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The Hepatitis Report:
A Critical Review
of the Research and
Treatment of
Hepatitis C Virus (Hepatitis C Virus) and
Hepatitis & HIV
Coinfection
by Michael Marco
and Jeffrey Schouten, M.D.
Version 1.0
July 2000
Credits &
Acknowledgments
Michael Marco is
Director of Treatment Action Group's (TAG) Infections and
Oncology Project, the author of
TAG's The OI
Report, The KS Project Report, The Lymphoma Project Report,
and editor of TAG's The
Wasting Report.
He is a member of the NIH Office Of AIDS Research's
Therapeutics Research Working
Group, the
National Cancer Institute's AIDS Malignancies Working Group
and AIDS Malignancies
Consortium, the
USPHS/IDSA Prevention of Opportunistic Infections Working
Group and a consultant to the
FDA's Oncologic
Drug Advisory Committee. mikemarco@aol.com
Jeffrey Schouten,
M.D., Attorney at Law, Clinical Assistant Professor of
Surgery, University of Washington
(UW) is an HIV
primary care provider at UW's Harborview Medical Center and
Vice-Chair of Washington's
Governor's
Advisory Council on HIV/AIDS. He is also a member of the
Adult AIDS Clinical Trials Group's
(AACTG) Community
Constituency Group, Executive Committee and Scientific
Agenda Steering Committee.
Additionally, he
is a member of the NCI's AIDS Malignancy Consortium, the
Conference on Retroviruses and
Opportunistic
Infections Planning Committee, and Publications Editor for
the Seattle Treatment Education
Project (STEP).
The Treatment
Action Group (TAG) fights to find a cure for AIDS and to
ensure that all people living with HIV
receive the
necessary treatment, care, and information they need to save
their lives. TAG focuses on the
AIDS research
effort, both public and private, the drug development
process, and our nation's health care
delivery systems.
We meet with researchers, industry, and government
officials, and resort when necessary
to acts of civil
disobedience, or to acts of Congress. We strive to develop
the scientific and political expertise
needed to
transform policy. TAG is committed to working for and with
all communities affected by HIV.
Acknowledgments.
First thanks go to the board, staff, consultants,
volunteers, and donors of TAG. Special
thanks go out to
Robert Huff for line-editing of the report, to Andrea Dailey
for her forceful and exacting
copy-edits, and
to board member Lynda Dee of AIDS Action Baltimore, whose
generous gift enabled us to
print this
report. Tremendous thanks goes out to my chief clinical
editor, Marion Peters, for her many hours
of editing,
mentoring, laughter and writing the Foreword. Likewise,
thanks to Thierry Poynard for his keen
insight and
generosity in writing The Clinician's View. Thanks to Jay
Hoofnagle, Leonard Seeff, Teresa Wright
and Douglas
Dieterich for helpful instruction and going out of their way
to assist me in my research. I must
thank the many
others who allowed me to interview them or made
contributions to this project, including:
Yves Benhamou,
Clifford Brass, Megan Briggs, Massimo Colombo, Lawrence
"Bopper" Deyton, Lorna Dove,
Juan Esteban,
Judith Fradkin, Jaime Guardia, Roy "Trip" Gulick, Bart
Henderson, Joseph Hoffmann, Leslye
Johnson, Michael
Joyner, Christine Katlama, Brian Klein, David Kleiner,
Thomas Kresina, Jay Lalezari,
James Learned,
Alexandra Levine, Karen Lindsay, Anna Lok, Jules Levin,
Patrick Marcellin, Henry Masur,
Cindy Mays, Donny
Moss, Alison Murray, Chris Papas, Billy Pick, Robert
Purcell, Stephen Rossi, Mark
Sulkowski, Norah
Terrault, David Thomas, Richard Whitley, and Kevin Young.
Finally, thanks go out to David
Berry, Todd
Goodale, Kurt Fulton, Mark Harrington, Rick Leeds, Donna
Masini, and Jeffrey Rindler for their
support, guidance
and fellowship.
If you would like
more information about TAG, contact us at:
Treatment Action Group
350 Seventh Ave., Ste. #1603
New York, New York 10036
(T) 212.972.9022 / (F) 212.971.9019
Internet: http://www.treatmentactiongroup.org
First
distribution: XIII International AIDS Conference, Durban,
South Africa, 9-14 July 2000.
.....The disease generally progresses at
a snail's pace, requiring the passage of 3 to 4
decades, in most instances, to reach
recognizable serious endpoints. It therefore
represents a daunting task for the
clinical investigator, few of whom are willing to devote
their research careers to this
exhaustive form of investigation...
–LB Seeff, Hepatology 1997; 26:21S-28S.
Because of the
ageing phenomena, all [natural history] studies which do
not take into
account both the age at infection and the duration of
infection are
meaningless.
–T Poynard,
e-mail correspondence, 23 June 2000.
The patient who has a liver disease
wants (or needs) to know about the natural history of
the disorder so as to plan for the
future. The patient should be informed regarding the likely
consequences, important milestones,
major complications, and available therapies, all
given with a large measure of compassion
and sensitivity.
–WC
Maddrey, AASLD, Postgraduate Course, 1999.
Physicians and
patients must carefully weigh the risks (which are
clinically
significant in
the case of treatment with interferon alfa-2b and ribavirin),
the benefits
(moderate in this instance), and the cost (substantial in
this
instance) of any
treatment option for a disease that has emerged as an
important public
health problem.
–TJ Liang, N Engl
J Med 1999; 340:1207.
This report is dedicated to the memory
of
Michael Wright
(1953 - 1992)
&
Bill Thorne
(1963 - 1999)
Table of
Contents
Foreword
Introduction
Epidemiology, Modes of Transmission, & Risk
Factors for Hepatitis C Virus Infection
Pathogenesis, Viral Dynamics, & Immunologic
Response of Hepatitis C Virus
Natural History, Clinical Manifestations, and
Prognostic Indicators of Disease Progression & Survival
of Hepatitis C Virus Infection
Diagnosis of Hepatitis C Virus Infection
Treatment of Hepatitis C Virus Infection: The
Interferon Story
Experimental Treatments & New Areas of
Research for Hepatitis C Virus Infection
Hepatitis and HIV Coinfection
Current Opinions & Controversies in Hepatitis
C Virus Infection
Research & Policy Recommendations
Clinician's Response
Forward
by Marion Peters,
M.D.
This TAG report
on hepatitis C virus (Hepatitis C Virus) is comprehensive
and will bring you completely up to date. It runs
the gamut of
Hepatitis C Virus infection with areas of interest for the
clinician, allied health care worker and educated
patient. It
contains information about epidemiology, natural history,
diagnosis, pathogenesis and treatment. It
is certainly an
enormous task to undertake but the authors have been largely
very successful. Many of the
chapters contain
the earliest literature in the area and are current to last
month's abstracts. It may be difficult
for some of us to
read an abstract with the same conviction of fact, as
abstracts have not been peer reviewed
rigorously, nor
is all the data usually available at the time presentation.
However, in a fast moving field such
as Hepatitis C
Virus, it allows the reader to know what is "hot" and where
the field is heading. We are clearly told what
data and trials
are peer reviewed, which are confirmed by other
investigators and which appear to be "outside
the envelope" but
interesting none the less. This report is generally superbly
referenced and will be of great
value to you.
The natural
history chapter reminds us that not all patients inexorably
deteriorate to end-stage liver disease,
liver
transplantation or death. It is clear that for the large
number of years that we have been following
patients, some
clinicians see the slowest rates of progression whilst
others see Hepatitis C Virus as "the evil empire".
Patients need to
know the facts, not colored by drug company hype, or
physician preference and this report
provides these
facts. Only by knowing that not all patients progress, can
individuals patients decide whether
treatment for
them is now or in the future. The epidemiology, risk factors
and modes of transmission are well
outlined with
perhaps an overabundance of information. You can skim it or
dive in for the total immersion,
whichever is your
preference. This is an excellent chapter with clear tables,
explaining the high rate of
transmission in
IVDU patients and the low sexual transmission rate.
The diagnosis of
Hepatitis C Virus is often complex with multiple tests and
the confusion of liver biopsy evaluation. Once
again the authors
have used excellent available reviews and references to
present readable current
state-of-the-art
information. The reader must be cautioned that this area is
not well regulated and Hepatitis C Virus RNA
tests are
changing rapidly. In addition, when tests are performed in
the hospital setting or the community,
often a different
laboratory is used at different times (the pressures of
managed care). In these cases, one
cannot
extrapolate from one bDNA to another PCR or even from one
PCR to another. Therefore, it is critical
that patients and
clinicians not put excessive weight on small (less than one
log) changes. Hepatitis C Virus RNA will
change little
from patient to patient but a lot from test to test.
The area of
co-infection with HIV is the youngest in the field and is a
moving target. Large cohort studies are
lacking and
treatment trials are small in number and patient size. This
is an area that is receiving a large
amount of
attention; treatment trials are underway and more
hepatologists are becoming involved working
side-by-side with
infectious disease specialists. The role of Hepatitis C
Virus in response to HIV therapy is largely
unknown. Viral
dynamics of Hepatitis C Virus is in its infancy, compared to
that of HIV. Markers of response to Hepatitis C Virus have
included
genotype, age of acquisition, gender, viral load and amount
of fibrosis on liver biopsy. Early studies
suggest that
these may be superceded by viral dynamics: those with rapid
response to interferon therapy are
more likely to
achieve a sustained response versus those who are slow
responders. Only time will tell if this
sweeping
statement is correct.
The chapters on
experimental therapies and current treatment are excellent.
Once again we are reminded
that at best only
half of Hepatitis C Virus patients respond to current
therapies. But only half may need therapy in the
long term.
Unfortunately clinicians cannot determine which patients
will progress to fibrosis and end-stage
liver disease and
so most patients are treated especially if they have some
scarring without cirrhosis. This is
an area that
requires intensive research from clinical, epidemiological
and immunological aspects. Interferon
remains the
mainstay of therapy with pegylated IFNs providing exciting
new advances. By combining IFN to
polyethylene
glycol, IFN remains in the circulation longer and thus only
weekly dosing is required. This
results in ease
of treatment as well as an apparent higher response rate,
including a surprisingly high rate in
cirrhotics (<10%
in all studies before pegylated IFN). We may need to look
carefully at these studies when
they are
published but early reports are very encouraging. Side
effects are not much different from those of
daily dose
interferon although there may be some populations in whom
dose finding is necessary before
putting patients
on long- acting weekly IFN. Newer therapies aimed at the
virus itself have been slow in
coming but are
clearly the next line of drugs. In particular, ribozymes may
be the next "breakthrough" in this
area.
Immunomodulators have been generally less promising with the
exception of IL-10 as an anti-fibrotic.
I would recommend
this report highly to those who want to be fully informed
about the area. Those who need
full references;
those who may not have the time or inclination to gather the
oldest and the latest information;
and those who
need to delve more deeply into particular areas of this
fascinating field will find this report
useful. Many
scientists and clinicians have worked with Michael Marco to
address specific areas of their
expertise. It is
a testament to them and to Michael that he has produced this
informative but easily readable
document. Not all of the statements in this report have been
validated. You will not agree with all of them. But
you will be
stimulated to learn more and to keep abreast of new
developments after reading these all
encompassing
chapters. You may not concur with all of the TAG policy
recommendations but you will be
forced to
re-evaluate and think about many important issues
surrounding Hepatitis C Virus. Good luck and enjoy.
Marion Peters is
Professor of Medicine and Chief of Hepatology Research, at
the University of California,
San Francisco.
Introduction
by Michael Marco
Clearly the problem of Hepatitis C Virus
will require a responsible partnership of public and private
organizations....If we are to make
progress against this perplexing epidemic, careful
and disinterested voices must prevail1.
Despite the wide publicity about hepatitis C
in the media, and the numerous
educational conferences and publications in
the medical literature, and the
dissemination of the NIH consensus statement
on hepatitis C, there are significant
deficits in the knowledge of primary care
physicians regarding hepatitis C2.
My appreciation
of and desire to study hepatitis C virus (Hepatitis C Virus)
research is something new. It started off as
mere curiosity
during my research of AIDS-related opportunistic infections
(OIs) when I thought about adding
a short chapter
on Hepatitis C Virus to TAG's OI Report because it was well
know that many individuals with HIV are also
coinfected
Hepatitis C Virus. Approximately two years later, it seems
laughable that one could simply write a "short
chapter" on
Hepatitis C Virus. It has become apparent to me that there
is a need for a thorough study, review, and critical
analysis of
Hepatitis C Virus research.
Many AIDS
treatment advocates have critically analyzed the numerous
facets of HIV clinical and basic
research with
great aplomb. They have produced a wealth of
patient-readable HIV treatment information so
that people with
HIV/AIDS can become experts in understanding their virus. In
my two years of researching
Hepatitis C
Virus, I found that there were only a few Hepatitis C Virus
treatment advocates, yet none had created one text that
contained a
complete overview of the virus, analyzed the research, and
offered important and sound Hepatitis C Virus
treatment
information as well as policy recommendations to move the
field of Hepatitis C Virus research forward. Since I
have been well
trained and mentored in researching and writing such
documents on HIV-related
complications, I
felt I would initiate TAG's Hepatitis Project and write a
report on Hepatitis C Virus, as well as on hepatitis
and HIV
coinfection. People with Hepatitis C Virus deserve the same
tools as those with HIV so that they can become
experts about
their virus.
I quickly
realized that people with Hepatitis C Virus were not the
only ones who needed to become experts. I found that
many primary care
physicians lack a complete breath of knowledge of the
epidemiology and clinical
management of
Hepatitis C Virus. This was blatantly obvious in the 1999
Hepatology article, "Current Practice Patterns of
Primary Care
Physicians in the Management of Patients with Hepatitis C"
by Shehab and colleagues from
Anna Lok's group
at the University of Michigan.2 In a survey of over 400
primary care physicians from the
Detroit area, 20%
and 8%, respectively, considered blood transfusion in 1994
and casual household contact
as significant
risk factors for Hepatitis C Virus; 43% overestimated the
likelihood of a sustained response to a course of
interferon
therapy, while 29% had no idea what the sustained response
rate was; 38% would not a refer an
Hepatitis C Virus
antibody-positive patient to a gastroenterologist even
though they had no experience in treating Hepatitis C Virus
patients on their
own. Another study by Villano and colleagues from Johns
Hopkins found that a majority of
the
intravenous-drug-using patients in their natural history
cohort tested Hepatitis C Virus antibody-positive their
first time
on study yet were
under the care of clinic or primary care physicians.3 This
striking lack of awareness by
health care
providers about Hepatitis C Virus epidemiology, risk
factors, and clinical management is unacceptable. Let us
hope that this
report gets into the hands of the physicians and patients
who need it.
I also wrote the
report in an attempt to quell the mass hysteria about
Hepatitis C Virus created by major weekly news
magazines as well
as by the obnoxious "get tested, get treated" Hepatitis C
Virus advertising campaign of a greedy
pharmaceutical
company. The push to immediately treat everyone who tests
positive for Hepatitis C Virus made my blood
boil, because
that is often the same message given to those who initially
test positive for HIV. For HIV, we
have only
clinical endpoint studies documenting a survival advantage
to starting potent, combination
antiretroviral
therapy before a patient's CD4 count drops below 200
cell/m3, yet with both viruses, we still
have not fully
answered the question, When should one initiate antiviral
therapy? (i.e., "When to start?").
This Hepatitis C
Virus report attempts to answer that question and documents
what we know and what we don't know
about the
epidemiology, natural history, diagnosis, and treatment of
Hepatitis C Virus. After an exhaustive analysis of
peer-reviewed
articles, over 40 researchers, clinicians, primary care
physicians, government heath
administrators,
industry representatives, and patients with viral hepatitis
were interviewed. Research and
treatment policy
recommendations have been issued and will need to be
implemented in order to carefully
find answers to
the many basic and clinical science questions in Hepatitis C
Virus research.
This large
report–which will grow still larger in version 2.0 to
include an analysis of the research and
treatment of
hepatitis viruses A and B (HAV and HBV)–is a collaborative
effort. Jeffrey Schouten was a great
partner who
worked with me over these two years, and he wrote selected
Hepatitis C Virus chapters and the section on
hepatitis and HIV
coinfection. Expert hepatitis researchers, including Marion
Peters, Thierry Poynard, Teresa
Wright, Jay
Hoofnagle, Leonard Seeff, and Douglas Dieterich went out of
their way in varying capacities to
help me, an AIDS
treatment advocate they had never met.
More
collaborative and concentrated efforts on the part of
industry, physicians, government, and the hepatitis
community alike
are needed if we are to effectively challenge, overcome, and
cure Hepatitis C Virus.
1 The Lancet.
Making sense of hepatitis [editorial]. Lancet 352:1485,
1998.
2 Shehab T,
Sonnad SS, Jeffries M, et al. Current practice patters of
primary care physicians in the management of patients with
hepatitis C.
Hepatology 30:794-800, 1999.
3 Villano SA,
Vlahov D, Nelson KE, et al. Persistence of viremia and the
importance of long-term follow-up after acute hepatitis C
infection.
Hepatology 29:908-14, 1999.
Epidemiology,
Modes of Transmission,
& Risk Factors
for Hepatitis C Virus (Hepatitis C Virus) Infection
by Michael Marco
My opinion is that we just can't tell for
sure about some of this because we are bad at
measuring human behavior.
——Davis
Thomas, e-mail correspondence
Background
During the 1970s
and 1980s, no one knew what was causing hepatitis in certain
individuals who had received
blood
transfusions. Screening tests for hepatitis A (HAV) and
hepatitis B (HBV) in the mid-1970s revealed
that about 25% of
these cases of transfusion-associated hepatitis (TAH) were
linked to hepatitis B but no
hepatitis A. The
remaining 75% of TAH cases, by default, were termed
non-A-non-B hepatitis (NANBH) (H.
Alter 1999). Ten
to twenty percent of individuals who had received multiple
blood transfusions (or used
plasma products)
developed NANBH, with a relative risk of 0.45% per unit
transfused (Donahue 1992).
Because primary
infection was usually asymptomatic or, at worst, mild,
clinicians did not initially consider
NANBH to be a
very serious disease. It was soon recognized, however, that
the seemingly benign NANBH
could develop
into a chronic hepatitis with markedly elevated liver
enzymes. Sometimes the hepatitis
resulted in
cirrhosis.
According to the
National Institutes of Health’s (NIH) Harvey Alter,
attitudes to NANBH changed in the late
1980s:
The NANBH agent remained a virologic
enigma....until researchers at the Chiron Corporation
used an ambitious molecular approach on large
volumes of high-titer infectious chimpanzee
plasma from the Centers for Disease Control
and Prevention (CDC). They extracted RNA,
cloned it into an expression vector, and
screened the expressed product with presumed
immune sera. A single positive clone was
found in the millions screened, and, within a year,
the entire genome was sequenced and the agent
was identified as a novel flavivirus the
hepatitis C virus (Hepatitis C Virus). (HJ Alter 1999).
In 1988 Choo and
colleagues characterized the hepatitis C virus (Hepatitis C
Virus), and shortly thereafter, an antibody
test was
developed to detect infection (Choo 1989; Kuo 1989). When
NIH researchers performed Hepatitis C Virus
assays on
archived blood samples, it was determined that 70% to 90% of
NANBH cases were actually Hepatitis C Virus
infections.
Prevalence of
Hepatitis C Virus Infection in the United States (U.S.)
Hepatitis C Virus
is considered the most common blood-borne infection and is
one of the leading causes for liver
transplantation
among adults in the U.S. After the Hepatitis C Virus
antibody test became available, epidemiology studies
were performed to
ascertain the incidence of the infection. The original
studies, however, were considered
flawed because
they were conducted with first-time blood donors,
individuals who had already been screened
for risk factors
such as infectious diseases.
A recently
published study by Miriam Alter and colleagues from the
Centers for Disease Control and
Prevention (CDC)
reported that an estimated four million persons nationwide
are Hepatitis C Virus- antibody-positive
(ab+), indicating
exposure to the virus. Roughly three-quarters of these have
detectable Hepatitis C Virus RNA, indicating
chronic infection
(MJ Alter, 1999b). These data hail from the CDC’s third
National Health and Nutrition
Examination Study
(NHANES III), conducted between 1988 and 1994, and involving
a sample of almost
40,000 persons
between the ages of 2 and 89 years.
Out of this
group, 21,241 individuals agreed to be both interviewed and
tested for antibodies to Hepatitis C Virus; of these,
1.8% were found
to be Hepatitis C Virus-antibody-positive. For the entire
U.S., this corresponds to approximately 3.9
million residents
infected with Hepatitis C Virus. Below is a breakdown of the
prevalence of Hepatitis C Virus-antibody-positivity
classified by
race or ethnic group and gender.
Prevalence of
Antibody to Hepatitis C Virus (Anti-Hepatitis C Virus)
According to Race
or Ethnic Group & Gender in NHANES III
Characteristic
No. Tested
Prevalence
(%) of
Anti-Hepatitis C Virus+ (95% CI)
Estimated No. Infected Nationwide
(95% CI)
All
Subjects
21,241
1.8 (1.5-2.3)
3,875,000 (3,102,000-4,840,000)
Race/Ethnic Group
Non-Hispanic White
7,965
1.5 (1.1-2.0)
2,359,000 (1,774,000-3,137,000)
Non-Hispanic Black
6,119
3.2 (2.6--4.0)*
762,000
(609,000-953,000)
Mexican Americans
6,268
2.1 (1.7-2.6)
261,000 (210,000-323,000)
Other
889
2.9 (1.4-5.8)
493,000 (245,000-993,000)
Gender
Male
10,076
2.5 (2.0-3.2)**
2,586,000
(2,012,000-3,323,000)
Female
11,165
1.2 (0.9--1.6)
1,289,000 (967,000-1,717,000)
* P<0.05 for
comparison with non-Hispanic whites (MJ Alter 1999b)
** P<0.05
Hepatitis C Virus
Prevalence in Blood Donors in Southern Europe
Several large
Hepatitis C Virus epidemiology studies have been published
in Italy, France, and Spain. Below is a
breakdown of
anti-Hepatitis C Virus prevelance in selected studies that
have been conducted since the early 1990s.
Hepatitis C Virus
Incidence Rates in Six Large Southern European Cohorts
N =
Anti-Hepatitis C Virus +
Country (Study)
173,038
0.63%
France (Anuelles 1992)
60,960
0.69%
France (Aymard 1993)
30,231
1.2%
Spain (Esteban 1991)
46,741
1.12%
&n | 
