The association between physical activity and cognition in men with and without HIV infection.

OBJECTIVES: HIV-associated neurocognitive disorders are highly prevalent, and physical activity (PA) is a modifiable behaviour that may affect neurocognitive function. Our objective was to determine the association between PA and neurocognitive function and the effect of HIV on this association. METHODS: PA was assessed in the Multicenter AIDS Cohort Study with the International Physical Activity Questionnaire. A neuropsychological test battery assessed global impairment and domain-specific impairment (executive function, speed of processing, working memory, learning, memory, and motor function) every 2 years. Semiannually, the Symbol Digit Modalities Test and Trail Making Test Parts A and B were performed. Adjusted logistic regression models were used to assess the PA-neurocognitive function association. Using longitudinal data, we also assessed the PA category-decline of neurocognitive function association with multivariate simple regression. RESULTS: Of 601 men, 44% were HIV-infected. Low, moderate, and high PA was reported in 27%, 25%, and 48% of the HIV-infected men vs. 19%, 32% and 49% of the HIV-uninfected men, respectively. High PA was associated with lower odds of impairment of learning, memory, and motor function [odds ratio (OR) ranging from 0.52 to 0.57; P < 0.05 for all]. The high PA-global impairment association OR was 0.63 [95% confidence interval (CI) 0.39, 1.02]. Among HIV-infected men only, across multiple domains, the high PA-impairment association was even more pronounced (OR from 0.27 to 0.49). Baseline high/moderate PA was not associated with decline of any domain score over time. HIV infection was marginally associated with a higher speed of decline in motor function. CONCLUSIONS: A protective effect of high PA on impairment in neurocognitive domains was observed cross-sectionally. Longitudinal PA measurements are needed to elucidate the PA-neurocognitive function relationship over time.

International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271.

Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (<10 and ≥10 years), and age (<35 and ≥35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers.

A Comparison of Five Brief Screening Tools for HIV-Associated Neurocognitive Disorders in the USA and South Africa.

Screening for HIV-associated neurocognitive disorders (HAND) is important to improve clinical outcomes. We compared the diagnostic sensitivity and specificity of the mini-mental state examination, International HIV dementia scale (IHDS), Montreal cognitive assessment, Simioni symptom questionnaire and cognitive assessment tool-rapid version (CAT-rapid) to a gold standard neuropsychological battery. Antiretroviral-experienced participants from Cape Town, South Africa, and Baltimore, USA, were recruited. The sensitivity and specificity of the five tools, as well as those of the combined IHDS and CAT-rapid, were established using 2 × 2 contingency tables and ROC analysis. More than a third (65165) had symptomatic HAND. In detecting HIV-D, the CAT-Rapid had good sensitivity (94 %) and weak specificity (52 %) (cut-point ≤10), while the IHDS showed fair sensitivity (68 %) and good specificity (86 %) (cut-point ≤10). The combined IHDS and CAT-rapid showed excellent sensitivity and specificity for HIV-D at a cut-off score of ≤16 (out of 20; 89 and 82 %). No tool was adequate in screening for any HAND. The combination IHDS and CAT-rapid tool appears to be a good screener for HIV-D but is only fairly sensitive and poorly specific in screening for any HAND. Screening for milder forms of HAND continues to be a clinical challenge.

Protein-free efavirenz concentrations in cerebrospinal fluid and blood plasma are equivalent: applying the law of mass action to predict protein-free drug concentration.

Efavirenz (EFV) is one of the most commonly prescribed antiretroviral drugs (ARVs) for the treatment of HIV. Highly protein-bound drugs, like EFV, have limited central nervous system (CNS) penetration when measured using total drug concentration gradients between blood plasma (BP) and cerebrospinal fluid (CSF). However, the more relevant pharmacologically active protein-free drug concentrations are rarely assessed directly in clinical studies. Using paired BP and CSF samples obtained from 13 subjects on an EFV-containing regimen, both the protein-free and total concentrations of EFV were determined. Despite a median (interquartile range [IQR]) total EFV BP/CSF concentration ratio of 134 (116 to 198), the protein-free EFV BP/CSF concentration ratio was 1.20 (0.97 to 2.12). EFV median (IQR) protein binding was 99.78% (99.74 to 99.80%) in BP and 76.19% (74.47 to 77.15%) in CSF. In addition, using the law of mass action and an in vitro-derived EFV-human serum albumin dissociation constant, we have demonstrated that the predicted median (IQR) protein-free concentration in BP, 4.59 ng/ml (4.02 to 9.44 ng/ml), compared well to that observed in BP, 4.77 ng/ml (3.68 to 6.75 ng/ml). Similar results were also observed in CSF and seminal plasma. This method provides a useful predictive tool for estimating protein binding in varied anatomic compartments. Our results of equivalent protein-free EFV concentrations in BP and CSF do not support prior concerns of the CNS as a pharmacological sanctuary from EFV. As CSF penetration of ARVs may increase our understanding of HIV-associated neurological dysfunction and antiretroviral effect, assessment of protein-free CSF concentrations of other highly protein-bound ARVs is warranted.

Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders.

Despite major advances in the development of antiretroviral therapies, currently available treatments have no effect on the production of HIV-Tat protein once the proviral DNA is formed. Tat is a highly neurotoxic and neuroinflammatory protein, but its effects may be modulated by antibody responses against it. We developed an indirect enzyme-linked immunosorbent assay and measured anti-Tat antibody titers in CSF of a well characterized cohort of 52 HIV-infected and 13 control individuals. We successfully measured anti-Tat antibodies in CSF of HIV-infected individuals with excellent sensitivity and specificity, spanning a broad range of detection from 10,000 to over 100,000 relative light units. We analyzed them for relationship to cognitive function, CD4 cell counts, and HIV viral load. Anti-Tat antibody levels were higher in those without neurocognitive dysfunction than in those with HIV-associated neurocognitive dysfunction (HAND) and in individuals with lower CD4 cell counts and higher viral loads. We provide details of an assay which may have diagnostic, prognostic, or therapeutic implications for patients with HAND. Active viral replication may be needed to drive the immune response against Tat protein, but this robust immune response against the protein may be neuroprotective.

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years.

Background: Neurocognitive (NC) impairment in people with HIV (PWH) is associated with important adverse outcomes, but no markers exist to predict long-term NC decline. We evaluated depressed mood and markers of persistent inflammation, oxidative stress and altered amyloid processing (all common in PWH) as predictors of NC worsening over 12 years. Methods: PWH were enrolled and followed longitudinally in the CNS HIV Antiretroviral Effects Research (CHARTER) study at six US sites. At entry we quantified biomarkers in blood of inflammation: (interleukin-6 [IL-6], C-reactive protein [CRP], monocyte chemoattractant protein type 1 [MCP-1], D-dimer, soluble sCD14 (sCD14), soluble tumor necrosis factor receptor - type II [sTNFR-II], neopterin, and soluble CD40 ligand [sCD40L], oxidative stress (protein carbonyls, 8-oxo-2'-deoxyguanosine [8-oxo-dG]) and altered amyloid processing [amyloid beta (Aß)-42, soluble amyloid precursor protein-α (sAPPα)] using commercial immunoassays. The Beck Depression Inventory-II (BDI-II) assessed depressed mood at entry. NC decline over 12 years was evaluated using the published and validated summary (global) regression-based change score (sRBCS). A factor analysis reduced dimensionality of the biomarkers. Univariable and multiple regression models tested the relationship between baseline predictors and the outcome of neurocognitive decline. Results: Participants were 191 PWH, 37 (19.4%) women, 46.6% African American, 43.5% non-Hispanic white, 8.83% Hispanic, 15.7% white, 1.6% other; at study entry mean (SD) age 43.6 (8.06) years, estimated duration of HIV infection (median, IQR) 9.82 [4.44, 14.5] years, nadir CD4 104/µL (19,205), current CD4 568/µL (356, 817), and 80.1% had plasma HIV RNA <50 c/mL. Participants were enrolled between 2003 and 2007; median (IQR) duration of follow-up 12.4 [9.69, 16.2] years. Three biomarker factors were identified: Factor (F)1 (IL-6, CRP), F2 (sTNFR-II, neopterin) and F3 (sCD40L, sAPPα). Participants with higher F1, reflecting worse systemic inflammation at baseline, and higher F3, had greater decline in global neurocognition (r â€‹= â€‹-0.168, p â€‹= â€‹0.0205 and r â€‹= â€‹-0.156, p â€‹= â€‹0.0309, respectively). Of the F1 components, higher CRP levels were associated with worse decline (r â€‹= â€‹-0.154, p â€‹= â€‹0.0332), while IL-6 did not (r â€‹= â€‹-0.109, p â€‹= â€‹0.135). NC change was not significantly related to F2, nor to demographics, nadir and current CD4, viral suppression or baseline NC comorbidity ratings. Individuals with worse depressed mood at entry also experienced more NC decline (r â€‹= â€‹-0.1734, p â€‹= â€‹0.0006). Together BDI-II (p â€‹= â€‹0.0290), F1 (p â€‹= â€‹0.0484) and F3 (p â€‹= â€‹0.0309) contributed independently to NC decline (p â€‹= â€‹0.0028); their interactions were not significant. Neither CRP nor IL-6 correlated significantly with depression. Conclusions: PWH with greater systemic inflammation and more depression at entry had greater NC decline over 12 years. Understanding the basis of this inflammatory state might be particularly important. These findings raise the possibility that targeted anti-inflammatory or antidepressant therapies may help prevent NC worsening in PWH with depression and inflammation.

7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests.

BACKGROUND AND PURPOSE: Validated neuroimaging markers of HIV-associated neurocognitive disorder in patients on antiretroviral therapy are urgently needed for clinical trials. The purpose of this study was to explore the relationship between cognitive impairment and brain metabolism in older subjects with HIV infection. It was hypothesized that MR spectroscopy measurements related to neuronal health and function (particularly N-acetylaspartate and glutamate) would be lower in HIV-positive subjects with worse cognitive performance. MATERIALS AND METHODS: Forty-five HIV-positive patients (mean age, 58.9 ± 5.3 years; 33 men) underwent detailed neuropsychological testing and brain MR spectroscopy at 7T. Twenty-four subjects were classified as having asymptomatic cognitive impairment, and 21 were classified as having symptomatic cognitive impairment. Single-voxel proton MR spectra were acquired from 5 brain regions and quantified using LCModel software. Brain metabolites and neuropsychological test results were compared using nonparametric statistics and Pearson correlation coefficients. RESULTS: Differences in brain metabolites were found between symptomatic and asymptomatic subjects, with the main findings being lower measures of N-acetylaspartate in the frontal white matter, posterior cingulate cortex, and precuneus. In the precuneus, glutamate was also lower in the symptomatic group. In the frontal white matter, precuneus, and posterior cingulate cortex, NAA and glutamate measurements showed significant positive correlation with better performance on neuropsychological tests. CONCLUSIONS: Compared with asymptomatic subjects, symptomatic HIV-positive subjects had lower levels of NAA and glutamate, most notably in the frontal white matter, which also correlated with performance on neuropsychological tests. High-field MR spectroscopy offers insight into the pathophysiology associated with cognitive impairment in HIV and may be useful as a quantitative outcome measure in future treatment trials.

HIV-1 reverse transcriptase sequence in plasma and cerebrospinal fluid of patients with AIDS dementia complex treated with Abacavir.

OBJECTIVE: To assess HIV-1 RNA levels and the relationship between HIV-1 reverse transcriptase (RT) genotype from plasma and cerebrospinal fluid (CSF) during treatment with abacavir (Ziagen, ABC) or placebo in combination with stable background therapy (SBG) in subjects with AIDS dementia complex (ADC) (study CNA3001). DESIGN: One-hundred and five HIV-1 infected adults with ADC were randomized to receive either ABC (600 mg twice daily) or ABC-matched placebo (twice daily) in addition to SBG for 12 weeks. METHODS: Plasma and CSF were collected for population sequencing at baseline and week 12 (CSF optional). Sequences were analyzed for mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI). RESULTS: Sixty out of sixty-seven subjects with baseline plasma HIV-RT sequence data harbored virus with > or = 1 NRTI-associated mutations; 50 out of 67 had the M184V mutation. At week 12, more subjects in the ABC group had plasma HIV-1 RNA < or = 400 copies/ml than the SBG group (46% versus 13%, P = 0.002). Non-response to ABC was associated with multiple baseline zidovudine (ZDV)/stavudine (d4T)-associated mutations. Baseline RT mutation patterns differed in 14 out of 21 (67%) paired samples from plasma and CSF. Four subjects experienced > 1 log10 copies/ml reductions in CSF HIV-1 RNA, two in the absence of reductions in plasma HIV-1 RNA and two with undetectable plasma HIV-1 RNA at baseline. CONCLUSIONS: Substantial decreases in plasma and CSF HIV-1 RNA following addition of ABC were not precluded by baseline HIV-1 NRTI-associated mutations, including the M184V mutation, but non-responders commonly harbored multiple ZDV/d4T-associated mutations. HIV-1 RNA responses and RT genotype appear to be discordant between CSF and plasma in some subjects.

The design of a diet restricted in saturated very long-chain fatty acids: therapeutic application in adrenoleukodystrophy.

Adrenoleukodystrophy is an inherited, progressive disorder of the CNS white matter and adrenal glands, associated with the pathognomonic accumulation of saturated very long-chain fatty acids, particularly C26:0. It has been previously demonstrated that the fatty acids that accumulate in adrenoleukodystrophy are, at least in part, of dietary origin. This observation, coupled with success of dietary phytanic acid restriction in a related disorder, Refsum's disease, encouraged us to develop a diet that would restrict dietary C26:0 intake. We report here the very long-chain fatty acids content of 135 common foods and development of a diet that restricts C26:0 intake to 3 mg, compared to 12 to 40 mg in the standard American diet. To limit C26:0 intakes it was found necessary to restrict fatty foods and the outer coverings of vegetables and fruits. In contrast to the success of phytanic acid restriction in limiting disease progress in Refsum's patients, administration of the very long-chain fatty acid-restricted diet to seven adrenoleukodystrophy patients for 3- to 24-month periods was found to be ineffective in lowering their plasma very long-chain fatty acids or in improving clinical status. Recently endogenous synthesis of C26:0 has been demonstrated and this may account for the failure of dietary therapy in adrenoleukodystrophy. It is possible that dietary restriction may augment other therapies in the future.

Serum neopterin level predicts HIV-related mortality but not progression to AIDS or development of neurological disease in gay men and parenteral drug users.

OBJECTIVE: To investigate the ability of elevated serum neopterin levels to predict independently mortality, progression to acquired immunodeficiency syndrome, and development of neurological disease. DESIGN: Cross-sectional and longitudinal study of gay and/or bisexual men and parenteral drug users. SETTING AND PATIENTS: Patients included human immunodeficiency virus (HIV)-negative and -positive gay and/or bisexual men and parenteral drug-using men and women who volunteered for an outpatient study of the natural history of HIV infection. RESULTS: Serum neopterin levels were significantly elevated in HIV-positive patients (mean, 18.0 nmol/L; SD, 19.2 nmol/L), compared with those in HIV-negative patients (mean, 7.5 nmol/L; SD, 5.5 nmol/L) (P < .001). No differences in the serum neopterin levels could be detected between gay men and parenteral drug users. In HIV-positive patients, women had a higher serum neopterin level than did men (P = .03). The elevated serum neopterin levels were associated with an advanced clinical stage of HIV infection. After adjusting for the CD4 lymphocyte count and other potential confounders, the serum neopterin level was a significant independent predictor of mortality. The elevated serum neopterin levels did not predict progression to acquired immunodeficiency syndrome or development of clinically significant neurological disease. CONCLUSION: An elevated serum neopterin level predicts mortality, but it does not predict progression to acquired immunodeficiency syndrome or development of neurological disease among HIV-infected individuals.

A comparison of cerebral SPECT abnormalities in HIV-positive homosexual men with and without cognitive impairment.

OBJECTIVE: To determine whether technetium Tc 99m exametazime (HMPAO) single-photon emission computed tomography (SPECT) can distinguish between human immunodeficiency virus (HIV)-positive homosexual men with normal neuropsychologic test results and HIV-positive homosexual men with abnormal neuropsychologic test results. DESIGN: Neurologic, neuropsychologic, magnetic resonance imaging, and Tc 99m HMPAO SPECT examinations were performed on 10 HIV-positive homosexual men without cognitive impairment and five HIV-positive homosexual men with cognitive impairment. PATIENTS: Human immunodeficiency virus-positive homosexual men from New York City were recruited for the study. MAIN OUTCOME MEASURES: Findings on SPECT scans were evaluated qualitatively for focal defects, heterogeneity of the cortical margin, white matter hypoperfusion, and decreased global cortical uptake. All SPECT focal defects were coregistered with magnetic resonance images; SPECT heterogeneity and global cortical uptake were also measured quantitatively. RESULTS: Coregistration with magnetic resonance imaging revealed that 63% of the focal SPECT defects corresponded to brain gyri and 37% corresponded to sulci. There was no significant difference in the frequency of qualitative or quantitative SPECT abnormalities between HIV-positive homosexual men ith and without cognitive impairment. However, after examining individual neuropsychologic test factors, impaired motor speed performance was associated with decreased quantitative global cerebral uptake. CONCLUSIONS: Qualitative SPECT abnormalities are not increased in frequency in HIV-positive homosexual men with global cognitive impairment compared with those in HIV-positive homosexual men without cognitive impairment. Impaired motor speed performance may be associated with decreased quantitative global cerebral uptake.

Factors associated with incident human immunodeficiency virus-dementia.

BACKGROUND: Antecedents to human immunodeficiency virus-dementia (HIV-D) are poorly understood. OBJECTIVE: To identify risk factors for HIV-D. METHODS: Subjects who are positive for HIV who have CD4+ counts either below 200/microL or below 300/microL with evidence of cognitive impairment were enrolled in this study. Neurologic, cognitive, functional, and laboratory assessments were done semiannually for up to 30 months. Human immunodeficiency virus-dementia was diagnosed using American Academy of Neurology criteria for probable HIV-1-associated dementia complex. RESULTS: One hundred forty-six nondemented patients were enrolled, 45 of whom subsequently met criteria for incident HIV-D. In univariate analyses using the Cox proportional hazards regression model, the following variables were significantly associated with time to develop dementia: cognitive: abnormal scores on Timed Gait, Verbal Fluency, Grooved Pegboard, and Digit Symbol tests; attention-memory, psychomotor, and executive function domain scores; and the diagnosis of minor cognitive/motor disorder; neurologic and medical: increased abnormalities on the neurologic examination, extrapyramidal signs, history of HIV-related medical symptoms; functional: higher reported role or physical function difficulties. Depression was also a strong risk factor, along with sex, hematocrit, hemoglobin, and beta2-microglobulin levels. In a multivariate model that used cognitive domain scores, covariates with significant hazard ratios included depression, executive dysfunction, and the presence of minor cognitive/motor disorder. CONCLUSION: Cognitive deficits, minor cognitive/motor disorder, and depression may be early manifestations of HIV-D.

Cerebral single-photon emission computed tomography abnormalities in human immunodeficiency virus type 1-infected gay men without cognitive impairment.

OBJECTIVE: To determine whether technetium Tc99m exametazime single-photon computed emission tomography (SPECT) can distinguish gay human immunodeficiency virus (HIV)-positive subjects, both with and without mild cognitive impairment, from gay HIV-negative control subjects. DESIGN: Twenty HIV-positive subjects (12 without cognitive impairment and eight with mild cognitive impairment) and 10 HIV-negative subjects underwent neurological, neuropsychological, magnetic resonance imaging, and technetium Tc 99m exametazime SPECT examinations. SETTING: Subjects were recruited from a natural history study of gay men with HIV infection. PATIENTS: Subjects from the cohort who had previously participated in a magnetic resonance imaging study were selected for the SPECT study. MAIN OUTCOME MEASURES: The SPECT scans were rated as abnormal if focal defects, confirmed by a horizontal profile analysis, were seen. RESULTS: Sixty-seven percent of HIV-positive subjects without cognitive impairment, 88% of HIV-positive subjects with mild cognitive impairment, and 20% of HIV-negative subjects had abnormal SPECT scans (P < .05 for both HIV-positive groups when each group was compared with HIV-negative subjects). CONCLUSION: Compared with gay HIV-negative control subjects, focal SPECT defects are seen with an increased frequency in HIV-positive gay men without cognitive impairment and in HIV-positive gay men with mild cognitive impairment.

Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study.

The authors conducted a pilot randomized, double-blind, placebo-controlled clinical trial of the transdermal administration of selegiline in HIV+ patients to obtain preliminary data to assess its safety, tolerability, and impact on HIV-associated cognitive impairment. Both selegiline and placebo were well tolerated with few adverse events. Improvements favoring the selegiline group were suggested on single tests of verbal memory and motor/psychomotor performance, warranting a larger study.

Incidence of and risk factors for HIV-associated distal sensory polyneuropathy.

OBJECTIVE: To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects. METHODS: We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported. RESULTS: At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan-Meier estimate of the 1-year incidence of SDSP was 36%. CONCLUSION: Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.

Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Neurological AIDS Research Consortium.

OBJECTIVE: To assess the safety and tolerability of lexipafant in HIV-associated cognitive impairment. BACKGROUND: Cognitive impairment is the most common neurologic complication of advanced HIV-1 infection. There is evidence that a variety of inflammatory mediators, including platelet-activating factor (PAF), may contribute to neuronal injury. We hypothesized that lexipafant, a PAF antagonist, might improve cognitive dysfunction in HIV-infected people. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the safety and tolerability of lexipafant 500 mg/day. The primary outcome measure for tolerability was the ability to complete the study on the originally assigned dosage of medication. Thirty patients with cognitive impairment were enrolled. RESULTS: Lexipafant was safe and well tolerated. Ninety-three percent in the placebo group and 88% in the lexipafant group completed the study at the originally assigned dosage. Trends toward improvement were seen in neuropsychological performance, especially verbal memory, in the lexipafant treatment group. CONCLUSIONS: This study shows that lexipafant, the first PAF antagonist used in HIV-associated cognitive impairment, is a safe and well tolerated compound. The observed trends toward improvement in neuropsychological test scores warrant the pursuit of a larger and longer efficacy trial to assess the impact of lexipafant on cognitive performance.

Clinical trials in HIV-associated cognitive impairment: cognitive and functional outcomes.

Cognitive and functional outcomes are of primary interest in the design of efficacy trials in HIV-associated cognitive impairment. In a longitudinal cohort study, weak associations were found between measures of cognitive performance and commonly used measures of daily functioning (mostly self-report measures) in HIV-infected individuals. Modifications of current functional scales or new functional instruments are needed to assess the clinical relevance of cognitive changes in clinical trials of HIV-associated cognitive impairment.

HIV-associated neurologic disease incidence changes:: Multicenter AIDS Cohort Study, 1990-1998.

This study examined the temporal trends in the incidence rates of HIV dementia, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma from January 1990 to December 1998 in the Multicenter AIDS Cohort Study. The incidence rates for HIV dementia, cryptococcal meningitis, and lymphoma decreased following the introduction of highly active antiretroviral therapy (HAART). The proportion of new cases of HIV dementia with a CD4 count in a higher range (i.e., 201 to 350) since 1996 may be increasing.

CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing.

The authors evaluated whether highly active antiretroviral therapy (HAART) with multiple CSF-penetrating drugs results in greater improvement in HIV-associated psychomotor slowing than HAART with a single CSF-penetrating drug. Both groups had improvement in CD4 count, plasma viral load, as well as two tests of psychomotor speed. Comparing the two groups, there were no differences in the mean change for CD4 count, viral load, or any of the neuropsychological tests. Multiple and single CSF-penetrating HAART may be equivalent for treating HIV-associated psychomotor slowing.

Neurologic signs and symptoms in a cohort of homosexual men followed for 4.5 years.

We traced the development of neurologic impairment in 207 homosexual men (123 human immunodeficiency virus [HIV]-positive and 84 HIV-negative controls) over 4.5 years of follow-up. We applied generalized estimating equations to logistic regression analyses with repeated measures to examine the differences between HIV-positive and HIV-negative subjects with respect to the likelihood of developing six neurologic outcomes derived from a factor analysis, significant neurologic impairment (modified Kurtzke disability score of > or = 3), or significant neuropsychological impairment. We found that, over time, HIV-positive subjects were more likely to develop clinically significant extrapyramidal signs and frontal release signs than HIV-negative subjects. Controlling for age or education, as CD4 count declined, the odds of developing significant extrapyramidal signs, abnormalities in alternating movements, frontal release signs, and a Kurtzke score > or = 3 increased. HIV-positive subjects were almost five times as likely (odds ratio [OR], 4.6; 95% CI, 1.6 to 13.4) as HIV-negative subjects to stay the same or worsen neurologically on the next visit, and those with CD4 < or = 200 were 4.8 times as likely (OR, 4.8; 95% CI, 2.2 to 10.7) to maintain or worsen neurologically relative to those with higher CD4 counts. We conclude that neurologic impairment becomes increasingly apparent over time in HIV-infected men, especially in those with low CD4 counts.