NATIONAL INSTITUTES OF HEALTH
CONSENSUS DEVELOPMENT CONFERENCE STATEMENT
Management of Hepatitis C: 2002
June 10-12, 2002PRELIMINARY 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
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:
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.
Consensus Development Panel
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
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 Paediatrics, 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, MarylandJake 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, MarylandDiane L. Lucas, Ph.D.
Program Director
National Institute on Alcohol Abuse
and Alcoholism
National Institutes of Health
Bethesda, Maryland
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, ConnecticutLouis 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
Elsa A. Bray
Senior Analyst
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, MarylandKaren Patrias, M.L.S.
Senior Resource Specialist
Public Services Division
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
John S. Cole III, Ph.D.
Program Director, Biological
Carcinogenesis Branch
Division of Cancer Biology
National Cancer Institute
National Institutes of Health
Bethesda, MarylandJennifer 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
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, DCSusan Rossi, Ph.D., M.P.H.
Deputy Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Marylan
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, MissouriKristine Scannell
Supervisory Librarian
Public Services Division
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
Jules L. Dienstag, M.D.
Associate Professor of Medicine
Harvard Medical School
Physician
Gastrointestinal Unit
Massachusetts General Hospital
Boston, MassachusettsJose 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
Marguerite A. Evans, M.S., R.D.
Program Officer
National Center for Complementary and
Alternative Medicine
National Institutes of Health
Bethesda, MarylandDoris B. Strader, M.D.
Assistant Chief
Gastroenterology/Hepatology/
Nutrition Section
Washington, DC, Veterans Affairs
Medical Center
Washington, DC
ames 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, MarylandDavid L. Thomas, M.D.
Associate Professor of Medicine
Division of Infectious Diseases
The Johns Hopkins University School of
Medicine
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, MarylandAlan 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
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
Carolyn Willard
Librarian
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
Conference Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases
Allen M. Spiegel, M.D., DirectorOffice 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. ,DirectorNational Cancer Institute
Andrew C. von Eschenbach, M.D., DirectorNational Center for Complementary and Alternative Medicine
Stephen E. Straus, M.D., DirectorNational Institute on Alcohol Abuse and Alcoholism
Raynard S. Kington, M.D., Ph.D., Acting DirectorNational Institute on Drug Abuse
Glen R. Hanson, D.D.S., Ph.D., Acting DirectorNational Institute of Allergy and Infectious Diseases
Anthony S. Fauci, M.D., DirectorNational Heart, Lung, and Blood Institute
Claude Lenfant, M.D., DirectorCenters for Medicare & Medicaid Services
Thomas A. Scully, AdministratorCenters for Disease Control and Prevention
David W. Fleming, M.D., Acting DirectorU.S. Food and Drug Administration
Lester M. Crawford Jr., D.V.M., Ph.D., Deputy CommissionerU.S. Department of Veterans Affairs
Anthony J. Principi, Secretary of Veterans Affairs