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CENTRAL NERVOUS SYSTEM AND COGNITION (I GRANT, SECTION EDITOR)
Treatment of HIV in the CNS: Effects of Antiretroviral Therapy
and the Promise of Non-Antiretroviral Therapeutics
Michael J. Peluso &Serena Spudich
#Springer Science+Business Media New York 2014
Abstract The growing recognition of the burden of neurolog-
ic disease associated with HIV infection in the last decade has
led to renewed efforts to characterize the pathophysiology of
the virus within the central nervous system (CNS). The con-
cept of the AIDS-dementia complex is now better understood
as a spectrum of HIV-associated neurocognitive disorders
(HAND), which range from asymptomatic disease to severe
impairment. Recent work has shown that even optimally treat-
ed patients can experience not only persistent HAND, but also
the development of new neurologic abnormalities despite viral
suppression. This has thrown into question what the impact of
antiretroviral therapy has been on the incidence and prevalence
of neurocognitive dysfunction. In this context, the last few
years have seen a concentrated effort to identify the effects
that antiretroviral therapy has on the neurologic manifestations
of HIV and to develop therapeutic modalities that might spe-
cifically alter the trajectory of HIV within the CNS.
Keywords HIV .AIDS .HIV-associated neurocognitive
disorder (HAND) .Asymptomatic neurocognitive impairment
(ANI) .Mildneurocognitivedisorder (MND) .HIV-associated
dementia (HAD) .AIDS dementia complex .Cerebrospinal
fluid (CSF) .Central nervous system (CNS) .Antiretrovirals .
Combination antiretroviral therapy (cART) .Central nervous
system penetration effectiveness (CPE) .Neopterin .
Neurofilament light chain .Proton-MR spectroscopy (MRS) .
Peripheral blood monocyte DNA .Neuroinflammation .CSF
escape .CD4 T lymphocyte .Neuropsychological testing .
Neurotoxicity
Introduction
The neurologic impact of HIV infection extends across the
disease course from early infection through end-stage disease
(Table 1). HIV RNA can be identified in the cerebrospinal
fluid (CSF) of individuals infected with HIV as early as 8 days
after estimated initial viral exposure [1•]. A subset of approx-
imately 10 % of individuals experience neurologic symptoms
in the setting of seroconversion and the acute retroviral syn-
drome. Evidence of neurologic injury can be seen in the
evaluation of CSF biomarkers as early as three months of
infection [2], and the increase in these markers tends to
correlate with progression of disease as evidenced by decreas-
ing CD4 count [3•].
The prevalence of clinically measurable HIV-associated
neurocognitive disorder (HAND) increases with advancing
systemic disease stage and has been defined by formal criteria
as asymptomatic neurocognitive impairment (ANI), mild
neurocognitive disorder (MND) and an advanced form,
HIV-associated dementia (HAD) [4]. Studies have shown that
even mild HAND can have a significant impact on quality of
life and function in daily activities [5–8]. Moreover, new
manifestations of CNS HIV-associated disease that may be
outside of the typical spectrum of HAND have recently been
described, including symptomatic CSF HIVescape [9,10]and
CD8 encephalitis [11,12]. With the more sophisticated un-
derstanding of these processes has come an effort to measure
the clinical impact associated with HIV in the CNS and to
determine if treatment can mitigate or reverse neurologic
damage.
Measuring the Clinical Effects of Treatment with cART
While the AIDS Dementia Complex was characterized at the
beginning of the epidemic in the 1980s, the definitions of a
broader spectrum of HAND have been formalized within the
M. J. Peluso
Department of Medicine, Brigham and Women’s Hospital,
75 Francis St, Boston, MA 02115, USA
e-mail: mpeluso@partners.org
S. Spudich (*)
Department of Neurology, Yale University School of Medicine,
PO Box 208018, New Haven, CT 06520, USA
e-mail: serena.spudich@yale.edu
Curr HIV/AIDS Rep
DOI 10.1007/s11904-014-0223-y
last decade [4] and the method of studying neurocognitive
manifestations of HIV disease in HIV-infected populations
has changed. This has made it difficult to compare the prev-
alence of HAND across populations before and after the
widespread availability of cART.
Neuropsychological (NP) testing remains the mainstay for
identifying the presence of HAND and evaluating the impact of
treatment on the disease course. NP testing batteries for HAND
include assessment of a number of neurocognitive domains
including verbal/language, attention/working memory,
abstraction/executive functioning, memory (learning and recall),
speed of information processing, sensory-perceptual skills, and
motor skills. In clinical practice, detailed testing batteries are
often impractical due to time and resource constraints, and so
abbreviated batteries can sometimes be used to identify abnor-
malities in the clinical setting. The patient’s own experience is
also of value in differentiating the milder forms of HAND, as the
primary difference between ANI and MND relates to the impact
that the disorder has on everyday functioning.
Descriptive Epidemiology of Neurocognitive Impairment
in the cART Era
A recent review sought to determine whether antiretroviral
therapy improves neurocognitive dysfunction in individuals
with HIV infection, and suggested that overall there is longi-
tudinal benefit on the individual level [13], with participants in
two-thirds of the included studies demonstrating significant
improvement in neurocognitive status with initiation of cART.
Of note, in many cases there was incomplete resolution of
baseline impairment, suggesting that treatment initiation may
not completely reverse neurocognitive and neuropsychologi-
cal abnormalities. Despite what appears to be a benefit of
initiating treatment, the effect of cART on the overall preva-
lence of neurocognitive impairment is less clear.
Broadly speaking, the widespread use of cART has resulted
in a significant decrease in the prevalence of HAD, the most
severely impairing manifestation of HAND. It has been esti-
mated that the prevalence of HAD was at least 16 % in the pre-
cART era [14], but HAD now occurs in up to 5 % of HIV-
infected patients [15]. Despite this improvement in the rates of
severe neurocognitive impairment in the cART era, the mor-
bidity and mortality of HIV-infected individuals with severe
impairment still exceeds that which is seen in control popula-
tions with unrelated severe neurocognitive deficits [16•].
While the most severe manifestations of HAND have de-
clined in the cART era, it is unclear whether the prevalence of
milder forms has decreased, persisted, or in fact increased in
the setting of evolving definitions, earlier diagnosis, and more
rigorous surveillance. While one might expect a significant
decline in HAND with the advent of cART, this has not been
the case in clinical studies. Initial work found high rates of
neurocognitive abnormalities in groups at high risk for im-
pairment in both time periods, but no significant differences in
prevalence between the eras [17]. Another study showed a
similar finding in pre-cART and cART groups [18], and more
recent work again found rates of neurocognitive impairment
to be similar across both eras [19•].
In the time period before the widespread availability of
cART, the prevalence of neurocognitive impairment increased
with successive disease stages [19•]. In the cART era, however,
impairment has become commonly recognized in the medically
Tabl e 1 Mechanisms and manifestations of HIV-associated neurologic disease across the stages of HIV infection
Central Nervous System Process
Clinical Manifestation
Disease Stage
Early
infection
Meningitis
Encephalitis
Subclinical injury
Asymptomatic neurocognitive impairment
Mild neurocognitive disorder
Latent
untreated
Meningitis
Stroke/CNS metabolic disease
Subclinical injury
Latent
treated
CSF HIV escape
CD8+ encephalitis
Antiretroviral neurotoxicity
CNS IRIS
Stroke/CNS metabolic disease
Advanced
untreated
CNS opportunistic infections
Stroke/CNS metabolic disease
HIV-associated dementia
CNS, central nervous system; CSF, cerebrospinal fluid; IRIS, immune reactivation inflammatory syndrome
Curr HIV/AIDS Rep
asymptomatic state of HIV infection. A number of studies have
also suggested that the overall patterns of neurocognitive im-
pairment may have shifted in the cARTera [18,19•]. While high
rates of mild neurocognitive impairment (NCI) persist at all
stages of infection, it appears that the characteristics of impair-
ment have shifted from primarily motor and cognitive/verbal
impairment in the pre-cART era to impairment primarily in
memoryandexecutivefunctioninthecARTera[13,19•,20].
Recognizing the CNS as an HIV-infected Compartment
The detection of HIV DNA in perivascular brain macro-
phages, microglial cells, and astrocytes [21–23] and the com-
partmentalization of HIV quasi-species in CNS tissues [24,
25] suggests the existence of a CNS reservoir of infection that
may lead to neurologic injury and create a sanctuary for
ongoing viral replication. Understanding the clinical impor-
tance of infection within the CNS compartment has critical
implications for HIV treatment and eradication strategies.
With the recognition that the CNS can serve as a site for
viral persistence has come a targeted effort to optimize the
delivery of antiretroviral agents to the CNS, which is segre-
gated from the plasma compartment by a number of barriers
that complicate drug delivery. These include the blood-brain,
blood-CSF, and CSF-brain barriers. The ability of antiretrovi-
ral drugs to penetrate these barriers and achieve therapeutic
concentrations in the CNS is determined by a number of
characteristics, including their molecular weight and lipophi-
licity, the extent to which they are bound to protein in the
plasma, and whether they are candidates for active transport
across the endothelial cells comprising the barrier. For exam-
ple, a study of the nucleoside reverse transcriptase inhibitor
(NRTI) tenofovir, a common component of cART regimens
worldwide, demonstrated that CSF concentrations of the drug
were only 5 % of those found in the plasma, and that lower
CSF concentrations of the drug were associated with detect-
able CSF HIV RNA [26]. Similarly, recent work studying the
pharmacokinetics of efavirenz has demonstrated overall poor
penetration of the drug into the CSF. Unlike the results of the
tenofovir study, however, the efavirenz levels achieved in the
CSF still exceeded those needed to inhibit viral replication
[27]. A case of resistance to the integrase inhibitor raltegravir
within the CNS compartment has also been reported [28].
The issues with CNS compartmentalization and the blood-
brain barrier have led to the development of scoring systems
aimed to predict or estimate the exposure and impact of a
given cART regimen in the CNS. The CNS penetration-
effectiveness (CPE) index represents an effort to quantitative-
ly estimate the relative ability of each antiretroviral agent to
penetrate the CNS and interfere with CSF HIV replication.
Each agent is assigned a “CPE score,”and a total regimen
score can be calculated by summing the scores for individual
agents [29].
Some studies have shown that antiretroviral regimens with
higher CPE scores tend to be more successful at achieving
HIV RNA suppression in the CNS [29,30]. However, while
more potent HIV RNA suppression in this compartment might
be expected to lead to better neurocognitive outcomes and
more effective treatment of HAND, this has not necessarily
been the case. Observational studies have suggested that the
initiation of regimens with higher CPE scores may produce a
cognitive benefit in patients with HIV-related neurological
disease [31,32], or that lower CPE scores were more likely
to be associated with clinical deterioration as measured by
serial neuropsychological testing [33]. Other studies have
shown that HIV-infected individuals treated with regimens
with higher CPE scores actually exhibit poorer neurocognitive
performance despite suppression [30] or only benefit if they
are on more than three drugs, which is the standard for most
cART regimens [34]. Still others show no effect of CPE score
[35]. A prospective study of individuals on long-term cART
and those starting cART found similar rates of neurocognitive
impairment in both groups, and a trend toward lower CPE
scores being associated with poorer performance that can
likely be attributed to a subset of subjects on monotherapy.
This study again suggested that nadir CD4 count was signif-
icantly associated with neurocognitive impairment in both
groups in a multivariate model [36].
More recently, in vitro drug efficacy data has been used to
derive a monocyte efficacy score based upon the expected
effectiveness of antiretroviral drugs within monocytes and
macrophages. In a prospective study of a cohort of subjects
on antiretroviral therapy, higher monocyte efficacy score corre-
lated with better neuropsychological testing performance [37].
Targeting Treatment Toward the CNS
Along with the recognition that the CNS might represent a
viral reservoir or sanctuary site has come an effort to specif-
ically target this compartment when developing treatment
regimens for patients with HIV. A recent evaluation of the
effect of targeted CCR-5 inhibition with maraviroc in early
SIV-infected macaques demonstrated markedly lower SIV
RNA and proviral DNA in the CNS in the maraviroc group,
suggesting decreased viral replication in these animals. Treat-
ment with maraviroc also lowered monocyte and macrophage
activation and decreased amyloid precursor protein immuno-
staining, suggesting a potential neuroprotective effect [38].
The results of CNS-targeted therapy in humans have been
less clear. A recent randomized controlled trial designed to
evaluate whether neurocognitive outcomes differ between
CNS-targeted or non-targeted regimens was terminated early
due to slow accrual and low likelihood of detecting a differ-
ence between the two groups. The 16-week follow-up data did
not show evidence of neurocognitive benefit for a CNS-
targeted strategy, though the study accrual did not reach the
Curr HIV/AIDS Rep
sample size calculated as necessary to detect a difference
between the planned outcome measures [39].
Because of the difficulties related to penetrating the barriers
to the CNS, there has been some effort to explore alternative
methods of drug delivery to this compartment. Recent work
studying zidovudine has demonstrated that solid lipid micro-
particles may represent a potential carrier system for drug
delivery to CNS via nasal administration [40]. It is unclear
whether similar methods could be used to deliver other drugs,
including those with poorer plasma-to-CSF penetration, to the
CNS.
Treatment in Early Infection
Numerous studies have demonstrated that CD4 nadir is an
important predictor of neurocognitive impairment in both eras
[19•,41]. In a study from the CHARTER cohort explicitly
addressing this question, higher CD4 nadir was associated
with lower odds of neurocognitive impairment and HAND
[42]. Similar observations of associations between symptom-
atic CSF HIVescape and nadir CD4 count have been made in
much smaller case series and reports [9,10]. Other predictors
of neurocognitive impairment in the pre-cART era, including
duration of infection (combining on- and off-treatment pe-
riods) and CSF viral suppression, no longer appear to correlate
with neurocognitive abnormalities in treated subjects [19•].
The importance of nadir CD4 as a predictor of
neurocognitive impairment and clinical neurologic syndromes
which develop despite cART suppression suggests that early
initiation of treatment might have a significant impact on the
neurocognitive outcomes of individuals with HIV infection.
Pathologic processes within the CNS associated with devel-
opment of neurologic damage in HIV, including viral inva-
sion, immune activation, and compartmentalization of HIV
variants are initiated during acute and early infection [1•,24,
43•]. Recent studies have suggested that these initial processes
morbidly impact the nervous system, in that levels of CNS
immune activation directly associate with elevation of CSF
markers of neuronal injury and neuropathy detected in sub-
jects studied during this early period [2,44]. However, it is
unknown whether early treatment will ameliorate these pro-
cesses or protect the nervous system from subsequent injury.
Neuropsychological performance and mood are abnormal in
subjects with early HIV infection compared with those in
HIV-uninfected control subjects or the general HIV-
uninfected population [45–47], with patterns of neuropsycho-
logical impairment paralleling those described in chronic in-
fection, including processing speed and learning deficits.
Some of these deficits may be attributable to comorbidities
which are prevalent in those at risk for HIV acquisition,
including substance abuse and co-infections such as syphilis
and hepatitis C [48], suggesting that interventions besides
cART alone may be important in addressing CNS injury.
A recent cross-sectional study of 200 HIV-infected subjects
and 50 HIV-uninfected comparison subjects engaged in the
US military is a first study to strongly suggest that early
diagnosis and management of HIV infection may ameliorate
or prevent neuropsychological impairment. These HIV-
infected subjects had low levels of confounding substance
abuse, and the majority initiated treatment within an estimated
three years of HIV acquisition, resulting in rates of
neurocognitive impairment similar to those seen in matched
HIV-uninfected controls [49•].
Measuring the Biological/Neuroimaging Correlates
of Treatment with cART
As a result of the challenges associated with neuropsycholog-
ical testing, including training effects and the frequency of
neuropsychological comorbidities found in patients with HIV,
efforts have been made to identify biological markers of
neurocognitive injury and impairment in individuals with
HIV infection and to determine if these markers correlate with
clinically relevant aspects of neuropsychological function.
From a cellular perspective, it is thought that the activity of
HIV within the central nervous system is primarily related to
neuroinflammation rather than direct viral activity. Neurons
lack the requisite surface receptors for viral entry, but are
subject to the downstream effects of a neuroinflammatory
cascade involving microglia and macrophages, which begins
within the first year of infection. Understanding the cellular
and systems-level events that occur over the time course of
HIV infection has become just as important as clinical out-
comes as the field of HIV shifts its focus to viral eradication.
CSF HIV
A key marker of antiretroviral activity within the CNS is the
quantification of HIV viral RNA after the initiation of therapy.
In patients with chronic HIV infection, the pre-cART viral
load within the CSF compartment is typically tenfold less than
in the plasma compartment [50], although a more marked ratio
between CSF and plasma is observed earlier in infection [43•].
Initiation of cART results in a notable decrease in CSF HIV
RNA levels [51], although the rate of decay may be slower in
individuals with neurocognitive impairment at baseline [50,
52]. Despite the typically brisk response of CSF HIV to
initiation of cART, not all subjects achieve or maintain com-
plete viral suppression within the CNS. Recent work has
recognized that a subset of individuals on chronic suppressive
therapy have elevated CSF HIV RNA levels as compared to
plasma, either in the context of neurologically asymptomatic
[53] or symptomatic [9,10] infection. The characterization
Curr HIV/AIDS Rep
and clinical significance of CSF “escape”in the setting of
cART is a topic of intensive current study.
Further research has suggested that pre-cART viral popu-
lations in the plasma and CSF may be identical during acute
infection, but subsequently diverge and compartmentalize as
the disease progresses from primary to chronic infection [24,
54,55]. The compartmentalized populations are thought to
also derive from different cell lineages trafficking across the
BBB, with early compartmentalized HIV apparently replicat-
ing in lymphocytes and CNS variants in later stages of disease
derived from longer-lived macrophages [25]. This work sug-
gests that in early infection, regimens with high CNS penetra-
tion may be less critical, since clearing the infection in the
plasma compartment will result in CNS viral decay once the
plasma is cleared. In chronic or advanced infection, however,
the CNS reservoir may become established and no longer as
closely tied to plasma viremia, implying that CNS penetration
might be more important at this later time point.
Eggers et al. further studied the dynamics of HIV popula-
tions within the CNS in response to therapy by sequencing the
env protein V3 loop. In general, env sequences from short-
lived cells such as lymphocytes and long-lived cells such as
macrophages are reflective of different HIV subpopulations.
With cART, virus from fast-replicating cells decays first,
which uncovers sub-populations present in slow-replicating
cells, presumably macrophages and microglia, likely crucial
sources of HIV which will be important to understanding
HAND [56].
Soluble CSF Biomarkers of Inflammation and Injury
CSF biomarkers have gained popularity as objective markers
of neuronal inflammation and injury in HIV infection,
allowing researchers to distinguish static neurological abnor-
malities from active processes affecting the nervous system.
Over the last 10 years, there has been an effort to describe the
changes in these biomarkers that occur with different mani-
festations of HIV infection in the CNS, including HIV-
associated dementia, other manifestations of HAND, and
CNS opportunistic infections. More recently, dynamic chang-
es in these biomarkers have been explored in the context of
antiretroviral therapy.
While viral suppression with antiretroviral therapy leads to
a decline in many markers of immune activation and inflam-
mation within the CNS, some remain persistently elevated
even in individuals with undetectable viral activity both within
and outside of the CNS. Elevations in soluble biomarkers of
immune activation, including CSF neopterin, MCP-1/CCL-2,
and IP-10/CXCL-10 are detected in patients with HIV prior to
cART treatment [57]. CSF neopterin, a biomarker of CNS
macrophage activation associated with neuronal injury, can be
persistently elevated in subjects on suppressive cART,
suggesting that immune activation persists even in the setting
of viral control [58].
The light subunit of the neurofilament protein (NFL) is a
major structural component of myelinated axons and has been
identified as a sensitive marker of axonal injury in HAD,
chronic neuroasymptomatic HIV infection, and primary HIV
infection. Antiretroviral treatment decreases CSF levels of
NFL. However, levels of this marker do not completely nor-
malize with viral suppression even in neuroasymptomatic
patients, possibly reflecting ongoing neuronal injury despite
the absence of measurable viral replication in the CNS [3•].
Neuroimaging Markers: Persistent Abnormalities
on Antiretroviral Therapy
Proton-magnetic resonance spectroscopy (proton-MRS) is a
non-invasive imaging modality that has been used to monitor
neuronal injury through the analysis of cerebral metabolites.
N-acetylaspartate and glutamate are markers of neuronal
health that deplete with injury [59,60]. Research over the last
ten years has suggested that reduced brain tissue volumes in
cortical and subcortical regions and cerebral metabolite ab-
normalities persist in individuals on stable cART [61], and
may even progressively worsen during cART [62,63]. Addi-
tionally, a recent study employing a positron emission tomog-
raphy imaging method which putatively quantitates activated
microglia similarly suggests ongoing immune activation in
patients on stable cART [64].
Some neuroimaging studies have suggested that neuronal
injury occurs during primary HIV infection as evidenced by
decreased N-acetylaspartate in the frontal cortex of newly
infected individuals [65,66]. A recent study by Sailasuta
et al. used proton-magnetic resonance spectroscopy to identify
cellular inflammation and found cerebral metabolites sugges-
tive of inflammation in subjects with acute HIVinfection prior
to initiation of cART, even in the absence of neuronal injury.
The markers of injury normalized after initiation of cART in
these subjects, suggesting that early cART might be neuro-
protective [67].
Studies of cerebral metabolites have shown brain-region
specific abnormalities that correlate with a number of disease
markers, including nadir CD4 count, in subjects with stable
HIV on cART [68,69], suggesting that delayed initiation of
cART may increase vulnerability to neurologic abnormalities.
A study comparing virologically suppressed individuals with
MND to healthy controls showed micro-structural alterations,
including loss of structural integrity and edema in a number of
brain regions in the MND subjects [70]. Another study eval-
uating brain tissue volume of structures on MRI suggested
that effective therapy could attenuate the shrinkage of the
frontal and temporoparietal cortices, insula, and hippocampus
and decreased rapidity of the expansion of the Sylvian fissure,
implying less rapid decline in higher-order functions [71].
Curr HIV/AIDS Rep
Peripheral Blood Monocyte HIV DNA
One prevailing theory regarding the cause of continued cog-
nitive impairment in the cART era is that a peripheral blood
monocyte HIV DNA reservoir that persists despite treatment
serves as a mechanism for the spread of the virus to the brain.
In a prospective study of cART-naïve HIV-infected Thai sub-
jects, there was a 14.5 increased odds ratio for HAND for each
tenfold increase in HIV DNA copy number. Moreover, HIV
DNA levels correlated with the inflammatory marker
neopterin in the CSF, as well as proton-MRS markers of
neuronal injury and glial dysfunction [72].
Could Antiretroviral Drugs Contribute to HAND?
The toxic effects of treatment with cART within the CNS are
also an important consideration in the era of HAND, particu-
larly in the setting of the growing concern that therapeutic
concentrations of antiretroviral drugs in the CSF can be asso-
ciated with neurotoxicity.
From a clinical perspective, the adverse reactions asso-
ciated with the NNRTI efavirenz are particularly notable
and include sleep disturbances, mood disorders, impaired
concentration, and in some cases, suicidality. While typi-
cally occurring within the first four weeks of treatment,
neuropsychiatric effects of efavirenz can persist [73]. The
mechanism of neurotoxicity is unknown, but recent work
has suggested that it may be related to drug levels due to
individual variability in metabolism and is more likely
associated with reversible dendritic changes rather than cell
death [74]. Recent in-vitro work studying efavirenz
metabolites demonstrated a dose-dependent toxic effect of
the 8-OH metabolite on neuronal dendrite morphology and
viability [75]. Further work in mice has shown that treat-
ment with efavirenz generated increased production and
decreased clearance of beta-amyloid through upregulation
of beta-secretase activity and down-regulation of microglial
amyloid-beta phagocytosis [76]. Additional work in rats
and macaques has suggested that antiretroviral agents can
result in the accumulation of reactive oxygen species and
the induction of neuronal injury [77].
Partly in the setting of concern for the toxic effects of
antiretroviral therapy in well-controlled patients has come
a movement toward less-drug regimens, which represent
an effort to simplify treatment and minimize the costs and
adverse reactions associated with these medications. As
their name suggests, these regimens typically consist of
dual- or mono-therapy and are slightly less systemically
efficacious compared with cART. Despite their relative
success at suppressing systemic virus replication, there is
concern that these regimens would inadequately suppress
viral reservoirs such as the CNS. A recent review of
studies of less-drug regimens consisting of ritonavir-
boosted protease inhibitors suggested that this may not
actually be the case. While symptomatic CSF viral escape
was observed to occur in subjects on monotherapy who
also failed in the plasma, asymptomatic CSF escape was
not more common than in standard cART and there were
no differences in functional outcomes [78]. This work
suggests that less-drug regimens might be a reasonable
clinical option in a specific subset of patients, but further
prospective work needs to be done to determine whether
the benefits of a simplified regimen outweigh the risks of
viral relapse and resistance.
Fig. 1 Biological, clinical, and
epidemiological impact of
antiretroviral therapy on central
nervous system manifestations of
HIV infection. CNS, central
nervous system; CSF,
cerebrospinal fluid; ANI,
asymptomatic neurocognitive
impairment; MND, mild
neurocognitive impairment;
HAD, HIV-associated dementia
Curr HIV/AIDS Rep
Non-antiretroviral Therapies
Prior Trials of Adjunctive Medications
A number of non-antiretroviral therapies have been suggested
in an effort to attenuate the inflammatory events that are
characteristic of CNS HIV infection and may underlie the
pathogenesis of HAND. Studies of memantine, selegiline,
and nimodipine have failed to demonstrate any benefit [79].
The neuropsychiatric agents valproic acid and lithium, which
affect glycogen synthase kinase-3β, and the selective serotonin
reuptake inhibitors citalopram and paroxetine have been hypoth-
esized to downregulate HIV replication and neuroinflammation;
however studies of these agents have not demonstrated improve-
ment in neurological outcomes related to HAND [80]. The
acetylcholinesterase inhibitor rivastigmine and the NMDA re-
ceptor antagonist memantine, both of which are commonly used
in Alzheimer’s dementia, also did not show benefit in terms of
cognitive performance. Although there were improvements in
secondary outcomes (processing speed and executive function)
in virally suppressed individuals on rivastigmine, cognitive func-
tioning did not differ between treatment and placebo groups [81].
While there was a suggestion of improvement in aggregate
neuropsychological scores at short-term follow-up in the open-
label group, there were no differences at the one-year time point
[82]. Similarly, the antibiotic minocycline has not shown a
benefit in randomized trials [83,84].
Adjunctive Medications Still Under Investigation
One class of non-antiretroviral drugs that remains promising is
the statin medications, which are inhibitors of the HMG-CoA
reductase enzyme and are thought to have widespread anti-
inflammatory effects. While an early, small study did not
show any appreciable effect on CSF HIV RNA levels or
markers of immune activation [85], recent work suggesting a
correlation between protease inhibitors, HAND, and cerebral
small-vessel disease [86•] could imply that the effects of
statins in this patient population remain incompletely explored
and warrant further investigation.
Also to be explored in the future is the possibility that,
despite the absence of HIV replication achieved by effective
cART, infected cells might generate pro-inflammatory viral
products such as tat, whose effects on the immune system may
require specific targeting by agents beyond antivirals [87].
Non-pharmacologic Approaches
Finally, non-pharmacologic therapy may have a significant
role to play in the treatment of individuals with HAND. A
recent review of approaches to cognitive rehabilitation within
this patient population suggests that a great deal remains
unknown about the therapies that might lead to better health
outcomes through functional improvement [20]. Other work
has suggested that exercise might also have a significant
impact on improving neurocognitive outcomes in HIV-
infected adults [88,89].
Conclusion
Even in the era of widespread access to antiretroviral therapy, the
burden of neurocognitive impairment associated with HIV infec-
tion remains significant and continues to evolve. Despite optimal
treatment, many individuals experience persistent HAND, CSF
viremia, and neuropsychological abnormalities that have a sig-
nificant impact on everyday functioning and quality of life.
Figure 1summarizes the biological, clinical, and epidemiological
impact of antiretroviral therapy within the CNS. While the results
of studies on the CNS effects of antiretroviral treatment continue
to be somewhat divergent, there are growing data supporting the
importance of the CD4 nadir as a marker for neurological risk
and suggesting that early initiation of antiretroviral therapy might
be the most important factor in reducing neuropsychological
morbidity for individuals with HIV. Still, there remains concern
that the overwhelming benefits of antiretroviral therapy might be
tempered by the risks associated with CNS viral compartmental-
ization and neurotoxicity, underscoring the need for further in-
vestigation aimed at clarifying the mechanisms behind the estab-
lishment and persistence of the CNS compartment, the
neurobiochemical effects of treatment targeted at this compart-
ment, and the individual and population level impact of antire-
troviral therapy in HIV-infected individuals.
Compliance with Ethics Guidelines
Conflict of Interest Michael J. Peluso and Serena Spudich declare that
they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
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