Drug Abuse and Hepatitis C Infection as Comorbid Features
of HIV Associated Neurocognitive Disorder: Neurocognitive
and Neuroimaging Features
Eileen M. Martin-Thormeyer & Robert H. Paul
Received: 23 February 2009 /Accepted: 6 May 2009
# Springer Science + Business Media, LLC 2009
Abstract Substance abuse and co-infection with hepatitis
C (HCV) are two highly relevant determinants of neuro-
cognitive and neuroimaging abnormalities associated with
HIV. Substance abuse and HCV are common in the HIV
population and there is increasing evidence that the CNS is
directly compromised by these comorbid conditions via
additive or synergistic processes. In this article we review
the current literature regarding mechanisms of neuronal
injury as well as the neuropsychological and neuroimaging
signatures associated with substance abuse and HCV status
among HIV patients. We discuss specific methodological
challenges and threats to validity associated with studies of
HIV and comorbid substance use disorders or HCV and
review potential strategies for minimizing their confound-
ing effects. Efforts to understand the interactions between
HIV, substance abuse and HCV co-infection will lead to
more complete models of neuropathogenesis of HIV and a
greater understanding of the variability in neuropsycholog-
ical expression of HIVAssociated Neurocognitive Disorder.
Comorbid medical and psychiatric conditions frequently
complicate the clinical presentation and neural mechanisms
of HIV-associated Neurocognitive Disorder (HAND). HIV
can compromise the capacity to carry out a range of critical
life tasks (Heaton et al. 2004) such as driving (Marcotte et
al. 1999), maintaining employment (Heaton et al. 1994),
adhering to complex medication regimens (Hinkin et al.
2004), and possibly abstaining from high risk sexual and
injection practices. Comorbid substance dependence or
hepatitis C virus (HCV) infection in the HIV-infected
individual will increase the risks of morbidity, mortality,
and serious personal, social and economic consequences
including incarceration, additional psychiatric and medical
hospital admissions, financial problems, and family discord.
In this article we review neurocognitive and neuro-
imaging studies of substance use disorders (SUDs) and
HCV infection, two disorders that are highly prevalent
among HIV+ individuals, focusing primarily on investiga-
tions conducted since the introduction of highly active
antiretroviral therapy (HAART). We discuss specific meth-
odological challenges and threats to validity associated with
studies of HIV and comorbid SUDs or HCV and review
potential strategies for minimizing their confounding
effects. This article focuses primarily on comorbidity
issues; we refer the interested reader elsewhere in this
special issue and to a recent comprehensive text
(Kalechstein and van Gorp 2007) for more extensive
reviews of HAND or neurocognitive aspects of substance
Supported by grants R01 DA12828 to EMT and 1R03 DA022137 and
5R01 NS052470 to RHP. Both authors report no conflicts of interest.
E. M. Martin-Thormeyer (*)
University of Illinois and Jesse Brown VA Medical Center,
Chicago, IL, USA
R. H. Paul
University of Missouri,
St Louis, MO, USA
R. H. Paul
St Louis, MO, USA
HIV and the Brain: A Brief Review
HIV disease is associated with a spectrum of neuro-
cognitive impairment ranging from mild but clinically
silent performance deficits on neurocognitive testing to
frank dementia. HIV-1 typically invades the brain within
2 weeks of initial infection, most likely via trafficking of
infected monocytes (Kanmogne et al. 2002), and facilitated
by compromise of the blood brain barrier. The virus infects
directly supportive cells of the brain, such as microglial
cells, astrocytes, and macrophages (Garden 2002) and the
term “HIVencephalitis” refers specifically to a constellation
of neuropathological changes including microgliosis, mul-
tinucleated giant cells, and myelin pallor associated with
direct CNS infection (e.g., Budka et al. 1991). The
distribution of central neuropathology due to direct or
indirect effects of primary HIV infection is not limited to
distinct brain regions, however neuropathology is preferen-
tially distributed, with primary involvement of deep white
matter and subcortical nuclei. Neuronal loss is evident in
prefrontal cortex and in hippocampus, but cortical involve-
ment is typically less severe than damage to basal ganglia,
particularly to caudate and putamen, where high levels of
viral aggregation are known to occur (Berger and Arendt
2000). Initial reports of HIV-associated dementia (the
“AIDS dementia complex” (Navia et al. 1986), now termed
“HIV Associated Dementia,” or HAD) emphasized the
behavioral and neurological consequences of the virus’s
predilection for basal ganglia and white matter; these
included prominent mental and motor slowing, impaired
attention, defects in memory retrieval, and relative sparing
of higher cortical functions; and positive neurological
findings such as bradykinesia, tremor, and postural insta-
bility (Berger and Arendt 2000; Beckley et al. 1998). Initial
studies employing structural MRI were able to detect CNS
abnormalities (Aylward et al. 1995), but primarily among
individuals with advanced disease. Advances in neuro-
imaging technology and data analytic methods, such as
morphometric analysis (e.g. Jernigan et al. 2005) and
magnetic resonance spectroscopy (MRS) have enabled
investigators to detect more subtle and nonlinear trends in
brain changes (e.g., Castelo et al. 2007) associated with
HAND among individuals with milder disease (for reviews
see Paul et al. 2002; Tucker et al. 2004; Pfefferbaum et al.
2002). A recent paper by Paul et al. (2008) demonstrated
that ratios of key brain metabolites detected subtle basal
ganglia abnormalities in a group of nondemented HIV+
subjects, but MRI did not, suggesting that MRS can be
more sensitive to early CNS changes compared among
HIV+ individuals without dementia. Finally, examination of
the microstructural integrity of the brain using diffusion
tensor imaging (DTI) has detected subtle changes in
neuronal myelination and axonal integrity and these highly
sensitive scans may have the resolution to reveal more
consistent brain changes that occur early in the disease
(Filippi et al. 2001; Pomara et al. 2001; Chang et al. 1999).
Since the introduction of HAART the incidence of HAD
has declined but rates of milder cognitive impairment have
not, indicating that currently available antiretroviral regi-
mens do not eradicate virus in brain completely, perhaps
due to insufficient CNS penetrance (Langford et al. 2006).
Post-HAART studies (e.g., Cysique et al. 2004) have
reported more variable features of HAD, with fewer cases
characterized primarily by psychomotor slowing. Impair-
ments in learning and memory, attention, motor and
executive functions are common in HAND but there is no
signature pattern of cognitive deficits (Dawes et al. 2008).
Similarly, more variability has been observed in clinical
course; cognitive deficits can progress, improve, fluctuate,
or remain static over time (Nath et al. 2008).
Neurocognitive function in persons living with HIV/
AIDS is affected by many factors in addition to direct
infection of the CNS (see Table 1 for a representative listing
of known and potential risk factors). Comorbid substance
dependence and hepatitis C disease are significant contrib-
uting factors to neurocognitive impairment, but additional
factors such as aging have assumed increased importance as
persons with HIV live longer. These issues are addressed
elsewhere in this special issue.
HIV and Substance Dependence: Clinical and Scientific
Investigators of neurocognition among both HIV+ and
HIV- substance dependent individuals (SDIs) must contend
with multiple methodological difficulties. In North Amer-
ica, the majority of SDIs abuse multiple substances and
“pure” dependence on a single substance is rare, providing
significant impediments to targeting effects of specific
drugs of abuse on the human CNS. Analysis of neuro-
Table 1 Factors affecting HIV-associated neurocognitive disorder
Substance Dependence and complications
Aging-related conditions: vascular disease, diabetes
Psychoactive and other medications
Toxoplasmosis and other CNS opportunistic conditions
Additional infections: hepatitis C, syphilis
cognitive findings is complicated significantly by direct and
indirect medical consequences of drug abuse, such as head
injury, cerebrovascular abnormalities and malnutrition (e.g.
Bell et al. 2006). Additionally, SUDs are accompanied in
turn by a spectrum of neuropsychiatric conditions, includ-
ing mood disorders, anxiety disorders such as PTSD and
social phobia, ADHD and learning disabilities, and person-
ality disorders (Grant et al. 2004a, b; Chilcoat and Breslau
1998; Compton et al. 2007; Biederman et al. 1998);
Neurobiological personality traits prevalent among SDIs,
such as sensation-seeking and antisociality (Zuckerman
1996; Gonzalez et al. 2005a; Vassileva et al. 2007a, b)
influence both neurocognitive function and risk behavior.
Concurrent psychoactive medication and opioid substitu-
tion therapies such as methadone are associated with
impaired cognitive performance (Mintzer and Stitzer
2002). Finally, combined antiretroviral therapy and metha-
done can increase HIV disease severity and decrease
methadone effectiveness (Bruce et al. 2006, 2008 [thereby
increasing SDIs’ disinclination to adhere with treatment
Empirical attempts to distinguish cognitive changes
associated with substance dependence from HAND are
complicated further by the absence of a gold standard to
index substance use. The majority of neurocognitive studies
of drug addiction employ the SCID-Substance Abuse
Module (First et al. 1996), the well-established Addictions
Severity Index (McLellan et al. 1985) or the newer Kreek-
McHugh-Schluger-Kellogg Scale (Kellogg et al. 2003).
However, clinical diagnostic systems such as DSM-IV
criteria do not provide an ideal proxy for brain exposure to
alcohol and illicit substances; a clinical diagnosis of
“abuse” or even “dependence” does not readily describe
the chronicity or amount/frequency of dose. Timeline-
follow back interviews have been used to obtain finer-
grained estimates of dosage and substance quantity but
administration time for these very detailed inquiries can be
prohibitive. Consequently, investigators have employed
numerous potential predictor variables, including estimated
total exposure, age of onset, duration of use, length of
abstinence, route of administration, and number of detox-
ifications, in efforts to capture addiction severity.
Cellular Effects of HIV and Substances of Abuse
In a recent review, Bell et al. noted that, “Given the
immune modulatory effects of some major classes of drugs,
together with the effects of drugs themselves on brain
tissue, it would be surprising if drug abuse did not influence
HIV- related brain disease” (2006, p. 187). Numerous in
vitro and animal studies have reported multiple common
mechanisms by which HIV and drugs of abuse confer
harmful effects at the cellular level. A range of substances
of abuse, including opiates, cocaine, methamphetamine,
and alcohol are all known to increase immunosuppression
and enhance viral replication (e.g., Liang et al. 2008;
Dhillon et al. 2007). Interactions between viral proteins
such as gp120 and tat and substances of abuse facilitate
breakdown of blood-brain barrier, release of TNF-α and
other neurotoxic cytokines, upregulate CCR5 expression
and increase oxidative stress (Hauser et al. 2006;
Khurdayan et al. 2004; Liang et al. 2008; Flora et al.
2003, 2005; Flores and McCord 1998; Theodore et al.
2006; Hu et al. 2005; Shiu et al. 2006). However, despite
clear laboratory evidence that HIV and substances of abuse
in combination result in significant cellular damage that can
exceed effects of one or the other, this pattern of activity
does not necessarily translate to human clinical or epide-
miological studies (Kapadia et al. 2005).
CNS Effects of HIV Among Substance Dependent
Neurological and epidemiological studies have typically
(but not invariably) reported more rapid disease progres-
sion, higher prevalence of dementia and more common
postmortem HIV encephalitis among injection drug users
(IDUs) compared with other risk groups (Bell et al. 1998;
Bouwman et al. 1998; Nath et al. 2001, 2002; Langford et
al. 2003; Lucas et al. 2006) but findings from neuro-
cognitive studies of HIV+ IDUs have been more variable,
particularly investigations conducted prior to the introduc-
tion of HAART. Some investigators reported significant
cognitive impairment among HIV+ compared with HIV-
IDUs (Egan et al. 1992; Marder et al. 1992; Starace et al.
1998), while others did not (Concha et al. 1992; Hestad et
al. 1993; Selnes et al. 1992). Virtually all studies reported
higher prevalence of abnormal neuropsychological test
scores among IDUs, regardless of serostatus, compared to
the general population (e.g. Hestad et al. 1993). It was
hypothesized that cognitive impairment was present in only
a subset of HIV+ IDUs that was not apparent from overall
group comparisons, or that the test batteries had not
included measures with adequate sensitivity to HIV-
associated cognitive deficits. Active drug use may have
also contributed to subjects’ inconsistent performance;
many of these studies recruited both in- and out-of-
treatment subjects and urine toxicology screening was not
Because recruitment for these early studies was based on
risk factors, opiates were the drug of choice for the vast
majority of participants, and many were also infected with
hepatitis C. More recent studies have recruited additional
groups of SDIs characterized by heavy use of substances
other than opiates, including cocaine, methamphetamine,
and cannabis and who do not necessarily inject drugs
(Basso and Bornstein 2003) in study samples characterized
by a broader range of age, education, and ethnic character-
istics. However, even in the post-HAART literature there
has been a relative paucity of well controlled cognitive
studies of neuroAIDS among SDIs (e.g., Basso and
Bornstein 2003; Chang et al. 2005; Cristiani et al. 2004;
Durvasula et al. 2000; Green et al. 2004) Additionally, few
studies (e.g., Rippeth et al. 2004; Jernigan et al. 2005;
Schulte et al. 2005) have employed experimental designs
that permitted comparisons of neurocognition among both
HIV+ and HIV- subjects with and without a history of
substance dependence, which hindered tests of hypothe-
sized additive or synergistic effects. Further, essentially no
studies to date have evaluated the neurocognitive perfor-
mance among HIV+ individuals who abuse prescription
drugs (e.g., opioids or anxiolytics); club drugs such as
MDMA (Ecstasy), ketamine, and GHB; steroids; or
investigate cognitive deficits among HIV+ individuals
receiving opioid substitution therapies such as methadone
In this section we review the available neurocognitive
studies of HIV that have included substance dependence
characteristics as independent variables of interest, with
special attention to evidence of additive or interactive
effects. For convenience these studies are grouped accord-
ing to substance of primary interest in a given investigation,
but the majority of subjects abused multiple substances, so
inferences regarding the effects of specific drugs of abuse
Alcohol Neurocognitive investigations have demonstrated
significant impairment of multiple cognitive domains
among HIV+ individuals with comorbid alcohol depen-
dence. Rothlind et al. (2005) administered a comprehensive
battery of neurocognitive tasks to groups of HIV+ and HIV-
individuals classified as either light or heavy alcohol
drinkers. They reported significant main effects of seros-
tatus and drinking level on overall neurocognitive function;
additionally, synergistic effects of HIV serostatus and
alcohol were apparent on measures of psychomotor and
visuomotor speed among individuals with heaviest drinking
rates. Green et al. (2004) tested well-matched groups of
HIV+ and HIV- men with and without a past history of
SCID-diagnosed alcohol use disorder with a comprehensive
neurocognitive test battery; they reported that HIV+
subjects with a positive alcohol diagnosis performed
measures of verbal reasoning, reaction time and auditory
processing significantly more poorly compared with HIV+
subjects without alcohol disorder, but this pattern of
differences was not evident among the HIV- groups.
Durvasula et al. (2006) evaluated neurocognitive perfor-
mance of a sample of 497 African-American males grouped
by HIV serostatus and alcohol history. Consistent deficits in
motor and mental speed were apparent among HIV+
individuals with a recent (12-month) history of alcohol
use, however the investigators cautioned that their findings
should be interpreted with care because complete data
regarding potential confounds such as drug use and head
injury were not available.
Investigators have also reported evidence of synergistic
effects of HIVand alcohol on performance of theory-driven
experimental cognitive tasks. Sassoon et al. (2007) admin-
istered a modified version of the Digit Symbol task that
permitted isolation of cognitive and motor components of
task performance, including associative learning, visual
perception and psychomotor speed, to groups with varying
HIV serostatus and alcohol history. They reported that
HIV+ persons with alcohol dependence were impaired on
multiple components of the task compared with subjects
with one risk factor. Similarly, Schulte et al. (2005)
examined multiple cognitive components of attention using
a match to sample version of the Stroop task to HIV+ and
HIV- groups with and without a history of alcohol
dependence. Their findings paralleled those of Sassoon et
al., in that a positive HIV serostatus in the context of
alcohol dependence impaired attentional function but
deficits were not observed among subjects with HIV
disease or alcohol dependence alone.
In comparison to the number of neuroimaging studies
focused specifically on HIV, fewer studies have examined
the combined effect (additive/synergistic) of HIV and
alcohol or substance abuse on neuroimaging indices.
Pfefferbaum and colleagues have been the most productive
in this area of study. Pfefferbaum et al. (2007) reported
reductions in the neuronal metabolite n-acetyl aspartate
(NAA) in the superior parietal-occipital cortex among
nondemented HIV patients with histories of alcoholism,
while no similar effects were evident among individuals
with HIV alone or diagnosis of alcoholism alone. Of
interest is that no such effect was observed when a ratio
of NAA to creatine (Cr) was examined because of a
significant reduction in Cr among the groups (thus Cr was
not a stable reference marker). Similarly Meyerhoff et al.
(1995) reported decreased levels of phosphodiester and
phosphorcreatine metabolites (both are indices of energy) in
the superior white matter among alcoholic HIV patients.
Pfefferbaum et al. (2006) also reported significantly
larger ventricle volume among HIV patients with histories
of alcoholism, and this effect was particularly strong in the
frontal and body regions of the lateral ventricles. Interest-
ingly, this group also reported that patients with alcoholism
exhibited significantly greater white matter hyperintensities
(WMHs) compared to HIV patients without alcoholism or
seronegative individuals with alcoholism. This finding is of
particular interest because other studies have not reported
significant differences in WMHs among HIValone patients
relative to healthy controls (Bornstein et al. 1992),
suggesting that a comorbid alcohol history may significant-
ly change the natural history of WMHs associated with
Most recently, Pfefferbaum et al. (2007) utilized DTI to
examine the impact of HIV and alcoholism on the micro-
structural integrity of the white matter. In this study, HIV
patients with histories of alcoholism exhibited significantly
lower fractional anisotropy (FA) in the corpus callosum
compared to HIV patients without alcoholism. In addition,
patients with HIV and alcoholism exhibited significantly
greater mean diffusivity (MD) in the body and genu of the
corpus callosum compared to the comparison groups. When
subdivided by AIDS vs. nonAIDS status, the lower FA and
increased MD in the corpus callosum were most pro-
nounced among individuals with AIDS. Collectively the
studies conducted by Pfefferbaum and colleagues demon-
strate that a comorbid history of alcoholism significantly
influences the macrostructural and microstructural integrity
of the brain as defined by in vivo MRS, MRI and DTI in a
manner that is not observed among HIV patients without a
history of alcoholism.
Cannabis Studies of the neurocognitive effects of cannabis
in general have reported variable results: primarily minimal
cognitive impairment, with evidence of neuroprotective
effects in some instances (Grant et al. 2003). Concurrent
cannabis use does not typically increase neurocognitive risk
among users of other substances, such as methamphetamine
(Gonzalez et al. 2004). Neurocognitive effects of cannabis
and HIV serostatus have not been well-studied and
available results are similarly inconsistent. Cristiani et al.
(2004) evaluated the effects of a positive history of
cannabis use among a sample of 282 HIV+ individuals,
and reported that cognitive impairment (primarily memory
deficits) was most prominent among cannabis users with
symptomatic HIV disease. Chang et al. (2006) studied
groups of HIV+ and HIV- individuals with and without a
history of cannabis use using MRS and neurocognitive
testing. They reported evidence of additive and interactive
effects of HIV serostatus and cannabis use on brain
metabolites, but cognitive deficits were apparent only
among HIV+ individuals, regardless of cannabis use.
Collectively, these studies suggest that although cannabis
effects on neurocognition are minimal among uninfected
individuals or those at early stages of HIV infection, the
risk for cognitive deficits among HIV+ cannabis users
increases with disease progression.
Stimulants: Cocaine Surprisingly, relatively few studies
have evaluated neurocognitive performance among HIV+
and HIV- users of crack or powder cocaine, and available
studies have reported inconsistent results. Durvasula et al.
(2000) reported that both HIV disease and cocaine use were
associated independently with cognitive defects, especially
on psychomotor tasks, in a sample of 237 African
American males, but there was no evidence that cocaine
use combined with a positive HIV serostatus increased
neurocognitive risk. Levine et al. (2006) studied the
integrity of sustained attention in 40 HIV+ individuals that
included a mixed group of 17 cocaine and methamphet-
amine users and 23 non drug using controls. Groups were
well matched on demographics, current mood, and meas-
ures of global neurocognitive function. They reported that
stimulant users performed significantly more erratically and
made more errors on the Continuous Performance Test, a
standardized measure of vigilance, compared to HIV+
controls and to age and education appropriate norms.
Similarly, few neuroimaging studies have investigated the
combined effects of HIV and cocaine use. A recent PET
study using C11-labeled receptor imaging reported that
abnormally decreased dopamine transporter density (DAT)
in basal ganglia was detectable among HIV+ subjects with
or without a positive cocaine history; however, these
abnormalities were most prominent among cocaine users
regardless of serostatus (Chang et al. 2008).
Stimulants: Methamphetamine Neurotoxic effects of meth-
amphetamine use have been well documented (Kalechstein
et al. 2003; Chang et al. 2007; Nordahl et al. 2003).
Investigators at the University of California-San Diego
have published a comprehensive series of reports that have
documented the additive and synergistic effects of meth-
amphetamine abuse and HIV on neurocognition and struc-
tural, biochemical and functional neuroimaging. Rippeth et
al. (2004) administered a comprehensive battery of neuro-
cognitive tests to groups of HIV+ and HIV- subjects with
and without a history of methamphetamine abuse. They
reported that either risk factor was associated with cognitive
impairment, with the highest rate among HIV+ metham-
phetamine users. In a follow up study, Carey et al. (2006)
examined the influence of HIV disease severity on
methamphetamine associated neurocognitive impairment
and reported that neurocognitive impairment was signifi-
cantly higher among HIV+ methamphetamine users with
advanced disease compared with subjects without signifi-
cant disease progression.
Taylor et al. (2004) reported a clear “dose dependent”
relationship between HIV and stimulant abuse risk group
and NAA levels in the anterior cingulate, with the highest
levels observed among healthy controls and the lowest
levels (i.e., greater injury to mature neurons) among
stimulant abusing seropositive individuals. No additive
effects were observed for NAA in the caudate and neither
myo-inositol (mI) nor choline (Cho) differed by group
status. In terms of morphometry, Jernigan et al. (2005)
reported significant reductions in the caudate, thalamus,
hippocampus and both frontal and temporal cortical volume
among HIV-positive individuals whereas, methamphet-
amine abuse in the absence of HIV was associated with
significant increases in caudate, lenticular nucleus and
nucleus accumbens volume. Individuals with both HIV and
methamphetamine exhibited no significant difference in
caudate volume relative to healthy controls, a finding
driven by the opposing effects of both HIV and metham-
phetamine. These results underscore the need to consider
both direct and opposing effects of stimulant abuse when
defining morphometric indices of the basal ganglia (partic-
ularly the caudate) among HIV-positive individuals.
Postmortem studies of potential cellular mechanisms of
combined effects of HIV and methamphetamine have
reported evidence of selective damage to frontal cortical
interneurons that are immunoreactive (IR) for the calcium-
binding protein calbindin (CB) (Langford et al. 2003). This
cellular damage was most prominent in the brains of HIV+
methamphetamine users with evidence of HIV encephalitis
at autopsy. In a follow up study, Chana et al. (2006)
reported that global neurocognitive impairment and mem-
ory scores were significant predictors of severity of CB-IR
neuronal damage, which was significantly more extensive
for HIV+ methamphetamine users with HIV encephalitis
compared with methamphetamine users without HIV
encephalitis and with HIV+ non methamphetamine users
without HIV encephalitis. These effects were selective for
CB-IR neurons rather than the result of generalized cellular
Polysubstance Dependence The first author’s group has
conducted a series of cognitive neuropsychological studies
in Chicago with a large cohort of crack and heroin users.1
These studies have been designed to minimize variability
by matching HIV+ and HIV- groups carefully on demo-
graphics, SUD parameters, and potentially confounding
comorbid disorders (e.g., PTSD, ADHD). Abstinence at
testing was verified in all subjects by rapid urine toxicology
screening and breathalyzer testing. These studies have
reported consistent evidence that compared to HIV-
controls, HIV+ SDIs show increased vulnerability to
specific cognitive deficits associated with abnormalities of
prefrontal-striatal networks. Impaired representative or
“working” memory, which requires online information
processing, storage, monitoring or updating, appears to
constitute a signature deficit among HIV+ drug abusers. In
a series of studies, HIV+ SDIs performed consistently more
poorly than matched HIV- SDIs on measures that stressed
working memory by a variety of means, including increase
in information load, time delay, and task complexity
(Bartok et al. 1997; Farinpour et al. 2000; Martin et al.
2001, 2003). Similar additive effects have been demon-
strated on decision making performance as captured on the
Iowa Gambling Task (Martin et al. 2004a) and on time-
driven prospective memory, a type of memory for future
intentions that requires active self-generated cueing for
successful retrieval (Martin et al. 2007).
Our current investigations have moved forward from
studies targeting aspects of “executive functions” toward
evaluating the integrity of nondeclarative memory functions
that are dependent primarily on integrity of striatal and (in
some instances) cerebellar systems. Surprisingly few
studies have investigated the effects of either a positive
HIV serostatus or substance abuse on these functions,
despite their common effects on striatum (cf. A. Martin et
al. 1993; van Gorp et al. 1999). Recently we reported
evidence of additive effects of HIV on SDIs’ performance
of two motor skill learning tasks, the Pursuit Rotor and the
Star Mirror Tracing Task (Gonzalez et al. 2008). This initial
investigation found no evidence of impairment of probabi-
listic learning measured by the Weather Prediction Task
(Knowlton et al. 1996), however the study sample was
primarily male; follow up analyses have indicated possible
gender effects on vulnerability to impaired performance on
this cognitive procedural learning task (Martin, unpublished
Nicotine Durazzo et al. (2007) reported that HIV-positive
individuals who smoke and drink heavily exhibited signif-
icantly lower volumes in the frontal, temporal and parietal
cortices compared to healthy controls, while nonsmoking
HIV patients who were heavy drinkers exhibited signifi-
cantly smaller volumes only in the frontal lobe. Further,
HIV-positive individuals with histories of smoking and
heavy drinking performed significantly worse on tests of
learning, memory and cognitive efficiency compared to
HIV-positive individuals with histories of drinking but not
smoking. These findings indicate that chronic cigarette
smoking, like alcohol and stimulants, alter the anatomical
and functional health of the brain in the context of HIV.
These are critically important findings; rates of cigarette
smoking have been estimated at up to 88% among
individuals in substance abuse treatment (Richter et al.
2002). These findings emphasize the need to include a
smoking cessation component in substance abuse treatment
programs, as this intervention might facilitate cognitive
recovery among abstinent SDIs.
1These studies included only SDIs in order to demonstrate that
additive effects of HIV could be detected reliably by theory-driven
cognitive measures. These findings have paved the way for additional
cognitive studies of non-SDI samples that are currently in progress in
Overall these studies have facilitated greatly our progress
toward an understanding of the neurocognitive effects of
HIV and substance dependence, particularly by delineating
the conditions under which additive or synergistic effects
are most likely to occur. Both HIV disease severity and
substance type appear critically important: some cognitive
deficits are apparent primarily among HIV+ SDIs with
symptomatic infection or who specifically abuse alcohol or
methamphetamine, although there is no selective impair-
ment of specific cognitive functions. Additional detailed
studies of cocaine are necessary, particularly given the very
high prevalence of crack among HIV+ SDIs, and nicotine
addiction. Neurocognitive studies of HIV+ SDIs must also
be broadened to include potential effects of club drugs and
abuse of prescription drugs including steroids.
Hepatitis C as a Comorbidity in HIV
Hepatitis C (HCV) has only recently been recognized as an
important “cognitive” comorbidity to HIVinfection yet in the
last few years interest among clinicians and researchers
regarding co-infection has developed at a rapid pace. The
interest in HCV-HIV co-infection is based in part on
observations that the prevalence of co-infection is very high
in some populations of HIV patients, co-infected individuals
exhibit more severe cognitive impairment than individuals
with mono-infection, and the mechanisms that drive these
cognitive symptoms largely remain unknown. Below we
review the extant literature in these areas and provide
recommendations for future studies that aim to delineate the
additive/synergistic effects of HCV-HIV co-infection.
Frequency of HIV-HCV Coinfection
HCV is a member of the Flaviviridae family of viruses
(along with yellow fever, dengue virus, and tick-born
viruses). The prevalence of HCV infection among the
general population is nearly two times the prevalence of
HIV, likely due to an increased probability of percutaneous
transmission of HCV compared to HIV (Alter et al. 1999).
World-wide, it is estimated that more than 170 million
individuals are infected with HCV, including nearly 3
million individuals in the United States (Armstrong et al.
2006). Unfortunately the vast majority of patients face a
chronic infection and many develop hepatic and extrahe-
patic complications (Vassilopoulos and Calabrese 2005).
Given the high rate of transmission through percutane-
ous exposure it is not surprising that individuals infected
with HIV through injection drug use (IDU) are at an
exceptionally high risk of being co-infected with HCV
compared to individuals infected with HIV through sexual
activity, although HCV can be transmitted by sexual
contact. Estimates of the prevalence of co-infection among
IDUs ranges from 44% as reported in the Johns Hopkins
HIV Clinical Cohort to as high as 90% in some European
countries (Sulkowski et al. 2002; Verucchi et al. 2004).
These numbers translate to approximately 300,000 individ-
uals in the US that are co-infected. Clearly, the possibility
that HIV-positive patients with histories of IDU are co-
infected with HCV is very high and the clinical needs of
these individuals require attention.
HCV and the Brain
There is a wealth of data generated in the field of HCV
mono-infection describing impairment in brain function
associated with HCV mono-infection. This literature is
relevant as it hints towards mechanisms that may interact
with or add to well-defined models of HIV neuropatho-
genesis (to be discussed in detail elsewhere in this issue). For
a more detailed review of the HCV-monoinfection literature
readers are referred to Forton et al. (2001, 2002, 2005).
HCV crosses the blood-brain-barrier and is present in both
the CSF and brain tissue (Laskus et al. 2002; Maggi et al.
1999; Murray et al. 2008). Further, some of the HCV
sequences observed in the peripheral mononuclear cells and
lymph nodes and the brain are very similar, suggesting that
the virus effectively crosses the BBB (perhaps by via infected
leukocytes; Forton et al. 2004; Laskus et al. 2004). However,
diversification has also been noted (Murray et al. 2008).
The specific brain targets infected by HCV remain a
matter of debate. Letendre et al. (2007) reported the
presence of HCV proteins in brain astrocytes using Western
blotting and immunostaining among co-infected patients.
More recently, Wilkinson et al. (2008) examined sections of
frontal cortex and subcortical white matter from 12 HCV
infected patients (six of whom were co-infected with HIV)
and found HCV presence in CD68 cells (macrophages and
microglia) and less involvement within brain astrocytes. Of
interest is that the HCV phenotype was identical between
HCV mono-infected samples and co-infected samples.
These findings are consistent with Letendre et al. (2007)
in that both studies demonstrated evidence of HCVantigens
in the brain, but they differ in terms of the primary cell
populations infected. As described by Wilkinson et al.
(2008), these differences may be associated with the
difference in patient populations or in the differences in
methods to determine which cells were primarily infected
(use of polyclonal antibodies against the NS5A protein vs.
monoclonal antibodies against the NS3 protein).
Nevertheless, the presence of HCV antigens in the brain
along with evidence of HCV diversification in the brain
(Bagaglio et al. 2005) suggest that the brain may represent a
site of persistent HCV viral replication among co-infected
patients. For example, Adair et al. (2005) demonstrated
down-regulation of oxidative phosphorylation genes in the
brains of HCV-infected patients. Functionally this finding is
of significance as oxidative phosphorylation is a critical
source of cell energy and neurons are susceptible to reduced
energy sources due to high metabolic rates. As described by
Adair, high levels of free radicals in the brain may be
produced as a consequence of disruption in energy-
dependent calcium homeostasis. The data suggested above
suggest that brain infection with HCV could potentially
lead to free radical damage. Alternatively, it is possible that
presence of HCV in the brain could produce an inflamma-
tory cascade not very different from HIV (Forton et al.
2008; Morgello 2005; Paul et al. 2007).
A number of MRS studies have demonstrated metabolite
abnormalities associated with HCV mono-infection. For
example, Forton et al. (2008) revealed elevations in the
myo-ml/creatine (Cr) ratio in the frontal white matter
among patients with chronic HCV mono-infection. In-
creased ml is believed to represent microglial activation and
astrogliosis (Bitsch et al. 1999), and therefore elevations in
the ml/Cr ratio may reflect consequences of proinflamma-
tory reactions to the presence of HCV in the brain (Forton
et al. 2008). Of interest is that Forton et al. (2008) also
demonstrate a significant inverted relationship between
elevated ml/Cr ratios and working memory performance
among patients infected with HCV suggesting that the
MRS metabolite disturbance may underlie functional
properties of the brain.
Evidence of HCV-mediated inflammation in the brain
has been observed by Letendre et al. (2005). Specifically,
HCV serostatus was found to associate with a range of
inflammatory indices (e.g., MCP-1, TNF-alpha and TNFR-
II). When all of the inflammatory indices were considered
together, HCV status was most strongly associated with
increased levels of sTNFR-II levels, and these relationships
remained significant after controlling for substance abuse
history and HIV serostatus. Collectively these findings
suggest a model of HCV-mediated brain involvement
characterized by HCV presence in the brain, disruption in
metabolic processes/oxidative stress, and pro-inflammatory
reactions that lead to impaired neuronal function.
The model defined above is intriguing but it is not
without limitations. As described by Letendre et al. (2007)
identification of HCV presence in the brain has proven
difficult and this may relate to low rates of viral replication
in the brain or the development of antibody complexes or
other immunological reactions. Thus the level of HCV in
the brain may not be sufficient to drive sustained brain
damage, or the virus is present but undetectable. Further, a
number of studies of HCV-mono-infected patients have
revealed relationships between liver disease and cognition
raising the possibility that liver dysfunction may also be
related either directly or indirectly to CNS compromise in
this population. As noted previously, Perry et al. (2005)
reported a significant relationship between neuropsycho-
logical performance and liver fibrosis stage In addition,
Hilsabeck et al. (2002, 2003) reported that poor cognitive
function among HCV mono-infected patients is associated
with increased severity of liver fibrosis.
Most recently, Morgello et al. (2005) contrasted neuro-
psychological performance between HIV patients from the
MHBB with evidence of HCV in the brain and liver,
patients with evidence of HCV only in the liver, and
patients with no evidence of HCV in either the brain or the
liver. Results revealed that individuals with evidence of
HCV in the brain performed significantly worse on Trail
Making B compared to individuals without evidence of
HCV sequences in the brain. However, neuropathological
results revealed a high level of abnormalities among
individuals with HCV sequences in the brain and among
individuals with HCV only in the liver. Specifically, both
groups exhibited Alzheimer type 2 gliosis in the brain
regardless of whether HCV was present in the brain. This
latter finding suggests that the brain does not have to be
directly infected with HCV to develop significant neuro-
pathological dysfunction. Further, with the exception of a
single neuropsychological measure (Trails B), performance
on neuropsychological tests was similar between individu-
als with and without evidence of HCV in the brain.
A number of other studies have demonstrated significant
neuropsychological impairment among individuals infected
with HCV alone. Interestingly, these studies have revealed
significant cognitive compromise in the absence of either
substance abuse or cirrhosis, suggesting a possible direct
impact of HCVon the brain. Interested readers are referred
to Perry et al. (2008) for a recent review though we provide
a brief review in this section. Hilsabeck et al. (2002, 2003)
have reported significant impairments among HCV mono-
infected patients on tests of psychomotor speed, sustained
attention, and working memory with impairment rates
(defined as performance more than one standard deviation
below that of controls) exceeding 80% on some measures.
Neuropsychological performances were generally more
impaired among individuals with greater liver damage but
individuals with only mild liver compromise also demon-
strated impaired neuropsychological functions.
Similar results were reported by Fontana et al. (2005)
using data obtained from a large clinical trial for the
treatment of HCV (the HALT-C trial). In this study, more
than one third of the sample met criteria for neuropsycho-
logical impairment as defined by performances at least one
standard deviation below that of controls on at least four
neuropsychological tests. Verbal memory and working
memory were most likely impaired in this cohort and no
significant correlations were observed between perform-
ances in these domains and liver severity. Most recently,
Huckans et al. (2009) examined neuropsychological func-
tion among HCV mono-infected patients with and without
histories of substance abuse compared to healthy controls
with no HCV and no substance abuse history. Collectively
individuals with HCV performed significantly more poorly
than individuals without HCV on tests of verbal memory,
attention, processing speed and mental flexibility. Further,
HCV mono-infected individuals without substance abuse
histories performed significantly more poorly than healthy
controls most of the same cognitive measures.
The studies above demonstrate that HCV mono-infection
is associated with significant impairment in neuropsycho-
logical domains typically characterized as “subcortical” in
nature, with predominant impact on attention, information
processing speed, and verbal memory. Further, evidence of
neuropsychological impairment among HCV mono-
infected individuals exists independent of comorbid sub-
stance abuse and severe liver disease, raising the possibility
of direct brain involvement from HCV.
HIV-HCV Co-infection and Everyday Functioning
There has been limited research conducted to date regard-
ing the impact of HIV-HCV co-infection on aspects of
everyday living yet this is an important area of study given
the synergistic effects of the viruses on psychological and
medical outcomes. Most studies have focused on quality of
life (QOL) among individuals with co-infection, with HCV-
HIV comorbidity resulting in more deleterious self-reported
QOL compared to individuals with HIV mono-infection
(Baum et al. 2008; Braitstein et al. 2005; Marcellin et al.
2007; Tillmann et al. 2006; Tsui et al. 2007; Vigil et al.
2008) and compared to individuals co-infected with HIV
and hepatitis B co-infection (Tillmann et al. 2006).
Predictors of reduced QOL among co-infected patients
include depressive symptoms, high levels of fatigue,
poverty, and substance abuse (Baum et al. 2008; Braitstein
et al. 2005; Marcellin et al. 2007; Tsui et al. 2007). In
addition, Vigil et al. (2008) reported that compromised
information processing speed and depressive symptoms
among HIV-HCV co-infected individuals were associated
with decline in instrumental activities of daily living while
compromised fine motor speed and dexterity predicted
decline in physical activities of daily living.
Individuals infected with both HIV and HCV utilize
healthcare services significantly more frequently than
individuals with HIV mono-infection (Baum et al. 2008)
and healthcare utilization, along with depression, physical
symptoms and limited access to HCV treatment, predicted
lower QOL in this population. These findings clearly
indicate that comorbid HCV infection in the context of
HIV results in significant individual burden and this
translates into additional utilization of healthcare resources.
Studies are needed that more completely describe the
impact of co-infection on other aspects of everyday
function such as medication adherence, employment, and
driving ability in order to understand the degree to which
co-infection interrupts independence in these areas as well
as the disease and host mechanisms that underlie the
Contribution of Substance Abuse and Depression
Individuals co-infected with HIV and HCV tend to report
greater illicit alcohol and substance abuse (e.g., Ryan et al.
2004; Cherner et al. 2005) and as warned by van Gorp and
Hinkin (2005) higher levels of abuse of these substances
may influence the prevalence of cognitive impairment in
To address this issue the second author’s group exam-
ined a cohort of co-infected patients compared to HIV
mono-infected patients on a computerized battery of
neuropsychological tests (Paul et al. 2008). In addition we
examined substance and alcohol use with a self-report
measure that quantified the duration, amount and frequency
of use of each alcohol, stimulants, heroin, and marijuana.
Consistent with previous studies we observed significantly
poorer cognitive function among co-infected patients,
particularly on tests of information processing speed and
psychomotor speed, relative to HIV mono-infected patients.
In addition, while the co-infected patients reported signif-
icantly more heroin use than mono-infected patients,
correlational analyses revealed no significant relationships
between the quantified exposure of each substance and
performance on any cognitive test among the co-infected
group. These findings, along with other studies that have
controlled for illicit substance abuse in analyses, suggest
that differential degrees of illicit substances and alcohol
among co-infected patients likely does not account for the
greater degree of neuropsychological impairment evidence
in this population.
Some studies have also reported that co-infected patients
experience more severe symptoms of depression or other
psychiatric conditions relative to HIV mono-infected
patients in several studies. This raises the possibility that
psychiatric disturbance may underlie the greater degree of
cognitive impairment in this population. Indeed, Clifford et
al. (2005) reported that 57% of the co-infected patients
reported depressive symptomatology in comparison to 32%
of HIV mono-infected patients. However, not all studies
have reported greater degrees of psychiatric symptoms
among co-infected patients. For example, Ryan et al. (2004)
provided detailed psychiatric results based on a structured
interview and reported no difference in current psychiatric
diagnoses between 62 co-infected individuals and 45 HIV
mono-infected individuals. Further, studies that have
identified more severe depressive symptoms among
co-infected patients have reported increased cognitive
impairment even after controlling for obvious psychiatric
symptoms. Thus, as in the case of substance abuse, it
appears that psychiatric symptoms do not provide sufficient
explanatory power to account for the neuropsychological
symptoms of co-infection
Interactions Between HIV and HCV: Focus
on Neuropsychological Status
A number of studies have demonstrated significant inter-
actions between HIV and HCV in terms of disease
morbidity and clinical outcomes. For the most part these
studies fall outside of the scope of this article, and readers
interested reviewing the impact of HIV on HCV disease
progression or the influence of HCV morbidity among HIV
patients are referred to Strider (2005) and Vassilopoulos
and Calabrese (2005). More directly related to this article is
the interaction of HCV and HIV on the central nervous
system (CNS) and more specifically, neuropsychological
function. As noted above, individuals infected with both
HCV and HIV express more severe neuropsychological
impairment than individuals with HIV alone but the
mechanisms underlying these effects remain unclear.
To date a handful of studies have examined neuropsy-
chological function among individuals co-infected with
HCV and HIV. Among these studies there is notable
variability in the methods to examine neuropsychological
function, the use of various comparison groups (e.g., HCV
alone, HIV alone, both mono-infected groups compared to
co-infected patients), and the focus on various laboratory
indices of disease burden. These methodological differ-
ences require some caution when drawing conclusions
regarding the impact of co-infection on cognitive outcome.
For example, a number of studies did not involve a
comprehensive neuropsychological assessment, and there-
fore, conclusions regarding the neuropsychological pattern
associated with co-infection remains premature. With that
caveat noted, there is some suggestion in the literature that
several domains of cognitive function are more likely
impacted by co-infection than others.
Decreased processing speed and psychomotor speed
among co-infected individuals is a commonly reported
outcome of the studies. For example von Giesen et al.
(2004) observed significantly slower reaction times among
co-infected patients compared to individuals with either
HIV or HCV mono-infection. A similar finding was
reported by Martin et al. (2004b), using a computerized
version of the Stroop task. In this study, co-infected
individuals recorded slower reaction times on the task
compared to mono-infected individuals and these results
were observed after controlling for differences in intelli-
gence and substance abuse histories. Of interest is that the
study relied on a voice-activated response system, and
therefore the reduced reaction times among co-infected
patients were not confounded by complications in periph-
eral motor function. Analyses also revealed that HCV status
was associated with slower performances on all conditions
of the Stroop task while HIV was associated with poorer
performance on the incongruent condition, suggesting a
specific deficit in slower processing speed associated with
Other studies have also demonstrated slower processing
speed among co-infected patients. Hilsabeck et al. (2005)
reported that 80% of a co-infected sample met criteria for
cognitive impairment compared to 69% of a HIV mono-
infected group that met criteria for impairment. Further, the
primary cognitive domain affected among the co-infected
group was psychomotor slowing, with 84% of the co-
infected group impaired in this domain compared to 56% of
the mono-infected group. A similar finding was reported by
Clifford et al. (2005). In this study, co-infected patients
performed significantly more poorly on the Symbol Digit
Modalities Test (SDMT) and Trail Making B, but no
differences were noted between the groups on Trail Making
A or the Symbol Search test.
Evidence of selective impairment in psychomotor speed/
information processing is not universal. Ryan et al. (2004)
reported nearly identical rates of impairment (44% vs. 43%)
in psychomotor speed as measured by Trail Making A,
Digit Symbol and Symbol Search between co-infected
patients and HIV mono-infected patients respectively. The
two groups also performed similarly across other domains
with the exception of executive function which was
measured by Trail Making B and Perseverative Responses
on the Wisconsin Card Sorting Test. Specifically, 43% of
the co-infected patients were impaired in the domain of
executive function versus 29% of the mono-infected
patients. Of further interest is that the group difference in
this domain was largely driven by poor performances on
the WCST which requires a low demand of motor and
processing speed. In addition, Cherner et al. (2002) recently
reported that HCV serostatus was a significant predictor of
performance among HIV-infected individuals in the
domains of learning, abstraction, and motor skills, with
only a trend noted for information processing speed (and
delayed recall). Of further interest is that HCV status did
not predict performance in the area of attention/working
memory or verbal fluency. Similar results were recently
reported by Hinkin et al. (2008).
Not all studies have reported greater cognitive impair-
ment among co-infected patients. For example, Perry et al.
reported no significant differences between co-infected
patients and a comparison group of HCV mono-infected
patients. In this study, 29 co-infected patients and 47 HCV
mono-infected patients completed Trail Making A and B,
Symbol Search, and the SDMT. Both groups demonstrated
poor performances when compared to expected values of
healthy control subjects, but the percentages of impaired
patients on the three tests did not differ by co-infection
status. Comparisons of the raw scores indicate that co-
infected patients performed worse than mono-infected
patients on the SDMT, and mono-infected patients per-
formed more poorly on Symbol Search, but neither
difference was statistically significant. When the two
groups were combined, there was a statistically significant
relationship between liver fibrosis stage and neuropsycho-
logical impairment but since the groups were aggregated it
is not clear if the relationship was driven by one group
more so than the other. Further, the strongest correlation
was observed between Symbol Search performance and
liver fibrosis stage (coefficient = 0.66) and this test was the
only one of the four on which HCV mono-infected patients
were more likely to be impaired than co-infected patients.
When taken collectively the majority of studies have
reported more severe neuropsychological impairment
among co-infected patients than mono-infected patients.
The one exception did not include a HIV mono-infected
group and the neuropsychological battery was limited in
scope, with no measures of attention, working memory,
learning and memory and only one test of executive
function. Other studies have demonstrated select impair-
ments in these domains (Hinkin et al. 2008), and therefore
the battery administered by Perry et al. may not have been
of sufficient breadth to capture impairments associated with
Future Directions for Studies of HIV and HCV
A number of open questions remain among studies of HIV-
HCV co-infection. The neuropsychological pattern, if a
specific pattern exists, has not been fully defined. In part
this is due to that fact that many studies conducted to date
have been based on retrospective data. This does not
discount the value of these studies, but it does create
limitations to the available neuropsychological tests admin-
istered in the parent study, and therefore, the opportunity to
identify a complete neuropsychological pattern. Clearly,
large studies are needed that include comprehensive
neuropsychological batteries. Studies are also needed that
examine inflammatory markers in the brain, as well as
evidence of HCV sequences present in the central com-
partment. Combined with more sensitive measures of liver
status and neuroimaging indices, these studies will help
elucidate the mechanisms associated with cognitive impair-
ment in co-infected patients.
To our knowledge only one study has examined DTI
findings among co-infected patients. Stebbins et al. (2007)
reported a trend toward lower whole-brain fractional
anisotropy (FA) and a highly significant increase in
whole-brain mean diffusivity (MD) among co-infected
patients relative to HIV mono-infected patients. Lower FA
and higher MD values typically refer to reduced neuronal
integrity, and as such the results of this study are consistent
with brain compromise among co-infected patients. How-
ever, substance abuse was also much more common among
this sample and it is possible that substance abuse histories
influenced the outcomes.
Future studies are needed to identify the neuro-
imaging signatures of co-infection. A number of studies
have employed MRS to examine white matter abnor-
malities in HCV-mono-infection and DTI represents an
alternate approach because FA provides a robust marker
of white matter integrity. Our lab (RP) is currently
conducting a NIDA-funded study of cognition, liver
disease, and multimodal neuroimaging (including DTI)
among co-infected and HIV mono-infected patients.
Results from this study are expected to shed new light on
the putative mechanisms involving CNS injury associated
Strategies for Approaching the Problem of Comorbid
In recent articles, investigators of neuroAIDS have empha-
sized the importance of developing a systematic approach
with empirically defined organizing principles to address
the inevitable confounds associated with neurocognitive
aspects of HIV. In 2005 a group of international neuroAIDS
experts was convened and charged with reviewing the
existing AAN guidelines (Janssen et al. 1991) for classify-
ing HIV-associated neurocognitive disorders and recom-
mending updates to reflect advances in neuroAIDS research
in the era of HAART (Antinori et al. 2007). Their report
includes a series of empirical guidelines for estimating the
influence of a particular confound (e.g., cerebrovascular
disease, depression, substance abuse) as either compatible
with HAND; contributing to HAND; or confounding the
assessment of HAND (e.g., precluding the judgment that
neurocognitive abnormalities can be attributed to direct
effects of HIV). The recommendations for evaluating the
contribution of comorbid substance use were formulated
using multiple variables, including DSM-IV criteria; recency
of drug use; ability to maintain employment or independent
living; and the presence or absence of withdrawal or
intoxication at testing. These guidelines are promising and
await longitudinal evaluation of their utility and validity.
In the Chicago studies led by the first author, both
exclusion criteria and research procedures are designed to
address potential confounding conditions. On recruitment,
exclusion criteria are restricted to a minimum number of
“deal breakers,” including 1) central neurological disorders;
2) closed head injury with more than 30 min loss of
consciousness; 3) open head injury of any type; 4) seizure
disorder; 5) schizophrenia; or 6) current neuroleptic or
narcotic medication. [In our experience, study candidates
are most commonly excluded for history of head injury or
psychoactive medication]. All subjects are required to pass
a rapid urine toxicology screen and breathalyzer testing;
otherwise their study visit is terminated with no payment.
In addition to hypothesis-driven neurocognitive tasks,
participants are administered measures of ADHD symp-
toms (Stein et al. 1995), reading (Wechsler 2001), PTSD
(Keane et al. 1987), antisociality (Levenson et al. 1995),
sensation seeking (Zuckerman 1996) and current psycho-
logical distress (Beck et al. 1996). Scores on these measures
can be employed both as covariates and as independent
variables of interest. For example, a recent study by our
group demonstrated that sensation seeking and decision
making both affected the tendency to engage in high risk
behavior but the patterns of predictors were different for the
HIV+ and HIV- groups (Gonzalez et al. 2005b).
Our experimental approach to comorbidity problems is
also influenced significantly by models that postulate that
in addition to substance-specific effects, all drugs of abuse
activate common neural circuitry that includes orbitofrontal
cortex, anterior cingulate and ventral striatum (Goldstein
and Volkow 2002; Kalivas and Volkow 2005) resulting in a
loss of inhibitory control. These inhibitory deficits contrib-
ute to behavioral features displayed by all SDIs, including
continuing drug use even after loss of any pleasurable
effects and despite full knowledge of future consequences,
features that persist among abstinent SDIs. These deficits
are readily demonstrable with measures of decision making
that require the subject to refrain from choosing attractive
but risky options in order to optimize future outcomes
(Bechara et al. 2001; Grant et al. 2000; Rogers et al. 1999;
Brand et al. 2008), go/no-go (Forman et al. 2004; Kaufman
et al. 2003) and stop-signal reaction time tasks (Fillmore et
al. 2002; Fillmore and Rush 2002) which require the
subject to inhibit ongoing motor responses but only under
certain conditions; and measures of delay discounting
(Kirby and Petry 2004; Petry 2001), which index the
individual’s ability to tolerate delayed reward. Consequent-
ly, one would predict that all SDIs should be vulnerable to
deficits on inhibitory tasks, regardless of HIV or HCV
serostatus. These deficits might serve as a proxy for
“nonspecific” effects of drug dependence and employed
as control tasks for comparison with measures of specific
aspect of cognition.
The HIV and addictions neuroscience literature has
reported a number of potentially significant influences on
vulnerability and clinical features of HAND among drug
users that remain to be studied. As an example, converging
evidence shows consistent evidence of sex differences
throughout different stages of the addictive process
(Wetherington 2007). Compared to men, escalation of drug
use and progression to addiction are more rapid, vulnera-
bility to relapse is higher and withdrawal symptoms are
more severe among women (Becker and Hu 2008).
Additionally, neural mechanisms of addictive behavior
among women are often distinct or even opposite of those
reported in men (e.g., Wang et al. 2007). For example, Kilts
et al. (2004) reported that amygdala activation decreased
with cue-induced craving for women but increased among
men, suggesting that additive or interactive effects of drug
abuse and HAND might result in dissimilar patterns of
brain activity and neurocognitive function for men and
women. Studies of interactions between estrogen, HAND,
and drug abuse will have critical translational implications
for treatment of substance dependence and for management
of HIV disease.
Comorbid influences on neurocognition and neurobehavio-
ral function are highly prevalent among individuals living
with HIV/AIDS. We have attempted to provide the reader
with a clearer understanding of the sequelae of comorbid
substance use disorder or HCV disease. Many questions
remain to be answered, but the field of comorbidity and
neuroAIDS research has moved steadily forward and will
continue to benefit from ongoing advances in neuro-
cognitive, neuroimaging and addiction neuroscience.
reviewers for their helpful comments on this article; and Edie Sullivan
for her very gracious assistance with our timeline.
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