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Treatment of HIV in the CNS: Effects of Antiretroviral Therapy and the Promise of Non-Antiretroviral Therapeutics

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The growing recognition of the burden of neurologic 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 concept 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 treated 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 specifically alter the trajectory of HIV within the CNS.
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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 [58]. 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 Womens 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 patients 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 [2123] 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 [4547], 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 escapein 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 Alzheimers 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.
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Papers of particular interest, published recently, have been
highlighted as:
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... Thus, there may be other factors that can explain the link between blood CD4/CD8 ratio and motor/psychomotor speed performance in this group of participants. Inflammation and immune activation in the CNS manifest after HIV transmission during the acute stage (before seroconversion) [48,58,59] and even persist among individuals with long-term HIV viral suppression [60,61]. Furthermore, elevated CSF WBC is common among HIV-infected people with neurological impairment despite the paucity of evidence of other CNS infections, as well as individuals who are neurologically asymptomatic [58,61]. ...
... Inflammation and immune activation in the CNS manifest after HIV transmission during the acute stage (before seroconversion) [48,58,59] and even persist among individuals with long-term HIV viral suppression [60,61]. Furthermore, elevated CSF WBC is common among HIV-infected people with neurological impairment despite the paucity of evidence of other CNS infections, as well as individuals who are neurologically asymptomatic [58,61]. ...
Article
Full-text available
Introduction CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). Methods This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART‐naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. Results In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002–0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04). Conclusions The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection.
... Human immunodeficiency virus (HIV) infection and its consequent immune deficiency are linked to a spectrum of comorbid infectious, cancerous, degenerative, and inflammatory maladies (Ong, 2008;Barreto-de-Souza et al., 2016;Margolis et al., 2016a, b;Grande et al., 2017;Tiberi et al., 2017). All have been reduced in severity as a result of global research efforts in disease pathogenesis, epidemiology, natural history and, most notably, antiretroviral therapy (ART) (Grant and Zolopa, 2012;Tan and McArthur, 2012;Ho and Marra, 2014;Lamers et al., 2014;Maartens et al., 2014;Peluso and Spudich, 2014;Elbirt et al., 2015). Significant global, political, and social research efforts have emerged to make ART available worldwide (Bezabhe et al., 2014;Govindasamy et al., 2014;Stricker et al., 2014). ...
Chapter
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain a common end-organ manifestation of viral infection. Subclinical and mild symptoms lead to neurocognitive and behavioral abnormalities. These are associated, in part, with viral penetrance and persistence in the central nervous system. Infections of peripheral blood monocytes, macrophages, and microglia are the primary drivers of neuroinflammation and neuronal impairments. While current antiretroviral therapy (ART) has reduced the incidence of HIV-associated dementia, milder forms of HAND continue. Depression, comorbid conditions such as infectious liver disease, drugs of abuse, antiretroviral drugs themselves, age-related neurodegenerative diseases, gastrointestinal maladies, and concurrent social and economic issues can make accurate diagnosis of HAND challenging. Increased life expectancy as a result of ART clearly creates this variety of comorbid conditions that often blur the link between the virus and disease. With the discovery of novel biomarkers, neuropsychologic testing, and imaging techniques to better diagnose HAND, the emergence of brain-penetrant ART, adjunctive therapies, longer life expectancy, and better understanding of disease pathogenesis, disease elimination is perhaps a realistic possibility. This review focuses on HIV-associated disease pathobiology with an eye towards changing trends in the face of widespread availability of ART.
... Human immunodeficiency virus (HIV)-infected patients suffer serious complications, of which the pathogenesis of HIV-associated neurocognitive disorders (HAND) is one of the least understood. Since the introduction of combined antiretroviral therapy (cART) in the early 1990s, higher prevalence of the less severe phenotypes of HAND were reported [1,2]. One key hypothesis to explain the occurrence of HAND despite inhibition of viral replication is the "bystander hypothesis". ...
Article
Full-text available
HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND. Electronic supplementary material The online version of this article (doi:10.1186/s12974-017-0829-2) contains supplementary material, which is available to authorized users.
... An evaluation of the effectiveness of dual therapy regimens in diverse patient population is also required. A potential concern with the use of dual therapy is the persistence of viral replication in reservoir sites such as the central nervous system (CNS) [83,84]. The evaluation of dual therapy regimens regarding penetration and effectiveness in potential reservoir sites, and specifically, CNS viral escape and the predictive value of CNS penetration effectiveness scores, requires further study. ...
Article
Full-text available
Objective: We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. Methods: A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Results: Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. Conclusions: The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the effectiveness and tolerability of dual therapy regimens, it remains unclear whether these potential benefits can be maintained long-term. Appropriately powered studies with longer follow-up periods are needed to more definitively assess potential toxicity reduction advantages with dual therapy.
Chapter
HIV-associated neurocognitive disorders (HAND) persist globally despite the effectiveness of suppressive combination antiretroviral therapy (cART) in dramatically reducing the prevalence of HIV-associated dementia, the severest sub-type of HAND. Nonetheless, less severe HAND can be disabling for employment and other activities of daily living, and it remains a large health burden. Success in preventing and treating HAND requires maximizing viral suppression in the central nervous system and other body compartments, modulating the potentially toxic and metabolic effects of early blood–brain barrier injury and virus persistence even in the absence of replication, and enhancing the potential for nervous system recovery. Recent pilot study successes in improving cART regimens for CNS efficacy (improving penetrance, targeting the HIV chemokine co-receptor CCR5 and delivery (nanoformulations) suggest that more complete and sustained suppression of HIV replication is achievable, and this may indeed even further reduce the prevalence of symptomatic HAND. Targeting associated pathogenic pathways with currently available FDA-approved drugs used for other disorders can also serve as adjunctive treatments to cART by adding broad suppression of neuroinflammation and oxidative stress, modulating neurotransmitter metabolism, and perhaps supporting neuroregeneration. Interest in neurotrophic factors is rapidly growing, with limited study thus far. Adjunctive cognitive behavioral therapy and aerobic exercise combined with each of these may further improve outcomes.
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Psychiatric factors play a significant role in the ongoing human immunodeficiency virus (HIV) pandemic. In less than four decades, advances in HIV medical care and research have transformed acquired immune deficiency syndrome (AIDS) from a rapidly fatal illness of unknown cause into a chronic, manageable illness. Vast strides have been made in clinical care and pathogenesis research in the fields of HIV prevention and psychiatric care, including pre- (PreP) and and post-exposure (PEP) prophylaxis. Although AIDS is an entirely preventable infectious illness, HIV transmission continues throughout the world. Transmission of HIV continues to be fueled by many factors, including stigma of HIV and mental illness as well as discrimination, criminalization, and risky behaviors. A comprehensive biopsychosocial approach to sexual health and mental health and diminution of stigma are key to both HIV prevention and HIV care. Integration of psychiatric care into HIV prevention and treatment entails use of a biopsychosocial approach that maintains a view of each individual with HIV as a member of a family, community, and society who deserves to be treated with dignity and compassion. This textbook provides an update on HIV medicine and psychiatry; introduces the concept of HIV/AIDS as “the great magnifier of maladies”; explores the paradoxes and disparities of HIV care; explains how HIV psychiatry is a paradigm for the psychiatric care of the medically ill (psychosomatic medicine); and sets the stage for an understanding of how integrated care can prevent transmission of HIV and reduce morbidity and mortality in persons with HIV.
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To date, the most effective treatment of HIV-1 is a combination antiretroviral therapy (cART), which reduces viral replication and reverses pathology. We investigated the effect of cART (RT and protease inhibitors) on the content of extracellular vesicles (EVs) released from HIV-1-infected cells. We have previously shown that EVs contain non-coding HIV-1 RNA, which can elicit responses in recipient cells. In this manuscript, we show that TAR RNA levels demonstrate little change with the addition of cART treatment in cell lines, primary macrophages, and patient biofluids. We determined possible mechanisms involved in the selective packaging of HIV-1 RNA into EVs, specifically an increase in EV-associated hnRNP A2/B1. More recent experiments have shown that several other FDA-approved drugs have the ability to alter the content of exosomes released from HIV-1-infected cells. These findings on cART-altered EV content can also be applied to general viral inhibitors (interferons) which are used to treat other chronic infections. Additionally, we describe unique mechanisms of ESCRT pathway manipulation by antivirals, specifically the targeting of VPS4. Collectively, these data imply that, despite antiretroviral therapy, EVs containing viral products are continually released and may cause neurocognitive and immunological dysfunction.
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Effective combination antiretroviral therapy has transformed HIV infection into a chronic disease, with HIV-infected individuals living longer and reaching older age. Neurological disease remains common in treated HIV, however, due in part to ongoing inflammation and immune activation that persist in chronic infection. In this review, we highlight recent developments in our understanding of several clinically relevant neurologic complications that can occur in HIV infection despite treatment, including HIV-associated neurocognitive disorders, symptomatic CSF escape, cerebrovascular disease, and peripheral neuropathy.
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The aim of the present study was to investigate the effects of naringin on learning and memory dysfunction induced by HIV-1-enveloped protein gp120 in rats, and to identify its potential mechanisms of action. Learning and memory ability was evaluated via Morris water maze test, P2X7 receptor and P65 protein expressions in the rat hippocampus were detected by western blot analysis, and P2X7 mRNA expression in the hippocampus was measured by RT-PCR. We also recorded P2X7 agonist BzATP-activated current in the hippocampus via patch clamp technique. The results showed that naringin treatment (30 mg/kg/d) markedly decreased the escape latency and target platform errors of rats treated with gp120 (50 ng/d), and further, that naringin treatment significantly decreased the expression of P2X7 and P65 protein and P2X7 mRNA in the hippocampus of gp120-treated rats. In addition, naringin treatment reduced BzATP-activated current in the hippocampus of gp120-treated rats. These results altogether demonstrated that naringin can improve gp120-induced learning and memory dysfunction via mechanisms involving the inhibition of P2X7 expression in the hippocampus.
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Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human "Swedish" mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aβ), and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide.
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The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.
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Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection. We prospectively studied individuals with primary HIV infection (PHI, <1 year after transmission) to assess the presence of and laboratory associations with PN in this early stage. Standardized examination and analysis of blood and cerebrospinal fluid (CSF) was performed in participants with laboratory-confirmed PHI. PN was defined as >1 of the following unilateral or bilateral signs: decreased distal limb position, vibration, or temperature sense, or hyporeflexia; symptomatic PN (SPN) as presence of these signs with symptoms. Analysis employed nonparametric statistics. 20/58 (35%) antiretroviral-naïve male subjects without diabetes evaluated at a median 107 days post HIV transmission (dpt) met criteria for PN. 13/20 (65%) of PN subjects met criteria for SPN; 6/20 (30%) had bilateral findings. PN subjects and no PN subjects (NPN) did not differ in median age, dpt, blood CD4 or CD8 counts, CSF or plasma HIV RNA levels, CSF white blood cell counts, or CSF:blood albumin ratio. PN and SPN subjects had elevated CSF neopterin (p=0.003 and p=0.0005), CSF MCP-1 (p=0.006 and p=0.01) and blood neopterin (p=0.006 and p=0.009) compared to NPN. PN subjects had a higher percentage of activated phenotype CSF CD8+ T lymphocytes than NPN subjects (p=0.009). Signs of PN were detected by detailed neurologic exam in 35% of men enrolled in a neurological study at a median 3.5 months after HIV transmission. PN during this early period may be mediated by systemic and nervous system immune responses to HIV.
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Our previous results demonstrated that a prodrug obtained by the conjugation of the antiretroviral drug zidovudine (AZT) with ursodeoxycholic acid (UDCA) represents a potential carrier for AZT in the central nervous system, thus possibly increasing AZT efficiency as anti-HIV drug. Based on these results and in order to enhance AZT brain targeting, the present study focuses on solid lipid microparticles (SLMs) as a carrier system for the nasal administration of UDCA-AZT prodrug. SLMs were produced by the hot emulsion technique, using tristearin and stearic acid as lipidic carriers, whose mean diameters were 16 and 7 μm, respectively. SLMs were of spherical shape and their prodrug loading was 0.57 ±0.03% (w/w, tristearin based) and 1.84 ±0.02% (w/w, stearic acid based). The tristearin SLMs were able to control the prodrug release, whereas the stearic acid SLMs induced a significant increase of the dissolution rate of the free prodrug. The free prodrug was rapidly hydrolyzed in rat liver homogenates with a half-life of 2.7 ± 0.14 min (process completed within 30 min). The tristearin SLMs markedly enhanced the stability of the prodrug (75 % of the prodrug still present after 30 min), whereas the stabilization effect of the stearic acid SLMs was lower (14 % of the prodrug still present after 30 min). No AZT and UDCA-AZT were detected in the rat cerebrospinal fluid (CSF) after an intravenous prodrug administration (200 μg). Conversely, the nasal administration of stearic acid based SLMs induced the uptake of the prodrug in the CSF, demonstrating the existence of a direct nose - CNS pathway. In the presence of chitosan, the CSF prodrug uptake increased six times, up to 1.5 μg/mL within 150 minutes after nasal administration. The loaded SLMs appear therefore as a promising nasal formulation for selective zidovudine brain uptake.
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HIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND. Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network. We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection. We found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03-7.9) and 2.6 (95% CI 1.03-6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6-70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1-21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age. Protease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.