Risk Of HIV-associated Neurocognitive Disorders Research Articles

NRF2 Antagonizes HIV-1 Tat and Methamphetamine-Induced BV2 Cell Ferroptosis by Regulating SLC7A11.

Methamphetamine (METH) and HIV-1 lead to oxidative stress and their combined effect increases the risk of HIV-associated neurocognitive disorder (HAND), which may be related to the synergistic ferroptotic impairment in microglia. Ferroptosis is a redox imbalance cell damage associated with iron overload that is linked to the pathogenic processes of METH and HIV-1. NRF2 is an antioxidant transcription factor that plays a protective role in METH and HIV-1-induced neurotoxicity, but its mechanism has not been fully elucidated. To explore the role of ferroptosis in METH abuse and HIV-1 infection and the potential role of NRF2 in this process, we conducted METH and HIV-1 Tat exposure models using the BV2 microglia cells. We found that METH and HIV-1 Tat reduced the expression of ferroptotic protein GPX4 and the cell viability and enhanced the expression of P53 and the level of ferrous iron, while the above indices were significantly improved with pretreatment of ferrostatin-1. In addition, NRF2 knockdown accelerated METH and HIV-1 Tat-induced BV2 cell ferroptosis accompanied by decreased expression of SLC7A11. On the contrary, NRF2 stimulation significantly increased the expression of SLC7A11 and attenuated ferroptosis in cells. In summary, our study indicates that METH and HIV-1 Tat synergistically cause BV2 cell ferroptosis, while NRF2 antagonizes BV2 cell ferroptotic damage induced by METH and HIV-1 Tat through regulation of SLC7A11. Overall, this study provides potential therapeutic strategies for the treatment of neurotoxicity caused by METH and HIV-1 Tat, providing a theoretical basis and new targets for the treatment of HIV-infected drug abusers.

Contributions of chronic tobacco smoking to HIV-associated brain atrophy and cognitive deficits.

Tobacco smoking is linked to cognitive deficits and greater white matter (WM) abnormalities in people with HIV disease (PWH). Whether tobacco smoking additionally contributes to brain atrophy in PWH is unknown and was evaluated in this study. We used a 2 × 2 design that included 83 PWH (43 nonsmokers, 40 smokers) and 171 HIV-seronegative (SN, 106 nonsmokers, 65 smokers) participants and assessed their brain structure and cognitive function. Selected subcortical volumes, voxel-wise cortical volumes and thickness, and total WM volume were analyzed using FreeSurfer. Independent and interactive effects of HIV and smoking were evaluated with two-way analysis of covariance on cognitive domain Z-scores and morphometric measures on T1-weighted MRI. Regardless of smoking status, relative to SN, PWH had smaller brain volumes [basal ganglia, thalami, hippocampi, subcortical gray matter (GM) and cerebral WM volumes (P = 0.002-0.042)], steeper age-related declines in the right superior-parietal (interaction: P < 0.001) volumes, and poorer attention/working memory and learning (P = 0.016-0.027). Regardless of HIV serostatus, smokers tended to have smaller hippocampi than nonsmokers (-0.6%, P = 0.055). PWH smokers had the smallest total and regional subcortical GM and cortical WM volume and poorest cognitive performance. Tobacco smoking additionally contributed to brain atrophy and cognitive deficits in PWH. The greater brain atrophy in PWH smokers may be due to greater neuronal damage or myelin loss in various brain regions, leading to their poor cognitive performance. Therefore, tobacco smoking may exacerbate or increase the risk for HIV-associated neurocognitive disorders.

Methamphetamine and HIV-Tat Protein Synergistically Induce Oxidative Stress and Blood-Brain Barrier Damage via Transient Receptor Potential Melastatin 2 Channel.

Synergistic impairment of the blood-brain barrier (BBB) induced by methamphetamine (METH) and HIV-Tat protein increases the risk of HIV-associated neurocognitive disorders (HAND) in HIV-positive METH abusers. Studies have shown that oxidative stress plays a vital role in METH- and HIV-Tat-induced damage to the BBB but have not clarified the mechanism. This study uses the human brain microvascular endothelial cell line hCMEC/D3 and tree shrews to investigate whether the transient receptor potential melastatin 2 (TRPM2) channel, a cellular effector of the oxidative stress, might regulate synergistic damage to the BBB caused by METH and HIV-Tat. We showed that METH and HIV-Tat damaged the BBB in vitro, producing abnormal cell morphology, increased apoptosis, reduced protein expression of the tight junctions (TJ) including Junctional adhesion molecule A (JAMA) and Occludin, and a junctional associated protein Zonula occludens 1 (ZO1), and increased the flux of sodium fluorescein (NaF) across the hCMEC/D3 cells monolayer. METH and HIV-Tat co-induced the oxidative stress response, reducing catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) activity, as well as increased reactive oxygen species (ROS) and malonaldehyde (MDA) level. Pretreatment with n-acetylcysteine amide (NACA) alleviated the oxidative stress response and BBB damage characterized by improving cell morphology, viability, apoptosis levels, TJ protein expression levels, and NaF flux. METH and HIV-Tat co-induced the activation and high protein expression of the TRPM2 channel, however, early intervention using 8-Bromoadenosine-5′-O-diphosphoribose (8-Br-ADPR), an inhibitor of TPRM2 channel, or TRPM2 gene knockdown attenuated the BBB damage. Oxidative stress inhibition reduced the activation and high protein expression of the TRPM2 channel in the in vitro model, which in turn reduced the oxidative stress response. Further, 8-Br-ADPR attenuated the effects of METH and HIV-Tat on the BBB in tree shrews—namely, down-regulated TJ protein expression and increased BBB permeability to Evans blue (EB) and NaF. In summary, the TRPM2 channel can regulate METH- and HIV-Tat-induced oxidative stress and BBB injury, giving the channel potential for developing drug interventions to reduce BBB injury and neuropsychiatric symptoms in HIV-infected METH abusers.

Brief Report: Frailty and HIV Disease Severity Synergistically Increase Risk of HIV-Associated Neurocognitive Disorders.

Frailty disproportionally affects people with HIV (PWH) and increased frailty in this already vulnerable population is associated with worse neurocognitive functioning. Whether frailty interacts with current and modifiable markers of HIV disease severity to synergistically increase risk for HIV-associated neurocognitive disorders (HAND), however, is unknown and important for informing the clinical care of aging PWH. UC San Diego's HIV Neurobehavioral Research Program. Participants were 178 PWH evaluated between 2014 and 2019. HIV disease severity was measured by current CD4 count and plasma HIV RNA. HAND diagnoses were made according to the Frascati criteria using a 7-domain neuropsychological battery, and the Fried phenotype criteria were used to assess frailty syndrome (0-5 symptoms). The independent and interactive effects of frailty and current HIV disease severity (ie, CD4 count and plasma HIV RNA) on HAND were examined using multiple logistic regressions. There was an interaction between CD4 count and frailty on HAND. Simple slopes showed that CD4 count and the likelihood of HAND were negatively associated at >1.25 symptoms of frailty, and conversely, frailty and HAND were negatively associated at 642 or less cells/mm. There were no significant independent or interactive effects of plasma HIV RNA and frailty on the likelihood of HAND. In addition to monitoring CD4 count, assessing for frailty may be critical in older adults with HIV to potentially mitigate poor neurobehavioral outcomes. Longitudinal follow-up studies are needed to determine the directionality of these findings.

Incidental Findings on Brain MRI in People with HIV Infection

Background: Incidental findings are a well-known complication of imaging studies done for both diagnostic and research purposes. Little is known about the rates and types of incidental findings found on brain MRI in patients with HIV infection, who may be at risk for HIV-Associated Neurocognitive Disorders (HAND). Methods: The parent study included 108 adults with HIV infection and 125 demographically-matched uninfected controls who completed MRI and neuropsychological testing. Incidental findings were classified by the study team as vascular, neoplastic, congenital, other neurologic, or non-neurologic. Categorical measures were compared using Pearson chi-square tests; continuous measures were compared using t-tests. Results: Among participants with HIV infection, 36/108 (33%) had incidental findings compared to 33/125 (26%) controls (p = 0.248). Rates of incidental findings were significantly correlated with increasing age in both participants with HIV infection (p = 0.013) and controls (p = 0.022). We found no correlation between presence of incidental findings and sex or race/ethnicity among either cohort, and no correlation with CD4 count or HAND status for the HIV-infected cohort. Conclusions: Incidental findings were common in both participants with HIV infection and controls, at higher rates than previously reported in healthy populations. There was no significant difference in prevalence between the groups.

HIV-Associated Neurocognitive Disorder (HAND): Relative Risk Factors.

This chapter will address the issue of risk for HIV-associated neurocognitive disorder (HAND), focusing on HIV-associated dementia (HAD), among persons living with HIV in relationship to the risk for other dementias. Advances in effective antiretroviral therapy (ART) have led to an increase in the prevalence of older persons surviving with HIV - in addition to older persons who become infected by HIV later in life. Hence, HIV is no longer a disease of younger persons, and additional attention has been brought to bear against the plight of older persons living with HIV - not only as it pertains to treatment but also to prevention. The additional risk caused by aging among older persons living with HIV is complex to asses, and HIV infection is a research area that requires a robust approach to multiple other factors causing neurocognitive impairment with older age. The long-term and potentially neurotoxic exposure to ART and the deleterious consequences of chronic infection with HIV and its associated neuro-inflammation have been described for health. This aids in the understanding of dementia risk factors in this patient population, but the comorbidities (HIV- and non-HIV-associated) occurring among older persons living with HIV must also be addressed to properly assess the overall impact on dementia risk in this group. This need also warrants our examination of the risk factors for other dementias (and comorbid dementias) in persons living with HIV versus the general population through the assessment and quantification of modifiable and non-modifiable risk factors identified as major contributors toward dementia.

B-07 Benzodiazepine Use Is Associated with an Increased Risk for HIV-Associated Neurocognitive Disorders

Abstract Objective Despite potential for dependence and adverse neurological effects, long-term benzodiazepine (BDZ) use is common among persons living with HIV (PLWH). As PLWH are at risk for CNS dysfunction, we retrospectively examined the association between BDZ use and HIV-associated neurocognitive disorders (HAND). Methods 306 PLWH (mean age = 45.1 years) underwent comprehensive neurobehavioral evaluations. Current BDZ use (BDZ+) was determined via self-report. Using propensity scores, 153 BDZ- individuals were matched to 153 BDZ+ participants on demographics, HIV disease characteristics, and comorbidities. Multiple regression models examined HAND and demographically-adjusted neurocognitive T-scores as a function of BDZ group, adjusting for estimated premorbid ability, current affective symptoms, and nadir CD4 count. Secondary analyses explored neurocognitive correlates of positive BDZ urine toxicology screens (TOX+). Results Median BDZ use was 24 months. Compared to BDZ-, BDZ+ had higher likelihood of HAND (OR = 2.14; p = .003) and poorer global (d = -0.33, p = .005), processing speed (d = -0.29, p = .013), and motor T-scores (d = -0.35, p = 0.003). Compared to BDZ+/TOX-, BDZ+/TOX+ users exhibited additional decrements in global (p = .033), executive function (p = .019), and delayed recall T-scores (p = .006). Conclusions BDZ use may elevate risk for HAND, potentially through diffuse neurocognitive slowing and acute compromise of recall and higher-order capacities. These effects are robust to psychosocial and HIV-specific factors and occur in comparison to a tightly-matched BDZ- group. Indications for BDZs (e.g., insomnia) may also impact neurocognition and/or manifest from latent neuropathology. Longitudinal studies should evaluate potential causal associations between HAND and BDZs. Given the extent of BDZ use and possibility of neurocognitive recovery post-abstinence, interventional studies should explore treatment alternatives to BDZs in PLWH.

Tissue Inhibitor of Metalloproteinase-2 Polymorphisms and Risk for HIV-Associated Neurocognitive Disorder.

The imbalance between MMPs and TIMPs is associated with the HIV dissemination tissue damage pathology neurodegenerative disorders, including HAND. Genetic variations in the TIMP gene may modulate the neurocognitive disorder in HIV patients. Hence, we evaluated the genetic variants of TIMP-2 (-418G/C, 303G/A) gene with the risk of HAND. Genotyping of TIMP-2 polymorphism was performed in 50 patients with HAND, 100 no HAND, and 154 healthy controls by PCR-RFLP. TIMP-2 -418GC and 303AA genotypes represented a predominant risk for HAND severity (OR = 1.55, P = 0.30; OR = 4.58, P = 0.24). The variant -418CC genotype, -418A allele, had exhibited a significant risk for the acquisition of HAND (OR = 12.55, P = 0.026; OR = 2.66, P = 0.004). TIMP-2 303GA, 303AA genotype, and 303A allele evinced a higher risk for HAND severity (OR = 1.82, P = 0.14; OR = 1.70, P = 0.63; and OR = 1.68, P = 0.12). In HIV patients, TIMP-2 -418CC genotype and -418C allele significantly occurred in comparison to healthy controls (OR = 10.10, P = 0.006; OR = 2.02, P = 0.009). In the intermediate and early HIV disease stage, TIMP-2 -418CC genotype was significantly increased compared with healthy controls (11.1% vs. 1.3%, OR = 14.63, P = 0.01; 16.9% vs. 1.3%, OR = 14.51, P = 0.002). In patients with HAND among tobacco and alcohol users, TIMP-2 -418CC genotype displayed a risk for HAND severity (OR = 3.96, P = 0.26; OR = 4.83, P = 0.19). On multivariate logistic regression, TIMP-2 303AA genotype, advanced stage, and gender had a risk for HAND severity (OR = 28.98, P = 0.02; OR = 2.35, P = 0.070; and OR = 2.36, P = 0.04). In conclusion, TIMP-2 -418G/C polymorphism independently, along with alcohol and tobacco, may have an impact on the acquisition of HAND and its severity. TIMP-2 303G/A polymorphism bare a risk for HAND severity.

Short Communication: A Quantitative System for Monitoring Blood-Circulating Viral Protein R of Human Immunodeficiency Virus-1 Detected a Possible Link with Pathogenic Indices

We developed a detergent-free enzyme-linked immunosorbent assay (ELISA) for HIV-1 viral protein R (Vpr), an accessory protein of human immunodeficiency virus type-1 (HIV), and detected soluble Vpr in ∼22% of HIV patients who were receiving combination antiretroviral therapy and were free of plasma HIV RNA. Notably, the levels of CD8-positive cell count, soluble intercellular adhesion molecule-1 (sICAM-1), and C-C motif chemokine ligand 2 (CCL2), all of which are markers of chronic inflammation in HIV patients, were higher in Vpr-positive patients than in Vpr-negative patients. Because sICAM1 and CCL2 are associated with an increased risk of HIV-associated neurocognitive disorder, we propose that an established Vpr-ELISA would be useful for monitoring the risk of HIV complications during latent HIV infection.

Screening for HIV-associated neurocognitive disorders in perinatally infected adolescents: youth-International HIV Dementia Scale validation.

Perinatal HIV infection has adverse cognitive consequences into adolescence. However, there are no screening tools that assess risk for HIV-associated neurocognitive disorders in adolescent populations. Such screening tools are needed urgently for clinical care in resource-poor settings with a high prevalence of HIV. To investigate the performance of the International HIV Dementia Scale (IHDS) as a screening tool for HIV-associated neurocognitive disorders in perinatally adolescents. The current study is a quantitative, quasiexperimental design. Perinatally HIV-infected adolescents aged 9-12 years were recruited from community health clinics into the Cape Town Adolescent Antiretroviral Cohort; matched HIV-negative controls from the same communities were enrolled. Each participant completed the IHDS and a comprehensive neuropsychological battery. The adult version of the IHDS was performed, except for two minor modifications. We evaluated the diagnostic validity of this modified instrument, the youth-IHDS (y-IHDS), using a four-step process that included sensitivity and specificity calculations, and generating receiver operating characteristic curves. Validity was measured against the youth HIV-associated diagnostic criteria. At a cut-off score of 10 or less, the y-IHDS demonstrated good sensitivity (94%) but poor specificity (24%) for detecting all forms of neurocognitive disorders, with an acceptable area under the curve value of 0.695. The y-IHDS requires minimal resources and is based on a screening tool for adult HIV-associated cognitive disorders that is already widely used globally. Hence, this brief, cost-efficient, and valid screening tool may be a useful addition for clinicians working in resource-poor contexts in which adolescent HIV is highly prevalent.

Assessing Risk of HIV-Associated Neurocognitive Disorder.

People with HIV (PLHIV) are aging, and 20% are at risk of developing a neurological complication known as HIV-associated neurocognitive disorder (HAND). Signs and symptoms of HAND may be subtle; however, treatment can improve clinical outcomes. The aim of the study was to identify and agree on a risk assessment and monitoring process for the regular review of patients at risk of HAND. Between March and September 2017, 25 experts from four community healthcare services participated in three rounds of a modified Delphi study to reach consensus on the items, monitoring period, and format of assessment tools to identify risk of HAND in PLHIV in the community. More than 80% consensus was reached at all three Delphi rounds. A flow chart, an initial assessment, and an annual monitoring tool were developed for an ongoing assessment of risk of developing HAND. Twenty percent of PLHIV may develop HAND, a treatable condition. The use of a modified Delphi method led to the successful development of two risk assessment tools to identify those at risk of HAND. The initial assessment tool may be used as a precursor to formal assessment by medical and nursing staff, whereas the annual monitoring tool may assist community-based health professionals in their ongoing assessment of risk of HAND in PLHIV, facilitating early formal medical review for this condition.

Protective Effects of Ginsenoside Rb1 against Blood-Brain Barrier Damage Induced by Human Immunodeficiency Virus-1 Tat Protein and Methamphetamine in Sprague-Dawley Rats.

Although antiretroviral therapy has helped to improve the lives of individuals infected with human immunodeficiency virus 1 (HIV-1), these patients are often still afflicted with HIV-1-associated neurocognitive disorders, which can lead to neurocognitive impairment and even dementia, and continue to hamper their quality of life. Methamphetamine abuse in HIV-1 patients poses a potential risk for HIV-associated neurocognitive disorders, because methamphetamine and HIV-1 proteins such as transactivator of transcription can synergistically damage the blood-brain barrier (BBB). In this study, we aimed to examine the effects of methamphetamine and HIV-1 Tat protein on the blood-brain barrier function and to determine whether ginsenoside Rb1 (GsRb1) plays a role in protecting the BBB. Sprague-Dawley rats were divided into four groups. The experimental groups received methamphetamine and HIV-1 Tat protein or both and the control group received saline or GsRb1 pretreatment. Oxidative stress-related factors, tight junction (TJ) proteins, blood-brain barrier permeability, and morphological changes were recorded in each group. The results showed that the group treated with Methamphetamine[Formula: see text]Tat showed a significant change at the ultrastructural level and in the levels of oxidative stress-related factors, TJ proteins, and BBB permeability, suggesting that the BBB function was severely damaged by HIV-1 Tat and methamphetamine synergistically. However, malondialdehyde levels and BBB permeability were lower and the oxidative stress-related factors superoxide dismutase and glutathione were higher in the GsRb1-treated group than in the Methamphetamine[Formula: see text]Tat-treated group, indicating that GsRb1 can protect the BBB against the toxic effects of HIV-1 Tat and methamphetamine. These results show that GsRb1 may offer a potential therapeutic option for patients with HIV-associated neurocognitive disorders or other neurodegenerative diseases.

Screening HIV-associated neurocognitive disorders (HAND) among HIV positive patients attending antiretroviral therapy in South Wollo, Ethiopia

BackgroundThe vast majority of people living with HIV/AIDS reside in low and middle income countries, particularly in Sub-Saharan Africa, including Ethiopia. Despite the huge number of service users in the local area, cognitive disorder among HIV patients has not been extensively studied and there is a dearth of knowledge on the subject. The objective of this study was to assess the prevalence and associated factors of HIV-associated neurocognitive disorder among people living with HIV/AIDS in antiretroviral therapy (ART) clinics. MethodsInstitution based cross sectional study was conducted from April to May, 2015 at Dessie Referral Hospital & Kombolcha Health Center. International HIV Dementia Scale was used to screen HIV associated neurocognitive deficits. Logistic regression analysis was used to assess predictors of neurocognitive disorders. ResultThe risk of HIV associated neurocognitive disorder was 36.4%. Those who had CD4 count of 500 cells/dl or less (AOR = 2.368 (1.524, 3.680)), no formal education (AOR = 4.287 (2.619, 7.016)), poor medication adherence (AOR = 1.487 (1.010, 2.180)) and older age (AOR = 3.309 (1.259, 8.701)) were found to be significantly associated with HIV associated neurocognitive disorders. ConclusionThe risk of HIV-associated neurocognitive disorder was found to be high among people living with HIV/AIDS. This emphasizes the need of regular cognitive screening for early identification and appropriate intervention.

Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders

This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.

Cognitive Performance Related to HIV-1-Infected Monocytes

The effect that HIV type 1 (HIV) has on neurocognition is a dynamic process whereby peripheral events are likely involved in setting the stage for clinical findings. In spite of antiretroviral therapy (ART), patients continue to be at risk for HIV-associated neurocognitive disorders (HAND), which might be related to persistence of inflammation. In a yearly assessment of HIV DNA levels in activated monocytes, increased HIV DNA copies were found in patients with persistent HAND. Furthermore, activated monocytes from patients with high HIV DNA copies secreted more inflammatory cytokines. Since these activated monocytes traffic to the CNS and enter the brain, they may contribute to an inflammatory environment in the CNS that leads to HAND.

Intraindividual variability in HIV infection: Evidence for greater neurocognitive dispersion in older HIV seropositive adults.

Both the prevalence and incidence of HIV infection among older adults are on the rise. Older adults are at increased risk of HIV-associated neurocognitive disorders, which have historically been characterized as an inconsistent or "spotty" pattern of deficits. Dispersion is a form of intraindividual variability (IIV) that is defined as within-person variability in performance across domains and has been associated with poorer neurocognitive functioning and incipient decline among healthy older adults. To our knowledge, no studies have yet examined dispersion in an aging HIV-infected sample. For the current study we examined the hypothesis that age and HIV infection have synergistic effects on dispersion across a battery of clinical and experimental cognitive tasks. Our well-characterized sample comprised 126 HIV-seropositive individuals (HIV+) and 40 HIV-seronegative comparison individuals (HIV-), all of whom were administered a comprehensive neuropsychological battery. Consistent with our hypothesis, an age by HIV serostatus interaction was observed, with the older HIV+ group demonstrating a higher level of dispersion relative to older HIV- and younger HIV+ individuals, even when potentially confounding demographic and medical factors were controlled. Our results demonstrate that older HIV+ adults produce greater dispersion, or intraindividual variability in performance across a range of tests, which may be reflective of cognitive dyscontrol to which this population is vulnerable, perhaps driven by the combined effects of aging and HIV infection on prefrontostriatal systems.

Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF). Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV. Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.

Spontaneous strategy use protects against visual working memory deficits in older adults infected with HIV.

Recent studies suggest that older human immunodeficiency virus (HIV)-infected adults are at particular risk for HIV-associated neurocognitive disorders (HAND), including dementia. Deficits in attention/working memory are posited to play a central role in the development of HAND among older adults. The aim of the present study was to examine the possible protective benefits of spontaneous strategy use during a visual working memory task in 46 older and 42 younger adults infected with HIV. Results revealed a significant interaction between age and strategy use, with older adults who used a meta-cognitive strategy demonstrating superior working memory performance versus non-strategy users. This effect was not observed in the younger HIV-infected sample and was not better explained by possible confounding factors, such as education, comorbid medical conditions, or HIV disease severity. Within the older group, strategy use was associated with better executive functions and higher estimated verbal intelligence. Findings from this study suggest that working memory declines in older HIV-infected adults are moderated by the use of higher-level mnemonic strategies and may inform cognitive neurorehabilitation efforts to improve cognitive and everyday functioning outcomes in older persons living with HIV infection.

Lopinavir with Ritonavir Reduces the HIV RNA Level in Cerebrospinal Fluid

Background. Combination antiretroviral (ARV) therapy can reduce human immunodeficiency virus (HIV) RNA levels in cerebrospinal fluid (CSF) and plasma and improve immunocompetence. However, HIV-associated neurocognitive disorders persist, possibly because some ARV drugs do not reach therapeutic concentrations in the brain. The primary objective of this study was to determine whether lopinavir plus ritonavir (LPV-rtv) used alone reduced the HIV RNA level in CSF. Methods. The study was an open-label, 24-week trial of sequential ARV therapy. Fifteen subjects were enrolled and received LPV-rtv therapy. Ten subjects reached the primary study end point at week 3, before at least 2 other ARV drugs were added to the treatment regimen. CSF and blood samples were obtained before treatment and after 3, 12, and 24 weeks of treatment. Results. LPV-rtv therapy alone reduced the HIV RNA level in CSF in all subjects (median change in HIV RNA level, -1.42 log 10 copies/mL), including 5 who had slower decreases in HIV RNA level in CSF than in plasma-an indicator of autonomous central nervous system infection. Among 9 subjects who completed 12 weeks of LPV-rtv-containing therapy, the HIV RNA level was below quantitation in the CSF samples from 8 subjects and in the plasma samples from 6 subjects. By week 24, HIV RNA levels were below quantitation in samples of both fluids from all 8 subjects. Conclusions. LPV-rtv therapy alone for 3 weeks consistently reduces the HIV RNA level in CSF by at least 10-fold in most individuals, including those likely to have autonomous HIV replication in the central nervous system. Because it penetrates the central nervous system in therapeutic concentrations and appears to reduce HIV replication in the central nervous system, LPV-rtv may benefit subjects who receive a diagnosis of or are at risk for HIV-associated neurocognitive disorders.