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American
Association for the Study of Liver Diseases 50th
Annual Meeting
Steven K. Herrine, MD
Introduction
Hepatitis C, its pathogenesis,
natural history, and approaches to treatment were
certainly a focal point of this year's meeting of the
American Association for the Study of Liver Diseases
in Dallas, Texas. Many of the seminal presentations
concerning this virus and its clinical sequelae will
be reviewed throughout the remainder of this meeting
coverage. This summary will specifically review data
presented on a variety of controversial areas in the
world of clinical Hepatitis C Virus.
Hepatitis C Virus/HIV
Coinfection
Background: Improved
therapies and subsequent survival of patients infected
with HIV have changed the approach to patients
coinfected with HIV and hepatitis C virus (Hepatitis C Virus). The
overall incidence of Hepatitis C Virus in patients infected with HIV
is approximately 8%. [1]
Progression to cirrhosis has been
reported to be more common and more rapid in this
patient population than in those infected with Hepatitis C Virus
alone. [2] In
addition to more rapid progression of liver disease,
the clinical progression of HIV disease appears to be
higher in those coinfected with Hepatitis C Virus. [3,4]
Hepatitis C Virus treatment success rates are lower in
these coinfected patients than in patients infected
with Hepatitis C Virus alone, especially in those with lower CD4
counts. Furthermore, significant decreases in CD4
counts have been noted during interferon (IFN) therapy
in coinfected patients. [5]
Treatment
of Patients With Coinfection
Much of the research presented at
this year's meeting concerned the treatment of
patients coinfected with Hepatitis C Virus and HIV. Sauleda and
colleagues from Barcelona reported a 50% virologic
response at 6 months of combination IFN/ribavirin (RBV)
therapy in 19 coinfected hemophiliacs. No worsening of
CD4 count was seen in patients receiving highly active
antiretroviral therapy (HAART). [6]
Another group from Barcelona reported a
virologic sustained response in 11.6% of 43 coinfected
patients treated with IFN monotherapy. [7]
Dr. Dieterich and colleagues reported
that reduction in Hepatitis C Virus RNA was more profound in
patients receiving IFN/RBV combination therapy than in
those receiving IFN monotherapy. These 24 coinfected
patients had significant fibrosis scores by biopsy.
Further data on the virologic and histologic response
of this cohort will prove very interesting. [8]
A more novel approach to therapy was
described by Dr. Schlaak and colleagues from Germany.
A small cohort of coinfected patients was given
interleukin (IL)-2, 2MU daily; a virologic response
was observed in 2/7. More work with this compound
seems indicated. [9]
Other
Topics in Hepatitis C Virus/HIV Coinfection
Other investigations in Hepatitis C Virus/HIV
coinfection included a report from Dr. Mika and
associates on the viral pharmacokinetics of Hepatitis C Virus in
HIV-infected patients. It is now well established that
during IFN treatment, two phases of Hepatitis C Virus RNA decline
are seen: there is a rapid decline shortly after IFN
administration, corresponding to clearance of free
virus, followed by a slower decline over the next
several days, which corresponds to clearance of
infected hepatocytes. In this study using IFN
alphacon-1 given daily for a 2-week induction period,
the first phase of kinetics was unchanged, but the
second phase was slowed in those patients with Hepatitis C Virus/HIV
coinfection. [10] This
change in the second phase of pharmacokinetics may
have implications in the design of further treatment
strategies, particularly in the use of pegylated
interferons. Finally, Zylberberg and associates
reported that a higher than expected rate of
antiretroviral hepatotoxicity was observed in those
HIV patients coinfected with Hepatitis C Virus versus those with HIV
infection alone. [12]
Hepatitis C Virus in
Renal Disease and Dialysis
Background: Estimates
of the prevalence of Hepatitis C Virus antibodies in patients on
hemodialysis (HD) range from 15%-48% in North America.
[12] The
incidence of Hepatitis C Virus in HD patients is on the decline,
probably due to blood product screening and tighter
infection control measures in HD units. Unlike the
non-HD population -- in part because baseline alanine
aminotransferase (ALT) levels are depressed in
patients on HD -- 50%-65% of patients with anti-Hepatitis C Virus
antibodies have normal aminotransferases. [13]
Although the natural history of Hepatitis C Virus
infection in the HD population is largely unknown,
liver failure is the cause of death in 8%-28% of
long-term renal transplant survivors. [12]
Viral load and genotype frequency in this
setting are comparable to non-HD populations.
End-of-treatment response rates (ETR) and sustained
response rates (SR) are also similar to those found in
non-HD patients when data are analyzed assuming
intention to treat. The use of ribavirin in patients
with endstage renal disease (ESRD) may be limited by
hemolytic anemia.
Epidemiology
Saab and associates emphasized
the fact that chronic hepatitis C infection continues
to represent a significant problem in the chronic HD
population. Seven dialysis centers participating in
the UCLA Hepatitis Screening Program provided data
regarding the incidence and prevalence of Hepatitis C Virus
infection. Of 1251 HD patients, 7.8% were infected
with Hepatitis C Virus using enzyme immunoassay (EIA)-III with
confirmatory RIBA-II. The incidence of Hepatitis C Virus infection
was found to be 260/100,000 patients. These data
compare to current nationwide data on Hepatitis C Virus prevalence
and incidence of 1.8% and 3/100,000, respectively. [14]
Progression
of chronic Hepatitis C Virus after renal transplantation is
suggested in a cohort study by Puoti and colleagues.
Of 430 renal transplant recipients, 112 were Hepatitis C Virus
RNA-positive (of which 49 had one or more liver
biopsies after transplant). Fifty-five percent had
mild to moderate inflammation, while 37% of these
patients had at least some fibrosis on their baseline
biopsies. Forty-eight percent of patients who had more
than one biopsy showed progression in both grade and
stage. Enrollment ALT, PCR, and immunosuppression were
not correlated with histology or progression. [15]
These findings are confirmed by
Zylberberg, who observed 28 renal transplant patients
with untreated Hepatitis C Virus who underwent at least two liver
biopsies. Fibrosis progressed significantly more
rapidly in these patients than in matched controls.
Twenty-one percent of this cohort progressed to
cirrhosis within 13 years of infection, with no
correlation to level or type of immunosuppression.
These data indicate that Hepatitis C Virus-infected patients who
have received renal transplants are at substantial
risk for fibrotic progression. [16]
Treatment
of Hepatitis C Virus in Patients With Renal Disease
Treatment of Hepatitis C Virus in patients
following renal transplant has led to a rather high
incidence of graft malfunction and even graft loss.
Degos and colleagues from France confirmed this
experience in a report of a planned study of 120
patients terminated due to side effects, including
"acute graft necrosis," myocardial
disorders, pancreatitis, neurologic/psychiatric
disorders, lymphoma, and infection. [17]
Accordingly, treatment efforts have
focused on this patient population prior to
transplantation. Angelico's group took a novel
approach by treating 10 patients on chronic HD with
intravenous beta-interferon (3MU tiw). Although
neither histologic or genotype data are provided, the
70% virologic SR at 6 months should provide the
impetus for further study. [18]
Ribavirin
in Renal Disease
Some of the most important data
arising from this meeting concerned the safety profile
of ribavirin in patients with abnormal renal function.
Dr. Glue and his colleagues presented elegant data
regarding the pharmacokinetics of ribavirin in
patients with varying levels of renal insufficiency.
Ribavirin levels were significantly increased in those
patients with renal insufficiency due to the combined
effects of higher oral bioavailability, decreased
volumes of distribution, and decreased clearance.
Furthermore, very little (<4%) of the ribavirin was
removed by hemodialysis. In a follow-up tolerability
study, most patients required dose reduction from a
starting dose of 200 mg/d of ribavirin. Based on these
data, the researchers recommended against the use of
ribavirin in patients with creatinine clearance of
< 50 mL/min. [19]
A similar experience was reported by Tan
and colleagues from The Netherlands. In a pilot study
of 5 patients on chronic HD given IFN alpha-2b (3MU
tiw) and ribavirin (200 mg/day), 2 patients had to
stop ribavirin therapy at 7 weeks due to unacceptable
hemoglobin concentrations. Dose reduction to 200 mg
tiw was not tolerated in these patients. In 2 other
patients, 200 mg tiw was tolerated, while the
remaining patient tolerated 200 mg/d. The study's
authors advised against ribavirin in HD patients. [20]
Alternative/Complementary
Therapies
Background: Many
practitioners have noted frequent use of complementary
and alternative medicine (CAM) in their patients with
chronic liver disease. Anecdotal evidence suggests
widespread use of silymarin compounds among patients
diagnosed with Hepatitis C Virus. The effects of silymarin are
assumed to be due to antioxidant and hepatoprotective
properties. Animal and in vitro studies with
silymarin have demonstrated its protective effect
against a variety of known hepatic insults, including
bile duct occlusion, hepatic ischemia, alcohol, iron,
acetaminophen, and carbon tetrachloride and phalloidin
toxin extracted from Amanita phalloides .
There are no published reports of silymarin toxicity. [21]
CAM
Leonard Seeff, MD, of the
National Institutes of Health, gave a probing review
of the status of CAM in chronic liver disease during
the annual postgraduate course. His well-attended
lecture provided a number of proposed definitions of
CAM and also addressed a recent NIH conference
designed to foster communication and understanding
between allopaths and naturopathic practitioners. The
formation of the National Center for Complementary and
Alternative Medicine (NCCAM) of the NIH, with an
operating budget of $50 million, should promote
research into these types of therapies. A lively
Meet-the-Professor Lunch with Dr. Seeff and Dr. Karen
Lindsay of the University of Southern California was
characterized by general acceptance of the further
investigation of CAM in chronic liver disease.
Prevalence
of CAM
Dr. Peyton and colleagues from
Arkansas reported on 117 patients with chronic Hepatitis C Virus.
Interview data revealed 36% of these patients were
currently taking herbal preparations. One third of
these users were doing so without the knowledge of
their physicians. The most commonly used herbs were
milk thistle, St. John's Wort, ginkgo biloba, ginseng,
and echinacea. [22]
Remarkably similar results were provided
by Jensen and coworkers from Chicago who interviewed
60 patients, all on IFN -- 87% reported taking
vitamins or supplements and 40% reported taking herbs,
most commonly milk thistle, St. John's Wort, ginseng,
and garlic extract. [23]
Dr. Berk and colleagues from Oregon
reported follow-up data on their 1996 findings, noting
an increase in herbal usage from 31% to 42%. Milk
thistle remains the most popular botanical used in
this population. Average monthly expenditure was
unchanged at $10-$30. [24]
Increasing
acceptance and use of CAM seems inevitable in the
practice of hepatology. The establishment of the NCCAM
should provide the impetus and funding to allow
further investigation of these approaches, which are
not limited to botanicals, but include use of other
such "healing systems."
Hepatitis C Virus
With Normal Transaminases
Background: It
has been estimated that at least 20% of those
individuals chronically infected with Hepatitis C Virus have
persistently normal serum aminotransferases. This
group of patients has been reported to have milder
histological activity and lower progression of
fibrosis. [25] Treatment
in this population has led to disappointing response
rates and ALT flares during IFN administration. [26]
More recent reports provide different
data: no difference in histology was observed between
patients with elevated ALT and those with persistently
normal ALT, according to Puoti and colleagues,
although 43% of these patients were infected with
genotype 2a. [27]
Natural
History of Patients With Normal ALT
The fact that patients with Hepatitis C Virus
antibodies and persistently normal ALT levels are
common is confirmed by data from the UK Hepatitis C Virus National
Register, which noted that 42.7% of patients match
this profile. [28]
Martinot-Peignoux and associates provided
valuable information on a cohort of 137 untreated
patients with Hepatitis C Virus antibodies and persistently normal
ALT. Thirty-one percent of these patients had
undetectable virus. In those patients with viremia,
liver biopsy was classified as mild in 80%. Follow-up
biopsy in a group of 18 patients (3.5 ± 1 years
later) showed moderate hepatitis in 66%, without a
change in fibrosis score. Although the number of
follow-up biopsies is insufficient to make a clear
conclusion, the observed progression in inflammation
lends credence to the theory that patients with
persistently normal ALT levels are at risk for
significant liver disease. [29]
Treatment
of Patients With Normal ALT
Dr. Jacobson and colleagues from
New York provided a preliminary report of IFN/ribavirin
combination therapy in 18 patients with persistently
normal ALT levels. In those patients for whom data
were available, 11 (61%) had a virologic response at
24 weeks. No ALT elevations were observed during
treatment. No data were provided on histology. [30]
The question of the natural history and
appropriateness of treatment of this group of patients
remains controversial. Only large controlled trials
will provide the required answers.
References
1.
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19.
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23.
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24.
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Hepatitis C Virus-related disease in the first decade of infection:
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Dallas, Texas; November 5-9, 1999. Abstract 1173.
29.
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the Study of Liver Diseases; Dallas, Texas; November
5-9, 1999. Abstract 185.
30.
Jacobson I, Lebovics E, Tobias H, et al.
Interferon alfa-2b and ribavirin in treatment-naive
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levels. Program and abstracts of the 50th Annual
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Association for the Study of Liver Diseases; Dallas,
Texas; November 5-9, 1999. Abstract 1193.
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