. In a 72-week
multinational trial with patients (n=264) randomized to either Pegasys 180 mg weekly or IFN a-2a 6 MIU tiw for
12 weeks followed by 3 MIU tiw for 36 weeks, QOL and fatigue were assessed
using a standardized 36-question short form health survey (SF-36) and a fatigue
severity scale (FSS). Measurements obtained at weeks 2 and 12 of treatment
demonstrated that compared with the control group, patients in the Pegasys
group had statistically better QOL scores in 7 of 8 domains and in both summary
assessments of the SF-36 (mental and physical). Patients in the Pegasys group also had lower FSS scores relative
to their standard IFN counterparts (P<0.05). This study suggested that early in the course of treatment,
Pegasys therapy might be associated with enhanced QOL and less fatigue.
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