NATIONAL INSTITUTES OF
HEALTH
CONSENSUS DEVELOPMENT CONFERENCE STATEMENT
Management of
Hepatitis C: 2002
June 10-12, 2002
PRELIMINARY DRAFT
STATEMENT
Revised DRAFT expected,
pending review of comments
JUNE 12, 2002
NIH Consensus Statements are prepared by a nonadvocate,
non-Federal panel of experts, based on (1) presentations by
investigators working in areas relevant to the consensus questions
during a 2-day public session; (2) questions and statements from
conference attendees during open discussion periods that are part of the
public session; and (3) closed deliberations by the panel during the
remainder of the second day and morning of the third. This statement is
an independent report of the panel and is not a policy statement of the
NIH or the Federal Government.
The statement reflects the panelís assessment of medical knowledge
available at the time the statement was written. Thus, it provides a
"snapshot in time" of the state of knowledge on the conference topic.
When reading the statement, keep in mind that new knowledge is
inevitably accumulating through medical research.
Introduction
1. What
is the natural history of hepatitis C?
2. What
is the most appropriate approach to diagnose and monitor
patients?
3. What
is the most effective therapy for hepatitis C?
4. Which
patients with hepatitis C should be treated?
5. What
recommendations can be made to patients to prevent transmission of
hepatitis C?
6. What
are the most important areas for future research?
Conclusions
Consensus
Development Panel
Speakers
Planning
Committee
Conference
Sponsors
Conference
Cosponsors
Introduction
The hepatitis C virus (HCV) is the leading cause of known liver
disease in the United
States. It is the most common cause of cirrhosis and a common cause
of hepatocellular
carcinoma (HCC); it is also the most common reason for liver
transplantation. At least 4 million
people in this country are believed to be infected with this virus.
Following the identification of
hepatitis A and hepatitis B, this disorder was categorized in 1974 as
"non-A, non-B hepatitis." In
1989, the hepatitis C virus was discovered and was found to account
for the majority of those
patients with non-A, non-B hepatitis. In March 1997, a Consensus
Development Conference was
held at the National Institutes of Health (NIH) regarding management
and treatment. This led to
an important, widely distributed NIH Consensus Statement that, for
several years, was broadly
accepted as the standard of care.
Now 5 years later, knowledge of hepatitis C has increased
dramatically, leading to the
need to reexamine the approaches to management and treatment.
Accordingly, the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has
convened a Consensus
Development Conference with the aim of reviewing the most recent
developments regarding
management, treatment options, and the widening spectrum of potential
candidates for treatment
and of updating the 1997 Consensus Statement.
This NIH Consensus Development Conference on Management of Hepatitis
C: 2002
convened June 10&endash;12, 2002. The primary sponsors of this
meeting were the NIDDK and the
Office of Medical Applications of Research (OMAR) of the NIH. The
cosponsors were the
National Institute of Child Health and Human Development (NICHD); the
National Cancer
Institute (NCI); the National Center for Complementary and
Alternative Medicine (NCCAM);
the National Institute on Alcohol Abuse and Alcoholism (NIAAA); the
National Institute on
Drug Abuse (NIDA); the National Institute of Allergy and Infectious
Diseases (NIAID); the
National Heart, Lung, and Blood Institute (NHLBI); the Centers for
Medicare & Medicaid
Services (CMS); the Centers for Disease Control and Prevention (CDC);
the U.S. Food and Drug
Administration (FDA); and the U.S. Department of Veterans Affairs
(VA).
The Agency for Healthcare Research and Quality (AHRQ) provided
support to the NIH
Consensus Development Conference on Management of Hepatitis C: 2002
through its Evidence-
based Practice Center program. Under contract to AHRQ, the Johns
Hopkins University
Evidence-based Practice Center developed the systematic review and
analysis that served as a
reference for discussion at the Conference.
This two-and-a-half-day conference examined the current state of
knowledge regarding
the management of hepatitis C and identified directions for future
research.
During the first day-and-a-half of the conference, experts presented
the latest hepatitis C
research findings to an independent non-Federal panel. After weighing
all of the scientific
evidence, the panel drafted a statement, addressing the following key
questions:
1. What
is the natural history of hepatitis C?
2. What
is the most appropriate approach to diagnose and monitor
patients?
3. What
is the most effective therapy for hepatitis C?
4. Which
patients with hepatitis C should be treated?
5. What
recommendations can be made to patients to prevent transmission of
hepatitis C?
6. What
are the most important areas for future research?
On the final day of the conference, the panel chairperson read the
draft statement to the
conference audience and invited comments and questions. A press
conference followed to allow
the panel and chairperson to respond to questions from the media.
The consensus panel's draft statement was posted to the Consensus
Program Web site&emdash;
http://consensus.nih.gov&emdash;on Wednesday, June 12, 2002.
1. What is the natural history
of hepatitis C?
The Virus
HCV is an RNA virus of the Flaviviridae family. There are 6 HCV
genotypes and more
than 50 subtypes. These genotypes differ by as much as 30 to 50
percent in their nucleotide
sequences. The virus also has a high propensity to mutate. The lack
of a vigorous T-lymphocyte
response appears to promote a high rate of chronic infection. The
extensive genetic heterogeneity
of HCV has important diagnostic and clinical implications, perhaps
explaining difficulties in
vaccine development and the lack of response to therapy. Genotype 1
accounts for 70 to
75 percent of all HCV infections in the United States and is
associated with a poorer response to
treatment.
HCV replicates preferentially in hepatocytes but is not directly
cytopathic, leading to
persistent infection. During acute infection, the level of viral
genomes/mL of plasma or serum
has been reported to range from 105 to 107. Chronic HCV RNA levels
are quite variable from
person to person and generally range from 50,000 to 5 million.
However, within the same
individual, RNA levels are relatively stable.
Epidemiology
According to the National Health and Nutrition Examination Survey
(NHANES) of
1988&endash;1994, 3.9 million Americans were infected with
hepatitis C, and of this group, 2.7 million
are estimated to have chronic infection. However, NHANES is a
population-based household
survey that largely excludes groups with a substantially increased
prevalence of infection, such
as persons who are incarcerated, homeless, or institutionalized due
to mental illness.
Although difficult to assess accurately, the incidence of HCV
infection declined sharply
in the late 1980s. Transmission from blood products was virtually
eliminated by the introduction
of a more sensitive test for anti-HCV antibodies in mid-1992.
Currently, approximately 35,000
acute HCV infections are estimated to occur each year. Because of the
high rate of persistent
infection, a fourfold increase in the number of persons with chronic
HCV infection is projected
to occur from 1990 to 2015. The prevalence of HCV is presently
believed to be at least
1.8 percent, making HCV the most common blood-borne infection in the
United States. Persons
aged 40 to 59 years have the highest prevalence of HCV infection, and
in this age group, the
prevalence is highest in African-Americans (6.1 percent).
HCV transmission occurs primarily through exposure to infected blood.
This exposure
exists in the context of injection drug use (IDU), blood transfusion,
solid organ transplantation
from infected donors, unsafe medical practices, occupational exposure
to infected blood, birth to
an infected mother, multiple heterosexual partners, and high-risk
sexual practices. High HCV
seroprevalence rates (from 15 to 50 percent) have been observed in
specific subpopulations, such
as the homeless, incarcerated persons, and hemophiliacs, with the
highest rates (70 percent to
more than 90 percent) reported in IDUs.
Acute Infection
After initial exposure, HCV RNA can be detected in blood in 1 to 3
weeks and is present
at the onset of symptoms. Antibodies to HCV are detected by enzyme
immunoassay (EIA) in
only 50 to 70 percent of patients at the onset of symptoms,
increasing to approximately
90 percent of these patients after 3 months. Within an average of 2
to 8 weeks, liver cell injury is
manifested by elevation of serum alanine aminotransferase (ALT).
Acute infection can be severe
but is rarely fulminant. Symptoms are uncommon but can include
malaise, weakness, anorexia,
and jaundice. Symptoms usually subside after several weeks as ALT
levels decline.
Chronic Infection
Chronic HCV infection is diagnosed by the detection of HCV RNA at
least intermittently
in the blood by either qualitative or quantitative tests for a period
of at least 6 months. In general,
prospective studies have shown that the majority of HCV-infected
persons develop chronic
infection. Factors associated with spontaneous clearance of HCV
infection appear to include
younger age, female gender, and certain major histocompatability
complex genes. African-
American men appear to be least likely to spontaneously clear the
virus.
The most important sequelae of chronic HCV infection are progressive
liver fibrosis
leading to cirrhosis, end stage liver disease (ESLD), and HCC.
Estimates of the proportion of
chronically infected persons who develop cirrhosis 20 years after
initial infection have been
substantially higher from retrospective studies (17 to 55 percent)
than from prospective studies
(7&endash;16 percent). The actual risk of progressive disease at
20 years is now considered to be closer
to the estimates from prospective studies. There is little evidence
that the risk of progression of
liver disease is affected significantly by virologic factors,
including viral load, viral genotype,
and quasispecies diversity. However, many host factors are observed
to increase this risk,
including older age at time of infection; male gender; and an
immunosuppressed state, such as
HIV infection. Hepatitis B appears to increase the risk of
progressive liver disease. Alcohol use
plays an important role in increasing the risk of progressive liver
disease, with strong evidence
for the detrimental effects of 60 g/day in men (equivalent to six
beers, four glasses of wine, or
three mixed drinks) and 40 g/day in women, but there is suggestive
evidence that lower amounts
can also increase the risk of liver damage associated with HCV. Other
factors, including iron
overload, nonalcoholic fatty liver disease, schistosomal coinfection,
potentially hepatotoxic
medications, and environmental contaminants, may also have important
effects.
In the United States, deaths associated with chronic HCV are
currently more likely to be
due to ESLD than to HCC. Data from death certificates in 1999 found
that approximately 4,000
deaths were attributed to HCV infection, but this is likely to be an
underestimate. The only
treatment option for persons who have developed ESLD (decompensated
cirrhosis) is
transplantation. Currently, HCV is the primary reason for liver
transplantation in the United
States. Little is known about the clinical course and risks of
HCV-related complications in
persons who have been infected longer than two decades.
HCV accounts for an estimated one-third of HCC cases in the United
States. HCC rarely
occurs in the absence of cirrhosis or advanced fibrosis. The
incidence of HCV-related HCC is
continuing to rise in United States and worldwide, in part because of
the increasing numbers of
persons who have been chronically infected for decades, the presence
of comorbid factors, and
the longer survival of persons with advanced liver disease due to
improved management of
complications. Risk factors for HCC in persons with chronic HCV
infection are largely the same
as those for the development of ESLD.
Extrahepatic Manifestations of HCV
Patients with chronic HCV can present with extrahepatic
manifestations or syndromes
considered to be of immunologic origin, such as rheumatoid symptoms,
keratoconjunctivitis
sicca, lichen planus, glomerulonephritis, and essential mixed
cryoglobulinemia. Cryoglobulins
have been detected in the serum of up to one-half of patients with
chronic HCV, but the clinical
features of essential mixed cryoglobulinemia are less frequent.
Chronic hepatitis C is also related
to porphyria cutanea tarda.
2. What is the most
appropriate approach to diagnose and monitor patients?
Various tests are available for the diagnosis and monitoring of
hepatitis C infection. Tests
that detect antibody against the virus include the EIAs, which
contain HCV antigens from the
core and nonstructural genes, and the recombinant immunoblot assays
(RIBAs). The same HCV
antigens are used in both EIAs and the RIBAs. Targeted amplification
techniques using either
polymerase chain reaction (PCR) or transcription-mediated
amplification (TMA) have been
developed to detect HCV RNA. Liver biopsy can provide direct
histologic assessment of liver
injury due to HCV but cannot be used to diagnose HCV infection.
HCV Serologic Assays
EIA tests are reproducible, inexpensive, and FDA-approved for use in
the diagnosis of
HCV. They are suitable for screening at-risk populations and are
recommended as the initial test
for patients with clinical liver disease. The very high sensitivity
and specificity of the third-
generation EIAs (sensitivity greater than 99 percent, specificity 99
percent) obviate the need for
a confirmatory RIBA in the diagnosis of individual patients,
particularly those with risk factors
for HCV. A negative EIA test is sufficient to exclude a diagnosis of
chronic HCV infection in
immune competent patients. Rarely, patients on hemodialysis and
patients with immune
deficiencies may have falsely negative EIAs. Conversely, falsely
positive EIAs may occur in
patients with autoimmune disorders. In these patients, assays for HCV
RNA are necessary for
diagnosis. RIBA remains a useful supplemental assay in the setting of
large-scale HCV screening
of blood products.
Qualitative HCV Assays
Persistent HCV infection in a patient with a positive EIA test should
be confirmed by a
qualitative HCV RNA assay. The automated, FDA-approved, qualitative
HCV PCR assay has a
lower limit of detection of 50 IU/mL. More recently, a
transcription-mediated amplification
assay has been developed with a lower limit of detection comparable
to the qualitative PCR
assay. This latter assay has yet to be approved for use by the FDA.
The specificity of these
assays exceeds 98 percent. A single positive qualitative assay for
HCV RNA confirms active
HCV replication, but a single negative assay does not prove that the
patient is not viremic. A
followup qualitative HCV RNA should be performed to confirm the
absence of active HCV
replication. Once HCV infection is confirmed, repeat testing for
qualitative HCV RNA by
qualitative PCR is not helpful in the management of untreated
patients. Almost all patients
remain viremic, and a negative result may merely reflect a transient
decline in viral titer below
the level of detection of the assay.
Quantitative HCV Assays
Testing for HCV RNA level (or viral load) by a quantitative assay,
either quantitative
PCR (qPCR) or branched DNA signal amplification assay (bDNA), can
provide accurate
information on HCV viral titer. An HCV RNA standard has been
introduced to permit
normalization of reported viral titers in international units (IU).
The reported IU does not
represent the actual number of viral particles in a preparation.
Significant variability exists
between available assays. The dynamic range of each assay needs to be
observed, and
appropriate dilutions of sample material should be performed to
obtain accurate quantitative
results. The clinical utility of serial HCV viral titers in a patient
is predicated on continued use of
the same specific quantitative assay used in the initial
determination of the viral titer. While there
is little correlation between disease severity or disease progression
with the absolute titer of HCV
RNA, quantitative determination of the HCV titer provides important
information in assessing
response to treatment.
Testing for serum ALT levels is the most inexpensive and noninvasive
means of
assessing disease activity. However, a single determination of ALT
levels gives limited
information about the severity of the underlying liver disease. In
most studies, a weak association
exists between the degree of ALT elevation and severity of the
histopathological findings on
liver biopsy. Serial determinations of ALT levels over time may
provide a better means of
assessing liver injury, but the accuracy of this approach has not
been shown. Patients who
initially have a normal ALT level should undergo serial measurements
over several months to
confirm the persistence of normal ALT levels. Although loss or
reduction in HCV RNA is the
primary indicator of response to antiviral therapy, the resolution of
elevated ALT levels with
antiviral therapy appears to be an important indicator of disease
response. Serial determinations
of ALT levels can be recommended as the general means of monitoring
patients but is not
adequate to assess progression to cirrhosis.
Various noninvasive tests have been examined for monitoring patients
with chronic
hepatitis C infection. These include routinely available laboratory
tests, such as liver-associated
chemistries, platelet count, and prothrombin time, as well as
specific serum markers of fibrosis
and inflammation that are not currently widely available or well
validated. No single test or panel
of serologic markers can provide an accurate assessment of
intermediate stages of hepatic
fibrosis. Similarly, quantitative tests of liver function and
radiologic imaging of the liver are
sensitive for diagnosing advanced cirrhosis but are not useful in
assessing hepatic fibrosis and
early cirrhosis.
Liver Biopsy
Liver biopsy yields information on fibrosis and histology assessment
that is not
obtainable by any other means. Various noninvasive methods based on
biochemical or serologic
tests have been evaluated in several studies. Liver enzymes have
shown little value in predicting
fibrosis. Extracellular matrix tests do predict severe stages of
fibrosis but cannot consistently
classify intermediate stages of fibrosis. Moreover, only liver biopsy
provides information on
possible contributions of iron, steatosis, and concurrent alcoholic
liver disease to the progression
of chronic hepatitis C toward cirrhosis. It is unusual for unexpected
etiologies of liver disease to
be discovered on liver biopsies from patients undergoing evaluation
of chronic hepatitis C. The
information obtained on liver biopsy does allow affected individuals
to make more informed
choices with regard to initiation or postponement of antiviral
treatment. Adult or pediatric
patients with persistently normal or slightly elevated ALT and
minimal or no fibrosis on liver
biopsy may be reassured of a favorable prognosis and decide to defer
antiviral therapy. Since a
favorable response to current antiviral therapy in patients infected
with genotype 2 or 3 occurs in
80 percent, the necessity of routine pretreatment liver biopsy in
these patients requires further
study. Baseline assessment of liver histology offers the standard by
which subsequent
comparisons may be made. There is little information, however, on the
appropriate interval for
subsequent evaluations.
Hepatocellular Cancer Screening
HCC complicates cirrhosis secondary to HCV. It is estimated that HCC
occurs after the
development of cirrhosis at a rate varying from 0 to 3 percent per
year. Few studies examine
specific screening strategies for HCC in patients with advanced HCV.
Alpha fetoprotein (AFP)
and ultrasound every 6 months were used in a single study of patients
with cirrhosis secondary to
HCV. Identification of HCC was not significantly increased in the
screened population.
Additional studies identifying new markers and testing specific
screening protocols are
warranted.
3. What is the most effective
therapy for hepatitis C?
Since the 1997 NIH Consensus Development Conference on the Management
of
Hepatitis C, several important therapeutic advances have occurred,
particularly with the
introduction of PEG-interferon with ribavirin therapy. Combination
therapy results in better
treatment responses than monotherapy. The highest response rates have
been achieved with
PEG-interferon in combination with ribavirin. Genotype determinations
now influence treatment
decisions. Methods of genotyping include PCR-based techniques and,
more recently, less
expensive serotyping (antibody) assays. Sustained viral response
(SVR), defined by the absence
of detectable qualitative HCV RNA in the serum by RT-PCR 24 weeks
after the end of
treatment, is currently the best indicator of effective therapy.
Treatment of Naïve Patients
Three large pivotal trials have examined the efficacy of
PEG-interferon plus ribavirin in
the treatment of chronic HCV infection. These trials excluded
patients with decompensated
cirrhosis and other comorbid conditions. Overall, PEG-interferon plus
ribavirin is more effective
than standard interferon-ribavirin combination or PEG-interferon
alone. SVRs were similar with
both forms of PEG-interferon (alpha 2a and alpha 2b) when used in
combination with ribavirin.
Factors associated with successful therapy include genotypes other
than 1, lower baseline viral
load, and less fibrosis or inflammation on liver biopsy. In all three
trials, an SVR of 42 to
46 percent was achieved for genotype 1 using a higher dose of
PEG-interferon and ribavirin for
48 weeks. An SVR of 76 to 82 percent was achieved for patients with
genotypes 2 and 3. It
appears that 24 weeks of treatment and a lower dose of ribavirin is
adequate for genotypes 2 and
3. Early viral response (EVR), defined as a minimum 2 log decrease in
viral load during the first
12 to 24 weeks of treatment, has been identified as predictive of
SVR. Those who fail to achieve
an EVR have only a small chance of achieving a SVR even if therapy is
continued for a full year.
Although SVR has not yet been correlated with improved survival
because of the
necessity for long-term followup, the absence of a detectable serum
HCV RNA has been
correlated with resolution of liver injury, reduction in hepatic
fibrosis, and a very low likelihood
of recurrent HCV infection. Additionally, in two large recent studies
from Japan, interferon
treatment was associated with a reduction in the development of
hepatocellular carcinoma, a
finding that was more pronounced among patients with SVR.
Re-treatment of Patients
Patients who may benefit from re-treatment include those whose HCV
infection failed to
achieve SVR. Decisions regarding re-treatment should be based upon:
(1) previous type of
response, (2) the previous therapy and the difference in potency of
the new therapy, (3) the
severity of the underlying liver disease, (4) viral genotype and
other predictive factors for
response, and (5) tolerance of previous therapy and adherence.
Relapsers achieve an initial end of treatment response (ETR) for
their HCV disease, but it
is not sustained over time (i.e., no SVR). Nonresponders never
achieve an EVR, ETR, or SVR.
Among the nonresponders, there is a subset of persons who have a
substantial reduction of HCV
RNA (1 to 2 log units or more) during therapy, and who can be
categorized as partial responders.
Even in the absence of SVR, treatment may be associated with improved
histology.
Preliminary results suggest that overall only 15 to 20 percent of
nonresponders treated
with standard interferon/ribavirin combinations achieved an SVR on
re-treatment using PEG-
interferon with ribavirin. Patients with genotypes 2 or 3 have better
response rates to re-treatment
than genotype 1.
The ability to achieve SVR following re-treatment with
PEG-interferon/ribavirin in
patients who relapsed following interferon monotherapy or standard
interferon/ribavirin therapy
is currently being evaluated. However, in cases where the same
regimen has been used for re-
treatment, virtually all patients relapse again after treatment is
stopped. Extending the duration of
re-treatment without changing the dose or regimen may reduce the
relapse rate, but this has not
yet been proven prospectively.
Patients whose HCV infection does not respond to the current optimal
therapy with PEG-
interferon and ribavirin present a significant problem, particularly
in the presence of advanced
fibrosis or cirrhosis. The possible role of maintenance therapy with
PEG-interferon alone in
preventing further progression of cirrhosis, clinical decompensation,
or development of
hepatocellular carcinoma is currently the focus of a large-scale,
multicenter United States trial,
HALT-C. Until the results of HALT-C or similar studies are available,
the role of long-term,
continuous therapy with PEG-interferon (or ribavirin or both) for
nonresponders must be
considered experimental.
Knowledge of the severity of the underlying liver disease is
important in recommending
re-treatment. Patients with advanced fibrosis or cirrhosis are at
increased risk for developing
hepatic decompensation and should be considered for re-treatment,
especially if they were
originally treated with interferon monotherapy. For the re-treatment
of patients with intermediate
degrees of fibrosis and disease activity, clinicians should consider
the factors enumerated above.
Side Effects of Treatment
In the registration trials of PEG-interferon and ribavirin,
significant side effects were
noted that resulted in discontinuation of treatment in approximately
20 percent of subjects. Major
side effects of combination therapy include influenza-like symptoms,
hematologic abnormalities,
and neuropsychiatric symptoms. The education of patients and
caregivers about side effects and
their prospective management is an integral part of treatment.
Frequent monitoring of HCV
therapy is necessary. Antidepressants, such as selective serotonin
reuptake inhibitors, may be
useful in the management of less severe depression associated with
antiviral therapy. Treatment
of cytopenias with hematopoietic growth factors may be useful and may
prevent dose reduction
or drug discontinuation. Severe hemolysis may occur in patients with
renal insufficiency. Lactic
acidosis may be a rare complication of combination therapy in
patients undergoing therapy for
HIV and HCV.
4. Which patients with
hepatitis C should be treated?
All patients with chronic hepatitis C are potential candidates for
antiviral therapy.
Treatment is recommended for patients who are at increased risk for
progression to cirrhosis.
These patients are characterized by measurable HCV RNA, a liver
biopsy with portal or bridging
fibrosis, and at least moderate inflammation and necrosis; the
majority have persistently elevated
ALT values. In some patient populations, the risks and benefits of
therapy are less clear and
should be determined on an individual basis or in the context of
clinical trials.
Many patients with chronic HCV have been ineligible for trials
because of injection drug
use (IDU), alcohol abuse, age, and a number of comorbid medical and
neuropsychiatric
conditions. Efforts should be made to increase availability of the
best current treatment to these
patients. Because a large number of HCV-infected persons in the
United States are incarcerated,
strategies should be developed to better prevent, diagnose, and treat
these individuals.
Normal ALT
Approximately 30 percent of patients with chronic HCV have normal ALT
levels, and
another 40 percent have ALT levels less than two times the upper
limit of normal. Although
most of these patients have disease that is histologically mild, some
patients may progress to
advanced fibrosis and cirrhosis. Experts differ on whether to biopsy
and treat these patients.
Numerous factors must be considered in recommending treatment,
including favorable
genotype, presence of hepatic fibrosis, patient motivation, symptoms,
severity of comorbid
illness, and the patient's age. SVR rates do not differ in patients
with normal or mildly elevated
ALT when treated with interferon monotherapy. Studies of
PEG-interferon with ribavirin have
not been completed in patients with normal ALT levels.
Mild Liver Disease
In patients with persistent ALT elevations, but with no fibrosis and
minimal
necroinflammatory changes, progression to cirrhosis is likely to be
slow; these patients should be
monitored periodically.
Advanced Liver Disease
Data on safety and efficacy of interferon (standard or pegylated)
with or without ribavirin
in patients with advanced fibrosis or compensated cirrhosis have been
largely derived from
subgroup analyses of larger trials. SVR is lower in patients with
advanced liver disease than in
patients without cirrhosis. An important goal of treatment in
advanced liver disease is to delay
histological disease progression, which is being evaluated in the
NIH-sponsored HALT-C trial.
Patients with decompensated cirrhosis should be referred to clinical
trials until safety and
efficacy data of treatment are established, or they should be
considered for liver transplantation.
In patients with ESLD, the main treatment option is liver
transplantation. There are ongoing
studies of antiviral therapy of patients awaiting liver
transplantation, but this approach may be
limited by potentially life-threatening side effects of
antivirals.
Recurrence After Transplantation
Hepatitis C frequently recurs following liver transplantation, and
disease progression is
accelerated compared to immunocompetent patients with HCV disease.
Once cirrhosis develops
in the allograft, the risk of complications is higher than in
immunocompetent cirrhotic patients.
Recurrence of hepatitis C after transplant correlates with HCV RNA
level at the time of
transplantation, the age of the organ donor, and the degree of
immunosuppression in the post-
transplantation period.
Children
Few data are available on the treatment of children and adolescents,
and further research
is needed. Studies of interferon monotherapy in children have been
largely uncontrolled, with
small numbers of highly selected patients. SVR rates are similar to
or even better than those in
adults, ranging from 33 to 45 percent (26 percent for genotype 1 and
70 percent for other
genotypes). Several studies of combination therapy in children are
under way. Promising new
therapies should also be studied in children.
Acute Hepatitis C
Acute hepatitis C is uncommonly recognized and diagnosed. Studies of
interferon
treatment for acute hepatitis C have been very heterogeneous and
limited by small sample size,
lack of randomization, variability in the timing of therapy after
onset of infection, dose and
schedule, and endpoints and followup. Although high SVRs have been
seen in small
uncontrolled trials with interferon monotherapy, recommendations on
whether treatment is
necessary, the timing of therapy, and which regimen to use remain
open.
Injection Drug Users
Recent experience has demonstrated the feasibility and effectiveness
of treating HCV in 20
people who use illicit injection drugs (known as injection drug users
or IDUs). This is important
because IDUs comprise the largest group of hepatitis C patients in
the United States, and
successful treatment may reduce transmission. Management of
HCV-infected IDUs is enhanced
by linking IDUs to drug-treatment programs. Efforts should be made to
promote collaboration
between experts in HCV and substance-abuse providers. HCV therapy has
been successful even
when the patients have not been abstinent from continued drug use or
are on daily methadone.
Few data are available on HCV treatment in active IDUs who are not in
drug treatment
programs.
HIV Coinfection
All HIV infected persons should be screened for HCV. Patients with
chronic hepatitis C
and concurrent HIV infection may have an accelerated course of HCV
disease. Therefore,
although there are no HCV therapies specifically approved for
patients coinfected with HIV,
these patients should be considered for treatment. Thus far, studies
have enrolled only patients
with stable HIV infection and well-compensated liver disease. In
coinfected persons, an SVR can
be achieved with HCV treatment. Preliminary data suggest better
responses to PEG-interferon
with ribavirin than to standard interferon with ribavirin. Although
treatment of HCV has not
jeopardized control of the HIV infection, additional data are
needed.
Alcohol and HCV
Alcohol is an important cofactor in the progression of HCV liver
disease to cirrhosis and
HCC. A history of alcohol abuse is not an absolute contraindication
to therapy; however,
continued alcohol use during therapy adversely affects the response
to treatment. Treatment of
HCV should be performed in conjunction with efforts to treat alcohol
abuse or dependence.
Heavy alcohol consumption of >80 g/day seriously compromises HCV
treatment. Safe levels of
alcohol consumption are still unclear.
5. What recommendations can be
made to patients to prevent transmission of hepatitis C?
The large global reservoir of individuals infected with HCV provides
a source of
transmission to others at risk. Direct percutaneous exposure is the
most efficient method for
transmitting HCV, and IDU accounts for over two-thirds of all new
infections. Needle and
syringe exchange programs and comprehensive risk-modifying
educational programs that are
highly effective in preventing HIV transmission are likely to be
useful for decreasing HCV
transmission. HCV is rarely transmitted by transfusion of blood
products or transplantation of
organs or tissues in the United States and other countries where
screening tests exclude
infectious donors.
The majority of other cases can be attributed to sexual transmission
and occupational
exposures to blood, although the actual risk of transmission through
these routes is low. Data
regarding transmissibility by sexual contact have been confounded in
part by other exposures,
including IDU, that can increase the risk of transmission of HCV. HCV
genotypes appear to
have no impact on the risk of transmission.
In the United States, the estimated seroprevalence of HCV is 2 to 3
percent among
partners of HCV-infected persons who are in long-term monogamous
relationships and is 4 to
6 percent among persons with multiple sex partners, sex workers, and
men who have sex with
men (those at risk for sexually transmitted diseases). For
heterosexual, discordant monogamous
couples, the risk of transmission is estimated to be 0 to 0.6 percent
annually, with the risk to
females being threefold greater than to male partners. Because of the
low risk of HCV
transmission, couples need not use barrier protection (condoms);
however, couples should be
advised that the use of condoms may decrease the risk of HCV
transmission. Based on studies in
persons at risk for sexually transmitted diseases, HCV transmission
is approximately 1 percent
annually. HCV-infected individuals with multiple sexual partners or
in short-term relationships
should be advised to use condoms to prevent transmission of HCV and
other sexually transmitted
diseases. The sharing of common household items, such as razors and
toothbrushes, is another
potential source of transmission of HCV. There is no evidence that
kissing, hugging, sneezing,
coughing, food, water, sharing eating utensils or drinking glasses,
casual contact, or other contact
without exposure to blood is associated with HCV transmission.
Health care workers may have a slightly higher prevalence of HCV
infection than the
general population, although they may have acquired infection from
nonoccupational sources.
Transmission from health care workers to patients has also been
documented, but it is rare and is
confounded by other risk factors.
The risk of HCV infection from needle sticks is estimated to be 2
percent. At this time,
antiviral prophylaxis is not recommended following needle stick
exposure. It is recommended
that the source and exposed individual should be tested for antibody
to HCV. If the source
individual is HCV EIA positive, an HCV RNA assay should be done. The
exposed individual
should be tested for HCV antibody and ALT at exposure and repeated at
4&endash;6 months. If
seroconversion occurs, recommendations for persons following acute
HCV infection should be
followed.
Percutaneous exposures, such as body piercing and tattooing, are
other potential sources
of transmission if contaminated equipment or supplies are used.
However, the rates of
transmission are less than 1 percent, and these data are confounded
by other risk factors.
Perinatal transmission has been documented. Higher maternal HCV RNA
load appears to
be associated with a greater risk for HCV transmission to the infant.
The risk of transmission is
approximately 2 percent for infants when the mother is HCV
seropositive; this risk increases up
to 7 percent when a pregnant woman has two positive assays for HCV
RNA. HCV transmission
may be increased to approximately 10 percent with maternal injection
drug use and up to
20 percent in women coinfected with HCV and HIV. There are no
prospective studies evaluating
the use of elective Cesarean section for the prevention of
mother-to-infant transmission of HCV.
There are currently no data to determine if antiviral therapy reduces
perinatal transmission.
Ribavirin and interferons are contraindicated during pregnancy.
Breast-feeding does not appear to transmit HCV. Children and
personnel should not be
excluded from daycare centers because of hepatitis C infection.
Standard universal precautions
should be used in any situation where blood or blood products are
used.
6. What are the most important
areas for future research?
- The development of reliable, reproducible, and efficient culture
systems for propagating the HCV virus is considered to be of the
highest priority. This goal is deemed essential not only for vaccine
development but also for progress in fundamental aspects of HCV
biology, hepatic tropism and viral replication. Furthermore, this
development will assist in new drug discovery, as well as enhance
understanding of the mechanisms of drug resistance.
- The role of genetic factors in the pathogenesis of HCV, including
immune responses to infection, reasons for spontaneous resolution and
variations in natural history, and responses to therapy, need further
examination.
- Priority should be given to developing less toxic therapies and
molecular-based agents that specifically inhibit viral replication
and/or translation of viral RNA.
- Hepatic fibrosis is the principal complication of chronic HCV
infection leading to the development of cirrhosis and ESLD. Directed
investigation examining the development and progression of fibrosis is
therefore essential for effective management of these patients.
Studies also are needed to examine fundamental mechanisms of fibrosis
in response to HCV. Studies are needed to define rates of progression
of fibrosis in patients with prolonged duration of HCV infection.
Similarly, the natural history of fibrosis in special populations
including children, HIV-coinfected patients, the elderly,
African-Americans, and HCV-infected patients with normal ALT levels
needs to be determined. Evaluation of progressive fibrosis will best
be accomplished with noninvasive tests capable of discriminating
intermediate stages of fibrosis. Research into the development of
noninvasive dynamic measures of hepatic fibrosis is strongly
encouraged.
- Given the growing epidemic of chronic HCV, the large number of
untreated patients, and a compelling number of important areas for
future research, we recommend that NIH establish a Hepatitis Clinical
Research Network. The goal of this network should be the conduct of
research related to the natural history, prevention, and treatment of
hepatitis C.
- Randomized controlled trials (RCTs) need to be carried out in
special populations of patients not represented in current trials to
determine the applicability of currently accepted treatment to these
subgroups and to determine optimal doses and duration of therapy.
These include children, patients with acute hepatitis, hemophiliacs,
IDUs in drug treatment programs, active drinkers who demonstrate
medication compliance, patients with depression stabilized with
selective serotonin reuptake inhibitors and other antidepressants, as
well as institutionalized patients and those coinfected with HIV.
Therapies need to be developed for difficult treatment groups,
including patients whose HCV infection does not respond to or relapse
after current therapy, patients with decompensated cirrhosis,
transplant patients, and patients with renal disease.
- Little information exists to describe the natural history of HCV
viremia of prolonged duration of 20 years or more. Studies are needed
to examine the pattern of HCV disease progression in persons infected
for at least two decades.
- Natural history studies are needed in special groups, such as
minorities, children, those older than 65, HCV-HIV coinfected
patients, IDUs, and persons with normal ALT levels. More investigation
is needed into the prevalence and clinical significance of extra
hepatic manifestations of HCV.
- There is a need to assess the effectiveness of infection control
strategies, including practices in hemodialysis units and safe
injection practices. Better understanding of the risk of specific
sexual practices and the effectiveness of risk reduction counseling
are needed. The effect of elective Cesarean section on
mother-to-infant transmission should be assessed.
- Trials are needed in combination therapy nonresponders or
intolerant patients that compare combinations of antifibrotic and
anti-inflammatory agents, as well as immunomodulatory drugs and drugs
that are directed specifically at HCV replication. Studies are also
needed to assess efficacy of alternative and nontraditional
medicines.
- Because studies of acute hepatitis C are small in number, greater
numbers of patients need to be included in clinical trials.
Evidence-based proof is needed to determine whom to treat and when to
start therapy. Delays in treatment for 2 to 3 months seem reasonable
to identify cases that spontaneously resolve. Weekly monotherapy with
PEG-interferon should be studied.
- Provision of educational programs for grades K&endash;12 is
necessary, as well as enhanced information related to risk factors for
HCV for dissemination to the general public and the medical
profession.
- There is a need to assess the effectiveness of supportive therapy
to ameliorate the side effects of antiviral therapy.
- There is a need to more clearly establish the role of liver biopsy
in the therapeutic management of patients with chronic hepatitis C.
Studies are needed that more clearly describe biopsy techniques and
side effects during trials. The relationship of pretreatment histology
to treatment outcomes needs better definition. The value of liver
biopsy in patients with normal liver function tests also needs
evaluation as does the need and timing for followup biopsies in
patients with stage 0&endash;1 fibrosis when treatment is
deferred. The relationship of pretreatment histologic characteristics,
including steatosis, iron deposition, and the pattern of fibrosis to
clinical outcomes including progressive fibrosis and response to
medical therapy, must be better defined. In addition, the requirement
for direct assessment of hepatic histology by liver biopsy in the
setting of nongenotype 1 infection should be critically evaluated. In
the absence of sensitive noninvasive markers of fibrosis, liver biopsy
remains essential for direct assessment of the degree of hepatic
fibrosis. However, the precise interval for monitoring progression of
fibrosis in HCV-infected patients, in particular those populations
most at risk for rapid progression, needs to be evaluated.
- International standardization of viral RNA titers is needed along
with a critical assessment of the utility of measuring viral kinetics
as valid prognostic indicators of SVR and other clinically meaningful
responses to therapy.
- Randomized controlled trials are needed to assess screening tests
in patients at greatest risk of HCC for predicting this
complication.
- Studies are needed to assess whether there are safe levels of
alcohol consumption in patients with HCV. Investigations into the role
of fatty liver, obesity, diabetes, and hepatic iron stores on the
natural history and responses to therapy are needed. Studies are
needed in HIV coinfected patients to determine treatment outcomes and
duration, maintenance therapy, treatment safety, and pathogenesis.
Conclusions
The incidence of HCV-related disease has diminished in the United
States since testing
for HCV has been widely applied in blood-banking practices. The virus
is transmitted by blood
and now occurs primarily through IDU, high-risk sexual practices, and
occupational exposure.
The majority of infections become chronic, and, therefore, the
prevalence of HCV infections has
increased over the past decade with more than 4 million Americans now
estimated to be infected.
HCV now accounts for the majority of cases of liver disease resulting
in cirrhosis and in HCC in
the United States. The disease spectrum associated with HCV infection
varies greatly and has
become increasingly better characterized: Various studies have
suggested that 3 percent to
20 percent of clinically infected patients will develop cirrhosis
over a 20-year period. Older
individuals, patients with continuous exposure to alcohol, and those
coinfected with HIV or
HBV demonstrate accelerated progression to more advanced liver
disease. Conversely, many
young European women with documented perinatal HCV exposure have no
symptoms, little or
no disease progression, and nearly normal liver findings over several
decades.
The diagnosis is often suggested by abnormalities in ALT levels and
is established by
EIA followed by confirmatory determination of HCV RNA. Several
sensitive and specific assays
are now automated for the purposes of quantitating the viral load.
Although there is little
correlation between viral load and disease manifestations, this assay
has proven useful in
identifying persons at higher risk of transmission, in identifying
those patients most likely to
benefit from treatment, and particularly in demonstrating successful
eradication, defined as
SVRs. Liver biopsy is useful in defining baseline abnormalities of
liver disease and in enabling
patients and health providers to reach a decision regarding antiviral
therapy. Noninvasive tests do
not currently provide the information that is obtained through liver
biopsy. A diagnostic test with
prognostic importance is the genotype of the virus. Genotype 1, most
commonly found in the
United States, is less amenable to treatment than other genotypes.
Clinical trials of antiviral
therapies, therefore, require genotyping information for appropriate
stratification of subjects.
28
Recent therapeutic trials in defined, selected populations have
clearly shown that
combinations of interferons and ribavirin are more effective than
monotherapy. Moreover, trials
using PEG-interferons have yielded improved SVR rates and fewer
neuropsychiatric side effects.
The results continue to show lower SVR rates in genotype 1
infections, in the presence of higher
baseline HCV RNA levels, and with more advanced stages of fibrosis.
Specifically, genotype 1
infections require therapy for 48 weeks, whereas shorter treatment is
feasible in genotype 2 and 3
infections. Early virologic response (> 2 log decreases in HCV
RNA) is associated with
achieving clinical improvement. SVR is lower in patients with
advanced liver disease than in
patients without cirrhosis.
Ongoing trials are exploring the usefulness of combination therapy
among various
populations. Preliminary experience in IDUs, individuals coinfected
with HIV, children, and
other special groups suggest similar responses are achievable in
these populations. In the
presence of acute hepatitis C, recommendations for antiviral
treatment must await further
evaluation of the rate of spontaneous clearance of the virus and
determination of the optimal time
to initiate treatment.
Preventive measures beyond blood-banking practices include prompt
identification of
infected individuals, awareness of the potential for perinatal
transmission, implementation of
safe-needle practices, and implementation of education to modify risk
behavior. Some of these
measures have been successfully implemented in the control of HIV
infections, and it stands to
reason that they may be applicable to reducing HCV transmission.
Future advances in the diagnosis and management of hepatitis C
require continued
vigilance concerning the transmission of this infection, extending
treatment to populations not
formally evaluated in treatment trials, and the introduction of more
effective therapies.
RECOMMENDATIONS
- Educate the American public on the transmission of HCV in order to
better identify afflicted individuals and institute preventive
measures.
- Develop reliable, reproducible, and efficient culture systems for
propagating HCV and expand basic research in the pathogenic mechanisms
underlying hepatic fibrosis.
- Promote the standardization and wide availability of diagnostic
tests for HCV infection and its complications, leading to early
diagnosis and the implementation of appropriate treatment
practices.
- Expand the delineation of disease manifestations, noninvasive
tests, and the role of the liver biopsy, so that the application of
current treatment practices may be refined.
- Establish a Hepatitis Clinical Research Network for the purpose of
conducting research related to the natural history, prevention, and
treatment of hepatitis C.
- Organize RCTs to extend treatment to special populations not
represented in current,clinical trials and to determine the
applicability of accepted antiviral drug combinations to populations
such as children and adolescents, patients with acute hepatitis,
hemophiliacs, IDUs in drug treatment programs, alcohol abusers,
patients with stabilized depression, those with coinfection with HIV,
patients with decompensated cirrhosis and HCV infections in transplant
recipients. Such an effort should lead to decreased morbidity and
mortality from the disease, as well as a decrease in the reservoir of
disease.
- Evaluate strategies to interrupt mother-to-infant transmission of
HCV.
- Evaluate new therapies in nonresponders to current treatments, to
include not just antiviral agents but also combinations of
antifibrotic drugs, immunomodulatory agents, and alternative
therapies.
- Encourage a comprehensive approach to promote the collaboration
between health professionals concerned with management of addiction
with specialists involved in various aspects of HCV and its
complications in order to deal with complex societal, medical, and
personal issues occurring in IDUs afflicted by the disease.
- Seek appropriate support from governmental agencies and the
private sector to address urgent research questions concerning
epidemiology and treatment of this disease.
