Severity Of HIV-associated Neurocognitive Disorders Research Articles

14 A Potential Behavioral Sign for Detection of Mild HIV-Related Neuropsychological Impairment

Objective:Even though the severity of HIV-associated neurocognitive disorders (HAND) has decreased with the introduction of combination antiretroviral therapy, mild forms of HAND remain prevalent. Many HIV-infected individuals live alone, so mild cognitive impairments are easily missed. It is important to check their neurocognitive and everyday functions during hospital visits; however, it is challenging for Japanese clinicians because many hospitals do not have enough clinical psychologists or neuropsychologists. Additionally, neuropsychological (NP) test results may not detect those mild cognitive impairments. A micro error has been given more attention as a new behavioral sign of the early stages of cognitive decline, especially among people with Mild Cognitive Impairment (MCI). The current study aimed to 1) develop a touch-panel HAND screening battery and 2) evaluate if the micro errors could differentiate individuals with HAND from their counterpart healthy individuals.Participants and Methods:Forty HIV-infected men (age: 49.0±8.51 years old, education: 18.5±2.17 years) and 44 healthy men (age: 45.4±8.49 years old, education: 14.4±2.27 years) completed the touch-panel HAND screening battery which assessed six NP domains by seven subtests, everyday functions, and depression. A micro error is defined as a subtle action disruption or hesitation occurring immediately before making final actions. We evaluated the micro errors in short-term memory (STM) and long-term memory (LTM) of verbal learning tests (VLT).Results:Mann Whitney U tests revealed that the HIV+ group made significantly more micro errors on both STM (HIV+: 1.45±0.90 times, Healthy: 0.52±0.84 times) and LTM (HIV+: 1.85±0.73 times, Healthy: 1.29±0.71 times) than the healthy group (STM: W=1362, p< .001, Effect Size (EF)= .548; LTM: W=1199.5, p= .002, EF= .363). An independent samples T-test showed that the HAND group made significantly more micro errors than the non-HAND group (t=1.822, p= .038, ES= .595) on STM; moreover, the Asymptomatic Neurocognitive Impairment (ANI) group made significantly more micro errors than the healthy group (W=446, p< .001, ES= .689). On LTM, no significant micro error differences between HAND and non-HAND (W=184.5, p= .539, ES= -.189) nor between ANI and healthy group (W=327.5, p= .103, ES= .241) were found.Conclusions:The present study suggests that a novel behavioral measure, micro errors, may be able to help detect even the mildest form of HAND, ANI. Given that the touch-panel HAND screening battery consists of NP and IADL tests, it is important to evaluate micro errors on these various measures. Additionally, the touch-panel screening battery requires minimal administrative staff involvement, which could be beneficial for busy HIV clinicians.

Neurological, Behavioral, and Pathophysiological Characterization of the Co-Occurrence of Substance Use and HIV: A Narrative Review.

Combined antiretroviral therapy (cART) has greatly reduced the severity of HIV-associated neurocognitive disorders in people living with HIV (PLWH); however, PLWH are more likely than the general population to use drugs and suffer from substance use disorders (SUDs) and to exhibit risky behaviors that promote HIV transmission and other infections. Dopamine-boosting psychostimulants such as cocaine and methamphetamine are some of the most widely used substances among PLWH. Chronic use of these substances disrupts brain function, structure, and cognition. PLWH with SUD have poor health outcomes driven by complex interactions between biological, neurocognitive, and social factors. Here we review the effects of comorbid HIV and psychostimulant use disorders by discussing the distinct and common effects of HIV and chronic cocaine and methamphetamine use on behavioral and neurological impairments using evidence from rodent models of HIV-associated neurocognitive impairments (Tat or gp120 protein expression) and clinical studies. We also provide a biopsychosocial perspective by discussing behavioral impairment in differentially impacted social groups and proposing interventions at both patient and population levels.

Blood and cerebrospinal fluid biomarker changes in patients with HIV-associated neurocognitive impairment treated with lithium: analysis from a randomised placebo-controlled trial

HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain–derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-β). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 + lymphocyte activation (CD38 + HLADR +). Alzheimer’s Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/β), Aβ38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (± 8.35) years and the median CD4 + T-cell count was 498 (IQR: 389–651) cells/μL. Biomarker concentrations between groups did not differ at baseline. However, both groups’ blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.

Neurocognitive outcomes in indonesians living with HIV are influenced by polymorphisms in the gene encoding purinergic P2X receptor 7

The advent of effective antiretroviral therapy (ART) has decreased the prevalence and severity of HIV-associated neurocognitive disorders (HAND), but milder forms of HAND remain despite optimal treatment. Neuronal injury and loss due to inflammation may mediate HAND. P2X7R encodes purinergic P2X receptor 7 which influences neuroinflammatory pathways and carries polymorphisms associated with sensory neuropathy in HIV patients. We assessed associations between P2X7R polymorphisms and neurocognitive outcomes in Indonesian patients (n ​= ​59) as they commenced ART and after 3, 6 and 12 months. Z-scores were calculated over 5 domains using local controls and evaluated as continuous variables. Optimal linear regression models identified polymorphisms influencing attention, memory, executive function, motor speed and total cognitive function at each time point. rs504677 was associated with lower executive and motor speed Z-scores at 0, 3, 6, and 12 months, and with memory at 0 and 12 months. Memory was positively influenced by carriage of the rs208296 minor allele at 0, 3 and 6 months and by carriage of the rs208307 minor allele at 0 and 12 months. Higher attention Z-scores associated with carriage of minor alleles of rs1653598 after 0 and 12 months. These also positively influenced executive function and motor speed after 0–6 months. This study identifies polymorphisms in P2X7R which influence domain-specific neurocognitive outcomes in HIV+ ​Indonesians prior to and shortly after commencing ART. This implicates purinergic P2X receptor 7 in the pathogenesis of HAND.

HIV-associated neurocognitive disorders at Moi teaching and referral hospital, Eldoret, Kenya

BackgroundHuman Immunodeficiency Virus (HIV) infection causes a myriad of neurological complications including cognitive deficits referred to as HIV-Associated Neurocognitive Disorders (HAND). With the introduction of combination antiretroviral therapy, there has been an epidemiological shift in cognitive disorders with a decline in the more severe HIV-Associated Dementia (HAD) to an increase in the less severe HAND: Asymptomatic Neurocognitive Impairment (ANI) and HIV-associated Mild Neurocognitive Disorder (MND). Central Nervous System (CNS) involvement in HIV interferes with cognitively demanding activities of daily living and hence a worse quality of life. Early diagnosis is delayed until symptoms are overt.MethodsWe conducted a cross sectional analytical study of HIV infected persons on antiretroviral therapy attending HIV clinic. A systematic random sampling was done to select 360 patients. An interviewer administered structured questionnaire was used to collect socio-demographic data while the CD4 count and viral load were retrieved from the Academic Model Providing Access to Healthcare (AMPATH) database. Pearson’s Chi Square test was used to compare proportions while independent sample t- test was used to compare continuous variables between the patients diagnosed with HAND and those without HAND. Logistic regression model was used to assess the factors associated with HAND.ResultsThe mean age of the study participants was 40.2 years. The overall prevalence of HAND was (81.1%) N = 292. Mild HAND (ANI and MND) was present (78.6%) N = 283, Severe HAND (HAD) (2.5%) N = 9. The factors associated with HAND were older age OR: 1.06 (95% CI: 1.03, 1.10), male gender OR: 0.48 (95% CI: 0.24, 0.97), Advanced WHO clinical staging OR: 2.45 (95% CI: 1.20, 5.01) and a higher level of education; secondary/tertiary OR: 0.16 (95% CI: 0.07, 0.38); 0.11 (95% CI: 0.04, 0.35).ConclusionThe prevalence of HAND in this study population was found to be high (81.1%). Older age and advanced WHO clinical staging were associated with an increased risk of hand while higher level of education and male gender were protective.

Blood-based inflammation biomarkers of neurocognitive impairment in people living with HIV.

Inflammation in people living with HIV (PLWH) correlates with severity of HIV-associated neurocognitive disorders. The objective of this study is to identify blood-based markers of neurocognitive function in a demographic balanced cohort of PLWH. Seven neurocognitive domains were evaluated in 121 seropositive Black/African American, Non-Hispanic White, and White Hispanic men and women using computerized assessments. Associations among standardized neurocognitive function and HIV-related parameters, relevant sociodemographic variables, and inflammation-associated cytokines measured in plasma and cellular supernatants were examined using multivariate and univariate regression models. Outlier and covariate analyses were used to identify and normalize for education level, CD4 T cell count, viral load, CNS and drug abuse comorbidities, which could influence biomarker and neurocognitive function associations. Plasma levels of chemokine (C-C motif) ligand (CCL) 8 significantly associated with memory, complex attention, cognitive flexibility, psychomotor speed, executive function, and processing speed. Plasma tissue inhibitor of metalloproteinases 1 associated with the aforementioned domains except memory and processing speed. In addition, plasma interleukin-23 significantly associated with processing speed and executive function. Analysis of peripheral blood cell culture supernatants revealed no significant markers for neurocognitive function. In this cohort, CD4 T cell count and education level also significantly associated with neurocognitive function. All identified inflammatory biomarkers demonstrated a negative correlation to neurocognitive function. These cytokines have known connections to HIV pathophysiology and are potential biomarkers for neurocognitive function in PLWH with promising clinical applications.

Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection.

Previously, we found that high levels of soluble insulin receptor (sIR) in the cerebrospinal fluid (CSF) of an HIV-infected women cohort were associated with the presence and severity of HIV-associated neurocognitive disorders (HAND). In this study we investigated if CSF from this population, HIV-1 Tat, and selected cytokines induces sIR secretion from human neuronal cells. Twenty-three (23) HIV-seropositive women stratified by cognitive status and five HIV- seronegative women were evaluated. Soluble IR levels were measured in the extracellular medium of neuronal cells (SH-SY5Y) that were exposed (for 24 h) to the CSF of patients. The levels of sIR, HIV-1 Tat, and cytokine levels (IL-2, IL4, IL-6, IFNγ, TNFα, and IL-10) were quantified in the CSF of participants by ELISA and flow cytometry. Neuronal secretion of sIR was measured after exposure (24 h) to HIV-1 Tat (0.5–250 nM), or specific cytokines. The effects of TNFα and HIV-1 Tat on sIR secretion were also evaluated in the presence of R7050 (TNFα antagonist; 10 nM). Neurons exposed to the CSF of HIV-infected women had higher sIR levels according to the severity of neurocognitive impairment of the participant. Increased CSF sIR levels were associated with the presence and severity of HAND and were positively correlated with CSF HIV-1 Tat levels in HIV-infected women with cognitive impairment. CSF levels of IL-2, IFNγ, and TNFα were significantly increased with HAND. However, only TNFα (5 pg/mL) and HIV-1 Tat (100 nM) induced a significant increase in neuronal sIR secretion after 24 h exposure, an effect that was antagonized when each were combined with R7050. Our data suggests that TNFα and HIV-1 Tat from the CSF of HIV-infected women may regulate the secretion of sIR from neuronal cells and that the effect of HIV-1 Tat on sIR secretion may depend on TNFα receptor activation.

Genetic variation of MMP-2(-735 C>T) and MMP-9(-1562 C>T) gene in risk of development of HAND and severity of HAND.

Astrocytes are susceptible to HIV-1 infection. Neurocognitive dysfunction has also been associated with the toxicity of certain antiretroviral drugs. HIV-1 induced neurological toxicity has been associated with deficiency of matrix metalloproteinases. Therefore, we evaluated the association of MMP-2(-735C>T) and MMP-9(-1562C>T) polymorphisms with respect to the susceptibility of developing HIV-associated neurocognitive disorders (HAND) and its severity. We enrolled 50 HIV-infected individuals with HAND, 130 without HAND and 150 unrelated healthy controls. Polymorphism for MMP-2-735C>T and MMP-9-1562C>T genes was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Individuals with the MMP-2 -735 CT genotype and -735T allele were at higher risk of developing HAND [odds ratio (OR)=5.27, 95% confidence interval (CI)=1.30-21.35, p=0.02 and OR =2.27, 95% CI=1.57-3.27, p=0.0001 respectively]. The MMP-2 -735 CT genotype and -735T allele of MMP-2 were associated with a reduced likelihood of severe HAND (OR =0.32, 95% CI=0.15-0.66, p=0.002 and OR =0.32, 95% CI=0.14-0.71, p=0.005). When evaluating gene-gene interaction models, the combined genotype MMP-2-735TT+MMP-9-1562CC and MMP-2-735CT+MMP-9-1562CT was associated with the risk of developing HAND (OR =4.84, p=0.0001, OR =1.81, p=0.03). However, individuals with the combined genotype of MMP-2-735TT+MMP-9-1562CC were found to be protective for severe HAND (OR =0.30, 95% CI=0.13-0.67, p=0.003). Individuals with the MMP-2 -735CT genotype, -735T allele and combined genotype MMP-2 -735TT+MMP-9 -1562CC had an enhanced risk of developing HAND. Those with the MMP-2 -735 CT genotype, -735T allele and combined genotype of MMP-2-735TT+MMP-9-1562CC were suggested to have protection from developing severe HAND.

Neural correlates of working memory training in HIV patients: study protocol for a randomized controlled trial.

BackgroundPotent combined antiretroviral therapy decreased the incidence and severity of HIV-associated neurocognitive disorders (HAND); however, no specific effective pharmacotherapy exists for HAND. Patients with HIV commonly have deficits in working memory and attention, which may negatively impact many other cognitive domains, leading to HAND. Since HAND may lead to loss of independence in activities of daily living and negative emotional well-being, and incur a high economic burden, effective treatments for HAND are urgently needed. This study aims to determine whether adaptive working memory training might improve cognitive functions and neural network efficiency and possibly decrease neuroinflammation. This study also aims to assess whether subjects with the LMX1A-rs4657412 TT(AA) genotype show greater training effects from working memory training than TC(AG) or CC(GG)-carriers.Methods/Design60 HIV-infected and 60 seronegative control participants will be randomized to a double-blind active-controlled study, using adaptive versus non-adaptive Cogmed Working Memory Training® (CWMT), 20–25 sessions over 5–8 weeks. Each subject will be assessed with near- and far-transfer cognitive tasks, self-reported mood and executive function questionnaires, and blood-oxygenation level-dependent functional MRI during working memory (n-back) and visual attention (ball tracking) tasks, at baseline, 1-month, and 6-months after CWMT. Furthermore, genotyping for LMX1A-rs4657412 will be performed to identify whether subjects with the TT(AA)-genotype show greater gain or neural efficiency after CWMT than those with other genotypes. Lastly, cerebrospinal fluid will be obtained before and after CWMT to explore changes in levels of inflammatory proteins (cytokines and chemokines) and monoamines.DiscussionImproving working memory in HIV patients, using CWMT, might slow the progression or delay the onset of HAND. Observation of decreased brain activation or normalized neural networks, using fMRI, after CWMT would lead to a better understanding of how neural networks are modulated by CWMT. Moreover, validating the greater training gain in subjects with the LMX1A-TT(AA) genotype could lead to a personalized approach for future working memory training studies. Demonstrating and understanding the neural correlates of the efficacy of CWMT in HIV patients could lead to a safe adjunctive therapy for HAND, and possibly other brain disorders.Trial registrationClinicalTrial.gov, NCT02602418.

Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice

The mechanisms leading to the neurocognitive deficits in humans with immunodeficiency virus type 1 (HIV-1) are not well resolved. A number of cell culture models have demonstrated that the HIV-envelope glycoprotein 120 (gp120) decreases the reuptake of glutamate, which is necessary for learning, memory, and synaptic plasticity. However, the impact of brain HIV-1 gp120 on glutamate uptake systems in vivo remains unknown. Notably, alterations in brain glutamate uptake systems are implicated in a number of neurodegenerative and neurocognitive disorders. We characterized the kinetic properties of system XAG (sodium-dependent) and systems xc- (sodium-independent) [3H]-L-glutamate uptake in the striatum and hippocampus of HIV-1 gp120 transgenic mice, an established model of HIV neuropathology. We determined the kinetic constant Vmax (maximal velocity) and Km (affinity) of both systems XAG and xc- using subcellular preparations derived from neurons and glial cells. We show significant (30-35%) reductions in the Vmax of systems XAG and xc- in both neuronal and glial preparations derived from the striatum, but not from the hippocampus of gp120 mice relative to wild-type (WT) controls. Moreover, immunoblot analysis showed that the protein expression of glutamate transporter subtype-1 (GLT-1), the predominant brain glutamate transporter, was significantly reduced in the striatum but not in the hippocampus of gp120 mice. These extensive and region-specific deficits of glutamate uptake likely contribute to the development and/or severity of HIV-associated neurocognitive disorders. Understanding the role of striatal glutamate uptake systems in HIV-1 gp120 may advance the development of new therapeutic strategies to prevent neuronal damage and improve cognitive function in HIV patients.

Neuropathogenesis of HIV-associated neurocognitive disorders: roles for immune activation, HIV blipping and viral tropism.

The purpose of this study is to discuss why HIV-associated neurocognitive disorders (HAND) persist despite apparently effective HIV suppression by highly active antiretroviral therapy (ART). As many as 50% of HIV-infected individuals suffer from HAND despite ART suppression of HIV replication to apparently undetectable levels in most treated individuals. Prior to ART, HIV-associated dementia (HAD), the severest form of HAND, affected nearly 20% of infected individuals; HAD now affects only nearly 2% of ART-treated persons, although less severe HAND forms persist. Recent studies link persistent immune activation, inflammation and viral escape/blipping in ART-treated individuals, as well as comorbid conditions, to HIV disease progression and increased HAND risk. Despite sustained HIV suppression in most ART-treated individuals, indicated by routine plasma monitoring and occasional cerebrospinal fluid (CSF) monitoring, 'blips' of HIV replication are often detected with more frequent monitoring, thus challenging the concept of viral suppression. Although the causes of HIV blipping are unclear, CSF HIV blipping associates with neuroinflammation and, possibly, central nervous system (CNS) injury. The current theory that macrophage-tropic HIV strains within the CNS predominate in driving HAND and these associated factors is now also challenged. Protection of the CNS by ART is incomplete, probably due to combined effects of incomplete HIV suppression, persistent immune activation and host comorbidity factors. Adjunctive therapies to ART are necessary for more effective protection.

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes

Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10–15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH ± HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.

Designer Adiponectin Receptor Agonist Stabilizes Metabolic Function and Prevents Brain Injury Caused by HIV Protease Inhibitors

HIV protease inhibitors (PI) are fundamental to combination antiretroviral therapy, which has revolutionized HIV clinical care and produced significant reductions in HIV-associated morbidity and mortality. However, PI administration is frequently associated with severe metabolic impairment, including lipodystrophy, dyslipidemia, and insulin resistance; all of which can contribute to cardiovascular and neurologic co-morbidities. Experimental and epidemiological data support a potentially important role for the adipokine adiponectin in both metabolic and neurologic physiology. This study examined if ADP355, a novel, peptide-based adiponectin receptor agonist, could neutralize the detrimental effects of PI treatment in experimental animal models. Adult male C57BL/6 mice were subjected to a clinically relevant, 4-week regimen of lopinavir/ritonavir, with daily injections of ADP355 administered only during the final 2 weeks of PI exposure. Comprehensive metabolic, neurobehavioral, and biochemical analyses revealed that ADP355 administration partially reversed PI-induced loss of subcutaneous adipose tissue, attenuated PI-induced hyperinsulinemia, hypertriglyceridemia, and hypoadiponectinemia, and prevented PI-induced cognitive impairment and brain injury. Collectively, these data reinforce the link between metabolic co-morbidities and cognitive impairment and suggest that pharmacological reactivation of adiponectin pathways could remediate key aspects of PI-induced metabolic syndrome in clinical settings. Furthermore, therapeutic targeting of adiponectin receptors could show utility in reducing the prevalence and/or severity of HIV-associated neurocognitive disorders.

Effect of HIV clade differences on the onset and severity of HIV-associated neurocognitive disorders

The effects of evolutionary pressure on human immunodeficiency virus-1 (HIV) have resulted in a variety of clades and recombinants. The functional implications of HIV clades on disease onset and progression of HIV-associated neurocognitive disorders (HAND) have been suggested by clinical and basic science studies, which will be reviewed in detail. Some clinical studies suggest that patients infected with clade D show the greatest propensity for developing HIV-associated dementia (HAD) followed by clades B, C, and A, respectively. However, there are conflicting reports. This review summarizes clinical studies that have assessed behavioral abnormalities and HIV clade type in HAND patients, focusing on the clades stated above. The limitations include variations in testing used to define the cohorts, patient sample size, lack of HIV clade characterization, combination antiretroviral therapy (cART) availability, and other factors, which are highlighted and compared between clinical studies performed primarily in Africa and India. Basic science studies provide substantial evidence that HIV clade differences can result in varying degrees of neuropathology and are also reviewed in some detail. These studies indicate that there are a number of clade differences, most notably in Tat, that result in different degrees of neurovirulence or neuropathological effects in vitro and in a mouse model of HAND. In order to confirm the hypothesis that HIV clade differences are important determinants of HAND pathogenesis, larger, longitudinal studies that employ standard definitions of HAND and HIV clade testing must be performed. In a larger sense, HAND continues to be highly prevalent despite the advent of cART, and therefore, further studies into HAND pathogenesis are critical to develop better therapies.

CSF Penetration by Antiretroviral Drugs

Severe HIV-associated neurocognitive disorders (HAND), such as HIV-associated dementia, and opportunistic CNS infections are now rare complications of HIV infection due to comprehensive highly active antiretroviral therapy (HAART). By contrast, mild to moderate neurocognitive disorders remain prevalent, despite good viral control in peripheral compartments. HIV infection seems to provoke chronic CNS injury that may evade systemic HAART. Penetration of antiretroviral drugs across the blood-brain barrier might be crucial for the treatment of HAND. This review identifies and evaluates the available clinical evidence on CSF penetration properties of antiretroviral drugs, addressing methodological issues and discussing the clinical relevance of drug concentration assessment. Although a substantial number of studies examined CSF concentrations of antiretroviral drugs, there is a need for adequate, well designed trials to provide more valid drug distribution profiles. Neuropsychological benefits and neurotoxicity of potentially CNS-active drugs require further investigation before penetration characteristics will regularly influence therapeutic strategies and outcome.

Antiretroviral neurotoxicity

Combination antiretroviral therapy (CART) has proven to effectively suppress systemic HIV burden, however, poor penetration into the central nervous system (CNS) provides incomplete protection. Although the severity of HIV-associated neurocognitive disorders (HAND) has been reduced, neurological disease is expected to exert an increasing burden as HIV-infected patients live longer. Strategies to enhance penetration of antiretroviral compounds into the CNS could help to control HIV replication in this reservoir but also carries an increased risk of neurotoxicity. Efforts to target antiretroviral compounds to the CNS will have to balance these risks against the potential gain. Unfortunately, little information is available on the actions of antiretroviral compounds in the CNS, particularly at concentrations that provide effective virus suppression. The current studies evaluated the direct effects of 15 antiretroviral compounds on neurons to begin to provide basic neurotoxicity data that will serve as a foundation for the development of dosing and drug selection guidelines. Using sensitive indices of neural damage, we found a wide range of toxicities, with median toxic concentrations ranging from 2 to 10,000 ng/ml. Some toxic concentrations overlapped concentrations currently seen in the CSF but the level of toxicity was generally modest at clinically relevant concentrations. Highest neurotoxicities were associated with abacavir, efavarenz, etravirine, nevaripine, and atazanavir, while the lowest were with darunavir, emtracitabine, tenofovir, and maraviroc. No additive effects were seen with combinations used clinically. These data provide initial evidence useful for the development of treatment strategies that might reduce the risk of antiretroviral neurotoxicity.

HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy

This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups). The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Neuropsychological Functioning and Antiretroviral Treatment in HIV/AIDS: A Review

This article presents a review of studies that have investigated the neuropsychological effects of antiretroviral treatment (ART) for HIV-1 infection. It provides a brief overview of the era of monotherapy, dual-therapy, and an extended overview of the current era of combination antiretroviral therapy (CART). This review highlights that while CART has had a dramatic effect on the incidence and the severity of HIV-associated neurocognitive disorders (HAND), HAND, in its mild form, still remains prevalent. New causes of this sustained prevalence are poor CNS penetration of some antiretroviral agents, drug resistance, poor adherence, potential neurotoxicity, co-morbidities such as the long-term CART side effects in relation to cardio-vascular disease, and chronic HIV brain infection that may facilitate the expression of new forms of neurodegenerative processes. The review emphasizes the need to address methodological limitations of published studies and the need for large and representative cross-disciplinary longitudinal investigations across the HIV illness span.