The hepatitis C virus (HCV) is one of the
leading known causes of liver disease in the United States. It is a common
cause of cirrhosis and hepatocellular carcinoma (HCC) as well as the most
common reason for liver transplantation. At least 4 million people in this
country are believed to have been infected with HCV. 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 identified and found to account for the majority of those patients with
non-A, non-B hepatitis. In March 1997, the National Institutes of Health (NIH)
held a Consensus Development Conference regarding management and treatment of
HCV. This led to an important, widely distributed NIH Consensus Statement
that, for several years, defined 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. This conference was convened 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 was held June 10&endash;12, 2002. The
primary sponsors of this meeting were the National Institute of Diabetes and
Digestive and Kidney Diseases (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 the 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
Consensus Development Panel. After weighing this 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 Development Panel's draft
statement was posted to the Consensus Program Web siteÐhttp://consensus.nih.govÐon
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 31 to 34 percent in their nucleotide sequences, whereas
subtypes differ by 20 to 23 percent based on full-length genomic sequence
comparisons. The lack of a vigorous T-lymphocyte response and the high
propensity of the virus to mutate appear 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
lower rate of response to treatment.
HCV replicates preferentially in hepatocytes
but is not directly cytopathic, leading to persistent infection. During
chronic infection, HCV RNA reaches high levels, generally ranging from 105 to
107 international units (IU)/mL, but the levels can fluctuate widely. However,
within the same individual, RNA levels are usually relatively stable.
Epidemiology
According to the National Health and Nutrition
Examination Survey (NHANES) of 1988&endash;1994, 3.9 million Americans
were infected with HCV, and of this group, 2.7 million were estimated to have
chronic infection. Because NHANES is a population-based household survey, it
does not include certain groups with a substantially increased prevalence of
infection, such as persons who are incarcerated, homeless, or
institutionalized.
Although difficult to assess accurately, the
incidence of HCV infections declined sharply in the late 1980s. Currently,
approximately 35,000 new HCV infections are conservatively estimated to occur
each year. However, the estimated prevalence of HCV in the United States is at
least 1.8 percent of the population, making HCV the most common chronic
blood-borne infection nationally. Because most persons with chronic HCV
infection have yet to be diagnosed but are likely to come to medical attention
in the next decade, a fourfold increase in the number of adults diagnosed with
chronic HCV infection is projected from 1990 to 2015. Currently, 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, blood transfusion before 1992, solid organ transplantation from
infected donors, unsafe medical practices, occupational exposure to infected
blood, birth to an infected mother, sex with an infected person, high-risk
sexual practices, and intranasal cocaine use. Transmission from blood products
and organ transplants was virtually eliminated by the introduction of a more
sensitive test for anti-HCV antibodies in mid-1992. High HCV seroprevalence
rates (from 15 to 50 percent) have occurred in specific subpopulations, such
as the homeless, incarcerated persons, injection drug users, and persons with
hemophilia who were treated with clotting factors before 1992. The highest
seroprevalence rates (70 percent to more than 90 percent) have been reported
in the last two of these groups.
Acute Infection
After initial exposure, HCV RNA can be
detected in blood within 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 more than 90
percent after 3 months. Within an average of 4 to 12 weeks, liver cell injury
is manifested by elevation of serum alanine aminotransferase (ALT). Acute
infection can be severe but rarely is fulminant. Symptoms are uncommon but can
include malaise, weakness, anorexia, and jaundice. Symptoms usually subside
after several weeks as ALT levels decline.
Chronic Infection
Persistence of HCV infection is diagnosed by
the detection of HCV RNA in the blood for at least 6 months. In general,
prospective studies have shown that 60 to 85 percent of HCV-infected persons
develop chronic infection. In the United States, over 90 percent of infections
involve genotype 1. 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, and HCC. Estimates of the proportion of chronically
infected persons who develop cirrhosis 20 years after initial infection vary
widely from 2 to 4 percent in studies of children and young women to as high
as 20 to 30 percent in middle-aged transfused subjects. The actual risk is
likely intermediate between these two ranges, on the order of 10 to 15
percent. There is little evidence that virologic factors, including viral
load, viral genotype, and quasi-species diversity significantly affect the
risk of progression of liver disease. However, many host factors increase this
risk, including older age at time of infection, male gender, and an
immunosuppressed state such as that associated with human immunodeficiency
virus (HIV) infection. Concurrent chronic hepatitis B also appears to increase
the risk of progressive liver disease. In addition, higher levels of alcohol
use play an important role in promoting the development of progressive liver
disease, with strong evidence for the detrimental effects of 30 g/day in men
(~ equivalent to 4 beers, 4 glasses of wine, or 3 mixed drinks) and 20 g/day
in women. Lower amounts of alcohol also may increase the risk of liver damage
associated with HCV. Other factors, including iron overload, nonalcoholic
fatty liver disease, schistosomal co-infection, potentially hepatotoxic
medications, and environmental contaminants, also may have important effects.
In the United States, deaths associated with
chronic HCV are currently more likely to be due to decompensated cirrhosis
than to HCC. Data from death certificates in 1999 indicate that approximately
10,000 to 20,000 deaths were attributed to HCV infection, but this is likely
underestimated. The only treatment option for persons who have developed
decompensated cirrhosis is liver 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 for 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 continues 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 decompensated cirrhosis. Some but not all studies suggest that
treatment with interferon and ribavirin may reduce the risk of developing HCC
in HCV patients with cirrhosis, but more data are needed.
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, lymphoma, and essential mixed cryoglobulinemia.
Cryoglobulins have been detected in the serum of up to one-half of patients
with chronic hepatitis C, but the clinical features of mixed cryoglobulinemia
are uncommon. Chronic hepatitis C is also related to porphyria cutanea tarda.
Psychological disorders including depression have been associated with HCV
infection in up to 20 to 30 percent of cases.
2. What is the most appropriate
approach to diagnose and monitor patients?
Various tests are available for the
diagnosis and monitoring of HCV infection. Tests that detect antibodies
against the virus include the enzyme immunoassay (EIA), which contains HCV
antigens from the core and nonstructural genes, and the recombinant immunoblot
assay. The same HCV antigens are used in both EIAs and the immunoblot assays.
Target amplification techniques using either polymerase chain reaction (PCR)
or transcription-mediated amplification (TMA) have been developed as
qualitative tests for HCV RNA, whereas both target amplification (PCR) and
signal amplification techniques (branched DNA) may be used to measure HCV RNA
levels. 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
version 3 (third-generation) EIAs (sensitivity of greater than 99 percent,
specificity of 99 percent in immunocompetent patients) obviate the need for a
confirmatory immunoblot assay in the diagnosis of individual patients with
clinical liver disease, 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 false-negative EIAs. Conversely,
false-positive EIAs may occur in patients with autoimmune disorders. In these
patients, an assay for HCV RNA is necessary for diagnosis of chronic
infection. The immunoblot assay is still useful as a supplemental assay for
persons screened in nonclinical settings and in persons with a positive EIA
who test negative for HCV RNA.
Qualitative HCV RNA Assays
Acute or chronic HCV infection in a patient
with a positive EIA test should be confirmed by a qualitative HCV RNA assay
with a lower limit of detection of 50 IU/mL or less (approximately 100 viral
genes/mL). However confirmation may be unnecessary in a patient who has
evidence of liver disease and obvious risk factors for HCV. The FDA-approved
manual and semiautomated, qualitative, HCV PCR assays have a lower limit of
detection of 50 to 100 IU/mL. More recently, a transcription-mediated
amplification assay has been developed with a lower limit of detection on the
order of 5 to 10 IU/mL, but it has yet to be approved for use by the FDA. The
specificity of these assays for detecting HCV RNA exceeds 98 percent. A single
positive qualitative assay for HCV RNA confirms active HCV replication, but a
single negative assay does not exclude viremia and may reflect only a
transient decline in viral level below the level of detection of the assay. A
followup qualitative HCV RNA should be performed to confirm the absence of
active HCV replication. Once HCV infection is confirmed, repeat testing using
a qualitative assay with a limit of detection of 50 IU/mL or less is not
helpful in the management of untreated patients, except for determining
whether an acute infection has resolved spontaneously.
Until future studies determine whether the
sustained viral response (SVR) will be sustained over the long term following
successful antiviral treatment, periodic measurements of HCV RNA may need to
be performed.
Quantitative HCV RNA Assays
Testing for HCV RNA level (or viral load) with
a quantitative assay such as quantitative PCR (qPCR) or branched DNA (bDNA)
signal amplification assay provides accurate information on HCV viral levels.
An HCV RNA standard has been introduced to permit normalization of reported
viral titers in IUs. The reported IU does not represent the actual number of
viral particles in a preparation. Significant variability exists between
available assays. The reportable range, accuracy, and precision of each assay
needs to be monitored, and appropriate dilutions of sample material should be
performed to obtain accurate quantitative results. The clinical utility of
serial HCV viral levels in a patient is predicated on continued use of the
same specific quantitative assay that was used in the initial determination of
the viral level. While there is little correlation between disease severity or
disease progression with the absolute level of HCV RNA, quantitative
determination of the HCV level provides important information on the
likelihood of response to treatment in patients undergoing antiviral therapy.
In clinical trials of combination interferon and ribavirin reported to date, a
positive response to antiviral therapy in patients infected with all common
genotypes (genotypes 1, 2, and 3) has been correlated with low viral levels.
ALT
Testing for serum ALT levels is the most
inexpensive and noninvasive, but relatively insensitive, means of assessing
disease activity. A single determination of ALT level 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 well documented.
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.
Nevertheless, pegylated interferon can cause mild elevations of ALT during
therapy, and ALT levels are insensitive in detecting disease progression to
cirrhosis.
Noninvasive Tests of Fibrosis
Various noninvasive tests of hepatic fibrosis
have been examined for monitoring patients with chronic HCV 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 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 provides a unique source of
information on fibrosis and assessment of histology. Liver enzymes have shown
little value in predicting fibrosis. Extracellular matrix tests can 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. Although unexpected
etiologies of liver disease are rarely discovered on liver biopsies from
patients undergoing evaluation of chronic hepatitis C, the information
obtained on liver biopsy allows affected individuals to make more informed
choices about the initiation or postponement of antiviral treatment. Thus, the
liver biopsy is a useful part of the informed consent process.
Adult or pediatric patients with persistently
normal or slightly elevated ALT levels and minimal or no fibrosis on liver
biopsy may be reassured of a favorable prognosis and decide to defer antiviral
therapy in the light of treatment side effects. Since a favorable response to
current antiviral therapy occurs in 80 percent of patients infected with
genotype 2 or 3, it may not always be necessary to perform liver biopsy in
these patients to make a decision to treat. The usefulness of a pretreatment
liver biopsy in this group as well as those with other genotypes requires
further study. In general, a baseline assessment of liver histology offers a
valuable standard for subsequent comparisons. However, the appropriate
interval for subsequent evaluations is yet to be determined.
Hepatocellular Carcinoma 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. The value of screening for AFP is
uncertain because there are no available data to demonstrate the clinical
impact of this screening on the management of HCC or associated mortality.
Studies of the performance characteristics of AFP and hepatic ultrasound show
that AFP has a poor sensitivity and a high rate of false-positive reactions.
Hepatic ultrasound is more sensitive than AFP testing but is also more
expensive, and it can lead to invasive and unnecessary evaluations of lesions
(e.g., regenerative nodules, hemangiomas, hepatic cysts) that are not HCC.
Despite the lack of evidence, screening for HCC with AFP testing and hepatic
ultrasound at 6-month intervals is a common practice in the United States.
However, such routine AFP or imaging screening should not be performed in
patients with HCV in the absence of cirrhosis because HCC is so rare in this
group. There is a great need for carefully designed studies on the reliability
and benefit of surveillance screening.
HIV Screening
Significant overlap exists for risk factors
for HCV and HIV. Therefore, patients with documented HIV infection should be
routinely screened for HCV. HCV patients at risk for HIV infection should be
offered testing for evidence of HIV infection with appropriate pretest and
posttest counseling.
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 combination therapy with ribavirin
and the introduction of pegylated interferons. Combination therapy results in
better treatment responses than monotherapy, but the highest response rates
have been achieved with pegylated interferon in combination with ribavirin.
Genotype determinations influence treatment decisions. Currently the best
indicator of effective treatment is an SVR, defined by the absence of
detectable HCV RNA in the serum as shown by a qualitative HCV RNA assay with
lower limit of detection of 50 IU/mL or less at 24 weeks after the end of
treatment.
Treatment of Naive Patients
Three large pivotal trials have examined the
efficacy of pegylated interferon plus ribavirin in the treatment of chronic
HCV infection. These trials excluded patients with decompensated cirrhosis and
comorbid conditions. Overall, pegylated interferon plus ribavirin was more
effective than standard interferon-ribavirin combination or pegylated
interferon alone. SVR rates were similar with both forms of pegylated
interferon (alfa-2a and alfa-2b) when used in combination with ribavirin.
Factors associated with successful therapy included genotypes other than 1,
lower baseline viral levels, less fibrosis or inflammation on liver biopsy,
and lower body weight or body surface area. Among patients with genotypes 2 or
3, SVRs with standard interferon and ribavirin were comparable to those with
pegylated interferon and ribavirin, and thus standard interferon and ribavirin
could be used in treating patients with these genotypes. In two trials, SVRs
of 42 to 46 percent were achieved for genotype 1 using pegylated interferon
and ribavirin for 48 weeks. Patients with genotypes 2 and 3 achieved SVRs of
76 to 82 percent after 24 weeks of treatment. Therefore, 24 weeks of treatment
appears to be sufficient for persons with genotypes 2 and 3, while patients
with genotype 1 need 48 weeks of treatment. In patients infected with genotype
1, a third study suggested that higher doses of ribavirinÐ1,000&endash;1,200
mg/day versus 800 mg/dayÐhad a slightly greater SVR at 48 weeks (51 percent
versus 40 percent).
Early viral response (EVR), defined as a
minimum 2 log decrease in viral load during the first 12 to 24 weeks of
treatment, is predictive of SVR and should be a routine part of patient
monitoring. Patients who fail to achieve an EVR at week 12 or week 24 of
treatment have only a small chance of achieving an SVR even if therapy is
continued for a full year. Treatment need not be extended beyond 12 to 24
weeks in these patients. Although an SVR is difficult to correlate with
improved survival because of the necessity for long-term followup, the absence
of detectable serum HCV RNA has been associated with resolution of liver
injury, reduction in hepatic fibrosis, and a low likelihood of a relapse of
the HCV infection. Additionally, in two large but uncontrolled long-term
followup studies from Japan, SVR after interferon treatment was associated
with a lower risk of HCC. Conversely, one observational Italian study with
long-term followup found no difference in development of HCC between those
with and without interferon treatment.
Retreatment of Patients
Selected patients who fail to achieve an SVR
may benefit from re-treatment with pegylated interferon-based regimens.
Decisions regarding re-treatment should be based on (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 this is not sustained
over time (i.e., no SVR). "Nonresponders" never achieve an ETR or an
SVR. Some nonresponders achieve a substantial reduction of HCV RNA (1 log unit
or more) during therapy and can be categorized as partial responders. Even in
the absence of SVR, treatment may be associated with improved histology. In
one study only nonresponders who had a decline in HCV RNA to an absolute level
of <100,000 copies/mL during the original treatment with interferon alone
achieved an SVR when re-treated with interferon and ribavirin.
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 pegylated interferon with
ribavirin. Patients with genotypes 2 or 3 have better response rates to
re-treatment than those with genotype 1.
Studies are currently being conducted with
pegylated interferon and ribavirin therapy in patients who relapsed after
interferon monotherapy or standard interferon and ribavirin therapy. However,
most patients relapse again when they are re-treated with the same regimen
that was used originally. 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.
Failure to respond to optimal therapy with
pegylated interferon and ribavirin presents a significant problem,
particularly in the presence of advanced fibrosis or cirrhosis. Currently,
several large-scale, multicenter U.S. trials are evaluating the role of
maintenance therapy with pegylated interferon alone in preventing further
progression of cirrhosis, clinical decompensation, or development of HCC.
Until the results of these studies are available, the role of long-term,
continuous therapy with pegylated interferon (or ribavirin or both) for
nonresponders should be considered experimental.
Knowledge of the severity of the underlying
liver disease is important in recommending re-treatment. Patients with
advanced fibrosis or cirrhosis have an increased risk of 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 (bridging fibrosis or cirrhosis
with minimal disease activity), clinicians should consider the factors
enumerated above in determining whether or not to re-treat.
Adherence
Patient adherence is critical to the success
of HCV treatment. Physicians should discuss the importance of adherence with
patients before embarking on therapy and regularly assess and take steps to
help their patients maximize their adherence. Such measures include management
of side effects, depression, and substance abuse.
Side Effects of Treatment
In registration trials of pegylated interferon
and ribavirin, significant side effects resulted in discontinuation of
treatment in approximately 10 to 14 percent of patients. Major side effects of
combination therapy include influenza-like symptoms, hematologic
abnormalities, and neuropsychiatric symptoms. The education of patients, their
family members, and caregivers about side effects and their prospective
management is an integral aspect of treatment. Frequent monitoring of
neuropsychiatric side effects, cytopenia, and adherence to HCV therapy is
necessary. Psychological conditions, particularly depression, are common among
persons with hepatitis C and are frequent side effects of interferon.
Patients' mental health should be assessed before beginning antiviral therapy
and monitored regularly during therapy. Antidepressants, such as selective
serotonin re-uptake inhibitors, may be useful in the management of depression
associated with antiviral therapy. In selected patients who develop persistent
cytopenias despite dose reductions, treatment with hematopoietic growth
factors may be useful to reduce symptoms and maintain adherence to antiviral
therapy. However, this therapy is costly and the optimal dosage is not yet
clear. Further, it is not known if the use of hematopoietic growth factors
will enhance the likelihood of SVR. Thus, the benefits of such treatment need
to be proven prospectively before it can be recommended. Severe hemolysis from
ribavirin may occur in patients with renal insufficiency, and trials of
pegylated monotherapy may be indicated in these patients. 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 with an increased risk of developing cirrhosis. These patients are
characterized by detectable HCV RNA levels higher than 50 IU/mL, a liver
biopsy with portal or bridging fibrosis, and at least moderate inflammation
and necrosis. The majority also 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 hepatitis C have
been ineligible for trials because of injection drug use, significant alcohol
use, age, and a number of comorbid medical and neuropsychiatric conditions.
Efforts should be made to increase the availability of the best current
treatments to these patients. Because a large number of HCV-infected persons
in the United States are incarcerated, programs should be implemented to
prevent, diagnose, and treat HCV infection in these individuals. Based on the
NHANES III data that demonstrate high prevalence of HCV in African American
and Hispanic populations, individuals who are uninsured or have publicly
funded healthcare are more likely to be infected with HCV. Efforts should also
be initiated to diagnose and treat infection in these individuals.
All patients with chronic hepatitis C should
be vaccinated against hepatitis A, and seronegative persons with risk factors
for hepatitis B virus (HBV) should be vaccinated against hepatitis B.
Normal ALT Levels
Approximately 30 percent of patients with
chronic HCV infection 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 mild disease, histologically, some 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. When patients with normal or minimally elevated ALT levels are
treated with monotherapy, their SVR rates are similar to those of patients
with higher ALT levels. Studies of pegylated interferon with ribavirin have
not been completed in patients with normal ALT levels.
Mild Liver Disease
Progression to cirrhosis is likely to be slow
in patients who have persistent ALT elevations but no fibrosis and minimal
necroinflammatory changes. These patients may not need treatment and should be
monitored periodically. However, decisions to treat such patients should be
individualized and may be based on the patient's desire to eliminate the HCV
infection or unwillingness to undergo subsequent liver biopsies to assess
disease progression.
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 largely been derived from subgroup
analyses of larger trials. SVR rates are lower in patients with advanced liver
disease than in patients without cirrhosis. Further studies are needed to
evaluate whether long-term anti-viral therapy will delay histological disease
progression to cirrhosis. Liver transplantation offers the primary treatment
option for patients with decompensated liver disease. Studies of antiviral
therapy are being conducted in patients awaiting liver transplantation, but
potentially life-threatening side effects of antivirals have been observed in
some patients.
Recurrence After Transplantation
Hepatitis C frequently recurs following liver
transplantation, and disease progression is accelerated compared with
immunocompetent patients with HCV disease. Once cirrhosis develops in the
allograft, the risk of complications is high. While recurrence of HCV
replication is almost universal after liver transplantation, the severity of
the recurrence of hepatitis C after transplant correlates with the degree of
immunosuppression in the posttransplantation period. Treatment of HCV
recurrence after liver transplantation should be considered experimental and
carried out in the context of clinical trials.
Children
Children should be screened for HCV if they
are born to HCV-infected women, received transfusions prior to 1992, or have
high-risk behavior since data suggest that response rates to treatment may be
higher than in adults. Children and adults with chronic HCV infection
generally have no symptoms. Little is known about 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 better than in adults, ranging from 33
to 45 percent (26 percent for genotype 1 and 70 percent for other genotypes).
Promising new therapies, including the pegylated interferons, should also be
studied in children. Some patients may benefit from treatment even if the
liver disease is mild. Given the long life expectancy of children and their
better tolerance to drugs, the long-term safety of these medications needs to
be studied in children.
Acute Hepatitis C
Acute hepatitis C is uncommonly recognized and
diagnosed because most patients do not develop symptoms at the time that the
infection is acquired. Studies of interferon treatment for acute hepatitis C
have been very heterogeneous and limited by small sample size; lack of
randomization; and variability in the timing of therapy after onset of
infection, dose, schedule, end points, and followup. High SVR rates (83 to 100
percent) have been reported by small uncontrolled trials with interferon
monotherapy. Accordingly, treatment of persons with acute hepatitis C is
warranted, but the timing of therapy and the type of regimen to use remains to
be determined from future trials.
Active Injection Drug Users
Recent, albeit limited, experience has
demonstrated the feasibility and effectiveness of treating chronic hepatitis C
in people who use illicit injection drugs, known as injection drug users (IDUs).
This is potentially important because injection drug use is the most common
risk factor for new HCV infections in the United States, and successful
treatment may reduce transmission. Management of HCV-infected IDUs is enhanced
by linking these patients to drug-treatment programs. Treatment for drug and
alcohol abuse should be made available to all patients who want and need it.
Access to methadone treatment programs should be fostered for HCV-infected
IDUs whether or not they are receiving treatment for HCV. Methadone treatment
has been shown to reduce risky behaviors that can spread HCV infection, and it
is not a contraindication to HCV treatment. Efforts should be made to promote
collaboration between experts in HCV and healthcare providers specializing in
substance-abuse treatment. HCV therapy has been successful even when the
patients have not abstained from continued drug or alcohol use or are on daily
methadone. However, few data are available on HCV treatment in active IDUs who
are not in drug treatment programs. Thus, it is recommended that treatment of
active injection drug use be considered on a case-by-case basis, and that
active injection drug use in and of itself not be used to exclude such
patients from antiviral therapy.
HIV Co-infection
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 co-infected 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
co-infected persons, an SVR can be achieved with HCV treatment. Preliminary
data suggest better responses to pegylated interferon with ribavirin than to
standard interferon with ribavirin. Thus treatment of HCV infection in
patients with HIV is recommended on a case-by-case basis. Although treatment
of HCV does not appear to compromise treatment of the HIV infection,
additional data are needed. Monitoring for potential adverse effects from
these treatments, including lactic acidosis, is strongly recommended.
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 a contraindication to therapy; however, continued alcohol use
during therapy adversely affects response to treatment, and alcohol abstinence
is strongly recommended before and during antiviral therapy. Efforts to
diagnose and treat alcohol abuse or dependence should be performed in
conjunction with treatment of HCV. Heavy alcohol consumption of >80 g/day
seriously compromises HCV treatment. Furthermore, safe levels of alcohol
consumption are still unclear, and even moderate levels of consumption may
accelerate disease progression in some patients.
5. What recommendations can be
made to patients to prevent transmission of hepatitis C?
The large 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
injection drug use accounts for more than two-thirds of all new infections in
the United States. Methadone treatment programs, needle and syringe exchange
programs, and comprehensive risk-modifying educational programs have been
shown to be effective in preventing HIV transmission and are likely to be
useful for decreasing HCV transmission. Ensuring access to sterile syringes
through physician prescription and pharmacy sales of syringes to IDUs can also
be helpful. IDUs should be educated about the importance of hand washing
before and after injection drug use, not using the others' injection
equipment, and avoiding any contact with blood from other persons. HCV
prevention education should be a high priority in correctional settings. The
majority of cases not attributed to injection drug use can be attributed to
sexual contact 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
injection drug use, that can increase the risk of transmission of HCV. HCV
genotypes appear to have no impact on the risk of 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.
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). One study found the risk of
HCV infection to be threefold higher for female than male sexual partners.
Thus, sexual partners of male and female patients with hepatitis C should be
tested for this infection. For heterosexual, discordant monogamous couples,
the risk of transmission is estimated to be only 0 to 0.6 percent annually.
Because of the low risk of HCV transmission, monogamous couples do not need to
use barrier protection (condoms) although they should be advised that condoms
may reduce the risk of transmission. However, 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. Sharing common household items that may be contaminated with blood,
such as razors and toothbrushes, is another potential source of transmission
of HCV that should be avoided. 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.
Healthcare workers have a similar or slightly
lower prevalence of HCV infection than the general population, although they
may have acquired their infection from occupational sources. Transmission from
healthcare workers to patients has also been documented, but is rare and
confounded by other risk factors. HCV-infected healthcare workers should use
standard (universal) precautions to prevent transmission and should not be
restricted in their employment.
The risk of HCV infection from a needle stick
injury is estimated to be 2 percent. At this time, immune globulin or
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 immunoblot
or HCV RNA assay should be done in the exposed individual. Since HCV RNA is
first detected in the blood 2 weeks after transmission, the exposed individual
should be tested for HCV antibody, HCV RNA, and ALT at exposure and again
between 2 and 8 weeks after injury. If seroconversion occurs, such persons
should be referred to a specialist knowledgeable in this area for
consideration of treatment.
Body piercing and tattooing are other
potential sources of transmission if contaminated equipment or supplies are
used. However, transmission through these activities is rare and confounded by
other risk factors.
The risk of perinatal transmission is
approximately 2 percent for infants of anti-HCV seropositive women. When a
pregnant woman is HCV RNA positive at delivery, this risk increases to 4 to 7
percent. Higher HCV RNA levels appear to be associated with a greater risk.
HCV transmission increases up to 20 percent in women co-infected 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. However,
avoiding fetal scalp monitoring and prolonged labor after rupture of membranes
may reduce the risk of transmission to the infant. There are currently no data
to determine whether antiviral therapy reduces perinatal transmission.
Ribavirin and interferons are contraindicated during pregnancy.
Breast-feeding does not appear to transmit
HCV. Infants born to HCV-positive mothers should be tested for HCV infection
by HCV RNA tests on two occasions between the ages of 2 and 6 months and/or
have tests for anti-HCV after 15 months of age. Positive anti-HCV in infants
prior to 15 months of age may be due to transplacental transfer of maternal
anti-HCV antibody.
Children and personnel should not be excluded
from day care centers, schools, or sports on the basis of HCV infection.
Standard (universal) precautions should be used in any situation where
exposure to blood occurs.
6. What are the most important
areas for future research?
- The development of reliable, reproducible,
and efficient culture systems for propagating the hepatitis C 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. Studies on
the mechanisms of development of resistance to current and future
antiviral therapies are particularly important.
- 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 decompensated liver disease. 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
and to define rates of progression of fibrosis in patients with prolonged
duration of HCV infection. Similarly, studies are needed to determine the
natural history of fibrosis in populations including children, HIV
co-infected patients, older adults, African Americans, Hispanics,
HCV-infected patients with normal ALT levels, and IDUs. 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 large number of persons with
chronic HCV, the large number of untreated patients, and a compelling
number of important areas for future research, we recommend that the 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 the optimal doses and duration of
therapy. These populations include children, patients with acute
hepatitis, and patients in drug treatment programs. Research is also
needed to define the best approaches to treating HCV in active drinkers,
prisoners, those co-infected with HIV, patients with concurrent renal
disease, and patients with major psychiatric illness. Therapies need to be
developed for difficult treatment groups, including patients whose HCV
infection does not respond to or who relapse after current therapy,
patients with compensated and decompensated cirrhosis, transplant
patients, and patients with adherence problems. Trials are also needed to
establish optimal doses and duration of therapy for all populations of
patients with chronic hepatitis C.
- Little information exists to describe the
natural history of HCV viremia lasting 20 years or more. Studies are
needed to examine the pattern of HCV disease progression in persons
infected for at least two decades, including those infected as infants and
as children.
- 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 factors that might
predict transmission (e.g., phase of infection), the risk of specific
sexual practices, and the effectiveness of risk reduction counseling is
needed. The effect of elective cesarean section on mother-to-infant
transmission should be assessed.
- Given the significant side effects of
accepted therapies, resources should be directed toward understanding side
effect management and increasing patient adherence to therapy.
- Trials are needed in combination therapy
nonresponders and those who cannot tolerate conventional therapies,
comparing 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 the 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 data are 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 pegylated interferon with or without ribavirin for 12 to
24 weeks should be studied.
- Provision of educational programs about HCV
for grades K&endash;12 and college-age students is necessary, as is
enhanced information related to risk factors for HCV for dissemination to
the general public and the medical profession. Healthcare professional and
healthcare advocacy organizations should be particularly active in this
area.
- Although it is likely that HCV is highly
prevalent in patient populations without health insurance or with publicly
funded healthcare payers, no data to support this are available. The
prevalence of HCV infection and the feasibility of management and
treatment in these populations should be studied.
- 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. Biopsy techniques and their side effects need to be
more clearly described during trials. The relationship of pretreatment
histology to treatment outcomes needs better definition. The value of
liver biopsy in patients with normal liver enzymes 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 non-genotype 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 the 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.
- RCTs are needed to assess screening tests
in patients at greatest risk of HCC.
- Studies are needed to assess whether there
are safe levels of alcohol consumption in patients with HCV and the effect
of higher levels of alcohol use on disease progression.
- Investigations are needed into the role of
fatty liver, obesity, diabetes, and hepatic iron stores in the natural
history of hepatitis C and responses to therapy.
- Studies are needed in HIV co-infected
patients to determine treatment outcomes and duration, maintenance
therapy, treatment safety, and pathogenesis.
Conclusions
The incidence of newly acquired hepatitis C
infection has diminished in the United States. This decline is largely due to
a decrease in cases among IDUs for reasons that are unclear and, to a lesser
extent, to testing of blood donors for HCV. The virus is transmitted by blood
and such transmission now occurs primarily through injection drug use, sex
with an infected partner or multiple partners, and occupational exposure. The
majority of infections become chronic, and therefore the prevalence of HCV
infections is high, with about 3 million Americans now estimated to be
chronically infected. HCV is a leading cause of cirrhosis, a common cause of
HCC and the leading cause of liver transplantation in the United States. The
disease spectrum associated with HCV infection varies greatly. Various studies
have suggested that 3 to 20 percent of chronically infected patients will
develop cirrhosis over a 20-year period, and these patients are at risk for
HCC. Persons who are older at the time of infection, patients with continuous
exposure to alcohol, and those co-infected with HIV or HBV demonstrate
accelerated progression to more advanced liver disease. Conversely,
individuals infected at a younger age have little or no disease progression
over several decades.
The diagnosis of chronic hepatitis C infection
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 partly automated for the purposes of detecting HCV RNA
and quantifying the viral level. Although there is little correlation between
viral level and disease manifestations, these assays have proven useful in
identifying those patients who are more likely to benefit from treatment and,
particularly, in demonstrating successful response to treatment as defined by
an SVR. Liver biopsy is useful in defining baseline abnormalities of liver
disease and in enabling patients and healthcare providers to reach a decision
regarding antiviral therapy. Noninvasive tests do not currently provide the
information that can be obtained through liver biopsy. Information on the
genotype of the virus is important to guide treatment decisions. Genotype 1,
most commonly found in the United States, is less amenable to treatment than
genotypes 2 or 3. Therefore, clinical trials of antiviral therapies require
genotyping information for appropriate stratification of subjects.
Recent therapeutic trials in defined, selected
populations have clearly shown that combinations of interferons and ribavirin
are more effective than monotherapy. Moreover, trials using pegylated
interferons have yielded improved SVR rates with similar toxicity profiles.
However, results continue to show that the SVR rate is less common in patients
with genotype 1 infections, higher HCV RNA levels, or more advanced stages of
fibrosis. Genotype 1 infections require therapy for 48 weeks, whereas shorter
treatment is feasible in genotype 2 and 3 infections. In genotype 1, the lack
of an early virologic response (< 2 log decrease in HCV RNA) is associated
with failure to achieve an SVR. The SVR is lower in patients with advanced
liver disease than in patients without cirrhosis.
Ongoing trials are exploring the usefulness of
combination therapy in various populations. Preliminary experience in IDUs,
individuals co-infected with HIV, children, and other special groups suggests
similar responses are achievable in these populations. Patients with acute
hepatitis C may be treated, but specific 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-injection
practices, linkage of drug users to drug treatment programs, and
implementation of community-based education and support programs 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 would be
valuable for 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
previously 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 affected individuals and
to 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.
- Promote the establishment of
screening tests for all groups at high risk of HCV infection, including
IDUs and incarcerated individuals.
- 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, and patients with acute
hepatitis. Effective approaches are needed for drug users receiving drug
treatment, alcohol abusers, prisoners, patients with stabilized
depression, those with co-infection with HIV, patients with decompensated
cirrhosis, and HCV infections in transplant recipients. Such efforts
should lead to decreased morbidity and mortality from the disease, as well
as a decrease in the reservoir of disease.
- Institute measures to reduce
transmission of HCV among IDUs, including providing access to sterile
syringes through needle exchange, physician prescription, and pharmacy
sales; and expanding the Nation's capacity to provide treatment for
substance abuse. Physicians and pharmacists should be educated to
recognize that providing IDUs with access to sterile syringes and
education in safe injection practices may be lifesaving.
- Evaluate strategies to interrupt
mother-to-infant transmission of HCV.
- Compare new therapies to current
treatments in nonresponders, 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 among health professionals concerned with
management of addiction, primary care physicians, and specialists involved
in various aspects of HCVÐto deal with the complex societal, medical, and
psychiatric issues of IDUs afflicted by the disease.
- Seek appropriate support from
governmental agencies and the private sector to address urgent research
questions concerning the epidemiology and treatment of this disease.
Consensus Development Panel
|
James L. Boyer, M.D.
Panel and Conference Chairperson
Ensign Professor of Medicine
Departments of Internal Medicine and Digestive DiseasesDirector, Liver
Center
Yale University School of Medicine
New Haven, Connecticut
|
Franco M. Muggia, M.D.
Director, Division of Medical Oncology
New York University School of Medicine
New York, New York
|
|
Eugene B. Chang, M.D.
Martin Boyer Professor of Medicine
Department of Medicine
University of Chicago
Chicago, Illinois
|
Charles L. Shapiro, M.D.
Associate Professor of Internal Medicine
Director of Breast Medical Oncology
Arthur G. James Cancer Hospital and Richard J. Solove Research
Institute
The Ohio State University
Columbus, Ohio
|
|
Deborah E. Collyar
President
PAIR: Patient Advocates in Research Program Director
Breast SPORE Advocacy Core
University of California, San Francisco
San Francisco, California
|
Stephen A. Spector, M.D.
Professor and Vice Chairman for Research
Chief, Division of Infectious Diseases
Department of Pediatrics
Member, Center for Molecular Genetics and Center for AIDS Research
Chair, Executive Committee Pediatric AIDS Clinical Trials Unit
University of California, San Diego
La Jolla, California
|
|
Laurie D. DeLeve, M.D., Ph.D.
Associate Professor of Medicine
Division of Gastrointestinal and Liver Diseases
Keck School of Medicine
University of Southern California
Los Angeles, California
|
Frederick J. Suchy, M.D.
Chairman and Professor
The Jack and Lucy Clark Department
of Pediatrics
Mount Sinai School of Medicine
New York, New York
|
|
Judith Feinberg, M.D.
Professor of Medicine
Division of Infectious Diseases
Department of Medicine
University of Cincinnati College of
Medicine
Cincinnati, Ohio
|
Patricia L. Tomsko, M.D., C.M.D.
Managing Partner
Rock Creek Geriatric Medicine
Rockville, Maryland
Deputy Medical Examiner
Montgomery County, Maryland
|
|
Thomas A. Judge, M.D.
Assistant Professor of Medicine
Division of Gastroenterology
Department of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
|
Barbara J. Turner, M.D., M.S.Ed.
Professor
Division of General Internal Medicine
Department of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
|
Speakers
|
Alfredo Alberti, M.D.
Professor
Clinica Medica 5
University of Padova
Padova, Italy
|
Patrick Marcellin, M.D.
Professor
Service d'Hépatologie and INSERM U 481
Hôpital Beaujon
Clichy, France
|
|
Miriam J. Alter, Ph.D.
Acting Associate Director for Epidemiology
and Public Health
Division of Viral Hepatitis
Centers for Disease Control and Prevention
Atlanta, Georgia
|
John G. McHutchison, M.D.
Medical Director
Liver Transplantation
Division of Gastroenterology
Scripps Clinic and Research Foundation
La Jolla, California
|
|
Bruce R. Bacon, M.D.
James F. King, M.D. Endowed
Chair in Gastroenterology
Professor of Internal Medicine
Director, Division of Gastroenterology
and Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
|
Jean-Michel Pawlotsky, M.D., Ph.D.
Professor
Bacteriologie-Virologie
Hôpital Henri Mondor
University of Paris XII
Créteil, France
|
|
Gary L. Davis, M.D.
Professor and Program Director
Liver Section
Division of Gastroenterology,
Hepatology, and Nutrition
University of Florida College of Medicine
Gainesville, Florida
|
Marion G. Peters, M.D., M.B.B.S.
Professor of Medicine
Chief of Hepatology Research
Division of Gastroenterology
Department of Medicine
School of Medicine
University of California, San Francisco
San Francisco, California
|
|
Adrian M. Di Bisceglie, M.D.
Professor of Internal Medicine
Chief of Hepatology
Division of Gastroenterology and
Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
|
Eve A. Roberts, M.D., F.R.C.P.C.
Professor of Pediatrics, Medicine,
and Pharmacology
Division of Gastroenterology and Nutrition
The Hospital for Sick Children
University of Toronto
Toronto, Ontario, Canada
|
|
Jules L. Dienstag, M.D.
Associate Professor of Medicine
Harvard Medical School
Physician
Gastrointestinal Unit
Massachusetts General Hospital
Boston, Massachusetts
|
Leonard B. Seeff, M.D.
Senior Scientist for Hepatitis C Research
National Institute of Diabetes and
Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
|
|
Brian R. Edlin, M.D.
Associate Adjunct Professor
Director
Urban Health Study
Family and Community Medicine
University of California, San Francisco
San Francisco, California
|
Mitchell L. Shiffman, M.D.
Professor of Medicine
Chief, Hepatology Section
Medical Director, Liver Transplant Program
Gastroenterology/Hepatology Section
Department of Internal Medicine
Virginia Commonwealth University
Health System
Medical College of Virginia
Richmond, Virginia
|
|
Hashem B. El-Serag, M.D., M.P.H.
Assistant Professor of Medicine
Houston VA Medical Center and
Baylor College of Medicine
Houston, Texas
|
Doris B. Strader, M.D.
Assistant Chief
Gastroenterology/Hepatology/
Nutrition Section
Washington, DC, Veterans Affairs
Medical Center
Washington, DC
|
|
Michael W. Fried, M.D.
Associate Professor of Medicine
Director of Clinical Hepatology
Division of Digestive Diseases
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
|
Mark S. Sulkowski, M.D.
Assistant Professor
Division of Infectious Diseases
Department of Medicine
The Johns Hopkins University
School of Medicine and the
Evidence-Based Practice Center
The Johns Hopkins University
Bloomberg School of Public Health
Baltimore, Maryland
|
|
Kelly A. Gebo, M.D., M.P.H.
Assistant Professor of Medicine
Division of Infectious Diseases
Department of Medicine
The Johns Hopkins University
School of Medicine and the
Evidence-Based Practice Center
The Johns Hopkins University
Bloomberg School of Public Health
Baltimore, Maryland
|
Norah A. Terrault, M.D., M.P.H.
Adjunct Assistant Professor of Medicine
Division of Gastroenterology
Department of Medicine
School of Medicine
University of California, San Francisco
San Francisco, California
|
|
H. Franklin Herlong, M.D.
Associate Professor
Division of Hepatology
Department of Medicine
The Johns Hopkins University
School of Medicine and the
Evidence-Based Practice Center
The Johns Hopkins University
Bloomberg School of Public Health
Baltimore, Maryland
|
David L. Thomas, M.D.
Associate Professor of Medicine
Division of Infectious Diseases
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
|
|
Jay H. Hoofnagle, M.D.
Director
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
|
Teresa L. Wright, M.D.
Professor of Medicine
University of California, San Francisco
Chief, Gastroenterology Section
Veterans Affairs Medical Center
San Francisco, California
|
|
Maureen M. Jonas, M.D.
Associate Professor of Pediatrics
Harvard Medical School
Associate in Medicine
Center for Childhood Liver Disease
Division of Gastroenterology and Nutrition
Children's Hospital Boston
Boston, Massachusetts
|
|
|
W. Ray Kim, M.D., M.Sc., M.B.A.
Assistant Professor of Medicine
Division of Gastroenterology and
Hepatology
Department of Internal Medicine
Mayo Clinic
Rochester, Minnesota
|
|
|
Karen L. Lindsay, M.D.
Associate Professor of Clinical Medicine
Department of Medicine
University of Southern California
Studio City, California
|
|
|
Anna S.F. Lok, M.D.
Professor of Internal Medicine
Director of Clinical Hepatology
Division of Gastroenterology
University of Michigan Health System
Ann Arbor, Michigan
|
|
Planning Committee
|
Leonard B. Seeff, M.D.
Senior Scientist for Hepatitis C Research
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
|
Lt. Col. Roger Gibson, Ph.D., D.V.M.,
M.P.H.
Program Director, Military Public Health
Senior Policy Analyst, Epidemiology
U.S. Air Force Biomedical Sciences Corps
Clinical and Program Policy
Office of the Assistant Secretary of
Defense (Health Affairs)
Falls Church, Virginia
|
|
Miriam J. Alter, Ph.D.
Acting Associate Director for Epidemiology and Public Health
Division of Viral Hepatitis
Centers for Disease Control and Prevention
Atlanta, Georgia
|
Jay H. Hoofnagle, M.D.
Director
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
|
|
Luiz H. Barbosa, D.V.M.
Senior Scientist
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland
|
Leslye D. Johnson, Ph.D.
Chief, Enteric and Hepatic Diseases Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Maryland
|
|
Eric B. Bass, M.D., M.P.H.
Co-Director
Evidence-Based Practice Center
Johns Hopkins University
Baltimore, Maryland
|
Barnett S. Kramer, M.D., M.P.H.
Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
|
|
Jacqueline S. Besteman, J.D., M.A.
Director, EPC Program
Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
Rockville, Maryland
|
Jake Liang, M.D.
Chief
Liver Diseases Section
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
|
|
John A. Bowersox
Communications Specialist
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
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Diane L. Lucas, Ph.D.
Program Director
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
Bethesda, Maryland
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James L. Boyer, M.D.
Panel and Conference Chairperson
Ensign Professor of Medicine
Departments of Internal Medicine and Digestive Diseases
Director, Liver Center
Yale University School of Medicine
New Haven, Connecticut
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Louis Marzella, M.D., Ph.D.
Medical Reviewer
Division of Clinical Trial Design and Analysis
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Rockville, Maryland
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Elsa A. Bray
Senior Analyst
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
|
Karen Patrias, M.L.S.
Senior Resource Specialist
Public Services Division
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
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John S. Cole III, Ph.D.
Program Director, Biological
Carcinogenesis Branch
Division of Cancer Biology
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
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Jennifer S. Read, M.D., M.P.H., M.S.
Medical Officer
Pediatric, Adolescent, and Maternal AIDS Branch
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
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Lawrence Deyton, M.D., M.S.P.H.
Chief Consultant for Public Health
Director, AIDS Program (132)
Director, Hepatitis C Program
U.S. Department of Veterans Affairs
Washington, DC
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Susan Rossi, Ph.D., M.P.H.
Deputy Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Marylan
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Adrian M. Di Bisceglie, M.D.
Professor of Internal Medicine
Chief of Hepatology
Division of Gastroenterology and Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
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Kristine Scannell
Supervisory Librarian
Public Services Division
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
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Jules L. Dienstag, M.D.
Associate Professor of Medicine
Harvard Medical School
Physician
Gastrointestinal Unit
Massachusetts General Hospital
Boston, Massachusetts
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Jose Serrano, M.D., Ph.D.
Director, Liver and Biliary and Pancreas Programs
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
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Marguerite A. Evans, M.S., R.D.
Program Officer
National Center for Complementary and
Alternative Medicine
National Institutes of Health
Bethesda, Maryland
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Doris B. Strader, M.D.
Assistant Chief
Gastroenterology/Hepatology/
Nutrition Section
Washington, DC, Veterans Affairs
Medical Center
Washington, DC
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James Everhart, M.D., M.P.H.
Chief, Epidemiology and Clinical Trials Branch
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
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David L. Thomas, M.D.
Associate Professor of Medicine
Division of Infectious Diseases
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
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Kelly A. Gebo, M.D., M.P.H.
Assistant Professor of Medicine
Division of Infectious Diseases
Department of Medicine
The Johns Hopkins University
School of Medicine and the
Evidence-Based Practice Center
The Johns Hopkins University
Bloomberg School of Public Health
Baltimore, Maryland
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Alan Trachtenberg, M.D., M.P.H.
Medical Officer
Office of Pharmacologic and Alternative Therapies
Center for Substance Abuse Treatment
Substance Abuse and Mental Health Services Administration
Rockville, Maryland
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John Whyte, M.D., M.P.H.
Acting Director, Division of Medical
Items and Devices
Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
U.S. Department of Health and
Human Services
Baltimore, Maryland
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Carolyn Willard
Librarian
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
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Conference Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases
Allen M. Spiegel, M.D., Director
Office of Medical Applications of Research
Barnett S. Kramer, M.D., M.P.H., Director
Conference Cosponsors
National Institute of Child Health and Human Development
Duane Alexander, M.D. ,Director
National Cancer Institute
Andrew C. von Eschenbach, M.D., Director
National Center for Complementary and Alternative Medicine
Stephen E. Straus, M.D., Director
National Institute on Alcohol Abuse and Alcoholism
Raynard S. Kington, M.D., Ph.D., Acting Director
National Institute on Drug Abuse
Glen R. Hanson, D.D.S., Ph.D., Acting Director
National Institute of Allergy and Infectious Diseases
Anthony S. Fauci, M.D., Director
National Heart, Lung, and Blood Institute
Claude Lenfant, M.D., Director
Centers for Medicare & Medicaid Services
Thomas A. Scully, Administrator
Centers for Disease Control and Prevention
David W. Fleming, M.D., Acting Director
U.S. Food and Drug Administration
Lester M. Crawford Jr., D.V.M., Ph.D., Deputy Commissioner
U.S. Department of Veterans Affairs
Anthony J. Principi, Secretary of Veterans Affairs
