MD Farshid Noorbakhsh

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J Psychiatry Neurosci 2009;34(2) 83
Editorial
Éditorial
NeuroAIDS: a watershed for mental health 
and nervous system disorders
Jennifer A. McCombe, MD; Farshid Noorbakhsh, MD, PhD; Craig Buchholz, MD; 
Michael Trew, MD; Christopher Power, MD
McCombe, Noorbakhsh, Power — Division of Neurology, Department of Medicine; Buchholz — Department of Psychiatry,
University of Alberta, Edmonton; Trew — Department of Psychiatry, University of Calgary, Calgary, Alta.
More than 15% of the world’s burden of disease is attributable
to interlocking neurologic and psychiatric (neuropsychiatric)
disorders; these syndromes include mood disorders, schizo-
phrenia, addiction, dementia, epilepsy and chronic pain disor-
ders.1 Neuropsychiatric disorders associated with HIV infec-
tion represent the convergence of a major global infectious
epidemic with nervous system disease, resulting in substantial
morbidity and mortality, especially as the disease progresses
to AIDS. HIV directly infects and injures the central and per-
ipheral nervous systems, culminating in a wide spectrum of
neuropsychiatric disorders (collectively termed neuroAIDS),
including neurocognitive disorders such as HIV-associated
dementia, minor neurocognitive disorder, mania/psychosis,
anxiety, depression, seizures, and myelopathy and neuropathy
with accompanying chronic neuropathic pain and physical
disabilities (Fig. 1). In fact, HIV entry into the nervous system
(neuroinvasion) occurs early after primary infection but per-
sists throughout the disease course because the virus chronic-
ally infects glial cells (neurotropism) and has ensuing potential
for nervous system disease (neurovirulence). However, only a
subset of people with HIV exhibit nervous system disease,
indicating selective vulnerability to a neuropsychiatric pheno-
type (neurosusceptiblity) caused by HIV, defined by age, level
of concurrent immunosuppression, comorbidities and both
host and virus genetic diversities.2 These neuropsychiatric
disorders are associated with diminished quality of life,3
increased health care costs4 and reduced survival.5 Several of
these disorders are also apparent in children with HIV who
also have developmental delay.6 In addition, systemic
immunosuppression increases the risk, particularly among
adults, of opportunistic processes within the nervous system,
including progressive multifocal leukoencephalopathy, toxo-
plasmic encephalitis, cryptococcal and tuberculous meningitis
and primary central nervous system lymphoma associated
with seizures, physical and cognitive disabilities, psychosis
and mood disorders.
With the advent and increasing global use of combination
antiretroviral therapy, there has been a reduction in the fre-
quency and severity of neuropsychiatric disorders classically
described in HIV infection, together with improved immune
status and a reduced incidence of opportunistic disorders. Like-
wise, the quality of life and survival time of individuals with
HIV/AIDS have increased steadily with greater availability of
combination antiretroviral therapy, leading to improved ner-
vous system health and function.7 Despite this progress, recent
data reveal that neuropsychiatric complications still occur in as
Correspondence to: Dr. C. Power, Division of Neurology, Department of Medicine, 6-11 Heritage Medical Research Centre, University
of Alberta, Edmonton AB  T6G 2S2; fax 780 407-1984; chris.power@ualberta.ca; www.BrainPowerLab.ualberta.ca
J Psychiatry Neurosci 2009;34(2):83-5.
© 2009 Canadian Medical Association
NeuroAIDS
Neurocognitive
impairment
Mood disorders
Addiction
Neuropathic
pain
Physical
disability
Epilepsy
Mania/
psychosis
Fig. 1: Overlap of NeuroAIDS-associated neuropsychiatric pheno-
types. The individual disease phenotypes depend on the affected
anatomic site, the stage of disease including premorbid status,
intercurrent illness (immunosuppression), age and, in some cases,
concurrent therapies.
many as 50% of people with HIV.5 Although the spectrum of
HIV-related neuropsychiatric disease has changed, even these
newer assessments of disease prevalence might underestimate
the true burden of neuropsychiatric disease.
The spectrum of neuropsychiatric disease among those
infected with HIV is captured by stratifying disorders into
3 categories:
1. premorbid illnesses in patients with HIV (e.g., schizophre-
nia, major depression, anxiety disorders, addiction, mental
retardation);
2. illnesses directly caused by HIV infection (e.g., neurocogni-
tive disorders, seizures, neuropathy and associated compli-
cations); and
3. illnesses related to the medications commonly used in the
treatment of HIV (e.g., delirium, pain, anxiety).
In North America, populations at high risk for HIV include
injection drug users, men having sex with men, Aboriginal
peoples, youth and prisoners. Infection, in many cases, is a
consequence of high-risk behaviours, including unprotected
sex or injection drug use. Premorbid conditions such as addic-
tion, mood disorders, anxiety disorders and psychosis can
place individuals at greater risk for high-risk behaviours and,
consequently, for HIV infection. It is important to recognize
these conditions in this “at risk” population, since previous
studies demonstrate that some conditions such as depression
may be associated with increased progression of HIV and
higher mortality.8,9 Antecedent illnesses may also affect how
and when a patient seeks medical attention, adherence to
medications and follow-up. Premorbid illnesses may there-
fore be important determinants of behaviours that influence
the spread of disease. Among men with antiretroviral drug
resistance, high-risk sexual activity has been associated with
depression, youth, alcohol abuse and sildenafil use,10 under-
scoring the diversity of factors that influence the spread of HIV.
High-risk behaviours also place individuals at risk of co-
infections, which may go unrecognized and have their own
neuropsychiatric consequences. Among these infections,
syphilis and hepatitis C virus infections are particularly
important contemporary issues. Hepatitis C virus is a com-
mon coinfection with HIV and may place patients at
increased risk for HIV-associated dementia11 and contribute
to mortality.12 Therapies for hepatitis C virus, including pegy-
lated interferon-α, also have neuropsychiatric effects that
complicate their use in coinfected patients.13,14 Finally, it has
been shown that there is a higher prevalence of smoking
among people with HIV,15 which may have negative impacts
on quality of life and mortality.16
The neuropsychiatric illnesses assumed to be directly
caused by HIV infection are diverse and often eclipsed by
overwhelming systemic medical issues, leaving the neuro-
psychiatric syndromes under-diagnosed and under-treated.
These illnesses include HIV-associated dementia and minor
neurocognitive disorder (or HIV-associated neurocognitive
disorders), painful distal sensory polyneuropathy, vacuolar
myelopathy and seizures.5,7,17 The underlying neurovirulent
mechanisms for these disorders are thought to involve HIV
infection of microglia and astrocytes (not neurons or oligo-
dendendrocytes) and have ensuing direct neurotoxic effects
mediated by induced host-encoded molecules (e.g., cyto-
kines, proteases, reactive oxygen species, eicosanoids, excito-
toxic amino acids) and neurotoxic actions exerted by virus-
encoded proteins (e.g., gp120, Vpr, Tat) on proximate
neurons.18 However, the literature increasingly reveals that
there is an under-recognized and under-treated burden of
mental health impairment19 that likely affects the quality of
life, employment and survival of patients with HIV. This is
complicated further by the lack of evidence on how best to
treat such impairment in a population where particular atten-
tion needs to be paid to side effects and drug interactions.20
Many people with HIV are now living longer than 20 years
after initial infection — long after AIDS has developed.21 The
mental health consequences of living with any chronic med-
ical illness must also be considered.22
Combination antiretroviral therapy has expanded such
that there now exist more than 25 approved antiretroviral
drugs with a multitude of options for therapy using several
drug classes and simplified once-daily regimens. Different
drug regimens, however, have varying degrees of central
nervous system penetrance. Thus, the central nervous system
may serve as a reservoir for HIV. Treatment may not provide
complete protection against nervous system damage in HIV
infection. Despite this, several studies have failed to show
differences in progression and treatment of HIV-associated
dementia between different therapy regimens.23,24 Treatment
with combination antiretroviral therapy also places the indi-
vidual, especially those with very low CD4+ lymphocyte
counts, at risk for immune reconstitution inflammatory syn-
drome. This syndrome seemingly results from the restitution
of the individual’s immune system when combination anti-
retroviral therapy is initiated and has a host of documented
neuropsychiatric sequelae.25,26 Neuroimmune reconstitution
inflammatory syndrome has recently been recognized in the
central nervous system and may be associated with neuro-
toxic CD8+ T cells infiltrating the brain to cause seizures, con-
fusion and physical disabilities.25
The medications used in the treatment of HIV also have
their own associated side effects, of which some are neuro-
psychiatric. Efavirenz is a non-nucleoside reverse transcrip-
tase inhibitor commonly used to treat HIV. It is associated
with acute central nervous system side effects in 50% of
patients and has neuropsychiatric side effects when used
chronically.27 Several of the antiretroviral drugs cause distal
sensory neuropathy associated with neuropathic pain, but
fortunately many of these drugs (e.g., didanosine, indinavir)
are no longer or rarely used. However, stavudine (d4T) is
part of the regimen recommended by the World Health
Organization for widespread global use. There is increasing
evidence of hypertension and diabetes in people with HIV. In
part, this is likely due to their prolonged survival and aging,
but hyperlipidemia, insulin resistance and diabetes are also
recognized side effects of protease inhibitors.28 It remains to
be seen how hypertension and diabetes will ultimately affect
the development of associated conditions such as vascular
dementia and stroke in this population. Finally, although
some evidence is being accumulated, little is known about
how HIV therapies interact with many of the therapies
McCombe et al.
84 Rev Psychiatr Neurosci 2009;34(2)
NeuroAIDS
J Psychiatry Neurosci 2009;34(2) 85
commonly prescribed to treat neuropsychiatric disorders.
The importance of this is highlighted in a recently published
case of bipolar disorder being exacerbated by an interaction
between lopinavir/ritonavir and valproic acid.29
In summary, among individuals infected with HIV, there is a
broad and burgeoning spectrum of common neuropsychiatric
syndromes that are evident at all ages and involve premorbid
disorders, direct HIV-induced disorders and conditions related
to HIV treatments (Fig. 1). The pathobiological mechanisms of
these disorders remain ill-defined and the available treatments
are limited. Prolonged survival among people with HIV owing
to effective combination antiretroviral therapies also leads to
the possibility of previously unrecognized complications. In-
deed, given the global estimates for HIV prevalence (> 33 mil-
lion infected worldwide and > 1 million in North America at
present) and increasing availability of combination antiretro-
viral therapies, the magnitude and severity of disease related to
the nervous system is a daunting challenge for already over-
burdened health care systems. These circumstances call for
heightened awareness and vigilance among caregivers in terms
of recognizing, preventing and treating these disorders because
of their adverse impact on quality of life, employment, health
care costs and ultimately survival. Moreover, new neuropsychi-
atric diseases may emerge with greater recognition of disease
phenotypes associated with different HIV subtypes (clades),
particularly in the developing world; the increasing prevalence
of drug-resistant strains of HIV; or unanticipated consequences
of new therapies. At the same time, there is increased interest in
applying new technologies and approaches to studying neuro-
psychiatric diseases, including genomics, epigenomics, metab-
olomics and lipidomics, which has prompted application of
systems biology to investigating neuropsychiatric disease path-
ogenesis.30 From these latter studies, new therapies (immuno-
therapies, small molecules and therapeutic vaccines) for neuro-
psychiatric diseases are being developed and could be
implemented in conjunction with combination antiretroviral
therapies in the future. These strategies might have substantial
impact on the burden of neuropsychiatric disease but perhaps
also on the overall HIV/AIDS epidemic given that the nervous
system is a viral reservoir that remains comparatively inacces-
sible to immune surveillance and regulation.
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Acknowledgements: The authors thank Leah DeBlock for assistance
with manuscript preparation and Dr. Glen Baker for helpful discus-
sions. F.N. is supported by Canadian Institutes of Health Research
and Alberta Heritage Foundation for Medical Research Fellowships.
C.P. holds a Canada Research Chair (Tier 1) in Neurological Infec-
tion and Immunity and is an Alberta Heritage Foundation for Medical
Research Senior Scholar.
Competing interests: None declared.


NeuroAIDS: a watershed for mental health and nervous system disorders

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NeuroAIDS: a watershed for mental health and nervous system disorders

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