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The NIH Consensus Conference on the
Management of Hepatitis C: 2002.
Part 1
Introduction
Alan Franciscus
Editor-in-Chief, Hepatitis C Virus Advocate
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The National Institutes of Health convened
the second Management of Hepatitis C Consensus Development
Conference on June 10, 2002 in Bethesda, Maryland. The first
Management of Hepatitis C Consensus Conference was held in March
1997 that established the current approaches that are utilized
in the management and care of Hepatitis C Virus. The statement
that will be issued as a result of this meeting will have far
reaching affects and consequences to the management, care and
treatment of hepatitis C and is therefore of extreme importance
to the community.
It is clear that major breakthroughs in the
management and care of Hepatitis C Virus have taken place in the
years since the first conference. Some statements listed in the
original consensus conference that have changed include:
Ψ
. persistent infection develops
in perhaps as many as 85% of patients with acute hepatitis C.
We now know that the true number of people that develop chronic
infection is more likely between 50-55% with a higher rate of
spontaneous recovery in some groups.
Ψ The only available treatment for
Hepatitis C Virus was various forms of interferon with the bulk
of available evidence pertains to the alpha interferons
(interferon alpha). Current Hepatitis C Virus medications
include interferon, combination of interferon and ribavirin,
pegylated interferon and pegylated interferon and ribavirin.
Ψ Treatment success was measured by
normalization of biochemical markers that is ALTs and with
elimination of hepatitis C by viral load. Sustained virological
response is the elimination of Hepatitis C Virus and is now the
end point of treatment.
Ψ The sensitivity on anti Hepatitis
C Virus tests and viral load tests were questioned at the first
consensus conference. Now these tests are considered very
sensitive and accurate.
Ψ At that time fibrosis was believed
to be irreversible. We now know that dramatic reversal of
fibrosis or scarring takes place with the elimination of
Hepatitis C Virus from successful Hepatitis C Virus treatment
and some reversal of fibrosis takes place even in people that do
not clear Hepatitis C Virus from treatment.
The first consensus conference has had many
detractors in the medical field and the community. First,
people with persistently normal enzymes (ALTs) were excluded
from treatment except under investigational studies. We now know
that approximately 20% of people with persistently normal
enzymes level have moderate to severe disease progression and
treatment should be evaluated under different criteria for these
patients.
Secondly, people who are drinking
significant amounts of alcohol or who are actively using illicit
drugs should be delayed until these habits are discontinued for
at least 6 months. This is the most controversial area that
will be addressed at this conference with many advocates
actively lobbying for treatment decisions on a case-by-case
basis based upon the opinion of the medical provider and patient
after extensive evaluation.
One of the most commonly used drugs by IDUs
is heroin. Treatment for heroin addiction, which has been
endorsed by a previous consensus statement, is opiate agonist
therapy (methadone). However, the vast majority of medical
providers will not treat this population. In addition the
majority of transplant centers will not list a patient on
methadone maintenance. The majority of cases of Hepatitis C
Virus are linked to active injection drug use and the current
government guidelines recommend against treating active
injection drug users. If methadone maintenance, the recommended
treatment, is not widely accepted as a concomitant therapy
during treatment for Hepatitis C Virus then how do can we give
hope to the largest population infected with Hepatitis C Virus
and explain this inconsistency.
Please note that there we no major
revelations in todays presentations, but the review of the data
and questions posed will provide us with many recommendations
for future research.
The following are the opening session
summaries for the NIH Consensus Conference on the Management of
Hepatitis C: 2002.
The Course and Outcome of Hepatitis C
Jay H. Hoofnagle, M.D.
Hepatitis C is caused by a small RNA virus
that belongs to the family flaviviridae and is the sole member
of the genus hepacivirus. First identified in 1989, the
hepatitis C virus (Hepatitis C Virus) has a single-stranded RNA
genome that is ~ 9.6 kilobases in length and encodes a single,
large polyprotein of ~ 3000 amino acids. The Hepatitis C Virus
polyprotein is cleaved post-translationally into multiple
structural and non-structural peptides: structural components
consist of a nucleocapsid core [C] and two envelope
glycoproteins [E1 & E2] and the non-structural proteins are
labeled NS2 through NS5. The specific functions of the
individual NS proteins have not been completely elucidated. NS3
has both helicase and protease activities and the NS5 region
contains the RNA-dependent RNA polymerase activity essential for
RNA viral replication. These enzymatic activities are potential
targets for antiviral compounds. Hepatitis C Virus RNA also has
important and highly conserved 5 and 3 untranslated regions (UTRs).
The 5 UTR has an internal ribosomal entry site (IRES) essential
for initiation of viral protein translation and the 3 UTR has
structured RNA elements essential for both viral replication and
translation.
There are neither robust cell culture
systems for propagation of Hepatitis C Virus nor simple small
animal models of the infection, so the replicative cycle of the
virus has largely been deduced from that of other flaviviruses.
Hepatitis C Virus replicates in the cytoplasm of hepatocytes
where it is not directly cytopathic. Persistent infection
appears to rely upon rapid production of virus and continuous
cell-to-cell spread along with a lack of vigorous T cell immune
response to Hepatitis C Virus antigens. The Hepatitis C Virus
RNA genome mutates frequently and circulates in serum not as a
single species but as a population of quasispecies with
individual viral genomes differing by 1 to 5 percent in
nucleotide sequence. Six major genotypes (1 to 6) and more than
50 subtypes (e.g.,1a, 1b, 2a, 2b) have been described. Different
isolates of Hepatitis C Virus differ by 515 percent, subtypes
by 1030 percent, and genotypes by as much as 3050 percent in
nucleotide sequence.
Hepatitis C can cause both acute and
chronic hepatitis. Knowledge of the course and outcome of
infection arises largely from studies in chimpanzees and
previous post-transfusion and more current post-needlestick
accident cases of hepatitis C. In acute hepatitis, Hepatitis C
Virus RNA can be detected in the serum within one to two weeks
after exposure, rising thereafter to levels of 10 5 to 10 7
viral genomes per ml. Serum alanine aminotransferase (ALT)
levels indicative of hepatocyte injury and necrosis start to
rise 2 to 8 weeks after exposure and usually reach levels of
greater than 10 times the upper limit of normal. About one-third
of adults with acute Hepatitis C Virus infection develop
clinical symptoms and jaundice, the symptomatic onset ranging
from 3 to 12 weeks after exposure. In self-limited acute
hepatitis C, symptoms last for several weeks and subside as ALT
and Hepatitis C Virus levels fall. Acute hepatitis C can be
severe and prolonged but is rarely fulminant. Antibody to
Hepatitis C Virus as detected by enzyme immunoassay (EIA) arises
at the time of or shortly after onset of symptoms, so that 30
percent of patients test negative for anti-Hepatitis C Virus at
onset of symptoms, making anti-Hepatitis C Virus testing
unreliable in diagnosis. Almost all patients eventually develop
anti-Hepatitis C Virus, although titers can be low or even
undetectable in patients with immune deficiencies.
Chronic hepatitis C is marked by
persistence of Hepatitis C Virus RNA for at least six months
after onset of infection. The chronicity rate of hepatitis C
averages 7080 percent, but varies by age, sex, race, and immune
status. During the evolution of acute to chronic infection,
Hepatitis C Virus RNA and ALT levels can fluctuate markedly,
some patients having periods during which Hepatitis C Virus RNA
is undetectable and ALT levels normal. Once chronic infection is
established, however, serum Hepatitis C Virus RNA levels tend to
be stable. Most patients with chronic hepatitis C have few if
any symptoms, the most common being fatigue, which is typically
intermittent. Right upper quadrant pain (liver ache), nausea,
and poor appetite occur in some patients. Serum ALT levels are
usually continuously or intermittently elevated, but the height
of elevations correlates poorly with disease activity and at
least one-third of infected persons have persistently normal ALT
levels. In these patients, the underlying disease is usually,
but not always, mild and non-progressive. Liver histology in
chronic Hepatitis C Virus infection demonstrates chronic
mononuclear cell infiltration in the parenchyma and portal
areas, focal hepatocyte necrosis, and variable degrees of
fibrosis.
The major long-term complications of
chronic hepatitis C are cirrhosis, end-stage liver disease, and
hepatocellular carcinoma (HCC), which develop only in a
proportion of patients and only after many years or decades of
infection. Progression to cirrhosis is often silent clinically
and some patients are not known to have hepatitis C until they
present with the complications of end-stage liver disease or HCC.
Once cirrhosis is present, the ultimate prognosis is poor.
Other complications of chronic hepatitis C
can be important and affect quality of life. The major
extrahepatic manifestations of chronic Hepatitis C Virus
infection are cryoglobulinemia, glomerulonephritis, seronegative
arthritis, sicca syndrome, and porphyria cutanea tarda.
Hepatitis C Virus-related cryoglobulinemia is the most common:
up to 40 percent of patients with chronic hepatitis C may have
low levels of cryoglobulins in serum, but only 1 percent have
symptomatic cryoglobulinemia with fatigue, arthralgias, skin
rash, renal disease, or neuropathy.
Thus, the course of hepatitis C is
variable, the severity of illness ranging from a transient,
self-limited and asymptomatic infection to a chronic,
progressive liver disease that leads ultimately to cirrhosis and
HCC.
References
1.Lauer GM, Walker BD. Hepatitis C virus
infection. N Engl J Med 2001;345:4152.
2.Robertson B, Myers G, Howard C, et al.
Classification, nomenclature, and database development for
hepatitis C virus (Hepatitis C Virus) and related viruses:
proposals for standardization. Arch Virol 1998;143:2393503.
3.Farci P, Alter HJ, Wong D, et al. A
long-term study of hepatitis C virus replication in non-A, non-B
hepatitis. N Engl J Med 1991;325:98104.
4.Alter MJ, Kniszon-Moran D, Nainan OV,
et al. The prevalence of hepatitis C virus infection in the
United States, 1988 through 1994. N Engl J Med 1999;341:55662.
5.Bellentani S, Tiribelli C. The
spectrum of liver disease in the general population: lesson from
the Dionysos study. J Hepatol 2001;35:5317.
The Burden of Hepatitis C in the United
States
W. Ray Kim, M.D., M.Sc., M.B.A.
Incidence and Prevalence
Disease frequency may be measured either by
the pool of existing cases (prevalence), or by the occurrence of
new cases (incidence). The most widely quoted data on the
prevalence of Hepatitis C Virus in the United States are derived
from the third National Health and Nutrition Examination Survey
(NHANES), a national survey of a representative sample of
non-institutionalized civilian Americans conducted between 1988
and 1994. Of 21,000 people tested for Hepatitis C Virus, 380
people (1.8 percent) carried antibodies against the virus
(anti-Hepatitis C Virus), of whom 280 (74 percent) had
detectable viral RNA in their serum. These numbers project to
3.9 million Americans (95 percent confidence interval (CI):
3.14.8 million) who have been infected with Hepatitis C Virus,
of whom 2.7 million (95 percent CI: 2.43.0 million) have
ongoing chronic infection. Hepatitis C is the most common
chronic blood-borne infection in the United States.
While Hepatitis C Virus is a reportable
infectious disease in the United States, the incidence of new
Hepatitis C Virus infection is much more difficult to estimate
than its prevalence. Since the majority of acute Hepatitis C
Virus infections are not accompanied by recognizable symptoms
and thus not reported, enumerating reported cases of acute
hepatitis C significantly underestimates the true incidence of
hepatitis C infection. Nonetheless, the Centers for Disease
Control and Prevention (CDC) estimate that the annual incidence
of acute Hepatitis C Virus infection in the United States
decreased from an average of approximately 230,000 new cases per
year in the 1980s to 38,000 cases per year in the 1990s.
It may be expected that the reduction in
new incident cases will eventually lead to a decrease in the
prevalence of Hepatitis C Virus. A report from CDC projected
that, following a peak in the mid-1990s at slightly above 2.0
percent, the Hepatitis C Virus prevalence would gradually
decrease to 1.0 percent by 2030. While the prevalence of
Hepatitis C Virus infection may be decreasing, the prevalence of
liver disease caused by Hepatitis C Virus is on the rise. This
is because there is a significant lag, often 20 years or longer,
between the onset of infection and clinical manifestation of
liver disease. CDC projects a fourfold increase in the number of
persons with longstanding (20 years or longer) infection between
1990 and 2015. Furthermore, it is uncertain whether the
projected decline in the Hepatitis C Virus prevalence based on
NHANES data (non-institutionalized civilians) translates to
other population groups known to have very high prevalence of
Hepatitis C Virus. Examples of these groups include patients at
Veterans Affairs (VA) hospitals, active intravenous drug users,
and prison inmates.
Mortality from Hepatitis C Virus
Chronic liver disease is one of the 10 most
common causes of death in the United States. There has been a
steady increase in the number of deaths from liver disease over
time. The increase was mainly attributable to viral hepatitis
and hepatic malignancies. On the other hand, the age-adjusted
death rate (deaths per 100,000 living persons, adjusted to 2000
population census) from liver disease has been relatively
constant.
Mortality statistics in the United States
are based on the underlying cause of death listed on death
certificates. As deaths attributable to viral hepatitis
primarily result from chronic liver disease and liver failure
and, in those cases, viral hepatitis may not necessarily be
listed as the underlying cause of death, it is likely that
deaths classified as viral hepatitis underestimate the true
incidence of deaths related to viral hepatitis. Further, until
1999, when the International Classification of Disease version
10 (ICD-10) began to be used to classify causes of death,
Hepatitis C Virus was not given an independent code, making it
difficult to estimate the total number of deaths attributable to
Hepatitis C Virus.
With these caveats in mind, there was a
sixfold increase in the number of deaths from viral hepatitis
(all types) between 1982 (n=814) and 1999 (n=4853). In 1999, the
first year Hepatitis C Virus was reported separately, the
majority (77 percent, n=3759) of deaths from viral hepatitis
were due to Hepatitis C Virus. During the same period, there was
a commensurate increase in the age-adjusted death rate from 0.4
to 1.8 deaths per 100,000 persons per year. To estimate the
degree of under-reporting of Hepatitis C Virus as the underlying
cause of death in the mortality data, the number of in-hospital
deaths from liver disease related to hepatitis C was enumerated
(see below for details). In 1998, there were an estimated 4500
in-hospital deaths in the United States for liver disease
related to Hepatitis C Virus (source: Healthcare Utilization
Project, AHRQ).
Morbidity and Health Care Cost from
Hepatitis C Virus
As chronic hepatitis C has a prolonged
natural history and it is only a relative minority of the
infected that require ongoing medical care for their hepatitis,
it is difficult to estimate the magnitude of morbidity at the
population level. A cost-of-illness study conducted by the
American Gastroenterological Association estimated that there
were 317,000 outpatient visits for the treatment of hepatitis C
in the United States in 1998. The cost for outpatient physician
services was projected to be $23.9 million. During the same
year, $530 million was spent for antiviral treatment of
Hepatitis C Virus.
Patients with more advanced stage liver
disease present with portal hypertension and hepatic
decompensation, as manifested by ascites, hepatic
encephalopathy, or gastrointestinal bleeding, which often
necessitates inpatient care, including liver transplantation.
End-stage liver disease and/or hepatocellular carcinoma related
to Hepatitis C Virus is already the most common indication for
liver transplantation in the United States. In 1999,
approximately one-third of available cadaveric livers were
transplanted into recipients with Hepatitis C Virus infection.
The nationwide impact of liver disease due
to Hepatitis C Virus has been estimated based on data derived
from the Nationwide Inpatient Sample of the Healthcare
Utilization Project. This database represents a 20 percent
stratified sample from all non-Federal, acute-care hospitals,
which account for approximately 95 percent of all
hospitalizations in the nation. As liver disease from Hepatitis
C Virus may not be the main reason for all hospitalizations with
a Hepatitis C Virus diagnosis, hospitalizations were divided
into three groups. These included hospitalizations in which
liver disease from hepatitis C was the primary reason for
hospitalization, those in which liver disease from Hepatitis C
Virus was a secondary reason, and those in which Hepatitis C
Virus was an incidental notation. Because of the uncertainty of
ascertainment of Hepatitis C Virus in the early 90s,
hospitalizations for other chronic hepatitis (non-A, non-B) were
also captured.
There was an almost fourfold increase
during the five-year period between 1993 (n=35,700) and 1998
(n=134,200) in the total number of hospitalizations in which
Hepatitis C Virus was mentioned in the discharge diagnosis. Some
of the increase was due to lack of ascertainment of Hepatitis C
Virus in the early 1990s, as there was a partially corresponding
decrease in the non-A, non-B hepatitis hospitalizations (from
69,600 in 1993 to 47,800 in 1998). The number of
hospitalizations in which liver disease was the principal
diagnosis increased from 10,100 to 32,800 and secondary
diagnosis from 6,000 to 27,100 between 1993 and 1998. As
expected, the increase in hospital services for Hepatitis C
Virus-related morbidity was accompanied by a similar increase in
hospital charges. Hospitalizations were given differential
weight depending on the relevance of hepatitis C (principal
diagnosis vs. incidental notation). After adjustment for
inflation (1998 US$), the total hospital charges for 1998 were
slightly over 1 billion dollars nationwide. This represents
doubling in three years ($528M for 1995) and tripling in five
years ($348M for 1993).
Summary
Hepatitis C infection is common, affecting
nearly 2 percent of the general population and a much higher
percentage of people under special circumstances. Since the
early 1990s, national statistics indicate that morbidity,
mortality, and health care utilization associated with
consequences of long-standing infection with hepatitis C are
increasing in epidemic proportions. Future projection studies
predict that the increase will continue in the foreseeable
future.
References
1.Alter MJ, Kruszon-Moran D, Nainan OV,
et al. The prevalence of hepatitis C virus infection in the
United States, 1988 through 1994. New Eng J of Med,
1999:341(8):55662.
2.Anonymous. Recommendations for
prevention and control of hepatitis C virus infection and
Hepatitis C Virus-related chronic disease. MMWR 1998, Centers
for Disease Control and Prevention (CDC): Atlanta, GA. 19.
3.Armstrong GL, Alter MJ, McQuillan GM,
Margolis HS. The past incidence of hepatitis C virus infection:
implications for the future burden of chronic liver disease in
the United States. Hepatology 2000;31(3):77782.
4.Anonymous. Compressed mortality file
<http://wonder.cdc.gov>. 2002 (accessed on 3/10), Centers for
Disease Control and Prevention.
5.Anonymous. The burden of
gastrointestinal diseases. 2001, The American
Gastroenterological Association: Bethesda, MD. 4160.
6.Kim W, Gross J, Poterucha J, Locke G,
Dickson E. Outcome of hospital care of liver disease associated
with hepatitis C in the United States. Hepatology 2001;33:2016.
Natural History of Chronic Hepatitis C
Leonard B. Seeff, M.D.
Introduction
The rationale for establishing the natural
history of any disease is to inform both the patient and
physician of future expectations and to assess the need for
treatment. Unfortunately, the characteristics of hepatitis Cits
silent onset, evolution to a generally asymptomatic and greatly
prolonged chronic phase, its co-mingling with other morbid
conditions, and the fact that treatment that alters the course
is now almost routinehave limited the ability to accurately
define its natural history. Several strategies have been used
for this purpose, all of which have their drawbacks but still
have provided useful information. Because of the many inherent
difficulties, there is much controversy regarding the natural
history of hepatitis C. The outcome of concern is increasing
fibrosis progression, culminating in cirrhosis and,
occasionally, advancement to hepatocellular carcinoma (HCC).
Some believe this sequence to be common; others believe that
serious progression is relatively limited. Both of these views
may be valid, both identifying a frequency of progression that
is modified by differing demographic characteristics of the
population studied and by varying intrinsic and extrinsic
factors. In essence, the controversy derives from the
uncertainty of whether or not fibrosis progression is linear.
Advancement from Acute to Chronic Hepatitis
The natural history is a product of the
outcome of the acute infection as well as the outcome of the
subsequent chronic hepatitis. A problematic issue is the actual
timing of evolution to chronic hepatitis. Traditionally, this
has been based on persistence of virus for at least 6 months.
However, viremia may persist beyond this time, although it is
believed that loss of virus after one year is exceptional.
Prospective study has indicated that chronic hepatitis evolves
in about 85 percent of acutely infected persons. On the other
hand, cross-sectional studies of large, untreated anti-Hepatitis
C Virus positive cohorts, consisting mainly of young persons,
many of them female, have reported absent virus in as many as
4550 percent of instances, implying a higher rate of
spontaneous recovery in some groups. Thus, spontaneous recovery
from acute hepatitis C occurs in 1545 percent of instances.
Progression to Cirrhosis
Once chronic hepatitis has developed, the
question then is: What are the long-term sequelae? Numerous
efforts have been made to define the frequency and rate of
progression to cirrhosis and HCC. Evident in all these studies
is that clinically overt liver disease is generally not seen in
the first two decades following the acute infection. This does
not imply that cirrhosis does not evolve during this period, but
the actual timing of its onset cannot be determined without
performing serial liver biopsies. Early reports, based largely
on retrospective studies, indicated that, at the end of two
decades of infection, about 20 percent had developed cirrhosis,
although some of the studies have reported rates of almost 50
percent. The drawbacks of retrospective studies are that
evaluation is limited to those who have achieved an end point
and that tracing to disease onset is hindered by the paucity of
symptoms at onset. Thus, ascertainment bias may exist using this
approach. Later prospective studies, mainly of Hepatitis C
Virus-infected transfusion recipients, reported a lower rate of
development of cirrhosis (716 percent), but most of these
studies were too short in duration to provide an accurate
assessment of the ultimate outcome. Even lower rates of
cirrhosis have been reported among several groups in whom it was
possible to trace back far in the past to the time of onset or
near onset. Thus, among children infected through transfusion in
the first years of life and traced 20 years later, and among
young women infected through receipt of Hepatitis C
Virus-contaminated Rh immunoglobulin and traced over
approximately the same time period, cirrhosis was noted to have
occurred in about 2 percent. A similar rate was noted in a
45-year follow up of young Hepatitis C Virus-positive military
recruits who had been bled at the time of serving on a military
base, the samples having been retained in a repository. The
common theme of this lower rate of cirrhosis is that it was
noted among persons infected at a young age.
Taking the numerous variety of studies into
account, a group of Australian investigators who reviewed the
worlds literature for the rate of cirrhosis development at 20
years concluded that the studies could be divided into 4 broad
categories: those performed in liver clinics, the mean cirrhosis
rate being 22 percent (95 percent CI, 1826 percent);
post-transfusion hepatitis studies, with a mean of 24 percent
(1137 percent); studies of blood donors, with a mean of 4
percent (17 percent); and studies of community-based cohorts,
with a mean of 7 percent (410 percent). They concluded that
selection bias accounted for the two higher rates, and that the
community-based cohort studies appeared more representative in
estimating disease progression at a population level. These data
provide useful figures for the frequency of progression to
cirrhosis two decades after acute infection that appears to
range between about 24 percent to 2025 percent, depending on
several factors, to be described below. However, many of those
infected are young and are destined to live for several more
decades. Therefore the question that must be posed is: What
happens after the first two decades with regard to liver disease
progression? Does fibrosis progression continue to increase at a
linear rate? Does the rate level off and remain the same
throughout life? Does fibrosis progression increase as age
advances? Certainly, many chronically infected persons are known
to live for a lifetime without succumbing to liver disease,
whereas others are known to develop end-stage liver disease 30
to 60 years after acute infection. Thus, these
questions can only be answered by
conducting markedly extended studies, few of which have been
accomplished for obvious reasons. Other approaches have been to
model the expected outcome based on preconceived notions, models
that may or may not turn out to be valid. Most important, is it
possible to predict in the individual Hepatitis C Virus-infected
person what the outcome is likely to be? The answer is a
qualified maybe, taking into account the many factors that might
enhance progression.
Factors That May Determine Progression
The differing outcomes suggest that there
are variables that may contribute to the rate of liver disease
progression. These can be considered as being viral-related,
host-related, or a consequence of external factors.
Viral-Related
Factors that might contribute include viral
load, viral genotype, and quasispecies diversity. There is
little evidence to indicate that viral load plays a role in
disease progression; there are suggestions that progression is
more likely following infection with genotypes 1a and 1b than
genotype 2, although this has been disputed, most studies now
reporting that there is no effect of genotype characteristics on
disease outcome. While the degree of quasispecies diversity
appears to play a role in evolution from acute to chronic
hepatitis, there is no evidence that it enhances progression of
already established chronic hepatitis.
Host-Related
One of the most important determinants is
age at the time of infection, the relationship being an inverse
one. What is not yet established is whether the relatively mild
disease seen two decades after infection of young people will
begin to accelerate with increasing age. This brings into
account the fact of duration of infection, since it is rare
although not unheard of, to identify end-stage liver disease in
under one-and-a-half to two decades. Perhaps the flourishing of
liver disease with time may be a consequence in part of
age-related immune depression. Certainly, an immune suppressed
state vigorously enhances disease progression as is noted among
infected persons with hypogammaglobulinemia and, especially, HIV
co-infection. Hepatitis B and schistosomal co-infection also
increase disease progression perhaps through induced immune
dysfunction as well as through direct cytotoxicity. Genetic
background also may be of importance. Genes of the major
histocompatability complex appear also to play a role, not so
much in fibrogenesis, but in clearance of the virus. HLA class I
antigens seem to be associated with viral persistence whereas
class II antigens (DRB1 alleles) are identified more frequently
in those who clear virus and therefore have milder disease.
Inheritance of high TGF-β 1 and angiotensinogen-producing
genotypes has been linked to fibrosis progression. Co-morbid
conditions such as hemochromatosis and non-alcoholic
steatohepatitis are also associated with advancing chronic liver
disease. In addition, outcome may be influenced by gender and
race. Females are reported to have a slower rate of progression,
a finding that seems to be emerging also among
African-Americans. Finally, the expression of the disease plays
a role in outcome. Hepatitis C Virus-infected persons with
raised aminotransferase levels are far more likely to develop
progressive liver disease than are those with normal serum
enzymes.
External Factors
Clearly, associated chronic alcoholism is a
powerful co-factor in liver disease progression. Yet to be
determined is what is the least amount of alcohol and the type
of drinking pattern that plays a role in advancing chronic
hepatitis C. Also of note are the data suggesting that smoking
may increase disease progression. Exposure to toxic products,
either in the form of administered drugs that may be hepatotoxic
or as environmental contaminants, may have important effects. It
is noteworthy that death associated with chronic hepatitis C in
the United States is more likely to be a result of end-stage
liver disease rather than HCC, whereas in Japan, virtually all
deaths are attributed to HCC. It has been suggested that the
difference is a consequence of a longer duration of Hepatitis C
Virus infection in Japan than in the United States, a view that
may or may not be valid. Another possible explanation is that
toxic environmental contaminants may play a contributory role in
Japan.
Progression From Cirrhosis to HCC
HCC rarely (if ever) develops in persons
with chronic hepatitis C without preceding cirrhosis or
significant fibrosis. The strongest evidence for a relationship
between Hepatitis C Virus infection and HCC comes from Japan,
but supporting evidence comes from many other countries
including the United States, Italy, Spain, Egypt, France, and
elsewhere. Recent evidence indicates that the incidence of HCC
increasing in the United States is presumed to be a consequence
of the mushrooming of hepatitis C infection in the 1960s and
1970s. The data in the United States indicate that once
cirrhosis has developed, HCC evolves at the rate of 14 percent
per year. The figure in Japan is even higher.
References:
1.Alter HJ, Seeff LB. Recovery,
persistence, and sequelae in hepatitis C infection: a
perspective on long-term outcome. Semin Liv Dis 2000;20:1735.
2.Poynard T, Bedossa P, Opolon P, for
the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Natural
history of liver fibrosis progression in patients with chronic
hepatitis C. Lancet 1997;349:82532
3.Tong MJ, El-Farra NS, Reikes AR, Co RL.
Clinical outcomes after transfusion-associated hepatitis C. N
Engl J Med 1995;332:14636.
4.Kenny-Walsh E for the Irish Hepatology
Research Group. Clinical outcomes after hepatitis infection from
contaminated anti-globulin. N Engl J Med 1999;340:122833.
5.Vogt M, Lang T, Frosner, et al.
Prevalence and clinical outcome of hepatitis C infection in
children who underwent cardiac surgery after implementation of
blood-donor screening. N Engl J Med 1999;341:86670.
6.Wiese M, Berr F, Lafrenz M, et al. Low
frequency of cirrhosis in a hepatitis C (genotype 1b)
single-source outbreak in Germany: a 20-year multicenter study.
Hepatology 2000;32:916.
7.Thomas DL, Astemborski J, Rai, et al.
The natural history of hepatitis C virus infection: host, viral,
and environmental factors JAMA 2000;284:4506..
8.Freeman AJ, Dore GJ, Law MG, et al.
Estimating progression to cirrhosis in chronic hepatitis C virus
infection. Hepatology 2001;34:80916.
9.Seeff LB, Hollinger FB, Alter HJ, et
al. Long-term mortality and morbidity of transfusion- associated
non-A, non-B and type C hepatitis: a National Heart, Lung, and
Blood Institute collaborative study. Hepatology 2001;33:45563.
10.Seeff LB. Why is there such difficulty
in defining the natural history of hepatitis C? Transfusion
2000;40:11614.
Fibrosis and Disease Progression
Patrick Marcellin, M.D.
Chronic infection with Hepatitis C Virus is
associated with the typical histological features of chronic
hepatitis including hepatocellular necrosis and inflammation
(activity or grade) and fibrosis (stage). While the activity of
the chronic liver disease can fluctuate over time, the stage of
fibrosis is believed to be progressive and largely irreversible.
In chronic hepatitis C, the rate at which fibrosis progresses
varies markedly. In some individuals, fibrosis ultimately leads
to cirrhosis, which is associated with the major complications
of the liver disease: portal hypertension, liver failure, and
hepatocellular carcinoma. In others, fibrosis does not appear to
progress even after decades of infection. For these reasons,
assessment of the stage and rapidity of progression of fibrosis
can be helpful in determining the prognosis and the need for
therapy in the individual patient. Factors associated with
fibrosis progression are not well defined and the role of necro
inflammatory activity is still controversial.
Assessment of the Stage of Fibrosis
Liver biopsy remains the gold standard to
assess fibrosis. Several systems for scoring liver fibrosis have
been proposed, each based upon visual assessment of portal and
periportal fibrosis. The more frequently used systems are the
Histology Activity Index (HAI: Knodell score), the Ishak
modification of the HAI score, and the METAVIR. The HAI scoring
system ranges from 0 to 22 and fibrosis is staged as 0, 1, 3,
and 4. This discontinous scale was developed to allow for clear
separation of mild (1+) from extensive (3+) fibrosis which has
important prognostic value. The HAI system is simple and has
been widely used, particularly in the large multicenter trials
of interferon and ribavirin therapy of chronic hepatitis C.
However, the intra- and inter-observer reproducibility of the
HAI is not very good and distinction between stages 1 and 3 may
be difficult. In addition, its discontinous scale complicates
statistical analysis in clinical trials.
The modification of the HAI scoring system
proposed by Ishak et al. is more sensitive in assessing
fibrosis. Fibrosis stage is scored continuously from 0 to 6,
which permits a better assessment of the effect of therapy on
fibrosis. The Ishak score is better validated and gives a more
accurate assessment of fibrosis.
The METAVIR scoring system is simple;
fibrosis stages are scored continuously from 0 to 4. This system
has been carefully validated in large groups of patients with
chronic hepatitis C and has shown good intra- and inter-observer
reproducibility.
Important limitations of these scoring
systems should be emphasized. Hepatic fibrosis may not be
homogenous throughout the liver and the liver specimen obtained
by needle biopsy may not accurately reflect the overall average
degree of fibrosis. The reliability of the assessment of
fibrosis stage increases with the size of the liver sample. In
most studies, a minimum length of 10 mm is required. Regardless
of biopsy length, however, fibrosis may be underestimated and
cirrhosis missed in some patients.
Factors Associated With the Stage of
Fibrosis
Most cross-sectional studies of large
numbers of liver biopsies have shown that the stage of fibrosis
is associated with patient age, the age at onset of infection,
male sex, a history of heavy alcohol consumption, and the
presence of immune deficiency, such as HIV co-infection or
immunosuppressive therapy. The mechanisms by which age and sex
affect the degree of fibrosis are not known. Alcohol, which by
itself can cause liver disease and fibrosis, may worsen fibrosis
in hepatitis C at amounts that are not injurious in non-infected
persons, but the amount of alcohol beyond which the progression
of fibrosis is increased is unknown.
Serum biochemical tests do not reliably
predict the stage of fibrosis. Currently available, indirect
serum markers of fibrosis are not reliable, particularly in
discriminating between mild and moderate degrees of fibrosis. In
cross-sectional studies, serum alanine and aspartate
aminotransferase (ALT and AST) levels do not correlate well with
fibrosis. However, patients with documented, persistently normal
ALT levels usually have mild degrees of hepatitis and either no
or mild stages of fibrosis. The association between fibrosis
stage and the necroinflammatory activity scores on liver biopsy
is controversial. Necroinflammatory activity is a dynamic
process in chronic hepatitis C and may fluctuate over time.
Therefore, the activity score reflects the severity of necrosis
and inflammation at a given point.
Factors Associated With Progression of
Fibrosis
From retrospective studies and from some
prospective studies done in patients infected by blood
transfusion at a relatively older age, it is estimated that 20
percent of patients with chronic hepatitis C develop cirrhosis
within 20 years of onset. In contrast, studies of cohorts of
women who did not drink alcohol and who were infected by Rh
immune globulin at a young age indicated that fewer than 5
percent developed cirrhosis within 20 years. These natural
history studies validate the importance of age, sex, and alcohol
intake in progression of fibrosis. Cross-sectional studies using
mathematical modeling performed on cohorts of patients with a
single liver biopsy suggest that the average rate of progression
of fibrosis in chronic hepatitis C is 0.133 METAVIR points per
year. Based on this rate, the estimate is that cirrhosis
develops in the average patient after 30 years. The average
delay to the development of cirrhosis ranges from 13 years in
infected men aged 40 or more years who drink more than 50 g of
alcohol to 42 years in infected women under 40 years of age who
do not drink alcohol. Furthermore, the progression of fibrosis
is probably not linear. For instance, the time required to
progress from stage 0 to 2 may be far longer than the time
required to progress from stage 3 to 4. Moreover, fibrosis
progression may accelerate with age (particularly after the age
of 50). Finally, fibrosis may remain mild and stable for decades
and may even regress spontaneously in some patients.
The progression of fibrosis is difficult to
predict in the individual patient particularly based upon
assessment at one point in time. There are no good clinical,
biochemical, or virological tests that predict progression of
fibrosis. High serum ALT levels have been associated with more
active liver disease and more rapid progression of fibrosis in
some prospective studies, which supports the use of monitoring
of ALT levels in assessing prognosis and need for therapy.
However, the validity of this approach and the level above which
the ALT elevations are predictive of more rapid progression is
not known. Virological factors such as serum Hepatitis C Virus
RNA level and Hepatitis C Virus genotype are not predictive of
fibrosis. Genotype 3 is associated with more liver steatosis
than other genotypes, and steatosis itself, as well as other
metabolic factors (such as lipid disorders, obesity, insulin
resistance, and diabetes) may also predispose to more rapid
progression of fibrosis.
Repeat liver biopsy is the only reliable
means of assessing the progression of fibrosis and is commonly
recommended every 3 to 5 years in untreated patients. A second
liver biopsy can distinguish patients with rapidly progressive
fibrosis, but may also merely indicate that the initial biopsy
underestimated the degree of fibrosis. Overall, the risk of
progression of fibrosis of more than one point in a 3 to 5 year
period is low. In patients with factors associated with a higher
risk of progression such as age beyond 50 years, alcohol
consumption, or high serum ALT levels, liver biopsy may be
recommended more frequently (2 to 3 years); in contrast, in the
younger patient with no other risk factors, liver biopsies may
be performed less frequently (every 5 to 6 years).
References
1.Ishak K, Baptista A, Bianchi L, Callea
F, De Groote J, Gudat F, Denk H, et al. Histologic grading and
staging of chronic hepatitis. J Hepatol 1995;22:6969.
2.Bedossa P, Poynard T. The METAVIR
cooperative study group. An algorithm for the grading of
activity in chronic hepatitis C. Hepatology 1996;24:28993.
3.Tong MJ, El-Farra NS, Reijes AR, Co RL.
Clinical outcomes after transfusion-associated hepatitis C. N
Engl J Med 1995; 332:14636.
4.Poynard T, Bedossa P, Opolon P for the
OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Natural history
of liver fibrosis progression in patients with chronic hepatitis
C. Lancet 1997;349:82532
5.Alter HJ, Seeff LB. Recovery,
persistence, and sequelae in hepatitis C virus infection: a
perspective on long-term outcome. Sem Liver Dis 2000;20:1735
Non-Invasive Monitoring of Patients With
Chronic Hepatitis C
Robert J. Fontana, M.D., and Anna S.F. Lok,
M.D.
Patients with chronic hepatitis C (CHC) are
at risk of developing cirrhosis, liver failure, and
hepatocellular carcinoma (HCC). However, specific symptoms and
physical findings of chronic liver disease are frequently absent
until patients develop hepatic decompensation. Thus, clinical
examination is often unreliable in assessing the severity of
liver disease in patients with CHC. Liver histology is the gold
standard for establishing the severity of liver injury and
fibrosis, but this procedure is associated with risks of
complications, discomfort, and expense. In addition, sampling
error may occur leading to erroneous staging. Nonetheless,
information on the extent of hepatic fibrosis or stage of liver
disease is important for prognostication as well as for
decisions on treatment. As a result, practicing physicians are
in need of simple, safe, inexpensive, and reliable means to
non-invasively assess the severity of liver disease in patients
with CHC.
The initial evaluation of patients with CHC
should include a thorough history and physical examination. A
PCR assay for Hepatitis C Virus RNA is recommended to confirm
the presence of viremia because up to 30 percent of individuals
who test positive for Hepatitis C Virus antibody (anti-Hepatitis
C Virus) may have resolved infection or a false positive EIA
result. Quantitative Hepatitis C Virus RNA levels and Hepatitis
C Virus genotypes do not correlate with disease severity, but
these results are useful in predicting the likelihood of an
antiviral treatment response. The initial evaluation should
include a comprehensive metabolic panel, prothrombin time, and
complete blood counts (CBC) with platelets. Serum aspartate and
alanine aminotransferase (AST/ALT) levels reflect liver injury,
but the correlation with histologic necroinflammatory activity
as well as the severity of hepatic fibrosis is poor (1,2) .
Serum albumin and bilirubin levels and prothrombin time reflect
hepatic function, but these values usually remain normal even in
patients with compensated cirrhosis. Thus, routine blood tests
cannot differentiate early (minimal fibrosis) from advanced
(compensated cirrhosis) stage of liver disease. Among the
routine blood tests, decreased platelet count is the earliest
indicator of cirrhosis (3). Other investigators have found that
as patients progress from chronic viral hepatitis to cirrhosis,
there is reversal of AST/ALT ratio to >1. (4)
Ultrasound is often recommended as part of
the initial evaluation of patients with CHC. Ultrasound and
other imaging techniques such as CT and MRI can be used to
diagnose cirrhosis based on the presence of an enlarged spleen,
small nodular liver, ascites, or varices. In addition, these
techniques may detect HCC. However, current imaging is unable to
assess the extent of hepatic fibrosis and to diagnose early
cirrhosis.
Other novel but less well-established
non-invasive means of assessing disease severity in patients
with compensated CHC are under development. Serum fibrosis
markers that reflect the balance between fibrogenesis and
fibrolysis have been proposed as a simple, non-invasive means of
assessing hepatic fibrosis. (5,6) To date, none of these markers
alone correlates well with hepatic fibrosis. Whether a panel of
markers such as hyaluronic acid, YKL-40, and PIIINP will replace
liver biopsies remains to be determined. (7,8) Contrast-enhanced
ultrasound doppler has also been proposed as a simple,
non-invasive means of detecting advanced hepatic fibrosis. (9)
However, this method has not yet been validated and will require
sophisticated instruments and operators for optimal performance.
Radionuclide liver spleen scans can detect the presence of
portal hypertension but are insensitive in the diagnosis of
early cirrhosis. Similarly, the use of various metabolic probes
to assess functional liver mass has been reported to be reliable
in differentiating patients with compensated from decompensated
liver disease, but these studies are cumbersome and have not
been proven to be useful in distinguishing patients with various
stages of hepatic fibrosis. (10)
The optimal frequency and types of tests
that should be performed for monitoring CHC patients who are not
on antiviral therapy have not been determined. In general, tests
for CBC and platelets and a comprehensive metabolic panel should
be performed every six months. As discussed above, a progressive
decrease in platelet counts or a reversal of the AST/ALT ratio
suggests the development of cirrhosis. Repeat testing of
anti-Hepatitis C Virus, Hepatitis C Virus RNA level, or
Hepatitis C Virus genotype is unnecessary and does not provide
any information on the stability or progression of liver
disease. For patients with known cirrhosis, alfa fetoprotein
testing and ultrasound should be included although the efficacy
of these tests in HCC surveillance is low. Upper endoscopy
should be performed in patients with cirrhosis, especially those
with clinical evidence of portal hypertension, to determine the
need for prophylaxis against variceal bleeding. Patients with
decompensated cirrhosis may need more frequent monitoring to
determine the optimal timing for transplant evaluation.
Monitoring may be less frequent in patients with persistently
normal aminotransferases and those with minimal hepatic fibrosis
after a long duration of infection (slow progressors). Because
of the variable natural course of CHC and the possibility of
sampling error, many hepatologists recommend repeat liver
biopsies in 45 years in patients who decide not to receive
antiviral treatment based on the finding of early disease at
initial evaluation. The availability of non-invasive tests that
correlate with progression of hepatic fibrosis will obviate the
need for repeat liver biopsies.
References
1.McCormick SE, Goodman ZD, Maydonovitch
CL, Sjorgen MH. Evaluation of liver histology, ALT elevation,
and Hepatitis C Virus RNA titer in patients with chronic
hepatitis C. Am J Gastroenterol 1996;91:151622.
2.Haber MM, West AB, Haber AD, Reuben A.
Relationship of aminotransferases to liver histological status
in chronic hepatitis C. Am J Gastroenterol 1995;90:12507.
3.Poynard T, Bedossa P, Metavir and
Clinivir Cooperative Study Groups. Age and platelet: a simple
index for predicting the presence of histological lesions in
patients with antibodies to hepatitis C virus. J Viral Hepat
1997;4:199208.
4.Williams AL, Hoofnagle JH. Ratio of
serum aspartate to alanine aminotransferase in chronic
hepatitis. Relationship to cirrhosis. Gastroenterology
1988;95:7349.
5.Oberti F, Valsesia E, Pilette C, et
al. Non-invasive diagnosis of hepatic fibrosis or cirrhosis.
Gastroenterology. 1997;113:160916.
6.Wong VS, Hughes V, Trull A, et al.
Serum hyaluronic acid is a useful marker of liver fibrosis in
chronic hepatitis C virus infection. J Viral Hepatitis
1998;5:187192.
7.Kamal SM, Turner B, Koziel MJ, Afdhal
NH. YKL-40 and PIIINP correlate with the progression of fibrosis
in chronic hepatitis C. Gastroenterology (Abstract)
2001;120:1895A.
8.Rosenberg WM, Burt A, Hubscher S, et
al. Serum markers predict liver fibrosis. Hepatology (Abstract)
2001;34:396A.
9.Albrecht T, Blomley MJK, Cosgrove DO,
et al. Non-invasive diagnosis of hepatic cirrhosis by
transit-time analysis of ultrasound contrast agent. Lancet
1999;353:157983.
10.Lotterer E, Hogel J, Gaus W, et al.
Quantitative liver function tests as surrogate markers for
end-points in controlled Clinical
Trials: A retrospective feasibility
study. Hepatology 1997;26:142633.
Use and Interpretation of Virologic
Tests
Jean-Michel Pawlotsky, M.D., Ph.D.
Two categories of tests are used in the
management of hepatitis C virus (Hepatitis C Virus)-infected
patients: (i) indirect tests that detect antibodies to Hepatitis
C Virus (anti-Hepatitis C Virus); (ii) direct tests that detect,
quantify, or characterize viral particle components, such as
Hepatitis C Virus RNA or core antigen. Direct and indirect
virological tests play a crucial role in the diagnosis of
infection, therapeutic choices, and assessment of the
virological response to therapy.
Indirect Tests
Anti-Hepatitis C Virus detection.
Anti-Hepatitis C Virus is typically detected using second- or
third-generation enzyme immunoassays (EIAs) that detect mixtures
of antibodies directed to various Hepatitis C Virus epitopes.
The specificity of currently available EIAs for anti-Hepatitis C
Virus is higher than 99 percent. Their sensitivity is more
difficult to determine in the absence of a more sensitive gold
standard. EIAs for anti-Hepatitis C Virus detect antibodies in
more than 99 percent of immunocompetent patients with detectable
Hepatitis C Virus RNA. EIAs are sometimes negative despite the
presence of active Hepatitis C Virus replication in hemodialysis
patients or patients with profound immunodeficiencies.
Immunoblot tests have been used in the past as confirmatory
assays. Given the good performance of the current anti-Hepatitis
C Virus EIAs, immunoblot tests no longer have utility in the
clinical virology setting. They are still useful in the blood
bank setting, where the positive predictive value of a positive
EIA result is significantly lower than in the diagnostic
setting.
Serological determination of Hepatitis C
Virus genotype. Hepatitis C Virus genotype can be determined by
detection of type-specific antibodies using a competitive EIA
(so-called serotyping). This assay provides interpretable
results in approximately 90 percent of immunocompetent patients
with chronic hepatitis C. Its sensitivity is lower in
hemodialysis or immunodepressed patients. The assay identifies
the type (1 to 6) but not the subtype of Hepatitis C Virus.
Concordance with molecular assays is in the order of 95 percent.
Currently, no serotyping assay is FDA-approved.
Direct Tests
Available Tests
Qualitative detection of Hepatitis C Virus
RNA. Qualitative (i.e., nonquantitative) Hepatitis C Virus RNA
detection assays are useful because they are significantly more
sensitive than most available quantitative assays. The
qualitative assays are based on the principle of target
amplification using either polymerase chain reaction (PCR) or
transcription-mediated amplification (TMA). The lower detection
cutoffs of the corresponding commercial assays are 50 Hepatitis
C Virus RNA international units (IU)/ml and 10 IU/ml,
respectively. Their specificity is of the order of 9899
percent. The PCR assay is FDA-approved.
Viral level quantification. Hepatitis C
Virus RNA level can be quantified by means of target
amplification techniques (PCR or TMA) or signal amplification
techniques (branched DNA assay). The lower detection cutoffs
of the current assays vary between 30 IU/ml and 615 IU/ml, and
the upper limit of linear quantification between 500,000 IU/ml
and 7,700,000 IU/ml. Samples with a viral level higher than the
upper limit of an assay should be retested after 1/10 or 1/100
dilution. Quantification is independent of the Hepatitis C Virus
genotype. The international unit, recently defined with
reference to the WHO Hepatitis C Virus RNA standard, should be
used in any Hepatitis C Virus RNA quantitative assay in order to
compare results given by different assays and to apply global
recommendations. Variations of less than 0.5 logs (i.e., of less
than threefold) should not be taken into account as they may
relate to the intrinsic variability of the assays. No Hepatitis
C Virus RNA quantification assay is approved currently in the
United States, but several are likely to be in the future.
Molecular determination of Hepatitis C
Virus genotype (genotyping). The gold standard for genotyping
is direct sequencing of the NS5B or E1 regions. In clinical
practice, Hepatitis C Virus genotype can be determined by direct
sequence analysis, reverse hybridization onto genotype-specific
oligonucleotide probes, or restriction fragment length
polymorphism analysis after PCR amplification of the 5
noncoding region. Typing errors are uncommon, but subtyping
errors may occur in 1025 percent of cases. These errors may be
related to the region studied (5 noncoding) rather than the
technique used. Subtyping errors have few clinical consequences
because only the genotype is useful for clinical decisions. No
genotyping assay is currently approved in the United States.
Detection and quantification of total
Hepatitis C Virus core antigen. Total Hepatitis C Virus core
antigen can be detected and quantified by means of EIA assay.
The Hepatitis C Virus core antigen titer (in pg/ml) correlates
closely with Hepatitis C Virus RNA level, and thus can be used
as an indirect marker of viral replication. However, the current
version of the assay does not detect Hepatitis C Virus core
antigen when Hepatitis C Virus RNA is below approximately 20,000
IU/ml. This assay is not FDA-approved.
Practical Use of Virological Tests
The phrase Hepatitis C Virus RNA detection
by means of a sensitive technique used in this presentation
refers to a technique with a lower limit of detection of 50 IU/ml
or less. Furthermore, in discussing Hepatitis C Virus RNA
quantitation, it is assumed that the results are within the
limits of its range of linear quantification of the assay.
Diagnosis of Hepatitis C Virus Infection
Acute hepatitis C. During acute hepatitis
of unknown origin, anti-Hepatitis C Virus should be tested by
EIA and Hepatitis C Virus RNA by a sensitive Hepatitis C Virus
RNA technique. The presence of Hepatitis C Virus RNA without
anti-Hepatitis C Virus is strongly indicative of acute hepatitis
C, a diagnosis that can be confirmed by subsequent
seroconversion. In the absence of both markers, acute hepatitis
C is unlikely. In the presence of both, it is difficult to
differentiate acute hepatitis C from an acute exacerbation of
chronic hepatitis C or from acute hepatitis of other cause in a
patient with chronic hepatitis C.
Chronic hepatitis C. In a patient with
chronic liver disease, the diagnosis of chronic hepatitis C can
be made based on detection of both anti-Hepatitis C Virus and
Hepatitis C Virus RNA using a sensitive technique. The lack of
anti-Hepatitis C Virus in the presence of Hepatitis C Virus RNA
is uncommon in immunocompetent patients with chronic hepatitis
C. It can occur (although rarely with the current EIAs) in
hemodialysis or profoundly immunodeficient patients.
Mother-to-infant transmission. The
diagnosis of Hepatitis C Virus infection in a baby born to an
Hepatitis C Virus-infected mother should be based on the
detection of Hepatitis C Virus RNA with a sensitive technique
rather than anti-Hepatitis C Virus, because antibodies are
passively transferred in utero and remain detectable for several
months to more than a year after delivery regardless of whether
transmission occurs. The optimal timing for Hepatitis C Virus
RNA testing for diagnosis is not known. Appropriate times are 6
to 12 months after birth.
Diagnosis of infection after an
occupational exposure. Hepatitis C Virus RNA is detectable in
serum within one to two weeks after an accidental parenteral
exposure. The diagnosis of acute infection should be based on
detection of Hepatitis C Virus RNA by a sensitive technique.
This testing can be performed at any time after the first week
after exposure, but antiviral treatment is not an emergency in
this setting and can be initiated after appearance of serum
aminotransferase elevations or clinical symptoms appear.
Prognosis of Hepatitis C Virus-Related
Disease
No virologic test (including viral load and
genotype) correlates with the severity of liver injury or
fibrosis, or predicts the natural course or outcome of disease
or presence of extra-hepatic disease. Virologic tests are not
helpful as prognostic markers.
Antiviral Treatment of Hepatitis C Virus
Infection
Decision to treat. Only patients with
detectable Hepatitis C Virus RNA should be considered for
treatment. Hepatitis C Virus genotype determination should be
performed before treatment as results may help in the decision
to treat as well as in determining the duration of treatment.
Thus, because of the high rates of response and need for 24
weeks of therapy only in patients with Hepatitis C Virus
genotypes 2 and 3, many investigators recommend therapy to all
such patients provided there are no contraindications. Because
response rates are only 4045 percent and therapy must be given
for 48 weeks in patients with genotype 1, the benefits of
therapy must be balanced against its risks and cost. In this
context, the assessment of the natural prognosis of infection by
liver biopsy examination may help in making the decision to
treat. In the absence of sufficient information, the same
applies to genotypes 4, 5, and 6.
Virologic followup and assessment of
response. Measurement of Hepatitis C Virus RNA levels before
treatment and again at 12 weeks has been proposed as an
appropriate approach to monitoring patients with chronic
hepatitis C who are treated with peginterferon and ribavirin.
This is particularly true for patients with genotype 1. In
patients infected with genotypes 2, 3, 4, 5, and 6, monitoring
of Hepatitis C Virus RNA levels may be less important, and there
is little data supporting its usefulness. The basis for this
will be discussed later in this conference. In all patients,
however, the virological response should be assessed by testing
for Hepatitis C Virus RNA by a sensitive technique at the end of
therapy. The presence of Hepatitis C Virus RNA at the end of
treatment is highly predictive of a relapse when therapy is
stopped. The absence of Hepatitis C Virus RNA at the end of 20
treatment indicates virological response and should lead to
retesting for Hepatitis C Virus RNA by a sensitive method 24
weeks later to document that the virological response is
sustained.
Followup of Untreated Patients
Repeat virological testing is not necessary
in untreated patients, as results have no prognostic value.
References
1.Thio CL, Nolt KR, Astemborski J,
Vlahov D, Nelson KE, Thomas DL. Screening for hepatitis C virus
in human immunodeficiency virus-infected individuals. J Clin
Microbiol. 2000;38:5757.
2.Pawlotsky JM, Bouvier-Alias M, Hezode
C, Darthuy F, Remire J, Dhumeaux D. Standardization of hepatitis
C virus RNA quantification. Hepatology 2000;32:6549.
3.Pawlotsky JM, Lonjon I, Hezode C,
Raynard B, Darthuy F, Remire J, Soussy CJ, Dhumeaux D. What
strategy should be used for diagnosis of hepatitis C virus
infection in clinical laboratories? Hepatology 1998;27:17002.
4.Manns MP, McHutchison JG, Gordon SC,
Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling
M, Albrecht JK.
Peginterferon alfa-2b plus ribavirin
compared with interferon alfa-2b plus ribavirin for initial
treatment of chronic hepatitis C: a randomised trial. Lancet
2001;358:95865.
5.Fried MW, Shiffman ML, Reddy RK, Smith
C, Marinos G, Goncales Jr FL, et al. Pegylated (40kDa)
interferon alfa-2a (PEGASYS) in combination with ribavirin:
efficacy and safety results from a phase III, randomized,
actively-controlled, multicenter study. Gastroenterology
2001;120 (suppl. A):55.
Hepatocellular Carcinoma (HCC) and
Hepatitis C Virus in the United States
Hashem B. El-Serag, M.D., M.P.H.
HCC in the United States
A progressive increase in HCC-related
mortality has been observed over the last 3 decades. According
to the United States vital statistics, the overall age-adjusted
mortality rate for HCC (ICD-9 155.0, which excludes
cholangiocarcinoma and metastatic liver cancer) has risen
significantly from 1.7 per 100,000 (95 percent CI, 1.7 to 1.8)
during 19811995 to 2.4 per 100,000 (2.4 to 2.5) during
19911995. The recent rise in HCC mortality in the United States
is a result of the rising incidence rate of HCC observed during
the same time period coupled with a dismal survival rate (5
percent at 5 years). Data from the population-based SEER
registries indicate that the age-adjusted incidence rate of HCC
(ICD-O 8170) has increased from 1.4 per 100,000 during 19761980
to 3.0 per 100,000 during 19961998, more than a twofold
increase. The latter rates probably underestimate the true
incidence by approximately 30 percent as they represent only
histologically confirmed HCC. During the same time, the temporal
trends for hospitalizations with primary liver cancer have
mirrored those of incidence and mortality. For example, data
from the national VA computerized database show that the overall
number of hospitalizations as well as the age-adjusted
proportional hospitalization rate for HCC have increased by 42
percent from 19811997, reaching a hospitalization rate of 4.1
per 10,000 (3.7 to 4.5) during 19931997.
Demographic Risk Factors for HCC
There are significant gender, ethnicity,
and geographic variations in the incidence of HCC in the United
States. Caucasians are two to three times less affected than
African Americans, who in turn are two to three times less
affected than Asians, Pacific Islanders, or Native Americans.
For all ethnic groups, men are two to three time more affected
than women. Asians men have the highest age-adjusted incidence
rates (up to 23 per 100,000). However, men and women of all
ethnic groups have been affected by the recent increase in
incidence. The reasons for these ethnic and gender variations
probably relate to the prevalence and time of acquisition of the
major HCC risk factors. It is known that the prevalence of
Hepatitis C Virus, HBV, and alcoholic cirrhosis is two- to
threefold higher in African-Americans and Hispanics than in
whites. Native American Eskimos and recent immigrants from
China, Taiwan, Korea, and Vietnam have high prevalence rates of
HBV similar to those in their original countries. There are
significant geographic variations within the United States in
HCC (irrespective of the demographic differences between these
regions): Hawaii had the highest age-adjusted incidence rate
(4.6/100,000), followed by San Francisco-Oakland (3.2/100,000)
and New Mexico (2.0/100,000), whereas Iowa and Utah have the
lowest rates of approximately 1.0/100,000.
We used hierarchical linear multivariate
analysis to examine the temporal trends in HCC incidence while
controlling for age, gender, and ethnicity as well as adjusting
for potential clustering of persons with similar demographic
characteristics within geographic regions. This analysis has
confirmed a twofold increase in HCC over a time period between
1975 and 1998 while adjusting for all the variables described
above.
Concomitant with the rising rates of HCC,
there has been a shift of incidence from typically elderly
patients to relatively younger patients between ages 40 to 60.
This shift reflects a cohort/period effect, affecting those who
were born after 1920 and who seem to have been exposed to
environmental agent(s) that have caused a cumulative increase in
the HCC risk in all age groups of these cohorts. One plausible
hypothesis is that these cohorts were infected with Hepatitis C
Virus during the 1950s1970s, when they were in their twenties
to forties, and are now presenting with Hepatitis C
Virus-related HCC. The full extent of this cohort/period effect
has not been realized yet (the incidence rates have not leveled
off yet).
Underlying Etiology for the Rising
Incidence of HCC in the United States
Due to the essential role of cirrhosis in
the development of HCC in the majority of cases, an increase in
the number of persons living with cirrhosis is the likely
explanation of the rising incidence of HCC. Declines in the
mortality rates due to cirrhosis (partly related to improved
management of esophageal varices and peritonitis) have been
observed in the United States over the last 25 years. In
addition, the incidence of cirrhosis related to Hepatitis C
Virus infection is rising. We carried out a population-based
study in which the computerized records of hospitalized HCC
patients during 1993 and 1998 (n=1,605) in all VA hospitals were
searched for specific risk factors. There was a threefold
increase in the age-adjusted rates for HCC associated with
Hepatitis C Virus from 2.3 per 100,000 (1.8 to 3.0) between 1993
and 1995 to 7.0 per 100,000 (5.9 to 8.1) between 1996and 1998.
Hepatitis C Virus infection accounted for at least half of the
increase in the number of HCC cases among United States
veterans. During the same time periods, age-adjusted rates for
HCC with either HBV (2.2 vs. 3.1 per 100,000) or alcoholic
cirrhosis (8.4 vs. 9.1 per 100,000) remained stable. The rates
for HCC without risk factors have also remained without a
statistically significant change from 17.5 (15.8 to 19.1)
between 1993 and 1995 to 19.0 per 100,000 (17.3 to 20.7) between
1996 and 1998. Thirty-eight percent of patients without specific
risk factors had a diagnosis of nonspecific cirrhosis, many of
whom were not tested for Hepatitis C Virus. Similar trends have
been observed from the large referral setting of M.D. Anderson
Medical Center, where we recently reviewed the medical records
of all patients residing in the United States who received a
pathological diagnosis of HCC during 19931998; all patients
were tested for Hepatitis C Virus and HBV. The number of
patients referred with HCC steadily increased from 143 in
19931995 to 216 in 19961998; of those, 26 patients (18
percent) and 66 patients (31 percent) were Hepatitis C Virus
positive during 19931995 and 19961998, respectively (P =
0.01). These data and a summary of all published HCC studies in
the United States indicate that Hepatitis C Virus is present in
approximately 2530 percent of cases, with more recent series
reporting a greater proportion of Hepatitis C Virus-related
cirrhosis.
The risk of HCC in Hepatitis C Virus:
Cirrhosis is present in virtually all cases
of Hepatitis C Virus-related HCC. Once cirrhosis is established,
HCC develops at an annual rate of 1 percent to 5 percent. The
more important figure, the incidence of cirrhosis in Hepatitis C
Virus-infected patients, is more difficult to determine. We have
examined the natural history of Hepatitis C Virus (i.e.,
non-treated) in a systematic review of the literature among all
subjects at risk for chronic Hepatitis C Virus infection
(excluding studies in which cohorts were selected from patients
with chronic liver disease and those where the onset time of
infection could not be identified). The incidence rates of
cirrhosis and HCC were determined in 21 studies. Even within
this selected groups of studies, large variations were found in
the estimates of cirrhosis (033 percent) and HCC (02.8
percent), time to cirrhosis (1323 yrs), and time to HCC (1731
yrs). Short duration of follow-up, small sample size, incomplete
documentation of risk factors (e.g., alcohol), and incomplete
screening for cirrhosis/HCC explain some of these variations.
Due to the significant heterogeneity in these results, pooled
estimates from studies are unlikely to be valid. Nevertheless,
in studies with the best-documented onset of infection, there is
an average incidence of cirrhosis of 1 percent per year and of
HCC of 0.05 percent per year (20 percent and 1 percent at 20
years, respectively) in patients with chronic Hepatitis C Virus
infection. The mode of Hepatitis C Virus acquisition appears to
affect the progression of Hepatitis C Virus; studies of
community-acquired or Anti-D IgG related Hepatitis C Virus
infection had more benign course than that associated with
transfusion or hemophilia. A graphic presentation of the
incidence rates of cirrhosis or HCC vs. the sample size/duration
of followup suggests the presence of publication bias and that
the true estimates could be significantly higher or lower than
those described above.
Host related factors seem to be more
important than viral factors in determining the progression of
Hepatitis C Virus infection to cirrhosis and HCC. These factors
include older age of Hepatitis C Virus acquisition, male gender
(x23), heavy alcohol intake > 50 gm/day (x550), HBV (x 515)
or HIV co-infection, and possibly increased hepatic iron. Most
important of all seems to be time elapsed since acquiring
Hepatitis C Virus infection with a median time of 30 years being
the time frame when most HCC starts appearing. All Hepatitis C
Virus genotypes have been implicated in Hepatitis C
Virus-related HCC. Diabetes and obesity are also emerging risk
factors; in a large case-control study among veterans (823
patients with HCC and 3,459 controls), we found diabetes to be
associated with a 1.5-fold increase in the risk of HCC in the
presence of other major HCC risk factors such as Hepatitis C
Virus, HBV, and alcoholic cirrhosis. Obesity has been shown to
increase the risk of hepatic steatosis and fibrosis in Hepatitis
C Virus-infected patients, and diabetes is a known risk for
NASH, which could progress to cirrhosis.
Due to the large pool of Hepatitis C
Virus-infected persons, it is likely that the rising incidence
of HCC will continue over the next several years. Despite having
a current Hepatitis C Virus prevalence similar to that of Japan
2030 years earlier, extrapolating the current Japanese HCC
trends (10 times that of the current United States rates) to
future trends in the United States may be inappropriate. (For
example, <40 percent in the United States is Hepatitis C
Virus-related vs. 90 percent of HCC in Japan; also, most
patients with end-stage liver disease in the United States die
from non-HCC cirrhosis related complications, whereas in Japan,
decompensated liver disease is unusual.)
References:
1.El-Serag HB, Mason AC. Rising
incidence of hepatocellular carcinoma in the United States. N
Engl J Med 1999;340:74550.
2.El-Serag HB, Mason AC. Risk factors
for the rising rates of primary liver cancer in the United
States. Arch Intern Med 2000;160:322730.
3.El-Serag HB, Mason AC, Key CR.
Temporal trends in survival of patients with hepatocellular
carcinoma in the US. Hepatology 2001;33:625.
4.El-Serag HB. Global Epidemiology of
Hepatocellular Carcinoma. Clin Liver Dis 2001;5:87107, vi.
5.El-Serag HB, Everhart JE. Improved
survival following variceal hemorrhage over an 11-year period in
the Department of Veteran Affairs. Am J Gastroenterol
2000;95:356673.
6.El-Serag HB, Richardson P, Everhart JE.
The role of diabetes in hepatocellular carcinoma among veterans:
A case-control study. Am J Gastroenterol 2001;96:24627.
7.Di Bisceglie AM. Hepatitis C and
hepatocellular carcinoma. Hepatology 1997;26:34s8s.
Screening for Hepatocellular Carcinoma (HCC):
A Systematic
Review
Kelly A. Gebo, Mollie W. Jenckes,
Geetanjali Chander, Khalil G. Ghanem, H. Franklin Herlong,
Michael Torbenson, Mark S. Sulkowski, Kirk A. Harris, Samer El-Kamary,
and Eric B. Bass
Introduction
Hepatocellular carcinoma (HCC) is one of
the most serious complications of chronic hepatitis C. For
patients with chronic hepatitis C, practices of screening for
HCC vary widely, largely because of uncertainty about the
efficacy of screening tests in this population.
Objective
We conducted a systematic review of the
literature to determine: (1) the performance characteristics of
screening tests for HCC in patients with chronic hepatitis C
(e.g., sensitivity, specificity); and (2) whether use of
screening tests for HCC in patients with chronic hepatitis C can
improve outcomes.
Methods
Literature Sources: Seven electronic
databases were searched through DIALOG for the period from
January 1996 to March 2002. Additional articles were identified
by searching references in pertinent articles, hand searching
relevant journals, and querying technical experts.
Eligibility Criteria: Exclusion criteria
for review included: non-English language, articles limited to
basic science or non-human data, previously reported data, and
meeting abstracts. Inclusion criteria for review were: study
designed to address our key question, information pertinent to
management of hepatitis C, and 30 or more study subjects with
hepatitis C. In addition, we required histologic confirmation of
at least 50 percent of the HCC cases for studies on performance
characteristics of screening tests, and at least six months of
follow-up for studies evaluating use of screening tests to
improve outcomes.
Assessment of Study Quality: Each eligible
article was reviewed by a pair of reviewers, including at least
one team member with relevant clinical training and/or one with
training in epidemiology and research methods. Paired reviewers
independently rated the quality of each study in terms of the
following categories: representativeness of study subjects (5
items); bias and confounding (4 items); description of therapy
(4 items); outcomes and followup (5 items); statistical quality
and interpretation (4 items). Reviewers assigned each response
level a score of 0 (criterion not met), 1 (criterion partially
met), or 2 (criterion fully met) to each relevant item on the
quality form. The score for each category of study quality was
the percentage of the total 26 points available in each category
and therefore could range from 0100 percent. The overall
quality score was the average of the five categorical scores. We
also documented source of funding.
Extraction of Data: The paired reviewers
also abstracted data on type of study and geographical location;
study groups; specific aims; inclusion and exclusion criteria;
screening regimen; demographic, social, and clinical
characteristics of subjects; and results. Differences between
the two reviewers in either quality or content abstraction were
resolved by consensus.
Synthesis
Results of Literature Search: We identified
3,104 potentially relevant citations, and 1,731 of these were
eligible for abstract review. Through the abstract review
process we identified 39 articles that could contain data on one
of our key questions about screening for HCC in patients with
chronic hepatitis C. After reviewing these 39 articles, we found
17 studies that answered question 1 regarding performance
characteristics of the screening tests and one study that
answered question 2 regarding outcomes with screening for HCC.
Data from these eligible studies will be presented in a series
of evidence tables and figures highlighting their distinguishing
characteristics, methodological strengths and limitations, and
key findings.
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