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Benzodiazepine use is linked to neurocognitive impairment (NCI) in the general population and people with HIV (PWH); however, this relationship may depend on age-related factors such as medical comorbidities, which occur at an elevated rate and manifest earlier in PWH. We retrospectively examined whether chronological age or medical burden, a clinical marker for aging, moderated the relationship between benzodiazepine use and NCI in PWH. Participants were 435 PWH on antiretroviral therapy who underwent neurocognitive and medical evaluations, including self-reported current benzodiazepine use. A medical burden index score (proportion of accumulated multisystem deficits) was calculated from 28 medical deficits. Demographically corrected cognitive deficit scores from 15 neuropsychological tests were used to calculate global and domain-specific NCI based on established cut-offs. Logistic regressions separately modeled global and domain-specific NCI as a function of benzodiazepine x age and benzodiazepine x medical burden interactions, adjusting for current affective symptoms and HIV disease characteristics. A statistically significant benzodiazepine x medical burden interaction (p = .006) revealed that current benzodiazepine use increased odds of global NCI only among those who had a high medical burden (index score > 0.3 as indicated by the Johnson-Neyman analysis), which was driven by the domains of processing speed, motor, and verbal fluency. No age x benzodiazepine interactive effects on NCI were present. Findings suggest that the relationship between BZD use and NCI among PWH is specific to those with greater medical burden, which may be a greater risk factor for BZD-related NCI than chronological age., (© 2022. The Author(s).)

We evaluated the impact of latent toxoplasmosis (LT) on neurocognitive (NC) and neurobehavioural functioning in young adults with and without chronic HIV infection, using a standardised NC test battery, self-reported Beck Depression Inventory, Frontal System Behavior Scale, MINI-International Neuropsychiatric Interview and risk-assessment battery. 194 young adults (median age 24years, 48.2% males) with chronic HIV infection (HIV+) since childhood and 51 HIV seronegative (HIV-) participants were included. HIV+ individuals had good current immunological status (median CD4: 479 cells/μl) despite a low CD4 nadir (median: 93 cells/μl). LT (positive anti-Toxoplasma IgG antibodies) was present in one third of participants. The impairment rates in the HIV- with and without Toxo were not significantly different (p=0.17). However, we observed an increasing trend (p<0.001) in impairment rates with HIV and LT status: HIV-/LT- (6.1%); HIV-/LT+ (22%), HIV+/LT- (31%), HIV+/LT+ (49%). In a multivariable analysis using the entire study group there were main effects on cognition for HIV and also for LT. Within the HIV+ group LT was associated with worse performance globally (p=0.006), in memory (p=0.009), speed of information processing (p=0.01), verbal (p=0.02) and learning (p=0.02) domains. LT was not associated with depressive symptoms, frontal systems dysfunction or risk behaviors in any of the groups. HIV participants with lower Toxoplasma antibody concentration had worse NC performance, with higher GDS values (p=0.03) and worse learning (p=0.002), memory (p=0.006), speed of information processing (p=0.01) T scores. Latent Toxoplasmosis may contribute to NC impairment in young adults, including those with and without chronic HIV infection., (Copyright © 2016 Elsevier B.V. All rights reserved.)

HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Older HIV-infected adults have a higher risk of neurocognitive impairment, but the underlying mechanisms are poorly understood. Here, we investigated the associations between levels of HIV DNA in peripheral blood, soluble markers of inflammation and cellular trafficking in blood and cerebrospinal fluid (CSF) and neurocognitive functioning among 18 younger (22-40 years) and 26 older (50-71 years) HIV-infected subjects, who were administered a comprehensive neurocognitive battery. Older HIV-infected individuals presented higher levels of inflammation in CSF and blood compared to younger individuals, but no difference was observed in HIV DNA levels. Among older participants, higher HIV DNA levels were significantly associated with more severe neurocognitive impairment (p = 0.005), particularly in the Executive Functions domain (p = 0.004). No association was observed between HIV DNA and neurocognition among younger individuals. Despite significantly increased inflammation observed in the older group, none of the inflammatory markers were associated with neurocognitive impairment among older HIV+ individuals (p > 0.05). Our study supports the involvement of peripheral HIV DNA reservoir in the pathogenesis of neurocognitive disorder during suppressive ART. Correlates of neurocognitive impairment might differ between younger and older adults, suggesting that future treatment and prevention strategies for HIV-associated neurocognitive disorders likely need to be tailored based on age.

Background: HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis., Methods: To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNγ, IL-2, TNFα) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART., Results: Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFα, IL-2, IFNγ and CD8+T-cells: IL-2 and IFNγ. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNγ expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNγ and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/μl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNγ expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF., Conclusions: Presence of IFNγ expressing CD8+ T-cells, absence of cytolytic CD8+ T-cells, high myeloid activation, and failure of ART to suppress HIV replication in CSF contribute to increased risk of HAND.

Background: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery., Methods: We investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change., Results: Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001)., Conclusions: NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection., Methods: This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non-CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16., Results: The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent-to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4(+) T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], -31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, -.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T., Conclusions: This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded. Clinical Trials Registration NCT00624195.

Background: Prior research has demonstrated neuropsychological (NP) impairment in persons with histories of injection drug use (IDU), hepatitis C virus (HCV) infection, and methadone maintenance treatment (MMT), individually, but little is known about the NP effects of these three risk factors in combination. This issue is particularly important in China, which is addressing its highly HCV-comorbid IDU epidemic with widespread government sponsored MMT, especially in light of recent evidence suggesting that methadone may be neuroprotective in some circumstances., Methods: We administered a comprehensive NP test battery to 195 Chinese heroin IDU individuals taking MMT (IDU+ group), the majority of whom were also HCV+ (87%; n=169), and compared their NP performance to that of 198 demographically comparable, non-IDU Chinese controls (IDU- group). All participants in both groups tested negative for HIV infection, which is also a common comorbidity in the Chinese IDU population., Results: The IDU+ group did not have an increased rate of global NP impairment, or perform significantly worse on any individual NP test measure. Within the IDU+ group, liver disease characteristics and reported details of heroin use were not significantly associated with NP performance., Conclusion: Failure to detect NP impairment in IDU+ subjects with or without HCV infection was surprising, particularly considering the previously demonstrated sensitivity of our NP battery to neurocognitive disorders associated with HIV infection in China. One possible explanation, which should be explored in future research, is the potential neuroprotective effect of methadone in the context of HCV infection and/or heroin withdrawal., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Here we evaluated whether neurocognitive disorders in HIV-infected individuals on effective antiretroviral therapy (ART) are associated with persistent monocyte activation as indexed by levels of soluble CD163 (sCD163), shed by monocyte/macrophages., Design: Chronically, HIV-infected individuals were examined at two consecutive visits median [interquartile range (IQR)] 16 (7-32) months apart. All patients were on ART and durably virologically suppressed (plasma HIV RNA <50 copies/ml) at all visits. Thirty-four age-matched HIV-seronegative patients were used as controls., Methods: A global deficit score (GDS) was calculated based on comprehensive neuropsychological assessment according to standard methods. Neuropsychological and medical data were used to assign neurocognitive status according to published guidelines for HIV-associated neurocognitive disorders (HAND) as follows: neuropsychologically normal (NP-nml), asymptomatic neuropsychological impairment (ANI) and minor neurocognitive disorder (MND). sCD163 in plasma and cerebrospinal fluid was measured using ELISA., Results: GDS-impaired patients had higher plasma sCD163 than those who were not impaired [median (IQR) 1401 ng/ml (1057-2258) versus 955 ng/ml (586-1313); Wilcoxon P=0.028]. Patients with MND (N=6) had significantly higher plasma sCD163 than ANI (P=0.04) or NP-nml (P=0.02). Whereas plasma sCD163 levels dropped in patients who were stably GDS-unimpaired after the first visit (P<0.032), levels remained elevated in those who remained GDS-impaired (P=0.50)., Interpretation: These findings are consistent with persistent monocyte/macrophage activation in neurophysiologically impaired HIV-infected individuals despite virally suppressive ART. Overall, these observations underscore the significance of monocyte/macrophage immune responses in HIV, persistent monocyte activation in HAND and the value of sCD163, as a plasma marker of neurocognitive impairment.

Cognitive impairment is common in HIV-infected individuals, as is syphilis. Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system early in disease. We hypothesized that HIV-infected patients with a history of syphilis or neurosyphilis would have more cognitive impairment than HIV-infected individuals without these infections. Eighty-two of 1574 enrollees in CHARTER, a prospective, observational study, had reactive serum rapid plasma reagin (RPR) tests. They were matched to 84 controls with non-reactive RPR by age, gender, ethnicity and HIV risk factor. Participants underwent comprehensive neuropsychological (NP) evaluations. RPR results were confirmed and serum fluorescent treponemal antibody absorption (FTA-ABS) test reactivity determined at a central laboratory. Sera from 101 of 166 participants were FTA-ABS reactive, indicating past or current syphilis. Among the 136 individuals without confounding conditions, compared with patients who had never had syphilis, those with prior syphilis had a greater number of impaired NP test domains (1.90 SD [1.77] versus 1.25 [1.52], P = 0.03), a higher global deficit score (0.47 [0.46] versus 0.31 [0.33], P = 0.03), and more were impaired in the NP learning domain (36 [42.9%] of 84 versus 13 [25.0%] of 52, P = 0.04). These effects of prior syphilis remained after controlling for education and premorbid intelligence.

Objective: To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls., Methods: We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV-) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm(3)) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests., Results: HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm(3), and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm(3)). NCI was diagnosed among 38 (19%, 95% confidence interval 14%-25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV- patients., Conclusions: HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.

Background: HLA-DR*04 was identified as a predictor of HIV-Associated neurocognitive disorder (HAND), low CD4 T-cell responses to HIV, and low plasma HIV RNA levels in a U.S. cohort. We hypothesized that low CD4 T-cell activation leads to poor immune control of HIV in the CNS, predisposing to HAND, but also provided fewer target (activated CD4 T-cells) for HIV replication. To assess the consistency of these HLA Class II associations in a new cohort and extend analysis to HLA Class I, HLA types, neurocognitive, and virologic status were examined in a cohort of former plasma donors in China., Methods: 178 HIV infected individuals in Anhui China, were HLA typed and underwent neurocognitive evaluations (using locally standardized norms), neuromedical, treatment and virologic assessments at baseline and at 12 months., Results: HLA DR*04 was associated with a higher rate of baseline neurocognitive impairment (p = 0.04), neurocognitive decline (p = 0.04), and lower levels of HIV RNA in plasma (p = 0.05). HLA Class I alleles (B*27,57,58,A*03,33) that specify a CD8 T-cell response to conserved HIV sequences were neuroprotective, associated with less impairment at baseline (p = 0.037), at month 012 (p = 0.013) and less neurocognitive decline (p = 0.023) in the interval. Consistent with the theory that effective CD8 T-cell responses require CD4 T-cell support, the HLA DR*04 allele reduced the neuroprotective effect of the Class I alleles. The presence of HLA-DR*04 and the Alzheimer associated allele ApoE4 in the same individual had a synergistic negative effect on cognition (p = 0.003)., Conclusions: Despite major background differences between U.S. and Anhui China cohorts, HLA DR*04 predicted neurocognitive impairment and lower plasma HIV RNA levels in both populations. HLA Class I alleles associated with CD8 T-cell control of HIV were associated with protection from HAND, but protection was reduced in the presence of HLA-DR*04.

Objective: Despite immune recovery in individuals on combination antiretroviral therapy (CART), the frequency of HIV-associated neurocognitive disorders (HANDs) remains high. Immune recovery is typically achieved after initiation of ART from the nadir, or the lowest historical CD4. The present study evaluated the probability of neuropsychological impairment (NPI) and HAND as a function of CD4 nadir in an HIV-positive cohort., Methods: One thousand five hundred and twenty-five HIV-positive participants enrolled in CNS HIV Antiretroviral Therapy Effects Research, a multisite, observational study that completed comprehensive neurobehavioral and neuromedical evaluations, including a neurocognitive test battery covering seven cognitive domains. Among impaired individuals, HAND was diagnosed if NPI could not be attributed to comorbidities. CD4 nadir was obtained by self-report or observation. Potential modifiers of the relationship between CD4 nadir and HAND, including demographic and HIV disease characteristics, were assessed in univariate and multivariate analyses., Results: The median CD4 nadir (cells/μl) was 172, and 52% had NPI. Among impaired participants, 603 (75%) had HAND. Higher CD4 nadirs were associated with lower odds of NPI such that for every 5-unit increase in square-root CD4 nadir, the odds of NPI were reduced by 10%. In 589 virally suppressed participants on ART, higher CD4 nadir was associated with lower odds of NPI after adjusting for demographic and clinical factors., Conclusion: As the risk of NPI was lowest in patients whose CD4 cell count was never allowed to fall to low levels before CART initiation, our findings suggest that initiation of CART as early as possible might reduce the risk of developing HAND, the most common source of NPI among HIV-infected individuals.

Reliable detection and quantification of longitudinal cognitive change are of considerable importance in many neurological disorders, particularly to monitor central nervous system effects of disease progression and treatment. In the current study, we developed normative data for repeated neuropsychological (NP) assessments (6 testings) using a modified standard regression-based (SRB) approach in a sample that includes both HIV-uninfected (HIV-, N = 172) and neuromedically stable HIV-infected (HIV+, N = 124) individuals. Prior analyses indicated no differences in NP change between the infected and uninfected participants. The norms for change included correction for factors found to significantly affect follow-up performance, using hierarchical regression. The most robust and consistent predictors of follow-up performance were the prior performance on the same test (which contributed in all models) and a measure of prior overall NP competence (predictor in 97% of all models). Demographic variables were predictors in 10-46% of all models and in small amounts; while test-retest interval contributed in only 6% of all models. Based on the regression equations, standardized change scores (z scores) were computed for each test measure at each interval; these z scores were then averaged to create a total battery change score. An independent sample of HIV- participants who had completed 8 of the 15 tests was used to validate an abridged summary change score. The normative data are available in an electronic format by e-mail request to the first author. Correction for practice effects based on normative data improved the consistency of NP impairment classification in a clinically stable longitudinal cohort after baseline.

While neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury.

Background: Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese individuals infected through contaminated blood products., Methods: Two hundred and one HIV-infected patients from Anhui, China, had neuropsychological tests at baseline and 12 months. DNA was genotyped for APOE epsilon2, epsilon3 and epsilon4 alleles; MBL2-A/O; CCR5-wt/Delta32; CCR5-59029-G/A; CCR2-180-G/A; SDF-1-G/A; IL4-589-C/T; MCP-1-2518-A/G; CX3CR1-745-G/A; -849-C/T polymorphisms and CCL3L1 copy number variants using real-time PCR. Univariate and multivariate analyses were performed., Results: The cohort included 61% men, with mean education 5.5 years, AIDS diagnosis 113 (55%), on antiretrovirals 114 (56%), mean baseline CD4(+) cell count 349 cells/microl and mean log10 RNA 4.09. At baseline, 37% had global neuropsychological impairment increasing to 44% after 12 months. Of 43 patients with the APOE epsilon4 allele, 58% were cognitively impaired compared with 31% without the epsilon4 allele (P = 0.001, odds ratio 3.09, 95% confidence interval 1.54-6.18). The mean global deficit score (GDS) for epsilon4-positive participants on antiretrovirals for 12 months was 0.88 (0.55) compared with 0.63 (0.54) for epsilon4-negative participants (P = 0.053, 95% confidence interval -0.004 to 0.51). For MBL2, 52% of patients with the O/O genotype declined in cognitive function over 12 months compared with 23% with A/A (odds ratio 3.62, 95% confidence interval 1.46-9.03, P = 0.004). No associations were observed for the other genetic variants., Conclusion: The APOE epsilon4 allele was associated with increased risk for cognitive deficits, whereas the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese individuals infected with HIV through contaminated blood products.

In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting "NeuroAIDS in Africa." This meeting was held in Cape Town, South Africa, and was affiliated with the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Presentations began with an overview of the epidemiology of HIV in sub-Saharan Africa, the molecular epidemiology of HIV, HIV-associated neurocognitive disorders (HANDs), and HAND treatment. These introductory talks were followed by presentations on HAND research and clinical care in Botswana, Cameroon, Ethiopia, The Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, and Zambia. Topics discussed included best practices for assessing neurocognitive disorders, patterns of central nervous system (CNS) involvement in the region, subtype-associated risk for HAND, pediatric HIV assessments and neurodevelopment, HIV-associated CNS opportunistic infections and immune reconstitution syndrome, the evolving changes in treatment implementation, and various opportunities and strategies for NeuroAIDS research and capacity building in the region.

Objective: To rigorously evaluate the time course of cognitive change in a cohort of individuals with HIV-associated neurocognitive disorders (HAND) initiating combination antiretroviral therapy (CART), and to investigate which demographic, laboratory, and treatment factors are associated with neuropsychological (NP) outcome (or "any NP improvement")., Methods: Study participants included 37 HIV+ individuals with mild to moderate NP impairment who initiated CART and underwent NP testing at 12, 24, 36, and 48 weeks thereafter. NP change was assessed using a regression-based change score that was normed on a separate NP-stable group thereby controlling for regression toward the mean and practice effect. Mixed-effect regression models adjusting for loss to follow-up were used to evaluate the time course of cognitive change and its association with baseline and time-varying predictors., Results: In persons with HAND initiating CART, cognitive improvement happens soon after initiation (13% at week 12), but more often 24, 36, and up to 48 weeks after initiation (up to 41%), with fewer than 5% demonstrating significant worsening. In multivariate analyses, unique predictors of NP improvement included more severe baseline NP impairment and higher CART CNS penetration index. Greater viral load decrease was associated with NP improvement only in univariate analyses., Conclusion: Clinically meaningful neuropsychological improvement seemed to peak around 24-36 weeks after combination antiretroviral therapy initiation and was prolonged over the 1-year study period. This study also provides new evidence that benefit may be maximized by choosing antiretroviral medications that reach therapeutic concentrations in the CNS.

The continuous replication of HIV-1 in the central nervous system, in particular the brain, and its potential long-term deleterious effect is the focus of this review. Cognitive deficits are observed in a significant percentage of HIV-1-infected patients. That may occur despite successful peripheral suppression of the HIV-1 replication. Compartmentalisation of HIV-1 in the brain, genetic mutation of HIV-1, age, HCV coinfection and poor intracerebral penetration, as well as possibly a direct toxic effect of antiretroviral drugs, are factors that may account for potential creeping damage of the brain after many years of treatment. Patients with neurological symptoms or cognitive deficits may require another approach to the treatment of their HIV infection.

Based upon prior findings with group means, a "prototypical pattern" of neuropsychological results with HIV infection has emerged: impaired executive functioning, motor skills, speed of information processing, and learning, with intact memory retention, most language skills, and visuospatial functioning. We examined neuropsychological results from 553 HIV+ adults to determine the number of patterns seen among individuals with HIV infection. Factor analysis of a relatively comprehensive neuropsychological battery identified 6 component factors: verbal memory (VeM), visual memory (ViM), processing speed (PS), attention/working memory (A/WM), executive function (EF), and motor (M). These factor scores were submitted to hierarchical cluster analysis, to determine the appropriate number of clusters or patterns in the cohort. Final cluster membership was then determined by K-means analysis, based on the Lange, Iverson, Senior, and Chelune (2002) method. A 6-cluster solution was found to be most appropriate. The definitions of the clusters were based upon ipsative scoring of factor scores to indicate relative strengths and weaknesses (independent of overall level of performance): Cluster 1: strong EF; Cluster 2: strong M, weak VeM and EF; Cluster 3: strong PS, weak ViM and EF; Cluster 4: strong VeM, weak M; Cluster 5: strong A/WM; Cluster 6: strong VeM, weak EF. Neuropsychological-impairment rates differed across clusters, but all 6 clusters contained substantial numbers of impaired and unimpaired individuals. Cluster membership was not explained by demographic variables or psychiatric or neuromedical confounds. Thus, there does not appear to be a single, prototypical pattern of neuropsychological impairment associated with HIV infection for this battery of representative neuropsychological tests.

HIV-1 often invades the CNS during primary infection, eventually resulting in neurological disorders in up to 50% of untreated patients. The CNS is a distinct viral reservoir, differing from peripheral tissues in immunological surveillance, target cell characteristics and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique selective environment. We sought to catalogue the genetic features of CNS-derived HIV-1 by analysing 456 clonal RNA sequences of the C2-V3 env subregion generated from CSF and plasma of 18 chronically infected individuals. Neuropsychological performance of all subjects was evaluated and summarized as a global deficit score. A battery of phylogenetic, statistical and machine learning tools was applied to these data to identify genetic features associated with HIV-1 neurotropism and neurovirulence. Eleven of 18 individuals exhibited significant viral compartmentalization between blood and CSF (P < 0.01, Slatkin-Maddison test). A CSF-specific genetic signature was identified, comprising positions 9, 13 and 19 of the V3 loop. The residue at position 5 of the V3 loop was highly correlated with neurocognitive deficit (P < 0.0025, Fisher's exact test). Antibody-mediated HIV-1 neutralizing activity was significantly reduced in CSF with respect to autologous blood plasma (P < 0.042, Student's t-test). Accordingly, CSF-derived sequences exhibited constrained diversity and contained fewer glycosylated and positively selected sites. Our results suggest that there are several genetic features that distinguish CSF- and plasma-derived HIV-1 populations, probably reflecting altered cellular entry requirements and decreased immune pressure in the CNS. Furthermore, neurological impairment may be influenced by mutations within the viral V3 loop sequence.

Previous research has found HIV-associated neuropsychological (NP) dysfunction to be associated with impaired driving skills. To determine whether specific impairments in visual attention impart an increased accident risk, we assessed 21 HIV seronegative (HIV-) and 42 seropositive (HIV+) participants on NP tests and the Useful Field of View (UFOV), a computerized test of visual attention. HIV+ participants performed significantly worse than the HIV- participants on the UFOV, particularly on the Divided Attention subtest. Poor UFOV performance was associated with higher accident rates in the past year, with a trend for NP impairment to also predict more accidents. The highest number of accidents occurred in the group with a "high risk" UFOV designation and NP impairment; this category correctly classified 93% of HIV+ participants as to who did, and did not, have an accident. Clinicians should attend to visual attention as well as general cognitive status in estimating which patients are at risk for impaired driving.

Objective: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence., Methods: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits., Results: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency., Conclusion: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

CCR2 is a minor coreceptor for human immune deficiency virus-1 (HIV-1) and its impact on HIV-1-related neuropsychological impairment (NPI) remains unknown. We studied the impact of CCR2-V64I polymorphisms on the development of NPI in 121 HIV-1 patients. The CCR2-64-I allele was associated with rate of progression to NPI when measured from the first study visit (Log Rank p=0.01) or from the estimated time of seroconversion (p=0.02). CCR2-V64I was not associated with plasma or CSF HIV-1 RNA load, suggesting that the impact of CCR2 on neuropathogenesis may involve alterations in inflammatory responses within the CNS rather than a direct impact on viral entry or replication.

Background: Neuropsychological (NP) impairment is a relatively common sequela in human immunodeficiency virus (HIV)-infected individuals with advanced disease. Early antecedents of NP dysfunction, however, remain poorly understood., Objective: To determine whether early markers of immunocompetence and viral replication in individuals who have undergone seroconversion would be of prognostic value in identifying subjects who would become cognitively impaired., Methods: Seventy-four subjects with estimable seroconversion dates and normal cognition at baseline (a median of 1 year after seroconversion) received NP and laboratory evaluations, including reverse transcription-polymerase chain reaction measurements of plasma (N = 74) and cerebrospinal fluid (n = 47) levels of HIV RNA. Subjects were followed up longitudinally, and were considered to have reached the end point if they became cognitively impaired., Results: Using Kaplan-Meier estimates, the subgroups with the most rapid progression to NP impairment were (1) subjects with early reductions in CD4 counts (<400 cells/microL at baseline; P =.007) and (2) those with elevated plasma HIV RNA values (>4.5 log10 copies/mL; P =.03) early after seroconversion. Using proportional hazards modeling, the highest-risk subjects had both CD4 counts less than 400 cells/microL and HIV RNA levels greater than 4.5 log10 copies/mL (risk ratio, 6.0; P =.01). In most subjects (7/9 [78%]), NP impairment developed before an acquired immunodeficiency syndrome-defining illness., Conclusions: Neurocognitive outcomes in HIV are strongly influenced by very early systemic virological and immunological events. Patients with high plasma levels of HIV RNA and low CD4 counts early after infection should be aggressively treated to prevent immunological decline and NP deterioration.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-alpha (TNFalpha) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease., Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive-motor impairment., Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive-motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment., Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement., Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive-motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.