Neuropsychological Impairment in Acute HIV and the Effect of Immediate Antiretroviral Therapy

OBJECTIVE:To investigate neuropsychological performance (NP) during acute HIV infection (AHI) before and after combination antiretroviral therapy (cART). DESIGN:Prospective study of Thai AHI participants examined at 3 and 6 months after initiation of cART. METHODS:Thirty-six AHI participants were evaluated pre-cART at median 19 days since HIV exposure and 3 and 6 months after cART with the Grooved Pegboard test, Color Trails 1 & 2 (CT1, CT2), and Trail Making Test A. Raw scores were standardized to 251 age- and education-matched HIV-uninfected Thais. To account for learning effects, change in NP performance was compared with that of controls at 6 months. Analyses included multivariable regression, nonparametric repeated measures analysis of variance, and Mann-Whitney U test. RESULTS:Baseline NP scores for the AHI group were within normal range (z-scores range: -0.26 to -0.13). NP performance improved on CT1, CT2, and Trail Making Test A in the initial 3 months (P < 0.01) with no significant change during the last 3 months. Only improvement in CT1 was greater than that seen in controls at 6 months (P = 0.018). Participants who performed >1 SD below normative means on ≥2 tests (n = 8) exhibited higher baseline cerebrospinal fluid HIV RNA (P = 0.047) and had no improvement after cART. CONCLUSIONS:Most AHI individuals had normal NP performance, and early cART slightly improved their psychomotor function. However, approximately 25% had impaired NP performance, which correlated with higher cerebrospinal fluid HIV RNA, and these abnormalities were not reversed by early cART possibly indicating limited reversibility of cognitive impairment in a subset of AHI individuals

Brief Report

Monocytes play a vital role in HIV-associated neurocognitive disorder (HAND), postulated to transport HIV into the brain and secrete pro-inflammatory cytokines. We analyzed cytokines released by cultured peripheral blood mononuclear cells enriched with the CD14 marker isolated from HIV-infected individuals with HAND and normal cognition (NC) in combination antiretroviral therapy naive and after 1 year on treatment. Interleukin-8 and monocyte chemoattractant protein-1 levels were higher in HAND compared with NC at baseline (P = 0.002 and P < 0.0001). These cytokines remained higher in HAND patients 1 year after combination antiretroviral therapy and were significant when NC patients who were initially HAND were excluded (P = 0.012 and P = 0.002). Both correlated with baseline CD14 peripheral blood mononuclear cell HIV DNA levels supporting the role of HIV DNA reservoir size and monocyte cytokines in HAND persistence

Development of normative neuropsychological performance in Thailand for the assessment of HIV-associated neurocognitive disorders.

International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male = 211, female = 266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20-34; 35-49; 50-65 years) and four educational levels (no education or primary education, less than secondary certificate, high-school/associates degree, bachelor's degree or greater). The Thai cohort was compared (using analysis of covariance, ANCOVA) on a number of measures to a seronegative US cohort (n = 236; male = 198, female = 38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p < .001) and memory (p < .001) and measures of psychomotor speed (p < .001). Education was a more powerful predictor of performance in the Thai cohort than in the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups

Development of normative neuropsychological performance in Thailand for the assessment of HIV-associated neurocognitive disorders.

International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male = 211, female = 266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20-34; 35-49; 50-65 years) and four educational levels (no education or primary education, less than secondary certificate, high-school/associates degree, bachelor's degree or greater). The Thai cohort was compared (using analysis of covariance, ANCOVA) on a number of measures to a seronegative US cohort (n = 236; male = 198, female = 38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p < .001) and memory (p < .001) and measures of psychomotor speed (p < .001). Education was a more powerful predictor of performance in the Thai cohort than in the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups

Trail Making Test A improves performance characteristics of the International HIV Dementia Scale to identify symptomatic HAND.

Although HIV-associated dementia (HAD) occurs in less than 5 % of individuals with access to combination antiretroviral therapy, rates of milder forms of HIV-associated neurocognitive disorder (HAND) are much higher. We sought to define an optimal cut point for the International HIV Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and mild neurocognitive disorder. We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study, subjects comprising 75 seropositive adults in Bangkok, Thailand, completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut point was determined by receiver operating characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut point of ≤ 10 (sensitivity, 53.3 %; specificity, 89.8 %). Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86 % and specificity of 79 %. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than 2 min to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings

HIV DNA in CD14+ reservoirs is associated with regional brain atrophy in patients naive to combination antiretroviral therapy.

ObjectiveTo examine associations between regional brain volumes and HIV DNA in peripheral CD14 cells (monocytes) among HIV-infected individuals naive to combination antiretroviral therapy (cART).DesignA prospective study of HIV-infected Thai individuals who met Thai national criteria for cART initiation. Enrolment was stratified by HIV DNA in a blinded fashion.MethodsCD14 cells were isolated from peripheral mononuclear cells to high purity (median 91.4% monocytes by flow cytometry), and HIV DNA was quantified by multiplex real-time PCR. Baseline regional brain volumes obtained by T1-weighted 1.5-Tesla MRI were compared between HIV DNA groups using analysis of covariance (ANCOVA).ResultsWe studied 60 individuals with mean (SD) age of 34.7 (7.0) years, CD4 T-lymphocyte count of 232 (137) cells/μl and log10 plasma HIV RNA of 4.8 (0.73). Median (interquartile range, IQR) HIV DNA copy number per 10 CD14 cells was 54 (102). Using our previously determined optimal cut-point of 45 copies/10 cells for this cohort, a threshold value above which CD14 HIV DNA identified HIV-associated neurocognitive disorders (HANDs), we found that CD14 HIV DNA  ≥ 45 copies/10 cells was associated with reduced volumes of the nucleus accumbens (P=0.021), brainstem (P=0.033) and total gray matter (P=0.045) independently of age, CD4 cell count and intracranial volume.ConclusionHIV DNA burden in CD14 monocytes is directly linked to brain volumetric loss. Our findings implicate peripheral viral reservoirs in HIV-associated brain atrophy and support their involvement in the neuropathogenesis of HAND, underscoring the need for therapies that target these cells

Sex differences in soluble markers vary before and after the initiation of antiretroviral therapy in chronically HIV-infected individuals.

ObjectiveTo evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment.DesignSoluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 men and 35 women) with chronic HIV infection and 18 HIV-uninfected controls (9 men and 9 women) from Thailand. Following enrollment, participants began combination antiretroviral therapy and were evaluated for expression of these markers after 48 weeks.MethodsPlasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multiparameter or standard ELISA assay.ResultsPrior to combination antiretroviral therapy, women with impaired cognition had elevated levels of neopterin and TNF-RII compared with women with normal cognition in both the plasma and CSF; however, levels did not differ between cognitively impaired or normal men. In a secondary outcome-hypothesis generating analysis, sex differences were also pronounced in plasma levels of MCP-1, IL-10, I-FABP, and sCD14 in response to treatment. Neopterin, IP-10, TNFα, TNF-RII, IFNα, MCP-1, IL-8, I-FABP, and sCD14 plasma levels remained elevated following 48 weeks of therapy in both sexes compared with uninfected controls.ConclusionWe provide evidence of sustained immune activation after 48 weeks of treatment and identify possible sex differences in biomarkers previously linked to cognitive impairment, chronic inflammation, and gut integrity that may contribute to immunological differences between sexes in relationship to disease progression and response to therapy

HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART

HIV DNA is a marker of HIV persistence that predicts HIV progression and remission, but its kinetics in early acute HIV infection (AHI) is poorly understood. We longitudinally measured the frequency of peripheral blood mononuclear cells harboring total and integrated HIV DNA in 19 untreated and 71 treated AHI participants, for whom 50 were in the earliest Fiebig I/II (HIV IgM−) stage, that is ≤2 weeks from infection. Without antiretroviral therapy (ART), HIV DNA peaked at 2 weeks after enrollment, reaching a set-point 2 weeks later with little change thereafter. There was a marked divergence of HIV DNA values between the untreated and treated groups that occurred within the first 2 weeks of ART and increased with time. ART reduced total HIV DNA levels by 20-fold after 2 weeks and 316-fold after 3 years. Therefore, very early ART offers the opportunity to significantly reduce the frequency of cells harboring HIV DNA

HIV DNA reservoir increases risk for cognitive disorders in cART-naïve patients.

OBJECTIVES: Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14(+) enriched monocytes predicted cognitive impairment and brain injury. METHODS: We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14(+) enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). RESULTS: The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14(+) HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14(+) HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. INTERPRETATION: Reservoir burden of HIV DNA in monocyte-enriched (CD14(+)) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS