INTRODUCTION
The unfolding epidemic of hepatitis C virus (HCV) infection is a serious
and growing problem. An estimated 170 million people around the world
are infected. In the United States, at least four million people have
been exposed to HCV, and 2.7 million of them have developed chronic
hepatitis C. Chronically infected persons can either remain
asymptomatic, progress very slowly, maintain mild to moderate liver
scarring or develop serious liver damage, such as cirrhosis or
hepatocellular carcinoma (HCC). Hepatitis C-related liver damage has
become the chief cause for liver transplantation in this country, and
ten to twelve thousand people die each year from HCV-associated
end-stage liver disease (ESLD). HCV disease is a particularly severe
problem for HIV-positive people. Up to a quarter of all people with HIV
in the U.S. may be coinfected with HCV. The progression of hepatitis C
is accelerated in HIV-positive individuals, and HCV-related ESLD has
become a leading cause of death in those with HIV.
The current state of
research on HCV infection lags far behind that on HIV. For example, it
is not yet possible to grow infectious hepatitis C virions in tissue
culture, and there is still no adequate animal model for HCV infection
or disease. These limits have seriously hampered the understanding of
HCV's replication cycle and have impeded development of new treatments.
The best current combination therapy for hepatitis C (pegylated
interferon and ribavirin) fails at least half those who undergo
treatment, and the range and severity of its side effects can seriously
affect patients' quality of life, adherence, and chances for a
successful outcome. Clearly more and better treatments are needed.
Although millions
of Americans are infected and at risk for progression to serious
disease, there is no federally funded infrastructure to coordinate
education, prevention, testing, care, and treatment for HCV infection.
The lack of a comprehensive plan to reduce HCV incidence—particularly
through increasing access to sterile syringes—means that existing
prevention programs have scattered and limited impact. Many individuals
lack access to costly HCV treatment, including the underinsured and
uninsured, while cash-strapped AIDS Drug Assistance Programs (ADAPs) are
in most cases unable to add expensive HCV care to their already
overburdened portfolios. Prisoners, among whom hepatitis C is endemic,
have had to resort to litigation to obtain treatment. Projections of HCV-related
morbidity and mortality in mono- and HIV coinfected individuals forecast
a significant upsurge in health care costs, illness, and loss of life
over the next twenty years. The time to step up action to address gaps
in research and policy is now.
TAG's
first hepatitis report, by Michael Marco and Jeffrey Schouten,
released in July of 2000, was written to provide affected individuals,
clinicians, researchers, educators and policy makers a detailed overview
of hepatitis C and HIV/HCV coinfection. The report concluded with a set
of research and policy recommendations (see
Appendix A). In the spring of 2003, TAG will publish a new version
of The Hepatitis C/HIV Coinfection Report that will include a revised
and expanded set of research and policy recommendations for HCV and HIV/HCV
coinfection research, prevention and care programs. These draft
recommendations have been developed following a comprehensive literature
review of more than 500 journal articles, abstracts from conferences on
HCV and HIV/HCV, updated treatment guidelines, and interviews with HCV
and HIV/HCV coinfected individuals, researchers, physicians, harm
reduction experts, health educators, public health officials, and
activists and advocates from both the HCV and HIV communities.
The growing voice
of HCV advocacy and the increasing attention given to HCV coinfection by
HIV activists suggest that the timing is right for a broad-based
coalition to press for a comprehensive research agenda and increased
access to treatment. With these recommendations, TAG is hoping to
broaden dialogue and collaboration among activists, policy makers,
researchers, funders, educators and, especially, people with HCV and
HIV/HCV coinfection.
1.
EPIDEMIOLOGY, TRANSMISSION & PREVENTION
1a.
Implement national surveillance for chronic hepatitis C infection.
Hepatitis C virus (HCV)
was identified in 1988, and the development of an antibody test soon
followed (Choo 1989; Kuo 1989). The Center for Disease Control's (CDC's)
third National Health and Nutrition Examination Study (NHANES III),
conducted from 1988 to 1994, estimated that 1.8% of the United States
population—or four million people—have been infected with HCV; 2.7
million remain chronically infected. Data from NHANES III may
significantly underestimate the true prevalence of HCV infection in the
United States since incarcerated and homeless individuals were not
included in the populations surveyed. HCV prevalence among this
country's 1.8 million incarcerated persons is estimated at 30% to 40% (Reindollar
1999). A 2002 survey of 597 homeless veterans found an HCV
seroprevalence of 41.7% (Cheung 2002). Epidemiological studies must
include high-risk and high- prevalence populations to obtain accurate
estimates of hepatitis C prevalence. The CDC's Sentinel Counties Study
of Viral Hepatitis provides data on the incidence of acute HCV
infections. At present, only a pilot program—sentinel surveillance for
physician-diagnosed chronic liver disease—tracks both acute and chronic
HCV infections.
National
surveillance of chronic hepatitis C infections is necessary to forecast
disease burden and provide a sound basis for planning allocation of
adequate resources for prevention, education, care, and treatment
programs. The recommendations from CDC's Guidelines for Viral Hepatitis
Surveillance and Case Management should be implemented (CDC 2002).
1b.
Increase access to sterile injection equipment.
Although the
majority of new HCV infections in the United States result from drug
injection using shared, unsterilized equipment, it has not been widely
and openly acknowledged that hepatitis C is a disease of drug users. HCV
prevalence among injection drug users (IDUs) is estimated at 70% to 90%
(Alter 1998; Donahue 1991; Garfein 1996; Thomas 1995). More than half of
new hepatitis C infections are acquired through drug injection using
shared, unsterilized equipment (Kim 2002). There is ample potential for
HCV transmission among new IDUs via shared syringes and other injection
drug equipment (Thorpe 2002; Vidal Trecan 2002).
Although CDC
recommends that syringes and injection equipment never be shared or used
more than once, its Guidelines for Prevention and Control of
Hepatitis C Virus Infection (1998) and Guidelines for the
Prevention of Opportunistic Infections among HIV-Infected Persons
(2002) state that shared injection equipment should be cleaned with
bleach and water. The efficacy of bleach for neutralizing HCV has not
been established (Hagen 2001).
Access to sterile
syringes and injection equipment is vital to hepatitis C prevention.
Research on the efficacy of bleach and identification of optimal
disinfection practices for injection drug equipment is necessary as
well. Policies that create barriers to risk reduction must be changed.
Inadequate access to sterile syringes and injection equipment,
restrictive one-for-one syringe exchange policies, limited access to
methadone, and the unavailability of drug treatment on demand continue
to fuel both the HCV and HIV epidemics. State and local barriers to
syringe exchange programs must be removed; program expansion will
require an increased commitment of resources and hence the overturning
of the federal ban on syringe exchange funding. Legislation must be
enacted to legalize pharmacy sale of syringes in the remaining states
that prohibit over-the-counter sales without prescriptions, and all
state and local public health programs must insure that pharmacy sale of
syringes is accessible and affordable.
Sources of HCV Infection 1995-2000
1c.
Provide HCV education for high-risk and high-prevalence populations.
More than three
million people in the United States are injection drug users; 94,000 are
between the ages of twelve and seventeen (National Household Survey on
Drug Abuse, 2000 and 2001). The incidence of HCV infection is highest
among new injectors, with an estimated 50% to 80% of injection drug
users (IDUs) becoming infected within a year of initiating injection
drug use (Garfein 1996). Education about HCV transmission must be
provided to young people before they begin injecting drugs. Information
about prevention, transmission, diagnosis, natural history, and
treatment of HCV must be provided and integrated within program
activities for staff and clients of detoxification facilities, drug
treatment programs, shelters, methadone maintenance programs,
correctional facilities, and AIDS service organizations. Hepatitis C
advocacy organizations can provide HCV educational materials and
information; AIDS service organizations can be an important source of
HIV-related information for clients of hepatitis C organizations.
Collaboration among these entities will benefit people with HCV, the
coinfected, active and recovering drug users, the homeless, and others
who are infected or at risk. Public health funding must be made
available to support education, and state-contracted agencies must
provide these services.
1d.
Clarify the risk of non-injection drug use (e.g., snorting or smoking)
associated HCV transmission.
Conflicting data
have emerged about the risk of HCV infection from intranasal (i.e.,
snorting or sniffing) drug use (Conry Cantilena 1996; Murphy, 2000).
There has also been speculation about HCV transmission from shared crack
pipes, since frequent users often have burned or split lips from heated
glass crack pipes. NHANES III participants were asked about drug-use
history; however they were not specifically asked if they had ever
injected drugs. Because drug-taking modes—snorting or smoking versus
injecting—were not recorded in NHANES III, no estimate of the actual
incidence of HCV transmission via intranasal drug use can be made from
that data. A study of HCV-infected blood donors revealed a significant
reluctance to disclose even one-time use of injection drugs. Forty-two
percent (103) of 248 HCV-positive donors who disclosed intravenous drug
use during a self- administered questionnaire about recreational drug
use had denied any intravenous drug use during their initial blood
donation screening (Conry Cantilena, 1996).
Research on the risk
of intranasal drug use must clarify questions about this mode of drug
administration as a potential route of transmission. Further
investigation of the risk of HCV infection from smoking crack or other
drugs is also needed. Studies must be designed to elicit accurate
information about drug use. Pending more definitive data, educators and
medical providers should incorporate appropriate and responsible
messages on intranasal transmission risk.
1e.
Clarify routes and risks of sexual HCV transmission.
HCV can be sexually
transmitted, although the relative risk of sexual transmission, and by
what means, remain controversial. Several studies have documented
higher-than-average anti-HCV prevalence among men who have sex with men
(MSM), sex workers, individuals who have had multiple partners, and
partners of HIV/HCV coinfected individuals (Alter 1988; Alter 2002;
Bodsworth 1996; Buchbinder 1994; Eyster 1991). Most research on sexual
HCV transmission has not collected information about specific sexual
acts.
Research on HCV
transmission must employ direct questions about sexual behaviors.
Mucosal transmission by oral, penile, vaginal, and anal routes must be
investigated as well as sexual practices that may involve the exchange
of blood. Information about the risk associated with specific sexual
practices is needed to inform prevention program messages as well as
individual decision-making about risk reduction to prevent HCV
transmission.
1f.
Sharpen the focus on mother-to-child HCV transmission.
Worldwide, 35% of
those infected with hepatitis C are women in childbearing years.
Infection through mother-to-infant transmission of HCV occurs in
approximately 5% of children born to mothers with HCV (Yeung 2001). The
risk of HCV transmission increases if the mother is coinfected with HIV
or is a current or former injection drug user (Thomas 1998; Yeung 2001).
At present, no interventions have been identified to prevent
mother-to-infant transmission of HCV. Screening pregnant women for
hepatitis C is not a routine part of prenatal care. The draft guidelines
from the National Institute of Health's Consensus Development
Conference on Management of Hepatitis C: 2002 do not offer any
guidance for HCV testing of infants or pregnant women. Voluntary testing
and counseling for hepatitis C should be offered as part of routine
prenatal care. Standardized diagnostic guidelines for mothers and
infants are necessary both in clinical practice and in research
settings. Further research to elucidate factors involved in
mother-to-infant transmission of HCV is needed to identify risk-
reduction and prevention strategies.
1g.
Institute CDC's recommendations for prevention of HCV transmission in
hemodialysis facilities.
People receiving
kidney dialysis are at risk for acquiring HCV infection when dialysis
centers do not practice proper infection control procedures. A study
that screened dialysis recipients for HCV antibodies at 40% of U.S.
dialysis centers during December of 2000 reported that 8.4% tested
positive (Tokars 2002). Other studies of dialysis recipients have
reported anti-HCV prevalence ranging from 10% to 36% among adults and
18.5% among children (CDC 2001).
In April of 2001,
the CDC issued recommendations for preventing transmission of pathogens
among chronic hemodialysis patients; they included stricter infection
control practices, regular monitoring of ALT levels, and HCV testing of
dialysis recipients (CDC 2001). All dialysis facilities must implement
these recommendations and be monitored by the appropriate licensing and
regulatory bodies.
1h.
Develop and implement HCV prevention strategies for the developing
world.
Globally, an
estimated 170 million people, or 3% of the world's population, may be
infected with hepatitis C (WHO 1999). HCV infections in the developing
world are mainly acquired from unscreened, contaminated blood
transfusions, unsterilized medical and dental equipment, and
unsterilized instruments used for circumcision, scarification,
tattooing, and traditional medicine. In parts of the developing world,
injection drug use is also a major mode of HCV transmission. In some
regions, it is estimated that 2.3 to 4.7 million new HCV infections
occur each year as a result of unsafe injections (Kane 1999).
Prevention of new
HCV infections must be a priority in resource-poor settings. This will
include implementing screening of donor organs, blood, and blood
products; offering training on viral inactivation techniques, infection
control procedures, and proper methods of sterilizing medical equipment
(including injection equipment); and promoting harm reduction and
providing access to sterile injection equipment for injection drug
users. Prevention interventions need to be adapted to specific regions,
cultures, and settings.
2.
PATHOGENESIS & NATURAL HISTORY
2a.
Establish prospective, longitudinal cohort studies of the natural
history of HIV/HCV coinfection in the era of HCV treatment and HAART.
It is estimated that
16-25% of HIV-positive individuals in the United States are coinfected
with HCV, with substantially higher rates of coinfection among
HIV-positive injection drug users (Thomas 2002; Sherman 2002). In the
era of highly active antiretroviral therapy (HAART), HIV-related
mortality has decreased significantly while HCV-related morbidity and
mortality have become prominent in coinfected individuals. End-stage
liver disease from HCV is now a leading cause of death in coinfected
individuals (Bica 2001; Martín-Carbonero 2001; Monga 2001; Quintana
2002).
Pre-HAART-era data
from cohorts of coinfected hemophiliacs and injection drug users
indicate that coinfection with HIV produces an accelerated course of HCV
disease (Eyster 1993; Rockstroh 1996; Sánchez Quijano 1995; Telfer
1994). In the HAART era, new questions and conflicting data about the
efficacy of HAART in coinfected individuals have emerged (Greub 2000;
Law 2002; Sulkowski 2002). We need to increase our understanding of the
complex interrelationship between these two viruses, as well as the
impact of HAART and immune restoration. So far, most studies that have
examined the effect of HCV on responses to HAART and clinical
progression of HIV disease have not collected information about the
progression or severity of underlying HCV disease. Without data on
actual liver histology, it is impossible to determine the severity of
HCV disease, which may in turn affect an individual's ability to respond
to HAART.
Well-designed,
prospective longitudinal cohorts will be essential to follow infected
populations, define prognostic factors and other cofactors for
progressive disease, observe changing treatment outcomes over time, and
generate productive hypotheses for pathogenesis, prevention, and
treatment studies. Because treatment modalities for HIV and HCV will
continue to evolve, cohort studies must be large enough and long enough
to measure and account for variations in treatment, as well as other
cofactors such as access to health care, drug use, ethnicity, and
gender. Barriers to enrollment such as invasive needle biopsies can be
addressed by being restricted to intensified substudies, if necessary.
In any case, full participation of coinfected persons and advocates will
be essential in planning and implementing such cohort studies.
2b.
Investigate the role of genetic and ethnic factors in susceptibility to
HCV infection, disease progression, and response to treatment.
Hepatitis C
infection is twice as prevalent among black Americans as white
Americans. The highest observed prevalence of hepatitis C in the United
States—a shocking 9.8%—occurs among black males aged 40 to 49 (Alter MJ
1999). African-Americans appear less likely to achieve spontaneous viral
clearance of HCV (Thomas 2000; Villano 1999). In addition, race appears
to have a substantial impact on the efficacy of interferon.
Significantly lower treatment response rates have been observed in
blacks than in whites, Latinos, or Asian-Americans (Jeffers 2002;
McHutchison 2000; Reddy 1999). Research is needed to understand the
mechanisms that account for these disparities and to identify strategies
to improve treatment response.
2c.
Investigate the role of sex differences in HCV disease progression.
High rates of
spontaneous viral clearance have been observed in two cohorts of
premenopausal women, and some evidence suggests that the course of
hepatitis C disease in this population may be less severe (Benhamou
1999; Kenny-Walsh 1999; Poynard 1997; Weise 2000). No research has
explored why female sex appears to be a favorable prognostic factor. The
role of hormones, immunological differences between males and females,
lower body mass, and socioeconomic factors all warrant further
investigation.
2d.
Investigate the influence of light-to-moderate alcohol consumption on
HCV disease progression.
A large body of data
has confirmed that alcohol consumption of more than 50 grams per day
accelerates the progression of HCV-related liver disease (Harris 2002;
Poynard 1997; Thomas 2000). The effect of light-to-moderate alcohol
consumption on hepatitis C disease progression is unknown. Without more
specific information, most clinicians simply recommend abstinence from
alcohol; data to support or modify recommendations of abstinence are
needed.
3.
DIAGNOSTICS
3a.
Educate primary care providers about hepatitis C infection, diagnosis,
prevention, and treatment.
Acute hepatitis C
infection is clinically silent for most infected people, with only 15%
to 20% of individuals developing symptoms (Koretz 1993). Symptoms, when
they occur—low-grade fever, fatigue, appetite loss, abdominal pain,
nausea, and vomiting—are typical of many common viral infections.
Chronic hepatitis C infection is also often asymptomatic, and both acute
and chronic hepatitis C infections may go undiagnosed by physicians who
fail to ask about the risk factors (Shehab 2001; Shehab 2002; Villano
1999).
Additionally, many
physicians are unaware of the proper procedures for diagnosing hepatitis
C (Shehab 1997). HIV-positive individuals (especially those with fewer
than 200 CD4 cells), injection drug users, and transplant recipients may
harbor occult hepatitis C infection (Beggren 2001; Beld 1999; Busch
2001; Lin 2002; Thomas 1995). Performing HCV RNA testing in these
populations, even when an antibody test result is negative, can
sometimes identify infections that might otherwise go undiagnosed.
Professional educational programs, cross-disciplinary training, and
public health initiatives are needed to increase knowledge of hepatitis
C transmission, prevention, diagnostics, care, and treatment among
health care providers at all levels.
3b.
Continue research on non-invasive testing methods to replace or reduce
the need for liver biopsy.
Liver biopsy is
still the only way to assess the condition of liver tissue. Information
from liver biopsy is used to assess the degree of inflammation, gauge
hepatic cell death and damage, identify other causes of liver injury,
and guide treatment decisions. Although fatalities from biopsy are
extremely rare (0.01-0.1%), liver biopsy can be painful, and occasional
complications such as hemorrhage or puncture of adjoining organs may
occur. The risk of complications and the potential pain of the procedure
have made liver biopsy unpopular with many patients. Sampling errors and
variations among observers may result in serious diagnostic errors
(Bejarno 2001). Providing sedation during the procedure can reduce
associated pain, while using ultrasound to guide the biopsy reduces the
risk of complications and sampling errors (Cadranel 2000; Pokorny 2002;
Soyer 1993).
Alternatives to
liver biopsy using panels of serum biochemical markers have been
proposed and are under investigation. Although these tests may serve as
substitutes when biopsy is contraindicated or refused, the information
they yield is far less precise. The identification, development, and
validation of a non-invasive, cost-effective replacement for liver
biopsy would be an important breakthrough. In the meantime, to reduce
the risk of pain, complications, and sampling errors, experienced
physicians guided by ultrasound should perform liver biopsy, and pain
management should be provided to those undergoing biopsy. A standardized
and simplified system for evaluating the results of liver biopsy in
research and clinical care settings should be instituted, and biopsies
should be read by pathologists who are skilled at reviewing liver
biopsies.
3c.
Identify and validate prognostic markers and effective screening methods
for early diagnosis of hepatocellular carcinoma (HCC).
Hepatocellular
carcinoma (HCC) is a known complication of hepatitis C. In the United
States, the incidence of HCC in the general population has increased
from a rate of 1.4 cases per 100,000 in 1976-1980, to 2.4 cases per
100,000 during the period 1991-1995 (El-Serag 1999). This rise may
reflect an epidemic of increased HCV transmission that occurred decades
earlier. The annual incidence of HCC in hepatitis C-infected cirrhotics
ranges from 1% to 4% (Di Bisceglie 1997; Lauer 2001).
HCC can be
identified by measuring alpha-fetoprotein (AFP) levels and by ultrasound
imaging, but the value of these tests for early detection of HCC in
cirrhotic individuals has not been sufficiently demonstrated. The
sensitivity and specificity of AFP levels in the detection of HCC varies
considerably (from 39-64% and from 76-91%) in different studies (Collier
1997). Some research has shown that ultrasound surveillance increases
early detection of HCC, but without reducing mortality (Larcos 1998;
Solmi 1996). HCC mortality is extremely high, with five-year survival
rates of less than 5% (El-Serag 1999). Better interventions to
facilitate the early diagnosis of HCC and reduce the high fatality rate
are urgently needed.
4.
CARE & TREATMENT
4a.
Develop integrated, multidisciplinary systems of care for individuals
with multiple co-morbidities (HCV, HIV, mental illness, addiction).
Individuals with
hepatitis C are often grappling with other issues: HIV coinfection, the
stress involved with illicit drug use, maintaining recovery from
addiction, severe, debilitating fatigue, poverty, homelessness, or
incarceration. HCV is more prevalent among the mentally ill; moreover,
individuals with HCV have a greater prevalence of depression (Zdilar
2000).
Our health care
system is not prepared to accommodate the needs of active users or
dually and triply diagnosed individuals. Multidisciplinary systems of
care have been proven successful in treating active users, coinfected
individuals with addiction and psychiatric co-morbidities, and
individuals in a methadone maintenance program (Backmund 2001;
Schwartzapfel 2002; Sylvestre 2002). Cross-disciplinary care should
become an integral part of the care and treatment of people living with
HCV and HIV/HCV coinfection.
4b.
Develop guidelines for the care and treatment of coinfected individuals.
No one has yet
integrated the recommendations from the Guidelines for the Use of
Antiretroviral Agents in HIV-Infected Adults and Adolescents (USPHS
2002) and the National Institutes of Health's 2002 Consensus
Statement on the Management of Hepatitis C (NIH 2002). Some
infectious disease doctors providing care for both HIV and HCV may be
more focused on HIV disease. Referral to a gastroenterologist is not
always feasible and, if available, the gastro-enterologist may not be
well informed about the clinical management of HIV. Adapting,
integrating, and updating existing recommendations from the HIV-HCV
International Panel under the aegis of an ongoing guidelines panel of
the U.S. Public Health Service could address these concerns. Such
guidelines would provide an essential resource for clinicians, treatment
educators, treatment advocates, and coinfected individuals.
4c.
Promote screening and vaccination for hepatitis A and hepatitis B among
individuals infected with HCV or coinfected with HIV/HCV.
Individuals infected
with HCV are at risk for severe, potentially fatal disease if they
become coinfected with hepatitis A (Koff 2001; Pramoolsinsap 1999; Vento
1998; Vento 2000). Coinfection with hepatitis B may accelerate
progression of an existing hepatitis C infection or even cause liver
failure and death (Koff 2001; Liaw 2000). Because of these risks, CDC
recommends vaccination against HAV and HBV for all individuals infected
with or at risk for HCV infection. Yet many are not receiving
vaccinations. A survey of primary care physicians found that only 1.6%
of their HCV patients were vaccinated against HAV and only 3% had been
vaccinated against HBV (Nicklin 1999).
Physicians, health
educators, and direct service staff need to be educated about the
importance of vaccination against HAV and HBV. Screening and vaccination
initiatives are needed. Vaccination should be available in correctional
facilities and outside of clinic and hospital-based settings, especially
in venues such as syringe exchange programs, substance abuse treatment
programs, shelters, and methadone maintenance clinics, where high-
prevalence and high-risk groups receive services. Screening and
vaccination should be provided free of charge. Public health funding
must be available for these services.
4d.
Develop strategies to enhance HAV and HBV vaccine immunogenicity in
HIV-positive individuals.
Although
vaccinations for hepatitis A and B are safe in HIV-positive individuals,
vaccine immunogenicity is decreased, especially those with low CD4 cell
counts (Bruguera 1992; Hess 1995; Neilson 1997; Puoti 2002). The CDC
estimates that only 66-75% of HIV-positive individuals develop
protective antibody responses after vaccination for HAV. The efficacy of
HBV vaccination in HIV-positive individuals is unclear, and an optimal
strategy to enhance immunogenicity is needed. Response testing after
vaccination and use of additional doses have been proposed as possible
interventions to improve HBV vaccine response in people with HIV (CDC
1993).
Research on
interventions to enhance the immunogenicity of HAV and HBV vaccines in
HIV-positive persons should be prioritized.
4e.
Increase research of treatment safety and efficacy in understudied
populations.
Most of the studies
of HCV treatment efficacy and safety have focused on populations with
favorable prognostic factors. Individuals with medical and psychiatric
co-morbidities have been excluded from the pivotal studies of
peg-interferon and ribavirin, and results from these trials may not be
applicable to a majority of individuals with HCV infection. More
research is urgently needed on the safety, efficacy, and optimal dosing
and duration of HCV treatment in HIV-positive individuals, cirrhotics,
African-Americans, active drug users, individuals on methadone
maintenance, the mentally ill, transplant recipients, individuals with
renal disease, individuals with autoimmune conditions, the elderly,
young children, adolescents, and non-responders and relapsers after
prior HCV treatment.
4f.
Provide full access to hepatitis C care and treatment for all those in
need.
Current treatments
for HCV can cost up to $40,000 per year. The uninsured, underinsured,
and those ineligible for patient assistance and entitlement programs go
untreated, even when treatment is urgently needed. Cash-strapped AIDS
Drug Assistance Programs (ADAPs) are unable to offer the latest HCV
treatments; fewer than ten of them have the resources available to
provide pegylated interferon and ribavirin.
Advocacy efforts to
increase access to HCV treatment must continue. Entitlement programs and
private insurers should cover the costs of HCV treatment, including
laboratory monitoring and medications to manage its side effects. ADAPs
must receive the necessary funding from Congress to cover HCV treatment.
Strategies must be developed to provide coverage for HCV therapy among
the uninsured who do not qualify for entitlements or patient assistance
programs.
4g.
Provide full access to hepatitis C prevention, care and treatment
services for incarcerated individuals.
In the United
States, 1.8 million individuals are incarcerated. HCV infection is
endemic among prisoners; a 1994 study of HCV prevalence among 4,513
inmates (87% male; 13% female) in the California correctional system
reported that 39.4% of the males and 53.5% of the females were
HCV-antibody-positive (Ruiz 1999). The need for HCV treatment remains
largely unmet in correctional systems. Policies about HCV treatment in
prison differ in every state, and incarcerated individuals do not have
uniform access to treatment for HCV. Some inmates have had to resort to
legal action to obtain treatment. This is an unacceptable situation.
State and national advocacy efforts to demand access to HCV treatment
for inmates must be intensified.
CDC's new guidance
document on Prevention and Control of Infections with Hepatitis
Viruses in Correctional Settings is a useful tool for advocates. CDC
recommends medical evaluation of all inmates who are HCV
antibody-positive and establishment of criteria for HCV treatment based
on current treatment guidelines, and that treatment should be conducted
in consultation with a specialist familiar with treatment regimens for
HIV and HCV (CDC 2003).
4h.
Increase research on strategies to manage side effects from HCV
treatment.
The side effects of
treatment for hepatitis C range from the uncomfortable to the life
threatening. In a recent 1,100-person phase III trial of peg-interferon
alfa-2a (with placebo or ribavirin) versus interferon alfa-2b, the rate
of treatment discontinuation due to adverse events and/or laboratory
abnormalities was 10% in the peg-interferon/ribavirin arm and 11% in the
standard interferon arm. Dose reductions were necessary for 32% of the
individuals in the peg-interferon/ribavirin arm (Fried 2002a).
Significant dose reductions may have an impact on the response to
treatment (Fried 2002a; McHutchison 2002).
A report on adverse
events from a recent trial comparing peg- interferon alfa-2b and
ribavirin to interferon alfa-2b and ribavirin found that more than 20%
of participants in each arm experienced fatigue, headache, fever, muscle
aches and stiffness, insomnia, nausea, hair loss, irritability, joint
pain, loss of appetite and weight loss, depression, and injection site
reactions (Manns 2001). The list of serious adverse events associated
with interferon treatment, although occurring in fewer than 1% of
individuals studied so far, is daunting and includes severe
neuropsychiatric complications and suicidal ideation, as well as skin,
kidney, blood, liver, heart, and autoimmune diseases and sensory organ
disorders (Fried 2002b).
Research to increase
the tolerability of, and adherence to, HCV treatment is a priority. More
research is needed to identify the proper threshold to initiate the use
of growth factors to treat anemia and neutropenia, and to study their
impact on HCV treatment efficacy. Interventions to decrease
neuro-pyschiatric side effects are a priority: the instruments used to
screen for depression—both prior to initiation of HCV treatment and
during treatment—have not been validated for this purpose. More
exploration of the instruments used to diagnose depression and
evaluation of the efficacy, side effects, and indications of selective
serotonin reuptake inhibitors (SSRI), other antidepressants, and
anti-anxiety agents is needed to optimize individual side effect
management strategies.
4i.
Identify optimal dosing strategies.
The two available
pegylated interferons—peg-interferon alfa-2a (Pegasys, manufactured by
Roche) and peg-interferon alfa-2b (Peg-Intron, manufactured by
Schering-Plough)—use different types of PEG molecules to prolong the
half-life of the interferon. Pegasys is premixed and given at a fixed
dose, while Peg-Intron is dosed by weight and mixed prior to injection.
Despite the lack of a head-to-head comparison, and despite the different
methods of dosing, similar efficacy of the two products has been
demonstrated. The overall rate of sustained virological response to
treatment with Pegasys and Peg-Intron, combined with ribavirin, is 54%
vs. 56%, respectively (Di Bisceglie 2002a).
Recent information
from a pivotal study of Pegasys found that individuals with genotype 2
or genotype 3 responded to 24 weeks of therapy and a lower dose of
ribavirin (800 mg) as well as those who received higher doses of
ribavirin over 48 weeks. Individuals with genotype 1 obtained better
responses with 48 weeks of treatment and a higher dose of ribavirin
(1,000-1,200 mg) (Hadziyannis; unpublished data). With Peg-Intron, the
recommended dose of ribavirin is 800 mg; this may be too low for
individuals with genotype 1 and viral loads over 2,000,000 copies. The
recommended duration of therapy (48 weeks) for Peg-Intron may be
unnecessarily long for individuals with genotypes 2 and 3.
The full range and
upper limit for weight-based dosing of Peg-Intron have not been
adequately defined. Obese individuals typically have lower response
rates, but it is unclear whether this is due to inadequate dosing of
peg-interferon and ribavirin or to other poor prognostic factors, viral
resistance, or a combination of these elements. For some, peg-interferon
dosing may be too high, and dose reduction may be necessary to reduce
hematologic problems.
In the absence of
more effective and less toxic therapies for hepatitis C, questions about
dosing variability must be addressed. More research needs to be
conducted on optimal dosing and duration of therapy in other
understudied populations, including individuals with acute hepatitis C
infection, those with renal disease, advanced liver disease,
non-responders to prior HCV treatment, those who have relapsed after
treatment, children, individuals with autoimmune disorders, and
transplant recipients.
5.
KEY RESEARCH QUESTIONS IN HIV/HCV COINFECTION
5a.
Investigate sequencing of treatment for HIV and HCV.
It is still unclear
when antiretroviral therapy should be initiated in coinfected
individuals. Some studies have found a blunted immune response to HAART
in coinfected individuals (Greub 2000; Law 2002). Earlier initiation of
HAART may help to preserve immune function. End-stage liver disease
(ESLD) occurs more frequently in individuals with low CD4 cell counts
(Goedert 2002; Ragni 2001). Thus, for coinfected individuals, it is now
critical to investigate whether earlier initiation of HAART—possibly
earlier than today's recommended thresholds of 200-350 CD4 cells—will
decrease the incidence and progression of ESLD among coinfected
individuals. Alternatively, since it may be possible to eradicate HCV in
people who experience a sustained virological response (SVR) to therapy,
early initiation of HCV treatment in HIV-positive individuals should
also be explored. Preemptive treatment of HCV—even if an SVR is not
achieved—may improve toleration of antiretroviral agents. Answering
these questions will require allocation of resources for long-term
treatment strategy studies.
5b.
Establish a universal definition of hepatotoxicity and characterize its
severity.
Coinfected
individuals often have elevated liver enzyme levels, which may be due to
liver disease, the hepatotoxicity of anti-HIV medications, or both
(Staples 1999). A universal definition of hepatotoxicity for research
and clinical practice is needed to increase the consistency and
interpretability of results from clinical trials, to guide
antiretroviral treatment decisions and to enable the collection of
consistent adverse event data.
Hepatitis C
coinfection significantly increases the risk of hepatotoxicity from
HAART (Lana 2001; Nunez 2001). Some individuals must discontinue HAART
altogether because of liver toxicity; in other instances, only one drug
must be switched. Hepatotoxicity has multiple causes, such as underlying
liver diseases unrelated to HCV, fatty liver, alcohol consumption,
genetic variation, antiretrovirals, or other medications. We need more
research to understand if HAART-related hepatotoxicity worsens HCV
disease, and to differentiate between transient elevations in liver
enzymes and clinically significant indications of clinical progression.
5c.
Explore pharmacokinetics and drug levels in coinfected individuals.
Up to 90% of
HIV-positive individuals receive at least one hepatotoxic drug
(Orenstein 2002). The potential for drug interactions in HIV-positive
individuals is abundant even without hepatitis C coinfection; often,
these individuals may be taking lipid lowering agents, methadone,
anti-anxiety medications, prophylaxis against opportunistic infections,
vitamins, herbs, supplements, and antiretrovirals.
Several important
antiretrovirals are metabolized by the liver. HCV-related liver damage
may diminish the liver's ability to metabolize these drugs. Drug levels
may be elevated in individuals with liver disease, increasing side
effects, interactions, and toxicities. The incidence of complications
from antiretroviral therapy among coinfected individuals needs further
investigation and documentation. The contribution of specific classes
and drugs to interactions, side effects, and complications needs further
study.
5d.
Support access to and research on liver transplantation for HIV-positive
individuals.
Although HAART has
significantly increased the survival of HIV- positive individuals, their
risk for end-stage liver disease remains significant. Some evidence has
emerged in the HAART era indicating that HIV-positive individuals have
post-transplantation outcomes equivalent to HIV-negative individuals
(Gow 2001; Kuo 2001; Prachalias 2001; Ragni 1999). UNOS, the United
Network for Organ Sharing, does not consider HIV infection to be a
contra- indication for organ transplantation. Despite the emerging
reports of favorable outcomes in HIV-positive individuals, insurers have
sometimes denied reimbursement for transplants when HIV is involved,
deeming it "experimental". Expanding an indication to include people
with HIV does not transform an established procedure into an
"experiment". Transplantation must be reimbursable for HIV-positive
individuals.
Prospective studies
of transplantation in HIV-positive individuals will provide vitally
important information about the specific risks for those undergoing
transplantation, as well as help to identify the optimal clinical
management strategies for improved and extended survival of HIV-positive
organ recipients.
6.
BASIC RESEARCH & DRUG DEVELOPMENT
6a.
Support and intensify research into the molecular biology and
immunopathogenesis of HCV.
The initial
identification of hepatitis C (Choo 1989) ushered in a decade of
productive virology and immunology research, as scientists began
investigating the genetic structure of the virus, the role of viral
proteins in HCV replication, the immune response to HCV, and how HCV
causes disease. During the 1990s, researchers made significant inroads
into understanding the structure and genetics of HCV. Scientists cloned
the genome of various HCV strains (Choo 1991; Kato 1990; Takamizawa
1991) and characterized the morphology of HCV through isolation of
virions using electron microscopy (Kaito 1994; Li 1995; Shimizu 1996).
Researchers also discovered the crystal structure of the key viral
proteins serine protease (Kim 1996; Love 1996), helicase (Cho 1998; Kim
1998; Yao 1997), and RNA-dependent RNA polymerase (Ago 1999).
Immunologists identified major epitopes recognized by HCV- specific
cytotoxic T lymphocytes (Battegay 1995; Cerny 1995; Kita 1993; Koziel
1993; Koziel 1995), cells which are believed to play a key role in liver
injury and cell death. Other groups made preliminary attempts at
developing a cell culture system to model the HCV replication cycle
using infectious complementary DNA clones (Kholykhalov 1997; Yanagi
1997) and subgenomic RNA replicons (Lohmann 1999).
In recent years,
researchers have provided detailed evaluations of cell-mediated immune
responses to HCV (Day 2002; Godkin 2002; Lauer 2002; Penna 2002; Rosen
2002a) and further clarified the viral replication cycle and viral-host
cell interactions (Bartenschlager 2002; Shirota 2002; Spahn 2001;
Takikawa 2000; Tellinghuisen 2002; Walewski 2001). Researchers still
lack an efficient, reproducible cell culture system that can support
viral replication and infection. However, the refinement of cell culture
models, including more robust replicon systems (Blight 2000; Ikeda
2002), as well as a surrogate tissue culture system using GBV-B in
tamarin hepatocytes (Beames 2000), enables the examination of the
expression and function of viral proteins. Replicon systems have
facilitated drug development efforts by allowing researchers to screen
compounds for activity against viral proteins involved in the
replication cycle, with the significant limitation that these replicons
cannot infect new cells. While chimpanzees are the only other animals
aside from human beings known to support HCV replication, progress has
been made towards making a viable chimeric mouse model of hepatitis C
infection (Mercer 2001). Despite these advances, numerous challenges
remain. Key aspects of HCV pathogenesis and the viral replication cycle
are not fully understood, and further work on cell culture systems and
animal models remains an urgent priority.
Continued
elucidation of the pathogenesis of HCV will be critical in leading to
new therapies. Researchers have not conclusively determined the
receptors involved in HCV's entry into cells, though the roles of CD81
(Meola 2000; Roccasecca 2003; Takikawa 2000), the low-density
lipoprotein receptor (LDL-R) (Germi 2002; Hennig 2002; Wunschmann 2000),
and most recently the asialoglycoprotein receptor (ASGP-R) (Saunier
2003), have been explored. The potential roles of HCV
proteins—particularly the core protein and NS5A—in the pathogenesis of
fibrosis progression, hepatic steatosis, and hepatocellular carcinoma
require investigation (Gimenez-Barcons 2001; Shi 2002; Tsutsumi 2002;
Yoshida 2001). Key foci in immunology research include clarifying the
correlates of the protective immune responses that enable clearance of
acute infection as well as defining mechanisms of long-term virological
control in chronic infection (Bassett 2001; Major 2002; Shata 2002;
Thomson 2003). Immunologists should also continue to explore the
associations between HCV disease progression, cytokines such as IL-10
and TNF-alpha, and genetic polymorphisms (Rosen 2002b; Tokushige 2003;
Yee 2001), and further investigate the possible contributions of
interactions among HCV and gamma-delta T cells, NK cells, and dendritic
cells to pathogenesis and immune evasion (Tseng 2001; Crotta 2002; Tseng
2002; Auffermann-Gretzinger 2001; Bain 2001).
Finally, efforts
must be made to increase the utility of the mouse model and enhance the
efficiency and reproducibility of in vitro cell culture systems. The
chimeric mouse model incorporating human hepatocytes shows promise,
though further work is necessary to better mimic the human immune
response to HCV in this model. The National Institute of Allergy and
Infectious Diseases (NIAID) Division of Microbiology and Infectious
Diseases (DMID) "Request for Proposals for the Hepatitis Animal Model
Network" (RFP-NIH-NIAID-DMID-99-19) provides a good vehicle for
supporting small animal model studies and should be expanded to
prioritize HCV research. DMID must also update its "Framework for
Progress on Hepatitis C" (NIAID 1997) and increase its commitment to
funding intramural and extramural basic research.
6b.
Support and accelerate the development of new therapeutic strategies.
The standard HCV
treatment using pegylated interferon and ribavirin has limited efficacy,
suboptimal tolerability, and significant expense. New treatment options
that are more potent, less toxic, and effective in those who relapse or
do not respond to current regimens are desperately needed. Anecdotal
reports suggest that many people with HCV are choosing—often based on
the advice of their doctors—to defer treatment due to the limitations of
interferon and ribavirin. The complicated calculus of when and whether
to initiate HCV treatment begins with an assessment of one's current
disease state and risk of disease progression. However, for many, these
considerations are superseded by the difficulties of managing treatment
(including the duration of treatment, the necessity of injecting
interferon, the risk of depression, and the potential impairment of
quality of life) as well as the lower likelihood of a sustained
virological response (SVR) among those with genotype 1, high viral
loads, and HIV coinfection. New and better treatments could mitigate
many of these concerns and make therapy for HCV more widely acceptable
and, ultimately, more successful.
The mechanisms of
action of interferon and ribavirin as treatment for HCV—as well as the
causes of viral resistance and treatment failure—are not fully
understood, and most likely involve multiple immunomodulatory and
antiviral effects (Gretch 2001; Lau 2002; Taylor 2001). Researchers and
drug companies are exploring several new viral targets and drug
candidates informed by a substantial body of basic research into the
molecular biology of HCV. Progress here has been delayed by the lack of
standard tools to screen potential drugs—an efficient, reproducible cell
culture system that can sustain viral replication and infection of new
cells, and a small animal model. Chimpanzees, the only other animal
model known to support HCV replication, have been used to study
pathogenesis and immune response, yielding data that may inform efforts
at finding a vaccine against HCV. However, chimpanzee research is
prohibitively expensive and ethically challenging, and the supply of
chimpanzees is extremely limited (Grakoui 2001; Lanford 2001; Lanford
2002).
Current drugs in
development include those targeting translation initiation (antisense
oligonucleotides and synthetic ribozymes), viral enzymes (serine
protease and helicase), and inhibitors of RNA synthesis (RdRp inhibitors
and IMPDH inhibitors), as well as antifibrotic compounds and
immunomodulators (Di Bisceglie 2002b; Tan 2002). Most of these drugs are
in very early stages of preclinical or clinical development. Vaccine
development has not advanced beyond a few animal studies (Himoudi 2002;
Matsui 2002; Pancholi 2003). During the 1990s, some drug and vaccine
studies were delayed by lawsuits initiated by Chiron against other
companies, claiming that their drug development programs infringed
Chiron's patents related to HCV (Cohen 1999). While these issues appear
to be largely resolved for now, the potential inhibitory effect of
intellectual property disputes on the development of new drugs and
diagnostics calls for scrutiny and vigilance.
Speeding the
development of new therapeutic strategies for HCV will require a
coordinated effort involving government, industry, research
institutions, private foundations supporting biomedical research, and
HCV advocates, especially people infected with hepatitis C. A strategic
partnership between public and private sectors could support exploration
of new targets and a better understanding of viral-host interactions
through techniques such as microarray analysis (Aizaki 2002; Bigger
2001), an intensive research and development program on tools for rapid
and high-throughput screening of candidate compounds, preclinical
research, and the establishment of a network to facilitate the
recruitment of patients into clinical trials.
NIAID's new
Partnerships for Novel Approaches to Controlling Infectious Diseases, a
collaboration between government, industry, and academia, has begun to
focus on hepatitis B and should be expanded to address HCV. Increased
leadership and coordination from the National Institutes of Health's
NIAID and National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK), in concert with advocacy from HCV and HIV
organizations, will be necessary to ensure progress on these fronts.
6c.
Include HIV/HCV coinfected individuals in early-phase HCV treatment
trials.
Preliminary data
suggest a poorer response rate to HCV treatment in coinfected persons
(Chung 2002; Perronne 2002). Because HCV is more aggressive in
HIV-positive individuals, the need for new, more effective treatments is
particularly urgent. Research on the safety and efficacy of HCV
treatment in coinfected persons has lagged; usually, patients and
clinicians must wait for a couple of years before these data are
available to them. Coinfected individuals must be offered the
opportunity to participate in clinical trials of new agents as soon as
it is safe to do so. A good benchmark here would be to ensure enrollment
of coinfected persons as soon as a safe and virologically active dose is
defined.
6d.
Establish a hepatitis C clinical research network.
The National
Institutes of Health's 2002 Consensus Statement on the Management of
Hepatitis C calls for the establishment of a Hepatitis Clinical
Research Network examining natural history, prevention, and treatment
(NIH 2002). Such a network would fill a void in current research
efforts, providing better data regarding pathogenesis, natural history,
long-term clinical outcomes, and determinants of variations in response
rates to current treatment. A clinical research network could also
provide a mechanism to test new therapies alone and in combination with
the standard of care. A well-designed network should support
investigation into optimizing the use of current treatments in
understudied populations, including injection drug users, cirrhotics,
and people with a history of depression. A new network could
systematically address many of the research recommendations in this
document, specifically those in sections
1d and
1e (research on transmission routes); all of section 2 (Pathogenesis
& Natural History); sections 3b and 3c (biopsy
alternatives and
HCC screening); sections 4e, 4h, and 4i (research
on treatment in understudied populations,
side effects, and
dosing strategies); and all of section 5 (Key
Research Questions in HIV/HCV Coinfection).
Much current
knowledge on HCV and HIV/HCV coinfection has come from clinic-based
cohort studies with relatively homogenous patient populations and
treatment follow-up rates generally limited to five years at most. The
existing multicenter networks that have studied HCV have a narrow focus
or limited capacity for large-scale, long-term research. For instance,
the Adult AIDS Clinical Trials Group (AACTG) and the American Foundation
for AIDS Research (amfAR) have sponsored studies on HIV/HCV coinfection,
while the industry-sponsored Hepatitis Research Network's Clinical
Trials Group has focused on treatment strategies. NIAID's Division of
Microbiology and Infectious Diseases (DMID) has begun to develop
research networks, including the Hepatitis C Research Recovery Network
and the Hepatitis C Cooperative Research Centers. This work should be
supported and expanded, given the pressing need for increased resources,
strong leadership, and strategic direction.
APPENDIX
A: The 2000 Recommendations
Recommendations from
TAG's
2000 Hepatitis Report are listed below, with progress on achieving
them and comments on their place in the current recommendations.
-
CDC should further
investigate the role of HCV sexual transmission in MSM.
See
recommendation 1e (Clarify routes and risks of sexual HCV
transmission).
-
CDC should update
its 1998 recommendations to suggest HCV testing for all persons with
HIV/AIDS.
HCV
testing has been recommended by CDC for all persons with HIV; also, see
recommendation 3a (Educate primary care providers about HCV
infection, diagnosis, prevention, and treatment).
-
More research
should be conducted to completely understand the immunologic responses
associated with control of HCV infection.
This
is still an important recommendation; see recommendations 5a and 6a (Investigate
sequencing of treatment for HIV and HCV and
Support and intensify research into the molecular biology and
immunopathogenesis of HCV).
-
The NIAAA
(National Institute on Alcohol Abuse and Alcoholism) should commence
studies on the effects of alcohol in patients with HCV. The findings
should be widely distributed to patients and community physicians in a
timely manner.
See
recommendation 2d (Investigate the influence of light-to-moderate
alcohol consumption on HCV disease progression).
-
Large natural
history studies should be initiated to determine the current natural
history of HIV/HCV coinfected individuals in the era of HAART.
This
remains an important issue; see
recommendation 2a (Establish prospective, longitudinal cohort
studies of the natural history HIV/HCV coinfection in the era of HCV
treatment and HAART).
-
NIH's ICDs
(Institutes, Centers, and Divisions) [i.e., NIAID (National Institute
of Allergy and Infectious Diseases), NIDDK (National Institute of
Diabetes and Digestive and Kidney Diseases), NHLBI (National Heart,
Lung, and Blood Institute)] should issue multiple RFAs for
cross-training of fellows in hepatology and infectious disease/HIV
research.
Although this is a good idea, it may not be necessary—a hepatitis C
clinical research network may be able to bring hepatologists and
infectious disease researchers together. The AACTG has an integrated
Liver Disease Subcommittee that allows for cross-disciplinary
collaboration. See
recommendation 6d (Establish a hepatitis C clinical research
network).
-
NIH's Office of
AIDS Research should make available some of its discretionary funding
for basic and clinical research on HIV/HCV coinfection.
OAR
has included research on HCV coinfection in its strategic plan. Funding
will be addressed in Version 2.0 of the full Hepatitis C/HIV Coinfection
Report.
-
The NIH should
explore the desirability and feasibility of a Hepatitis Clinical
Trials Network. The network would carry out phase I to phase IV
clinical studies with nested basic science research.
See
recommendation 6d (Establish a hepatitis C clinical research
network).
-
Future HCV
treatment trials should stratify for HIV serostatus and enroll both
HIV-positive and HIV-negative people in order to gather these critical
data.
See
recommendation 6c (Include HIV/HCV coinfected individuals in
early-phase HCV treatment trials).
-
HCV treatment
should be mandated in all state and federal prison systems.
Access to HCV treatment should be mandated; see
recommendation 4g (Provide full access to hepatitis C care and
treatment for incarcerated individuals).
-
Transplant centers
in the U.S. should consider HIV-positive people for liver
transplantation.
There have been successful liver transplants in HIV-positive recipients
in the U.S; we are moving towards research to establish safety,
efficacy, and the development of a standard of care for transplantation
in HIV-positive individuals. See
recommendation 5d (Support access to and research on liver
transplantation for HIV-positive individuals).
-
HCV patients must
have access to their HCV RNA levels at timely intervals (e.g., week
24) while on HCV treatment studies.
This
is an important concern; new data about 12-week early stopping rules in
individuals with HCV monoinfection, and the longer half-life of HCV
virions in HIV/HCV coinfected individuals should be considered in study
design and reimbursement.
-
Schering-Plough
must unbundle Rebetron® so that ribavirin can be purchased separately.
Unfortunately, this has not made HCV treatment more financially
accessible unless individuals are purchasing their ribavirin from a
compounding pharmacy. See
recommendation 4f (Provide full access to hepatitis C care and
treatment for all those in need).
-
Research should be
conducted to determine the lowest effective dose of ribavirin to
minimize unnecessary toxicity.
Although issues about ribavirin dosing have been fairly well resolved,
issues about the dosing of peg-interferon remain. See recommendations 4h
and 4i (Increase
research on strategies to manage side effects from HCV treatment;
and
Identify optimal dosing strategies).
-
All 50 U.S. states
should add ribavirin to their Medicaid and ADAP formularies.
Currently, Medicaid programs in all 50 states cover ribavirin and
Schering's Peg-Intron®; however, serious access problems remain. See
recommendation 4f (Provide full access to hepatitis C care and
treatment for all those in need).
-
Industry should
conduct drug interaction studies of anti- HIV drugs in HIV/HCV
coinfected people while drugs are in development so that potential
hepatotoxicity and drug interactions are defined prior to approval.
See
recommendations 5b, 5c, and 6c (Establish
a universal definition of hepatoxicity and characterize its severity;
Explore pharmacokinetics and drug levels in coinfected individuals;
and
Include HIV/HCV coinfected individuals in early-phase HCV treatment
trials).
-
FDA should grant
Hoffmann-La Roche's PEG-IFN NDA (new drug application) a "priority
review" because of the unmet need for therapies for HCV patients with
cirrhosis.
Roche's Pegasys® was approved in October of 2002.
-
HCV-treating
physicians should fully explain the risk and benefits of IFN/RBV
combination therapy with their patients as well as estimates of
treatment response according to host and viral characteristics.
See
recommendation 3a (Educate primary care providers about HCV
infection, prevention, and treatment).
-
Industry must
actively recruit African-Americans in all phases of HCV clinical
trials. These studies should have the statistical power to assess
racial differences in viral clearance and response rates.
NIH
is currently funding a study on HCV treatment responses in
African-Americans; Roche has an ongoing safety and efficacy study as
well. See
recommendation 2b (Investigate the role of genetic and ethnic
factors in susceptibility to HCV infection, progression, and response to
treatment).
-
Hepatitis
treatment advocates should be included in all facets of NIH
decision-making about hepatitis clinical and basic science research,
including protocol development, scientific agenda committees, and
grant reviews.
See
recommendations 6a and 6d (Support
and intensify research into the molecular biology and immunopathogenesis
of HCV infection; and
Establish a hepatitis C clinical research network).
REFERENCES
Ago H,
Adachi T, Yoshida A, et al. Crystal structure of the RNA-dependent RNA
polymerase of hepatitis C virus. Structure Fold Des
7(11):1417-26. 1999.
Aizaki H, Harada T, Otsuka M, et al. Expression profiling of liver cell
lines expressing entire or parts of hepatitis C virus open reading
frame. Hepatology 36(6):1431-8. 2002.
Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis
C virus infection in the United States, 1988 through 1994. N Engl J
Med 341:556-62. 1999.
Alter MJ, Moyer LM. The importance of preventing hepatitis C virus
infection among injection drug users in the United States. J Acquir
Immune Defic Syndr 18 (S1): S6-S10. 1998.
Alter MJ. Prevention of spread of hepatitis C. Hepatology 36 (5,
Suppl 1): S93-S98. 2002.
Auffermann-Gretzinger S, Keeffe EB, Levy S. Impaired dendritic cell
maturation in patients with chronic, but not resolved, hepatitis C virus
infection. Blood 15;97(10):3171-6. 2001.
Backmund M, Meyer K, Von Zielonka M, et al. Treatment of hepatitis C
infection in injection drug users. Hepatology 34(1):188-193.
2001.
Bain C, Fatmi A, Zoulim F, et al. Impaired allostimulatory function of
dendritic cells in chronic hepatitis C infection. Gastroenterology
120(2):512-24. 2001.
Bartenschlager R, Lohmann V. Replication of hepatitis C virus. J Gen
Virol 81(Pt 7):1631-48. 2000.
Bassett SE, Guerra B, Brasky K, et al. Protective immune response to
hepatitis C virus in chimpanzees rechallenged following clearance of
primary infection. Hepatology 33(6):1479-87. 2001.
Battegay M, Fikes J, Di Bisceglie AM, et al. Patients with chronic
hepatitis C have circulating cytotoxic T cells which recognize hepatitis
C virus-encoded peptides binding to HLA- A2.1 molecules. J Virol
69(4):2462-70. 1995.
Beames B, Chavez D, Guerra B, et al. Development of a primary tamarin
hepatocyte culture system for GB virus-B: a surrogate model for
hepatitis C virus. J Virol 74(24):11764-72. 2000.
Bejarno PA, Koehler A, Sherman KE. Second opinion in liver biopsy. Am
J Gastroenterol 96 (11): 3158-64. 2001.vBeld M, Penning M, van
Putten M, et al. Low levels of hepatitis C virus RNA in serum, plasma
and peripheral blood mononuclear cells of injecting drug users during
long antibody-undetectable periods before seroconversion. Blood
94 (4): 1183-91. 1999.
Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in
human immunodeficiency virus and hepatitis C coinfected patients.
Hepatology 30(4):1054-58. 1999.
Berggren R, Jain M, Hester J, et al. (abstract # 562) False-negative
hepatitis C antibody is associated with low CD4+ cell counts in
HIV/HCV-coinfected individuals. 8th Conference on Retroviruses and
Opportunistic Infections, Chicago Illinois, 2001.
Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage
liver disease in patients with human immunodeficiency virus infection.
Clin Infect Dis 32 (3): 492-97. 2001.
Bigger CB, Brasky KM, Lanford RE. DNA microarray analysis of chimpanzee
liver during acute resolving hepatitis C virus infection. J Virol
75(15):7059-66. 2001.
Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA
replication in cell culture. Science 290(5498):1972-4. 2000.
Bodsworth NJ, Cunningham P, Kaldor J, et al. Hepatitis C virus infection
in a large cohort of homosexually active men: independent associations
with HIV-1 infection and injecting drug use but not sexual behavior.
Genitourin Med 72(118):118-122. 1996.
Bruguera M, Cremades M, Salinas R et al. Impaired response to
recombinant hepatitis B vaccine in HIV-infected persons. J Clin
Gastroenterol 14(1):27-30. 1992.
Buchbinder SP, Katz MH, Hessol NA, et al. Hepatitis C virus in sexually
active homosexual men. J Infection 29:263-269. 1994.
Busch MP, Laycock ME, Mohr, et al. (abstract # 235) Failure of serologic
assays for diagnosis of hepatitis B and C virus infections in patients
with advanced HIV. 8th Conference on Retroviruses and Opportunistic
Infections. Chicago, Illinois, 2001.
Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France:
results of a prospective nationwide survey. For the Group of
Epidemiology of the French Association for the Study of the Liver(AFEF).
Hepatology 32(3): 477-81. 2000.
Centers for Disease Control and Prevention. Recommendations of the
Advisory Committee on Immunization Practices (ACIP): Use of vaccines and
immune globulins in persons with altered immunocompetence. MMWR
Recommendations and Reports 42 (No. RR-4).
http://www.cdc.gov/mmwr/preview/mmwrhtml/00023141.htm. 1993.
Centers for Disease Control and Prevention. Recommendations for
prevention and control of hepatitis C virus (HCV) infection and
HCV-related chronic disease. MMWR:47 (No. RR-19).
http://www.cdc.gov/mmwr/preview/mmwrhtml/00055154.htm. 1998. Centers
for Disease Control and Prevention. Alter MJ, Lyerla RL, Tokars JI, et
al. Recommendations for preventing transmission among chronic
hemodialysis patients. MMWR Recommendations and Reports 50
(RR05);1-43.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5005a1.htm. April 27,
2001.
Centers for Disease Control and Prevention. Guidelines for Viral
Hepatitis Surveillance and Case Management. Atlanta, GA June, 2002.
Centers for Disease Control and Prevention. Prevention and Control of
Infections with Hepatitis Viruses in Correctional Settings. MMWR
Recommendations and Reports 52 (RR01);1- 33.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5201a1.htm. January 24,
2003.
Cerny A, McHutchison JG, Pasquinelli C, et al. Cytotoxic T lymphocyte
response to hepatitis C virus-derived peptides containing the HLA A2.1
binding motif. J Clin Invest 95(2):521-30. 1995.
Cheung RC, Hanson AK, Maganti K, et al.Viral hepatitis and other
diseases in a homeless population. J Clin Gastroenterol 34 (4):
476- 80. 2002.
Cho HS, Ha NC, Kang LW, et al. Crystal structure of RNA helicase from
genotype 1b hepatitis C virus. A feasible mechanism of unwinding duplex
RNA. J Biol Chem 273(24):15045-52. 1998.
Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from
a blood-borne non-A, non-B viral hepatitis genome. Science
244:359-362. 1989.
Choo QL, Richman KH, Han JH, et al. Genetic organization and diversity
of the hepatitis C virus. Proc Natl Acad Sci USA 88:2451-2555.
1991.
Chung RT, Anderson J, Alston B, et al. (abstract LB15) A randomized,
controlled trial of pegylated interferon alpha-2a with ribavirin vs.
interferon alpha-2a with ribavirin for the treatment of chronic HCV in
HIV co-infection: ACTG 5071. 9th Conference on Retroviruses and
Opportunistic Infections. Seattle, Washington, 2002b.
Cohen J. The scientific challenge of hepatitis C. Science
285(5424):26-30. 1999.
Collier J, Sherman M. Screening for hepatocellular carcinoma.
Hepatology 27 (1): 273- 78. 1998.
Conry-Cantilena C, VanRaden M, Gibble J, et al. Routes of infection,
viremia and liver disease in blood donors found to have hepatitis C
virus infection. N Engl J Med 334: 1691-1696. 1996.
Crotta S, Stilla A, Wack A, D'Andrea A, et al. Inhibition of natural
killer cells through engagement of CD81 by the major hepatitis C virus
envelope protein. J Exp Med 195(1):35-41. 2002.
Day CL, Lauer GM, Robbins GK, et al. Broad specificity of virus-specific
CD4(+) T-helper-cell responses in resolved hepatitis C virus infection.
J Virol 76(24):12584-95. 2002.
Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology
26(3 Suppl 1): 34S-38S. 1997.
Di Bisceglie AM, Hoofnagle JH. Optimal therapy of hepatitis C.
Hepatology 36 (5 Suppl 1): S 121-S127. 2002a.
Di Bisceglie AM, McHutchison J, Rice CM. New therapeutic strategies for
hepatitis C. Hepatology 35(1):224-31. 2002b.
Donahue JG, Nelson KE, MuZoz A, et al. Antibody to hepatitis C virus
among cardiac surgery patients, homosexual men and intravenous drug
users in Baltimore, Maryland. Am J Epidemiology 134(10):
1206-1211. 1991.
El-Serag HB, Mason AC, et al. Rising incidence of hepatocellular
carcinoma in the United States. N Engl J Med 340(10):745-50.
1999.
Eyster ME, Alter HJ, Aledort LM, et al. Heterosexual transmission of
hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Ann
Intern Med 115(10):764-8. 1991.
Eyster ME, Diamondstone LS, Lien J-M, et al. Natural history of
hepatitis C virus infection in multitransfused hemophiliacs: effect of
coinfection with human immunodeficiency virus. J Acquir Immune Defic
Syndr 6(6):602-610. 1993.
Fried MW, Shiffman ML, Reddy RK, et al. Peginterferon alfa-2a plus
ribavirin for chronic hepatitis C virus infection. N Engl J Med
347(13):975-82. 2002a.
Fried MW. Side effects of therapy of hepatitis C and their management.
Hepatology 36(5 Suppl 1):S237-244. 2002b.
Garfein RS, Vlahov D, Galai N, et al. Viral infections in short-term
injection drug users: the prevalence of the hepatitis C, hepatitis B,
human immunodeficiency, and human T-lymphotropic viruses. Am J of
Public Health 86(5):655-661. 1996.
Germi R, Crance JM, Garin D, et al. Cellular glycosaminoglycans and low
density lipoprotein receptor are involved in hepatitis C virus
adsorption. J Med Virol 68(2):206-15. 2002.
Gimenez-Barcons M, Franco S, Suarez Y, et al. High amino acid
variability within the NS5A of hepatitis C virus (HCV) is associated
with hepatocellular carcinoma in patients with HCV-1b-related cirrhosis.
Hepatology 34(1):158-67. 2001.
Godkin AJ, Thomas HC, Openshaw PJ. Evolution of epitope-specific memory
CD4(+) T cells after clearance of hepatitis C virus. J Immunol
169(4):2210-4. 2002.
Goedert JJ, Eyster ME, Lederman MM, et al. End-stage liver disease in
persons with hemophilia and transfusion-associated infections. Blood
100(5):1584-89. 2002.
Gow PJ, Multimer D. (Correspondence) Liver transplantation for an
HIV-positive patient in the era of highly active antiretroviral therapy.
AIDS 15(2): 291-2. 2001.
Grakoui A, Hanson HL, Rice CM. Bad time for Bonzo? Experimental models
of hepatitis C virus infection, replication, and pathogenesis.
Hepatology 33(3):489-95. 2001.
Gretch D. Mechanism of interferon resistance in hepatitis C. Lancet
358(9294):1662-4. 2001.
Greub G, Ledergerber M, Battegay P, et al. Clinical Progression,
survival and immune recovery during antiretroviral therapy in patients
with HIV- |
