a topic below for an index of articles:
Financial or Socio-Economic Issues
Math Models or Methods to
Religion and infectious diseases
Stigma or Discrimination
If you would like to submit an article to this website, email us at email@example.com for a review of this paper
Financial or Socio-Economic Issues
Math Models or Methods to
Religion and infectious diseases
Stigma or Discrimination
If you would like to submit an article to this website, email us at firstname.lastname@example.org for a review of this paper
Financial or Socio-Economic Issues
Math Models or Methods to
Religion and infectious diseases
Stigma or Discrimination
If you would like to submit an article to this website, email us at email@example.com for a review of this paper
“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”
Co-occurring Hepatitis C, Substance Use, and Psychiatric Illness:
Treatment Issues and Developing Integrated Models of Care
Journal of Urban Health: Bulletin of the New York Academy of Medicine,
Dec 2004 Vol. 81, No. 4,
Diana L. Sylvestre, Jennifer M. Loftis, Peter Hauser, Sander Genser,
Helen Cesari, Nicolette Borek, Thomas F. Kresina, Leonard Seeff, and
Dr. Sylvestre is with the Department of Medicine, University of
California, San Francisco; Drs. Loftis and Hauser are with the School of
Medicine, Oregon Health and Sciences University, and the Northwest
Hepatitis C Resource Center, Portland VA Medical Center; Drs. Genser,
Borek, Kresina, and Francis and Ms. Cesari are with the Center for AIDS
and Other Medical Consequences of Drug Abuse, National Institute on Drug
Abuse, National Institutes of Health; Dr. Seeff is with the National
Institute of Diabetes, Digestive and Kidney Diseases, National
Institutes of Health.
Correspondence: Thomas F. Kresina, PhD, Center for AIDS and Other
Medical Consequences of Drug Abuse, National Institute on Drug Abuse,
National Institutes of Health, 6001 Executive Boulevard, MSC 9593,
Bethesda, MD 2089209593. (E-mail: Tk13v@nih.gov)
Hepatitis C virus (HCV) infection is transmitted by injection drug use
and associated with psychiatric conditions. Patients with drug use or
significant psychiatric illness have typically been excluded from HCV
treatment trials noting the 1997 National Institutes of Health Consensus
Statement on HCV that indicated active drug use and major depressive
illness were contraindications to treatment of HCV infection. However,
the 2002 NIH Consensus Statement recognized that these patients could be
effectively treated for HCV infection and recommended that treatment be
considered on a case-by-case basis. Treating HCV infection in these
patients is challenging, with drug use relapse possibly leading to
psychosocial instability, poor adherence, and HCV reinfection.
Interferon therapy may exacerbate preexisting psychiatric symptoms.
Co-occurring human immunodeficiency virus or hepatitis B virus provide
additional challenges, and access to ancillary medical and psychiatric
services may be limited. Patients with co-occurring HCV infection,
substance use, and psychiatric illness can complete interferon treatment
with careful monitoring and aggressive intervention. Clinicians must
integrate early interventions for psychiatric conditions and drug use
into their treatment algorithm. Few programs or treatment models are
designed to manage co-occurring substance use, psychiatric illness, and
HCV infection and therapy. The National Institute on Drug Abuse convened
a panel of experts to address the current status and the long-range
needs through a 2-day workshop, Co-occurring Hepatitis C, Substance
Abuse, and Psychiatric Illness: Addressing the Issues and Developing
Integrated Models of Care. This conference report summarizes current
data, medical management issues, and strategies discussed.
Current surveillance data indicate that acute hepatitis C virus (HCV)
infection has diminished in the United States partly because of enhanced
prevention and testing efforts among injection drug users (IDUs) and
blood donors.2 HCV transmission continues primarily through injection
drug use (approximately 65%--70% of cases), sex with infected or
multiple partners (approximately 15%--20% of cases), or occupational
exposure (approximately 5% of cases). The prevalence of HCV infections
in the United States is high, with approximately 3 to 4 million
Americans estimated to be infected.
Chronic HCV infection is the leading cause of cirrhosis and
hepatocellular carcinoma in the United States and the dominant reason
for liver transplantation.2 Studies demonstrated that up to 20% of
chronically infected patients will develop cirrhosis over a 20-year
period, and these patients are at risk for hepatocellular carcinoma.
Persons at special risk for progression include those older at the time
of infection, alcoholic, or co-infected with human immunodeficiency
virus (HIV) or hepatitis B virus. Conversely, individuals infected at a
younger age have a far lower rate of disease progression.
Clinical trials showed that the combination of interferon (IFN) and
ribavirin was more effective than IFN alone for any genotype, but that
the greatest therapeutic yield came with the use of pegylated IFN plus
ribavirin.2 Genotype 1, the most common HCV variant in the United
States, is less responsive to treatment than genotypes 2 and 3. A
sustained virologic response (SVR) is also less common in patients with
higher HCV ribonucleic acid (RNA) levels or more advanced stages of
fibrosis, especially cirrhosis, and in individuals with HIV/HCV
co-infection.3 Persons with genotype 1 who fail to achieve an early
virologic response (<2 log decrease in HCV RNA at week 12 of treatment)
rarely develop an SVR.4 Initial studies of combination therapy in IDUs,
patients with comorbid psychiatric illness, and children indicated that
an SVR can be achieved in these populations.
Although the incident data for acute HCV infection in drug users has
declined, drug use incidence has not. The prevalence of heroin use has
grown over the past decade, with increasing numbers of users presenting
for substance use treatment. The National Institute on Drug Abuse and
the Community Epidemiology Work Group,5 using ethnographic research,
focus groups, and community-based sources, reported that heroin abuse
indicators increased nationally in 2002, particularly among young
Caucasian and suburban populations. Primary heroin treatment admissions
increased in Chicago, Illinois; San Diego, California; Boston,
Massachusetts; and Newark, New Jersey, and continued to account for a
large proportion of admissions in Baltimore, Maryland; Los Angeles,
California; and New York City. In Denver, Colorado, and Dallas, Texas,
heroin-related calls to the regional poison control center increased,
heroin-related deaths were reported in Detroit, Michigan; Honolulu,
Hawaii; Newark; Minneapolis/St. Paul, Minnesota; San Diego, California;
and Seattle, Washington. Opiate-related deaths surpassed cocaine deaths
in Washington, DC, and Minneapolis/St. Paul.
National seroprevalence studies have shown that exposure to HCV occurs
in up to 90% of IDUs.6 For IDUs in methadone maintenance treatment, as
many as 96% of tested individuals were seropositive for HCV antibody,
and 62% were positive for HCV RNA.7 This compares to prevalence data
from cohort studies of drug users who do not inject drugs, with the
highest prevalence data reported at approximately 40% for individuals
with more than 21 years of drug use.8 Studies have shown that HCV
seroconversion in IDUs can occur rapidly in the initial 1--3 years of
drug use.9 Thus, the prevalence of HCV infection in IDUs remains high.
Psychiatric disorders are also associated with HCV infection and
injection drug use. Recent studies have shown that many patients with
HCV infection also have diagnoses of depression, posttraumatic stress
disorder (PTSD), psychosis, or anxiety.10--13 Compared to the overall
population, individuals with chronic HCV infection have a higher
prevalence of psychiatric disorders. For example, in a sample of 931
persons receiving treatment at inpatient and outpatient public health
settings in four Eastern states, the prevalence of HCV infection was
19.6%, or 11 times greater than the rates observed in the general
population. Injection drug use and use of crack cocaine were risk
factors for HCV infection, and a lifetime history of injection drug use
was associated with a 31-fold increased risk of HCV infection.
Similarly, there is a 6% to 44% prevalence of preexisting depression
among HCV-infected patients.14,15
Taken together, these reports indicated that substance use and
psychiatric disorders in patients with HCV infection are common and
could be significant barriers to treatment of HCV infection. In the
following sections, strategies for addressing the issues of co-occurring
HCV, substance abuse, and psychiatric illness are presented. Although
IFN can lead to severe neuropsychiatric side effects, the published
evidence suggested that many patients with psychiatric or substance use
diagnoses can be treated safely and effectively. Figure 1 provides a
flow diagram that illustrates the comanagement and integration of care
for patients with HCV, substance use disorders, and psychiatric
SCREENING AND ASSESSMENT OF PSYCHIATRIC, SUBSTANCE USE, AND
Substance users have a high frequency of co-occurring psychiatric
illness. Psychiatric screening and consultation should be considered
prior to initiating IFN therapy. For the purposes of screening and
monitoring patients for depression before and during IFN therapy, a
number of self-rated or clinician-rated scales are available and are
listed in the Table. Commonly used self-rated instruments are the Zung
Self-Rating Depression Scale,36 the Beck Depression Inventory (BDI),37
and the self-rated version of the Montgomery Asberg Depression Rating
Scale.25 A recent report38 examined the sensitivity and specificity of
the BDI and other instruments for predicting eventual psychiatric and
antidepressant treatment during IFN therapy. The BDI performed best in
this analysis and is now the preferred screening tool at Veterans
Affairs Medical Centers. These cost-effective tools can provide
increased accuracy in assessing
patient depressive symptomatology as well as improved objective
measurement of changes in mood states during IFN therapy.39
Gender-specific definitions of levels of hazardous alcohol consumption
have been established,28 but are not specific to HCV infection or
treatment with IFN. However, heavy alcohol is a key factor in disease
progression for both HCV infection and HIV/HCV co-infection. Thus,
screening for alcohol consumption in multimorbid patients is imperative.
The CAGE questionnaire, focusing on cutting down, annoyance by
criticism, guilty feeling, and eye-openers, or the Michigan Alcoholism
Screening Test (MAST) can be utilized. However, the Alcohol Use
Disorders Screening Test (AUDIT) and the abbreviated version, the
AUDIT-C, are best for identifying hazardous use or alcohol use disorders
and can be used for stratification of risk to guide prevention and
treatment strategies.19,20,23,29 Because of minimization and denial, the
AUDIT-C does not measure actual alcohol exposure. Biomarkers of alcohol
use have been used, such as carbohydrate-deficient transferrin,
hemoglobinassociated aldehyde, and fatty acid ethylesters (in
hair),40,41 but there are no sensitivity, specificity, or risk-level
standards for HCV-infected populations.
Brief screens for other drug use problems, including the Drug Abuse
Screening Test (DAST), CAGE Adapted to Include Drugs (CAGE-AID), and the
Two-Item Conjoint Screen (TICS) and tests for drugs in urine, blood, or
saliva focus on endstage problems (consequences rather than use) and
have no specific focus on tobacco or injection drug use. The ASSIST 2.1
(Alcohol, Smoking, and Substance Involvement Screening Test)18,
developed by World Health Organization for primary care screening,
assesses (1) lifetime use of 10 drug "classes," (2) substancespecific
recent use, (3) substance-specific severity, (4) current global risk,
and (5) injection drug risk and shows reliability in international
trials. However, its limitations include self-report, length, frequency
assessment of alcohol use, and the need for further validation with
biomarkers. The Patient Screening Questionnaire (PSQ) has been developed
to identify psychiatric and substance use disorders prior to the start
of antiviral therapy. This 10-item instrument screens for psychotropic
medication use, past psychiatric in- and outpatient care, as well as
past substance use.42
Analog scales have been used to assess substance use, psychiatric
disease, and cognitive performance. In an ongoing study to assess the
combined effects of methamphetamine,
HIV infection, and neurocognitive functioning, the individuals who were
co-infected with HCV showed higher levels of cognitive impairment and
markers of immune activation than those who were HCV seronegative. In
this study, individuals with impaired memory also had higher HCV plasma
RNA levels. Although no HCV RNA was found in cerebrospinal fluid (CSF),
higher plasma HCV RNA correlated with a higher CSF HIV viral load.
Currently, one individual with HIV/HCV co-infection treated with IFN
alone showed a decline in the CSF HIV viral load. This is consistent
with possible additive or interactive HCV and HIV contributions to
neurocognitive impairment in these co-infected substance-using patients.
Additional screening tools may be required to assess the individual and
combined neurocognitive comorbidities caused by (1) HIV infection, (2)
progression of liver disease, and (3) chronic alcohol consumption.
For patients with co-occurring illnesses, there is also the need for
assessing function in areas such as driving, employment, self-care,
risky behaviors, and adherence. Lessons learned from HIV-infected
patients in these areas suggested that neuropsychological (NP)
impairment is associated with lower employment percentage and decreased
probability of receiving antiretroviral treatment. NP test results can
be used to monitor response to treatment.43 For HCV infection, autopsy
and imaging studies are providing evidence of HCV viral replication in
the brain and abnormal metabolites consistent with central nervous
system inflammation in the striatum and white matter,13 suggesting an
extrahepatic manifestation of HCV infection that may contribute to
neurocognitive impairment. On standard NP tests, HCV-infected patients
showed defects of mental and motor speed, "complex" attention (sustained
or divided), and short-term working memory, but not IQ or episodic
memory.44 This is similar to results found in other patients with
cirrhotic or noncirrhotic liver disease, but there are indications that
problems emerge earlier among patients with HCV infection.45
The cognitive functioning of HCV-infected drug users has not been
characterized. Studies with this population of patients need to consider
drug use patterns, level of sobriety or withdrawal when tested, and the
lack of test norms that reflect race, ethnicity, socioeconomic status,
and frequent comorbidities of drug use (head trauma, learning disorders,
malnutrition, HIV, other central nervous system infections, depression,
antisocial personality disorder, PTSD). Moreover, classical NP tests
such as the Trail-Making Test may provide evidence of impairment without
localization or etiology. Computerized tests based on developments in
cognitive neuroscience and mapping neuropathology have been useful with
HIV-positive patients and may be applicable to those with HCV
infection.46 Such tests address (1) verbal working memory (with
circuitry including the dorsolateral prefrontal cortex and striatum);
(2) decision-making parameters such as risk, impulsivity, and delayed
versus immediate reward; (3) mental speed; and (4) divided attention.
These tests showed significant correlations with HIV infection and, in
the case of verbal working memory, cytokine activity in polydrug users.
Data from drug users grouped by HCV infection and HIV serostatus using a
reaction time version of the Stroop task to evaluate the integrity of
the prefrontal cortical systems mediating response inhibition showed
greater Stroop interference in the co-infected group compared with those
without infection.47 In addition, the HCV monoinfected patients
responded more slowly than did those who were HCV negative. However,
studies are needed in HCV-infected drug users whose drug/use history and
many comorbid conditions are well characterized to develop practice,
brief, and informative assessment of neurocognitive function in patients
with HCV infection and co-occurring illnesses.
HEPATITIS C VIRUS TREATMENT AND SUBSTANCE USERS: MANAGEMENT CHALLENGES
Most care providers withhold IFN-based treatment for active drug users
who are chronically HCV infected.48 However, calls for an individualized
approach to treating HCV-infected patients2,49,50 are based on a limited
number of studies that revealed HCV treatment efficacy in drug-using
cohorts. A study of 50 heroin addicts enrolled in an inpatient methadone
detoxification unit showed an overall SVR of 36%, even though half of
the patients relapsed to heroin injection.51 Although the SVR was lower
(24%) in the drug users, outcomes were not statistically different from
those who maintained sobriety. Only 2 of the 50 patients developed IFN-induced
severe depression. The impact of a history of psychiatric and substance
use disorders on HCV treatment was studied in 33 veterans; 19 had a
history of psychiatric disease, 5 of the 14 nonpsychiatric patients had
a remote history of injection drug use, and 13 of the 19 psychiatric
patients reported a history of drug or alcohol dependence.52 Psychiatric
diagnoses included PTSD, depression, schizoaffective disorder,
obsessive-- compulsive disorder, anxiety, and mixed personality
disorder. Although patients with psychiatric disease were more likely to
develop neuropsychiatric adverse events caused by IFN-based treatment,
their dropout rate and SVR were equivalent to those without psychiatric
disease. However, virological response rates were low in both groups,
and only 30% completed a year of IFN therapy. Overall, 5 patients (2 in
the nonpsychiatric cohort and 3 in the psychiatric cohort) developed
neuropsychiatric side effects requiring treatment discontinuation.
In a more recent study53 of HCV treatment in 50 methadone patients, 62%
(46% depression, 12% anxiety, 2% obsessive compulsive disorder, and 2%
schizophrenia) reported a preexisting psychiatric diagnosis, and the
end-of-treatment response (ETR) rate was 64%. Of the subjects, 30% were
sober for less than 6 months, and 36% relapsed to hard drug use during
the study. Pretreated with antidepressants was given to 47% of patients,
and 88% were taking antidepressants by the end of IFN therapy. There was
no significant difference in ETR between subjects with short sobriety
compared to those whose sobriety was more lengthy, and relapse to drug
use overall did not lead to a significant reduction in treatment
outcomes. Although the dropouts in the study had a modestly higher
prevalence of preexisting psychiatric disease than the entire study
population (73% vs. 62%, respectively), there was no statistically
significant correlation of psychiatric illness with treatment
Furthermore, a long-term follow-up of 27 former IDUs54 treated for HCV
infection indicated a limited likelihood of HCV reinfection because of
recidivism. Although 33% of the patients returned to injection drug use,
only 1 became reinfected, with a defined risk factor of sharing
equipment. Taken together, these data warrant the use of the current
standard of care, pegylated IFN, for drug users and methadone patients
in clinical trials to expand the outcome data of these preliminary
HEPATITIS C VIRUS TREATMENT, EVALUATION, AND MANAGEMENT OF PSYCHIATRIC
AND SUBSTANCE USE COMORBIDITY
A growing number of studies provided preliminary support for the use of
IFN-based therapy for patients with HCV infection who have active
psychiatric illnesses and substance use disorders.38,49,51,53--55 These
studies showed that patients with current and past histories of
significant psychiatric illness, including substance use disorder, can
successfully complete a course of IFN therapy, and that SVR rates were
similar to those without such difficulties. Furthermore, patients with a
past history of major depressive disorder or substance use may not be at
increased risk for the development of IFN-induced depression.56 Further
studies are needed to detail definitively the treatment efficacy of IFN-based
treatments for patients with HCV, substance use disorders, and
Given the very high frequency of co-occurring psychiatric and substance
use disorders among patients with HCV infection and that antiviral
therapy may exacerbate symptoms of psychiatric illness, psychiatric
screening strategies for all patients represent optimal care (see
Screening and Assessment of Psychiatric, Substance Use, and
Neurocognitive Disorders; Table). Regular monitoring of psychiatric
symptoms during IFN therapy is also important. The Department of
Veterans Affairs Medical Center treatment recommendations for
individuals with HCV infection state that patients not exhibiting
depression before IFN therapy should be evaluated for depression at
least monthly. Patients with depression scores on the BDI, for example,
indicating moderate-to-severe depression should be considered for
antidepressant treatment and preferably followed by a mental health
For patients with a history of substance use disorders, regular
monitoring using rating scales such as the Addiction Severity Index (ASI)
or Alcohol Abstinence Self- Efficacy Scale (AASE) and coordination of
care with addiction specialists are also recommended. In patients with
co-occurring HCV infection and substance use disorders, possible IFN-induced
drug cravings and the risk for drug relapse could seriously compromise
their treatment and recovery (see Neurochemistry of the Addicted,
Psychiatrically Ill, and Hepatitis C Virus--Infected Patient). A
comanagement model of care that uses frequent psychiatric and substance
use symptom monitoring and early intervention for reemergence or
development of neuropsychiatric side effects and substance use is
advocated (Fig. 1).
Several reports suggest that antidepressants, primarily selective
serotonin reuptake inhibitors (SSRIs), are efficacious in ameliorating
IFN-induced major depression in patients with HCV infection.56,58--60
SSRIs can alleviate IFN-induced depression, fatigue, and anxiety as well
as cognitive and behavioral slowing.61,62. Importantly, increased
depression following IFN therapy is related to the depletion of serum
serotonin (Fig. 2) thus, SSRIs may act on the specific neurochemical
targets (particularly serotonin), mediating these depressive side
effects (see Neurochemistry of the Addicted, Psychiatrically Ill, and
Hepatitis C Virus--Infected Patient). However, there are currently no
large, placebo-controlled studies that have investigated the use of
antidepressant treatment for IFN-induced depression in patients with HCV
infection. In addition to using antidepressant treatment to manage
preexisting and IFN-induced depression, the use of antidepressants in
conjunction with IFN therapy may also serve to decrease relapse
potential in patients with substance use disorders. Although the
literature is not in complete agreement, treatment with antidepressant
medications has been shown to reduce the risk of drug relapse in
patients with a history of substance use disorders.63--65 Additional
studies are needed to understand better the effects of substance use and
psychiatric illness on IFN treatment outcomes in patients with HCV
To improve access to antiviral therapy for patients with co-occurring
HCV infection and psychiatric and substance use disorders, future
research should identify behavioral and pharmacological interventions
that will enhance adherence to antiviral therapy and reduce the
reemergence of psychiatric symptoms and substance use.
NEUROCHEMISTRY OF THE ADDICTED, PSYCHIATRICALLY ILL, AND HEPATITIS C
The majority of cases of HCV infection occur in IDUs, a substantial
fraction of whom have current neurocognitive dysfunction or a history of
psychiatric illness. The development of addiction, which has a
neurochemical basis and is characterized by states of drug craving and
extended abstinence, has an impact on several separate, yet interrelated
neurobiological processes.66 In animal models of addiction, changes in
dopaminergic neurotransmission within a highly limited band of
structures, including specific parts of the nucleus accumbens, amygdala,
and prefrontal cortex, typically underlie the motivational effects
associated with dependence. 67--70 Changes in the signals mediated by
several neurotransmitters, including dopamine, opioid peptides, and
corticotropin-releasing factor, and in the regulation of transcription
factors within the neurons of this reward circuit may underlie the
vulnerability to relapse that characterizes addiction in humans.68,71,72
In addition, alterations in gene expression appear to be involved in the
long-term neuroadaptive changes associated with the motivational aspects
of drug dependence.73
Overlapping and additive neurochemical mechanisms validate the concern
that IFN-based treatment of HCV infection may exacerbate preexisting
depression or drug use behaviors. In animal models and human studies,
there is a direct role for proinflammatory cytokines in the development
of depression. Specifically, current literature favors the hypothesis
that a relative serotonin depletion plays a central role in IFN-induced
depression.74,75 As shown in Fig. 2, the neurochemical events that
mediate IFN-related depression are a metabolic increase in the
catabolism of tryptophan, specifically through IFN stimulation of the
enzyme indoleamine 2,3-dioxygenase, leading to the peripheral depletion
of tryptophan, a serotonin precursor.76,77 Thus, the etiology of IFN-induced
depression may derive partly from the antiserotonergic effects of IFN,
which is consistent with the large body of evidence pointing to a
general link between serotonin and depressive disorders, as well as the
efficacy of SSRI antidepressants in treating IFN-induced depression (see
HCV Treatment, Evaluation, and Management of Psychiatric and Substance
Use Comorbidity). However, the mechanism by which IFN produces
depression remains unclear and is most probably multifactorial. IFN also
modulates neurochemical pathways of other cytokines, the
hypothalamicpituitary-adrenal (HPA) axis, and
hypothalamic-pituitary-thyroid axis as well as dopaminergic,
nonadrenergic, and cholinergic neurotransmission.78--81 IFN increases
interleukin 6 (IL-6) production, which correlates with symptoms of
depression and anxiety.82 IFN enhances levels of IL-1 and tumor necrosis
factor-α (TNF-α), which influences noradrenergic activity. IL-1, IL-6,
and TNF-α are also potent stimulators of the HPA axis.84,85 These
neurochemical changes may occur in the presence of elevated
glucocorticoid concentrations, and immune activation is associated with
a decrease in the sensitivity of the glucocorticoid receptors in
patients with major depression, thus contributing to altered regulation
of the HPA axis.85
Taken together, these observations suggested that IFN-mediated
alterations in the HPA axis and perturbations in neurotransmission,
especially those related to dopamine or serotonin, may have an additive
impact on drug users with depression who are treated for HCV infection.
However, whether these neurological events will lead to
disproportionately destabilizing neurochemical changes or increase the
vulnerability to reinstitution of drug taking remains unclear.
INTEGRATING HEPATITIS C VIRUS TREATMENT INTO HEALTH CARE VENUES
The medical management of HCV infection in multimorbid patients
necessitates the integration of IFN-based treatment into health care
settings that care for substanceusing and psychiatrically ill patients
(Fig. 1). The panel identified the following as venues to address
IFN-based treatment of HCV through clinical trials and health services
Former IDUs comprise a population that has a high prevalence of HCV
infection. Seroprevalence rates range from 67% to 96%, with noninjection
(opium smokers) populations exhibiting significantly lower seropositive
prevalence rates. Although studies have begun to test the safety,
tolerability, and efficacy of antiviral treatment for HCV infection in
patients on methadone maintenance, they have excluded active drug users
and individuals with severe psychiatric illness or decompensated liver
disease. Methadone clinics represent a unique resource to provide
screening for HCV infection and psychiatric illness, thereby identifying
potential candidates for treatment of substance use and HCV
No national surveillance and no systematically collected national data
are available regarding HCV among inmates. Based on Centers for Diseases
Control and Prevention estimates, assuming needle sharing as the primary
risk factor, between 17% and 21% of current inmates are infected with
HCV.86 Medical care for inmates is episodic and not given in the context
of public health. Therefore, there is no consistent consensus on the
treatment of HCV in correctional settings. Some prison systems have
developed guidelines for the management of HCV that are not necessarily
implemented. Incarcerated individuals, who exhibit drug addiction and
psychiatric illness, can be effectively treated for HCV infection with
IFN-based therapies. On release, the HCV-infected individual has an
impact on the community in terms of disease transmission, costs for
medical care, and recidivism. Prevention and treatment interventions
would benefit inmates, their families, their partners, and the public
health of communities to which inmates return.
A unique group model that operates as a walk-in clinic for
addiction-related HCV has been operating in Oakland, California, since
1998. It was specifically structured to reduce barriers to HCV diagnosis
and treatment in less-stable drug users. The clinic is held three times
weekly, and its focus is on peer support and interactive education about
HCV diagnosis and the treatment process. Attendees are offered on-site
blood testing, referrals for biopsy, and comprehensive HCV treatment for
interested participants as warranted. To date, over 1,500 low-income
addicts have been screened in this cost-effective program, and over 200
have been treated; treatment outcomes appear to be only modestly lower
than for nonaddicted patients despite the complexities of the patients
Community Mental Health Clinics and Psychiatric Hospitals-
The HCV treatment for persons with severe mental illness (SMI) in public
mental health settings presents unique challenges and opportunities,
including medical, psychosocial, housing, daily living, legal, and
vocational services. Models of care that integrate mental health and
substance use treatment can be effective,87,88 but are not routinely
implemented because of limited financial and human resources.24
Guidelines to treat HCV in persons with SMI are not available, and there
are no national HCV guidelines for persons receiving treatment at
community mental health centers or state psychiatric hospitals. Care
practices vary greatly by state and community, and HCV-related service
needs are not uniformly addressed. Models of care developed for
community-based psychiatric care of persons with SMI, including
assertive community treatment (ACT) and intensive case management, can
provide a valuable framework for treating HCV in public mental health
settings. ACT teams provide a range of services, such as sexual
education, reproductive counseling, and medication support services.89
These programs can be expanded to include services related to HCV.
Intensive case management can also be utilized to monitor symptoms and
provide integration of psychiatric and medical teams.
One community model in a mental health clinic setting utilizes a service
team, comprised of a nurse, an infectious disease specialist, a
psychiatric specialist, and an administrator, who provide education and
assist in the development of services, including best practices outlined
by the Centers for Disease Control and Prevention for HCV care:
screening, testing, immunization, risk reduction counseling and
referral, and support for medical care.
SUMMARY AND DIRECTIONS FOR FUTURE RESEARCH
There are vast gaps in the understanding of the optimal management of
HCV treatment in substance users and patients with comorbid psychiatric
illness. Clinical research and trials are needed to understand further
how to select patients who can successfully undergo therapy and to
define better the impact of intervening drug use, the minimally
appropriate length of sobriety, and the impact and management of the
spectrum of preexisting psychiatric conditions. Information is needed on
interventions when relapse to substance use occurs and whether different
drugs of abuse present unique outcomes. Clinical research is needed for
a better understanding of the individual and cumulative impact of the
potential barriers to HCV treatment in patients with co-occurring HCV,
substance abuse, and psychiatric illness, as well as for new approaches
to the medical management of these patients and novel interventions that
promote a SVR to HCV treatment.
Existing data suggest that selected substance users can be candidates
for HCV treatment, even in the setting of psychiatric disease and
relapse to drug use. In light of the vast impact of HCV in this
population and their limited access to HCV treatment and life-saving
liver transplantation, the urgent need for further clinical study is
Co-occurring Hepatitis C, Substance Use and Psychiatric Illness:
Addressing the Issues and Developing Integrated Models of Care took
place December 5--6, 2003, in Bethesda, Maryland. The conference was
sponsored by the Center for AIDS and Other Medical Consequences of Drug
Abuse (CAMCODA); National Institute of Drug Abuse and Division of
Digestive Diseases and Nutrition; National Institute of Diabetes,
Digestive, and Kidney Diseases (NIDDK); National Institutes of Health;
Department of Health and Human Services; and Veterans Administration.
1. Hoofnagle JH, Tralka TS. Introduction: The National Institutes of
Health Consensus Development conference: management of hepatitis C.
Hepatology. 1997;26(suppl 1):1S.
2. Seeff LB, Hoofnagle JH. Appendix: the National Institutes of Health
Consensus Development Conference Management of Hepatitis C 2002. Clin
Liver Dis. 2003;7:261--287.
3. Sherman KE. Implications of peginterferon use in special populations
infected with HCV. Semin Liver Dis. 2003;23(suppl 1):47--52.
4. Zeuzem S, Heathcote EJ, Shiffman ML, et al. Twelve weeks of follow-up
is sufficient for the determination of sustained virologic response in
patients treated with interferon alpha for chronic hepatitis C. J
5. Community Epidemiology Work Group. Epidemiologic trends in drug
abuse. In: Proceedings of the Community Epidemiology Work Group December
2001. Ed. Moira O'Brian. Vol. 1. Bethesda, MD: National Institute on
Drug Abuse, NIH, DHHS; 2002:1--68. NIH Publication 02--5109.
6. Patrick DM, Buxton JA, Bigham M, Mathias RG. Public health and
hepatitis C. Can J Public Health. 2000;91(suppl 1):S18--S23.
7. McCarthy JJ, Flynn N. Hepatitis C in methadone maintenance patients:
prevalence an public policy implications. J Addict Dis. 2001;20:19--31.
8. Quaglio G, Lugoboni F, Pajusco B, et al. Facors associated with
hepatitis C virus infection in injection and noninjection drug users in
Italy. Clin Infect Dis. 2003;37:33--40.
9. Hagan H, Des Jarlais DC. HIV and HCV infection among injection drug
users. Mount Sinai J Med. 2000;67:423--428.
10. Osher FC, Goldberg RW, McNary SW, Essock SM, Butterfield MI,
Rosenberg SD. Substance abuse and the transmission of hepatitis C among
persons with severe mental illness. Psychiatr Serv. 2003;54:842--847.
11. Klinkenberg WD, Caslyn RJ, Morse GA, et al. Prevalence of human
immunodeficiency virus, hepatitis B, and hepatitis C among homeless
persons with co-occurring severe mental illness and substance use
disorders. Compr Psychiatry. 2003;44;293--302.
12. Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM.
Hepatitis C, interferon alfa, and depression. Hepatology.
13. Forton MD, Taylor-Robinson SD, Thomas HC. Cerebral dysfunction in
chronic hepatitis C infection. J Viral Hepat. 2003;10:81--86.
14. Miyaoka H, Otsubo T, Kamijima K, Ishii M, Onuki M, Mitamura K.
Depression from interferon therapy in patients with hepatitis C. Am J
15. Pariante CM, Orru MG, Baita A, Farci MG, Carpiniello B. Treatment
with interferonalpha in patients with chronic hepatitis and mood or
anxiety disorders. Lancet. 1999; 354:131--132.
16. DiClemente CC, Carbonari JP, Montgomery RP, Hughes SO. The Alcohol
Abstinence Self-Efficacy scale. J Stud Alcohol. 1994;55:141--148.
17. McLellan AT, Luborsky L, Woody GE, O'Brien CP. An improved
diagnostic instrument for substance abuse patients: the Addiction
Severity Index. J Nerv Mental Dis. 1980; 168:26--33.
18. WHO ASSIST Working Group. The WHO Alcohol, Smoking and Substance
Involvement Screening Test (ASSIST): development, reliability and
feasibility. Addiction. 2002;97: 1183--1194.
19. Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro M. AUDIT—the
Alcohol Use Disorders Identification Test: guidelines for use in primary
health care. World Health Organization, Department of Mental Health and
Substance Abuse, 2001. Accessed September 3, 2004. Available at:
20. Bradley KA, Bush K, Dobie DJ, et al. Two brief alcohol-screening
tests from the Alcohol Use Disorders Identification Test (AUDIT):
validation in a female Veterans Affairs patient population. Arch Intern
21. Bohn MJ, Babor TF, Kranzler HR. The Alcohol Use Disorders
Identification Test (AUDIT): validation of a screening instrument for
use in medical settings. J Stud Alcohol. 1995;56:423--432.
22. Reinert DF, Allen JP. The alcohol Use Disorders Identification Test
(AUDIT): a review of recent research. Alcohol Clin Exp Res.
23. Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. The AUDIT
alcohol consumption questions (AUDIT-C): an effective brief screening
test for problem drinking. Arch Intern Med. 1998;158:1789--1795.
24. Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis
services for clients with severe mental illness. Psychiatr Serv.
25. Svanborg PM, Asberg M. A comparison between the Beck Depression
Inventory (BDI) and the self-rating version of the Montgomery Asberg
Depression Rating Scale (MADRS). J Affect Disord. 2001;64:203--216.
26. Beck AT, Steer RA, Ball R. Comparison of Beck Depression
Inventories-IA and -II in psychiatric outpatients. J Pers Assess.
27. Flemenbaum A, Zimmermann RL. Inter- and intra-rater reliability of
the Brief Psychiatric Rating Scale. Psychol Rep. 1973;32:783--792.
28. NIAAA. Helping Patients with alcohol problems: a health
practitioners guide. January 2003. NIH Publication 03--3769. Accessed
September 3, 2004. Available at:
29. Fiellin DA, Reid MC, O'Connor PG: Screening for alcohol problems in
primary care. Arch Intern Med. 2000;160:1977--1989.
30. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol
and other drug abuse: criterion validity in primary care practice. Wisc
Med J. 1995;94:135--140.
31. Gavin DR, Ross HE, Skinner HA. Diagnostic validity of the drug abuse
screening test in the assessment of DSM-III drug disorders. Br J Addict.
32. Rumpf H-J, Hapke H, Meyer C, John U. Screening for alcohol use
disorders and at-risk drinking in the general population: psychometric
performance of three questionnaires. Alcohol Alcohol. 2002;37:261--268.
33. Deployment Health Clinical Center. PTSD Checklist—Military Version
(PCL-M). Accessed September 3, 2004. Available at:
34. Brown RL, Leonard T, Saunders LA, Papasouliotis O. A two-item
conjoint screen for alcohol and other drug problems. J Am Board Fam
35. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania:
reliability, validity and sensitivity. Br J Psychiatry.
36. Zung WW, Wonnacott TH: Treatment prediction in depression using a
self-rating scale. Biol Psychiatry. 1970;2:321--329.
37. Beck AT, Ward C, Mendelson M, Mock JE, Erbaugh JK. An inventory for
measuring depression. Arch Gen Psychiatry. 1961;4:561--571.
38. Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of
neuropsychiatric symptoms associated with interferon-alpha-2b and
ribavirin therapy for patients with chronic hepatitis C. Psychosomatics.
39. Wright IA. Monitoring depression in patients undergoing
alpha-interferon and ribavirin therapy for hepatitis C. Gastroenterol
40. Bean P. Update on new biomarkers for detecting excessive alcohol
use. AlcoholMD.com Web site. November 2002. Available at:
41. Wolff K, Farrell M, Marsden J. A review of biological indicators of
illicit drug use: practical considerations and clinical usefulness.
42. Portland VA Medical Center, Mood Disorders Center. Patient Screening
Questions (PSQ). Accessed September 3, 2004. Available at:
43. Martin EM, Pitrak DL, Novak RM, Pursell KJ, Mullane KM. Reaction
times are faster in HIV-seropositive patients on antiretroviral therapy:
a preliminary report. J Clin Exp Neuropsychol. 1999;21:730--735.
44. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment
in patients with chronic hepatitis C. Hepatology. 2002;35:440--446.
45. Forton DM, Thomas HC, Murphy CA, et al. Hepatitis C and cognitive
impairment in a cohort of patients with mild liver disease. Hepatology.
46. Ernst T, Chang L, Jovicich J, Ames N, Arnold S. Abnormal brain
activation on functional MRI in cognitively asymptomatic HIV patients.
47. Martin EM, Novak RM, Fendrich M, et al. Stroop performance in drug
users classified by HIV and hepatitis C virus serostatus. J Int
Neurophysiol Soc. 2004;10:298--300.
48. Stephenson J. Former addicts face barriers to treatment for HCV.
JAMA. 2001;285: 1003--1005.
49. Davis GL, Rodrigue JR. Treatment of chronic hepatitis C in active
drug users. N Engl J Med. 2001;345:215--217.
50. Edlin BR, Seal KH, Lorvick J, et al. Is it justifiable to withhold
treatment for hepatitis C from illicit-drug users. N Engl J Med.
51. Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of
hepatitis C infection in injection drug users. Hepatology. 2001;
52. Ho SB, Nguyen H, Tetrick LL, Opitz GA, Basara ML, Dieperink E.
Influence of psychiatric diagnoses on interferon-alpha treatment for
chronic hepatitis C in a veteran population. Am J Gastroenterol.
53. Sylvestre DL. Treating hepatitis C in methadone maintenance
patients: an interim analysis. Drug Alcohol Depend. 2002;67:117--123.
54. Dalgard O, Bjoro K, Hellum K, et al. Treatment of chronic hepatitis
C in injecting drug users: 5 years' follow-up. Eur Addict Res.
55. Van Thiel D, Friedlander L, Molloy P, Fagiuoli S, Kania R, Caraceni
P. Interferon-alpha can be used successfully in patients with hepatitis
C virus-positive chronic hepatitis who have a psychiatric illness. Eur J
Gastroenterol Hepatol. 1995;7:165--168.
56. Hauser P, Khosla J, Aurora H, et al. A prospective study of the
incidence and open-label treatment of interferon-induced major
depressive disorder in patients with hepatitis C. Mol Psychiatry.
57. San Francisco and Miami Centers of Excellence in Hepatitis C
Research and Education and the Hepatitis C Technical Advisory Group
DoVA. Treatment Recommendations for Patients With Chronic Hepatitis C.
Version 1.0. Washington, DC: Veteran's Health Administration, Department
of Veterans' Affairs; 2002.
58. Levenson J, Fallon H. Fluoxetine treatment of depression caused by
interferon-alpha. Am J Gastroenterol. 1993;88:760--761.
59. Gleason O, Yates W. Five cases of interferon-alpha-induced
depression treated with antidepressant therapy. Psychosomatics.
60. Schramm T, Lawford B, Macdonald G, Cooksley W. Sertraline treatment
of interferonalfa- induced depressive disorder. Med J Aust.
61. Loftis J, Socherman RE, Whitehead AJ, Hauser P.
Interferon-alpha-induced depression: time course and antidepressant
response of symptom dimensions for patients with hepatitis C. Psychosom
Med. In press.
62. Capuron L, Gumnick JF, Musselman DL, et al. Neurobehavioral effects
of interferonalpha in cancer patients: phenomenology and paroxetine
responsiveness of symptom dimensions. Neuropsychopharmacology.
63. Pettinati HM. The use of selective serotonin reuptake inhibitors in
treating alcoholic subtypes. J Clin Psychiatry. 2001;62:26--31.
64. Naranjo CA, Knoke DM. The role of selective serotonin reuptake
inhibitors in reducing alcohol consumption. J Clin Psychiatry.
65. Srisurapanont M, Kittiratanapaiboon P, Jarusuraisin N. Treatment for
amphetamine psychosis. Cochrane Database Syst Rev. 2001:CD003026.
66. McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a
chronic medical illness: implications for treatment, insurance, and
outcomes evaluation. JAMA. 2000;284:1689--1695.
67. Koob GF, Bloom FE. Cellular and molecular mechanisms of drug
dependence. Science. 1988;242:715--723.
68. Wise RA, Bozarth MA. Brain substrates for reinforcement and drug
self-administration. Prog Neuropsychopharmacol. 1981;5:467--474.
69. Kalivas PW, Stewart J. Dopamine transmission in the initiation and
expression of drug- and stress-induced sensitization of motor activity.
Brain Res Brain Res Rev. 1991;16:223--244.
70. Robinson TE, Berridge KC. The neural basis of drug craving: an
incentive-sensitization theory of addiction. Brain Res Brain Res Rev.
71. Kreek MJ, Koob GF. Drug dependence: stress and dysregulation of
brain reward pathways. Drug Alcohol Depend. 1998;51:23--47.
72. Stimmel B, Kreek MJ. Neurobiology of addictive behaviors and its
relationship to methadone maintenance. Mt Sinai J Med. 2000;67:375--380.
73. Nestler EJ, Hope BT, Widnell KL. Drug addiction: a model for the
molecular basis of neural plasticity. Neuron. 1993;11:995--1006.
74. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R.
Association between decreased serum tryptophan concentrations and
depressive symptoms in cancer patients undergoing cytokine therapy. Mol
75. Bonaccorso S, Marino V, Puzella A, et al. Increased depressive
ratings in patients with hepatitis C receiving interferon-alpha-based
immunotherapy are related to interferonalpha- induced changes in the
serotonergic system. J Clin Psychopharmacol. 2002;22:86--90.
76. Taylor MW, Feng GS. Relationship between interferon-gamma,
indoleamine 2,3 dioxygenase, and tryptophan catabolism. FASEB J.
77. Brown RR, Ozaki Y, Datta SP, Borden EC, Sondel PM, Malone DG.
Implications of interferon-induced tryptophan catabolism in cancer,
auto-immune disease and AIDS. Adv Exp Med Biol. 1991;294:425--435.
78. Boyer P. Do anxiety and depression have a common pathophysiological
mechanism. Acta Psychiatr Scand Suppl. 2000;406:24--29.
79. Leonard BE, Song C. Changes in the immune system in rodent models of
depression. Int J Neuropsychopharmacol. 2002;5:345--356.
80. Jones TH, Wadler S, Hupart KH. Endocrine-mediated mechanisms of
fatigue during treatment with interferon-alpha. Semin Oncol.
81. Pollak Y, Yirmiya R. Cytokine-induced changes in mood and behavior:
implications for "depression due to a general medical condition,"
immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol.
82. Bonaccorso S, Puzella A, Marino V, et al. Immunotherapy with
interferon-alpha in patients affected by chronic hepatitis C induces an
intercorrelated stimulation of the cytokine network and an increase in
depressive and anxiety symptoms. Psychiatry Res. 2001;105:45--55.
83. Foucart S, Abadie C. Interleukin-1 beta and tumor necrosis
factor-alpha inhibit the release of 3H-noradrenaline form mice isolated
atria. Naunyn Schmiedebergs Arch Pharmacol. 1996;354:1--6.
84. Dunn AJ. Effects of the IL-1 receptor antagonist on the IL-1 and
exotoxin-induced activation of the HPA axis and cerebral biogenic amines
in mice. Neuroimmunomodulation. 2000;7:36--45.
85. Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of
hypercortisolism in major depression. Horm Behav. 2003;43:60--66.
86. Spaulding A, Lau D, Weinbaum C, et al. Developing a framework for
correctional management of hepatitis C. A review of current and future
management of the disease in prisons. In press.
87. Drake RE, Mercer-McFadden C, Mueser KT, McHugo GJ, Bond GR. Review
of integrated mental health and substance abuse treatment for patients
with dual disorders. Schizophr Bull. 1998;24:589--608.
88. Druss BG, Rohrbaugh RM, Levinson CM, Rosenheck RA. Integrated
medical care for patients with serious psychiatric illness: a randomized
trial. Arch Gen Psychiatry. 2001; 58:861--868.
89. Phillips SD, Burns BJ, Edgar ER, et al. Moving assertive community
treatment into standard practice. Psychiatr Serv. 2001;52:771--779.