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HIV-associated neurocognitive disorders (HAND) remain a major challenge for people with HIV in the antiretroviral therapy era. Cocaine use may trigger/exacerbate HAND among African American (AA) adults, especially women. Between 2018 and 2019, 922 adults, predominantly AAs, with/without HIV and with/without cocaine use in Baltimore, Maryland, were enrolled in a study investigating the association of HIV and cocaine use with neurocognitive impairment (NCI). Neurocognitive performance was assessed with the NIH Toolbox Cognition Battery (NIHTB-CB). NCI was considered to be present if the fully adjusted standard score for at least two cognitive domains was 1.0 standard deviation below the mean. Although the overall analysis showed HIV and female sex were associated with NCI, the associations were dependent on cocaine use. Neither HIV [adj prevalence ratio (PR): 1.12, confidence interval (95% CI): 0.77-1.64] nor female sex (adj PR: 1.07, 95% CI: 0.71-1.61) was associated with NCI among cocaine nonusers, while both HIV (adj PR: 1.39, 95% CI: 1.06-1.81) and female sex (adj PR: 1.53, 95% CI: 1.18-1.98) were associated with NCI in cocaine users. HIV was associated with two NIHTB-CB measures overall. In addition, HIV was associated with a lower dimensional change card sort score (an executive function measure) in cocaine users and not in nonusers. Cognitive performance was poorer in female than in male cocaine users. The adverse effect of HIV on cognitive performance predominantly affected cocaine users. However, cocaine use may moderate the impact of HIV and female sex on cognitive performance, highlighting the importance of reducing cocaine use in NCI prevention among the AA population.

Background: Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established., Methods: AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI., Results: In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46-56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development., Conclusions: NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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., (© 2020. Springer Nature Switzerland AG.)

Background: Mental health conditions are common among persons with HIV (PWH). An understanding of factors associated with prescription medication use for these conditions and clinical impact of the prescription medications may improve care of mental health disorders in PWH., Methods: Psychotropic medication use was examined among PWH within the AIDS Clinical Trials Group A5322 (HAILO) study. Multivariable logistic models and Cox regression models estimated the association between psychotropic medications (any/none) with baseline and incident slow gait (>1 s/m) and neurocognitive impairment (NCI) for more than 4 years., Results: Of 1035 participants, the median age was 51 years.81% were men, 30% black, non-Hispanic, and 20% Hispanic. Psychotropic medication use was similar between men (34%) and women (38%; P = 0.19). PWH using psychotropic medications had greater odds of baseline slow gait {odds ratio 1.61, [95% confidence interval (CI): 1.23 to 2.10]; P < 0.001}. Men but not women using psychotropic medications had an increased risk of developing slow gait [hazard ratio 1.85; (1.29 to 2.65) vs 0.77; (CI: 0.35 to 1.68), P interaction = 0.045]. The sex-specific odds ratios for medication use and NCI were qualitatively but not statistically different [men: 1.79; (1.14-2.80); women: 1.27; (0.56-2.90); P interaction = 0.47]. Psychotropic medication use was associated with an increased risk of incident NCI [hazard ratio 2.18; (95% CI: 1.23 to 3.84), P = 0.007] in both men and women., Conclusions: Psychotropic medications are associated with impairment in functional outcomes of aging, with a greater risk of baseline NCI and incident slow gait among men. Further investigation is needed to optimize outcomes in PWH and prescription of psychotropic medications among both men and women.

Given that neurocognitive impairment is a frequent complication of HIV-1 infection in Spanish-speaking adults, the limited number of studies assessing HIV-associated neurocognitive disorders (HAND) in this population raises serious clinical concern. In addition to being appropriately translated, instruments need to be modified, normed, and validated accordingly. The purpose of the current study was to examine the diagnostic utility of the HIV Dementia Scale (HDS) and International HIV Dementia Scale (IHDS) to screen for HAND in Spanish-speaking adults living with HIV infection. Participants were classified as either HAND (N = 47) or No-HAND (N = 53) after completing a comprehensive neuropsychological evaluation. Receiver operating characteristic analyses found the HDS (AUC = .706) was more sensitive to detecting HAND than the IHDS (AUC = .600). Optimal cutoff scores were 9.5 for the HDS (PPV = 65.2%, NPV = 71.4%) and 9.0 for the IHDS (PPV = 59.4%, NPV = 59.1%). Canonical Correlation Analysis found the HDS converged with attention and executive functioning. Findings suggest that while the IHDS may not be an appropriate screening instrument with this population, the HDS retains sufficient statistical validity and clinical utility to screen for HAND in Spanish-speaking adults as a time-efficient and cost-effective measure in clinical settings with limited resources.

Purpose of Review: This article critically reviews the utility of "phenotypes" as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging., Recent Findings: The main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited. Three paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths.

Background: The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment., Methods: With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data., Findings: 5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0·0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0·002), executive function (p<0·0001), motor function (p<0·0001), and working memory (p=0·001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0·03) and motor function (p=0·02)., Interpretation: A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains., Funding: National Institute of Mental Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

To characterize the relationship between dispersion-based intra-individual variability (IIVd) in neuropsychological test performance and brain volume among HIV seropositive and seronegative men and to determine the effects of cardiovascular risk and HIV infection on this relationship. Magnetic Resonance Imaging (MRI) was used to acquire high-resolution neuroanatomic data from 147 men age 50 and over, including 80 HIV seropositive (HIV+) and 67 seronegative controls (HIV-) in this cross-sectional cohort study. Voxel Based Morphometry was used to derive volumetric measurements at the level of the individual voxel. These brain structure maps were analyzed using Statistical Parametric Mapping (SPM2). IIVd was measured by computing intra-individual standard deviations (ISD's) from the standardized performance scores of five neuropsychological tests: Wechsler Memory Scale-III Visual Reproduction I and II, Logical Memory I and II, Wechsler Adult Intelligence Scale-III Letter Number Sequencing. Total gray matter (GM) volume was inversely associated with IIVd. Among all subjects, IIVd -related GM atrophy was observed primarily in: 1) the inferior frontal gyrus bilaterally, the left inferior temporal gyrus extending to the supramarginal gyrus, spanning the lateral sulcus; 2) the right superior parietal lobule and intraparietal sulcus; and, 3) dorsal/ventral regions of the posterior section of the transverse temporal gyrus. HIV status, biological, and cardiovascular disease (CVD) variables were not linked to IIVd -related GM atrophy. IIVd in neuropsychological test performance may be a sensitive marker of cortical integrity in older adults, regardless of HIV infection status or CVD risk factors, and degree of intra-individual variability links with volume loss in specific cortical regions; independent of mean-level performance on neuropsychological tests., Competing Interests: Compliance with Ethical Standards: Conflict of Interest: All authors have declared that he or she has no conflict of interest. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study. Data Analysis: The data were analyzed by L.J. Hines, J.T. Becker and V. Maruca, with assistance from J. Sanders.

The ε4 allele of the apolipoprotein E (ApoE) gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε4, HIV disease, age, neuropsychological impairment, and death in a large, well-characterized study sample. A total of 2846 men participating in the Multicenter AIDS Cohort Study had ApoE genotyping and neuropsychological test data available for analysis. We found a significant association between HIV infection and time to death (from any cause), as well as older age, race, and education. But, ApoE status was not significantly associated with time to death. Similarly, we found a significant association between HIV infection and time to incident cognitive impairment, as well as age, education, and HIV serostatus; Apoε4 status was not related to incident cognitive impairment. There were no significant interactions between ApoE, HIV infection, and age on cognitive impairment. These data replicate and strengthen prior findings of the lack of association between ApoE ε4 and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male study in which the majority of participants were less than 65 years of age (range 22-87 years), it appears reasonable to conclude that the ε4 allele is not significantly interacting with HIV serostatus.

Introduction: The purpose of this study was to characterize brain volumetric differences in HIV seropositive and seronegative men and to determine effects of age, cardiovascular risk, and HIV infection on structural integrity., Methods: Magnetic resonance imaging was used to acquire high-resolution neuroanatomic data in 160 men aged 50 years and over, including 84 HIV seropositive and 76 seronegative controls. Voxel-based morphometry was used to derive volumetric measurements at the level of the individual voxel. Data from a detailed neuropsychological test battery were recombined into four summary scores representing psychomotor speed, visual memory, verbal memory, and verbal fluency., Results: Both age and HIV status had a significant effect on both gray matter (GM) and white matter (WM) volume. The age-related GM atrophy was primarily in the superior temporal and inferior frontal regions; the HIV-related GM loss included the posterior and inferior temporal lobes, the parietal lobes, and the cerebellum. Among all subjects, the performance on neuropsychological tests, as indexed by a summary variable, was related to the volume of both the GM and WM. Contrary to our predictions, the CVD variables were not linked to brain volume in statistically adjusted models., Conclusion: In the post-HAART era, having HIV infection is still linked to atrophy in both GM and WM. Secondly, advancing age, even in this relatively young cohort, is also linked to changes in GM and WM volume. Thirdly, CNS structural integrity is associated with overall cognitive functions, regardless of the HIV infection status of the study volunteers.

The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy.

In the United States, the term "Hispanic" has been used to refer to a person or groups of persons who originate from Spanish-speaking countries. However, this term fails to account for variables such as nationality, ethnicity, race, and cultural origin as well as the extent of assimilation to a new culture. In addition, factors such as the individual's generation, specific migratory status, years of education in each country, fluency, and day-to-day language usage contribute to variance in neuropsychological testing outcomes, which are sensitive to these factors. We have noted that the usage of the terms "Hispanic" and "Latino" is problematic in HIV-associated neurocognitive disorder (HAND) research; therefore, we propose grouping individuals by nationality or by the Spanish-speaking culture to which they belong. The rationale for not using these terms is based upon the sociodemographic findings among Spanish speakers infected with HIV and how these terms inadequately describe the rich heterogeneity of this population.

Peripheral neuropathy (PN) is the most common neurological complication of HIV infection,affecting over one third of patients. The research diagnosis of PN is complicated by the need for expensive, time-consuming, and noxious diagnostic tests. We investigated whether nerve conduction studies (NSC) and quantitative sensory tests (QST) provide added value for the diagnosis of PN for research purposes or whether the easily obtainable clinical measures (sensory and motor symptoms, sensitivity to pain and vibration, tendon reflexes, motor function) are sufficient.

Objective: To determine whether higher viral concentrations in the cerebrospinal fluid (CSF) and/or peripheral blood were associated with greater severity of cognitive impairment in HIV-1-seropositive subjects with cognitive-motor impairment., Methods: Cognitive performance measurements and viral load were obtained from HIV-1-seropositive individuals with cognitive-motor impairment entering a clinical trial before the introduction of highly active antiretroviral therapy (HAART). CSF viral load (UltraSensitive Roche HIV-1 Monitor test with detection limit of 50 copies/ml) was available from 179 patients, and peripheral (plasma or serum) viral load from 111 patients. Of these patients, 62% met the 1993 Centers for Disease Control (CDC) criteria for AIDS, and 19% had clinically significant cognitive impairment (i.e., global deficit score > or = 0.5). Possible associations between viral load and cognitive scores were examined with general linear regression models with and without adjustment for age, education, study site, antiretroviral use, CD4 cell count, and CDC stage., Results: The mean CSF viral load was 2.83 log(10)/ml +/- 0.94 (SD) (undetectable in 19.5%). Mean peripheral viral load was 4.11 log(10)/ml +/- 0.90 (SD). No statistically significant associations emerged between either CSF or peripheral viral load and the global deficit score, or any of the seven cognitive domain deficit scores., Conclusions: Among these HIV-1-sero-positive individuals with mainly minor HIV-1-associated cognitive deficits and not receiving HAART, no association between CSF or blood concentration of HIV-1 RNA and cognitive performance could be found. These results suggest that the severity of HIV-1-associated cognitive impairment is not directly related to concurrent viral concentration in the CSF or the peripheral blood.

Objective: To demonstrate the relationship between epidermal nerve fiber density (ENFD) in the leg and the phenotype of HIV-associated distal sensory polyneuropathy (HIV-DSP) in a multicenter prospective study (ACTG A5117)., Methods: A total of 101 HIV-infected adults, with CD4 cell count <300 cells/mm(3) and who had received antiretroviral therapy (ART) for at least 15 consecutive weeks, underwent standardized clinical and electrophysiologic assessment. All 101 subjects were biopsied at the distal leg (DL) and 99 at the proximal thigh (PT) at baseline. ENFD was assessed by skin biopsy using PGP9.5 immunostaining. Associations of ENFD with demographics, ART treatment, Total Neuropathy Score (TNS), sural sensory nerve action potential (SNAP) amplitude and conduction velocity, quantitative sensory testing (QST) measures, and neuropathic pain were explored., Results: ENFD at the DL site correlated with neuropathy severity as gauged by TNS (p < 0.01), the level of neuropathic pain quantified by the Gracely Pain Scale (GPS) (p = 0.01) and Visual Analogue Scale (VAS) (p = 0.01), sural SNAP amplitude (p < 0.01), and toe cooling (p < 0.01) and vibration (p = 0.02) detection thresholds. ENFD did not correlate with neurotoxic ART exposure, CD4 cell count, or plasma HIV-1 viral load., Conclusions: In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.

Assessment of cytokines in body fluids or cells provides important information in understanding the disease process and designing treatment strategies. Recent introduction of antibody-based protein arrays have provided investigators simultaneous and specific detection of multiple analytes in a single sample using minimum volumes. In this study, we used a biochip array system capable of measuring 12 cytokines and growth factors (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1alpha, IL-1beta, IFN-gamma, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF)) in HIV patients with immunological and virological discordance (discordant) to find out differences if any, in their plasma cytokine profiles when compared with concordant HIV-infected individuals. A sandwich chemiluminescent assay was performed with plasma specimens of 110 HIV patients (55 discordant, 55 concordant) and 22 normal healthy individuals followed by enzyme-linked immunosorbent assay (ELISA) to the confirm levels of cytokines and growth factors that showed significant differences in the two groups. The discordant HIV patients showed significantly higher levels of plasma VEGF (P = 0.001) and EGF (P = 0.034) levels when compared with concordant patients. Overall, the patients showed significantly higher levels of TNF-alpha, MCP-1 and VEGF when compared with the normal healthy controls (P < 0.05). ELISA for VEGF (P < 0.001) and EGF (P = 0.004) confirmed the comparison obtained with biochip array, between the discordant and concordant patients. The results of cytokine quantitation by biochip array and ELISA confirmed that this technology is not only comparable but also has a good potential in the future applications involving measurement of multiple cytokines with limiting specimens.

Background: Distal sensory polyneuropathy (DSP) is the most common neurologic complication of human immunodeficiency virus (HIV) infection. Risk factors for DSP have not been adequately defined in the era of highly active antiretroviral therapy., Methods: The authors evaluated 101 subjects with advanced HIV infection over 48 weeks. Assessments included a brief peripheral neuropathy (PN) screen (BPNS), neurologic examination, nerve conduction studies, quantitative sensory testing (QST), and skin biopsies with quantitation of epidermal nerve fiber density. Data were summed into a Total Neuropathy Score (TNS). The presence, severity, and progression of DSP were related to clinical and laboratory results., Results: The mean TNS (range 0 to 36) was 8.9, with 38% of subjects classified as PN-free, 10% classified as having asymptomatic DSP, and 52% classified as having symptomatic DSP. Progression in TNS from baseline to week 48 occurred only in the PN-free group at baseline (mean TNS change = 1.16 +/- 2.76, p = 0.03). Factors associated with progression in TNS were lower current TNS, distal epidermal denervation, and white race. As compared with the TNS diagnosis of PN at baseline, the BPNS had a sensitivity of 34.9% and a specificity of 89.5%., Conclusions: In this cohort of advanced human immunodeficiency virus (HIV)-infected subjects, distal sensory polyneuropathy was common and relatively stable over 48 weeks. Previously established risk factors, including CD4 cell count, plasma HIV RNA, and use of dideoxynucleoside antiretrovirals were not predictive of the progression of distal sensory polyneuropathy (DSP). Distal epidermal denervation was associated with worsening of DSP. As compared with the Total Neuropathy Score, the brief peripheral neuropathy screen had relatively low sensitivity and high specificity for the diagnosis of DSP.

We determined the extent of expression of three cytokines (IFN-gamma, IL-4, and TNF-alpha ) in brain tissue infected with human immunodeficiency virus-1 (HIV-1). The selections were IFN-gamma as a Th1 cytokine, IL- 4 as a Th2 cytokine, and TNF-alpha as a pro-inflammatory cytokine (and because of its prior implication in brain tissue damage due to HIV-1 infection). Based on current models for pathogenesis of HIV-1-associated dementia (HAD), in the periphery, Th1 cytokines are considered to be salutary, whereas Th2 cytokines are regarded as deleterious. However, we hypothesized that in the CNS these roles are reversed. Post-mortem temporal lobe tissue specimens from 16 HIV-1-seropositive patients and 11 HIV-1-seronegative controls were stained for IFN-gamma, IL-4, and TNF-alpha utilizing immunohistochemistry and alkaline phosphatase. HIV-1 infection causes alterations of brain cytokine expression that include increased IFN-gamma expression for HIV-1-seropositive vs. HIV-1-seronegative individuals. There was increased expression of IFN-gamma for HIV-1-seropositive individuals with or without HAD, with or without the broader category of neuropsychiatric impairment (NPI), and with or without opportunistic infections (OIs) compared to HIV-1-seronegatives. A significant inverse correlation between IFN-gamma vs. IL-4 in HIV-1-seropositives with HAD and in seronegative individuals was observed. There was an inverse correlation in seropositives between IFN-gamma vs. TNF-alpha, a positive trend with HAD, significant without HAD, significant with NPI and significant without OIs. Between IL-4 vs. TNF-alpha there was a correlation (trend) in seropositives, a trend with NPI, significant without NPI, and a trend without OI. Due to HIV-1 infection of the brain and neurological disease there is a prominent increased expression of IFN-gamma, an inverse expression of IFN-gamma vs. TNF-alpha, and TNF-alpha vs. IL-4. The inverse correlation between increased IFN-gamma and decreased IL-4 expression is consistent with the stimulation of activated macrophages, and T cells, greater toxicity in the HIV-1-infected brain, and is supportive of the significance of IFN-gamma in HIV-1-infected patients.

Background: The purpose of the study was to examine the relationship between age and plasma viral load in HIV-1-infected individuals., Design: The experimental method was to recruit older (> 50 years of age) and younger (18-39 years of age) HIV-1-infected individuals. The plasma viral load was measured using the Roche Molecular Systems UltraSensitive Roche HIV-1 Monitor test reflexively with the standard Amplicor HIV Monitor test to quantify viral load in the range of 50-750,000 copies of HIV-1 RNA/ml plasma., Subjects: A total of 135 HIV-1-seropositive individuals (at Centers for Disease Control and Prevention early symptomatic stage B or late symptomatic stage/AIDS C) were enrolled as part of a larger cohort also consisting of HIV-1-seronegative individuals., Results: A generalized linear models statistical analysis was conducted in order to evaluate age category as a predictor of plasma viral load. The result was a significant effect of age category, with older age associated with a lower plasma viral load. The association held controlling for antiretroviral therapy usage, disease stage, antiretroviral medication adherence, HIV-1 serostatus duration, alcohol and substance use, recent sexually transmitted disease, and sociodemographics (except income)., Conclusion: Older age was associated with lower levels of HIV-1 replication in this sample, independent of antiretroviral therapy usage, regimen adherence, and disease stage. It is suggested that the effect may be caused by changes in viral evolution or immunological monitoring specific to older individuals with HIV-1 infection.

Infection of the brain by HIV-1 often results in cognitive- motor disorders, the most severe form being HIV-1 associated dimentia (HAD). However, the etiology and pathogenesis of neuroAIDS at the molecular level is still not fully understood and controversial issues remain, including the significance of abortive infection and localized viral load. This paper proposes that quantitative comparison of HIV-1 proviral and RNAloads across the brain will clarify some of these issues. It was hypothesized that there are differences in ratios of multispliced and unspliced HIV RNA in different regions of brain by analogy with prior findings of brain regional differences in virus and strains of HIV-1. A competitive RT-PCR method was used to compare ratios of multispliced to unspliced HIV-1 RNA's across brain regions of one case with HAD. Statistical analysis results showed that data obtained by repeated assays for each RNA preparation were not significantly different. Significant differences were detected between specimens obtained from different regions of the brain. The ratio of MS/US RNA in the frontal lobe was significantly greater than in the basal ganglia, medial temporal lobe, and another site in the temporal lobe. It must be noted that our approach has been the analysis of macroscopic brain regions separated by several centimeters; future studies will analyze microscopic analysis of these brain regions. The current study was preformed to produce results on gross differences in neuroanatomical locations at cm distances. Future studies will be performed to compare different regions with microscopic anatomic specificity.

A neuropsychological battery for testing HIV-1-infected individuals in Spanish was developed. We refer to this battery as the HIV/University of Miami Annotated Neuropsychological test battery in Spanish (HUMANS). The HUMANS battery includes recommendations of the National Institute of Mental Health Neuropsychology Workgroup on HIV-1 infection and measures processes in the following 7 cognitive domains: attention, verbal and visual memory, information processing speed, abstraction and executive functioning, language, visuospatial and visuoconstructive, and motor. Administration requires approximately 3 to 4 hr. The English version of the battery is sensitive to HIV-1 serostatus and Centers for Disease Control clinical disease stage. We report on the test selection, translation, and adaptation of this parallel English battery into Spanish using methods to eliminate linguistically and culturally biased items in some tests. The importance of standardized neuropsychological instruments equivalent in different languages to test HIV-1-positive individuals for impairment is emphasized. Validation and reliability studies are in progress.

In young adults, a major neurologic complication of HIV-1 infection is cognitive motor impairment. Epidemiologic findings suggest that increasing age is a significant risk factor for HIV-1-associated dementia as the AIDS-defining illness. Findings from the few studies that have directly measured cognition in younger and older HIV-1-infected adults, however, have been mixed, in part, because of small sample sizes and other methodologic differences between studies. The authors present preliminary findings on cognitive functioning in symptomatic HIV-1-infected younger (aged 20-39 years) and older (aged 50 years or older) adults. Independent of age, HIV-1 infection was accompanied by learning and memory retrieval deficits, which were significantly associated with high plasma viral loads in the young adults. Relative to the younger and older HIV-1-negative (HIV-1-) groups, only the younger HIV-1-positive (HIV-1+) group had significantly longer reaction times (RTs). Within the older HIV-1+ group, however, longer simple and choice RTs were significantly correlated with higher viral loads and lower CD4 cell counts. Although HIV-1 infection affects cognition independent of age, longitudinal studies involving large numbers of older individuals are needed to determine whether there are age differences in the prevalence, nature, and severity of HIV-1-associated cognitive dysfunction.

Older HIV-1-seropositive individuals largely have not been investigated with respect to their psychosocial characteristics. In this article, the authors review research reported to date regarding the psychosocial context of this growing subgroup of HIV-1-infected individuals. Specifically, the authors consider the characteristics of mood state, life stressor burden, social support network, and coping strategies that individuals older than 50 years are more likely to adopt in adjusting to HIV-1 infection. The authors also separately consider issues of caregiving burden. Data supporting a theoretically based stressor-support-coping model are presented and related to targeting psychotherapeutic interventions for this age group.

Background: This study compared the effects of a supportive-expressive group intervention (GI) with an educational control condition (EC) on long-term psychosocial adjustment in gay men with HIV infection., Method: Subjects (n = 85) were randomized after stratification for disease stage and use of antiretroviral medication. GI consisted of 4 months of weekly group sessions followed by 5 monthly maintenance sessions plus written educational material, whereas the EC subjects received educational material only., Results: There were no between-group differences in effects on distress, coping or social support in analyses examining 4 time points over 15 months. Both conditions decreased in distress over time on the Hopkins Symptom Checklist and Beck Depression Inventory., Conclusions: Several explanations are offered for the reason why no additional benefit of the GI was found on outcome measures studied when compared with the EC condition and recommendations are made for future psychosocial intervention research with HIV-infected persons., (Copyright 2003 S. Karger AG, Basel)

Objective: To develop a neuropsychological test battery in Spanish for the cognitive evaluation of HIV 1 infected patients., Development: Departing from the suggestions presented by the work group of the National Institute of Mental Health (USA), a neuropsychological assessment battery was developed. It was named HUMANS (HIV/University of Miami Annotated Neuropsychological test battery in Spanish). This battery includes the following domains: 1) attention and speed of processing information, 2) memory, 3) executive function, 4) language, 5) visuospacial/visuoconstructive abilities, and 6) motor abilities. Administration takes about 3 4 hours. The English parallel version of this battery has been successfully used in English for over a decade with HIV 1 infected patients. In the paper the development and adaptation to Spanish language of the HUMANS neuropsychology section is presented., Conclusions: HUMANS neuropsychological test battery fulfill the recommendations presented by the work group of the National Institute of Mental Health for evaluating HIV 1 infected patients. Studies regarding validity and reliability are still required.

Although persons 50 years of age and older account for 10% of all US AIDS cases, the mental health needs of this growing group remain largely overlooked. The current study delineated patterns and predictors of psychological symptoms amongst late middle-aged and older adults living with HIV/AIDS in two large US cities. In late 1998, 83 HIV-infected individuals 50-plus years of age (M = 55.2, Range = 50-69) completed self-report surveys eliciting data on psychological symptomatology, HIV-related life-stressor burden, social support, barriers to health care and social services, and sociodemographic characteristics. Based on the Beck Depression Inventory, 25% of participants reported 'moderate' or 'severe' levels of depression. HIV-infected older adults also evidenced an elevated number of symptoms characteristic of somatization. A hierarchical multiple regression analysis revealed that HIV-infected older adults who endorsed more psychological symptoms also reported more HIV-related life-stressor burden, less support from friends, and reduced access to health care and social services due to AIDS-related stigma. As the impact of HIV on older communities continues to increase, geropractitioners must be prepared to provide care to greater numbers of HIV-infected older adults, a substantial minority of whom will present with complex comorbid physical and mental health conditions.

Background: The Medical Outcomes Study HIV (MOS-HIV) Health Survey is a widely used instrument to assess quality of life in HIV-1-infected individuals. Its cognitive functional status subscale measures functional status owing to neuropsychological (NP) impairment., Objectives: To determine the concurrent validity of the Dutch four-item MOS-HIV cognitive functional status subscale and its clinical significance in predicting NP test performance., Design: Cross-sectional analysis of baseline data collected between October, 1994, and March, 1997, in the Netherlands and in Flanders, Belgium., Subjects: A total of 85 HIV-1-infected homosexual men who participated in an ongoing longitudinal research project designed to study the effects of a support group., Results: The MOS-HIV cognitive functional status subscale showed significant associations with NP test performance overall and, specifically, with the domains of abstraction, language and visuospatial abilities, controlling for CD4 cell count and Centers for Disease Control and Prevention (CDC) clinical disease stage. A trend toward significance was also found in the memory domain., Conclusions: To our knowledge, this is the first report of a cognitive functional status subscale used with HIV-1-infected subjects in a language other than English. The MOS-HIV cognitive functional status subscale seems particularly sensitive to changes in NP test performance in early HIV-1 infection. These results suggest the potential for clinical utility of a brief functional status self-report measure related to cognitive abilities in early HIV-1 infection for the screening and diagnosis of HIV-1 associated cognitive-motor disorders.

Treatment advances such as the advent of highly active antiretroviral therapy (HAART) have translated into greater life expectancy for HIV-infected individuals, which will ultimately result in a "graying" of the HIV/AIDS epidemic. In addition, older individuals are engaging in a higher rate of high risk behaviors than had been previously expected. As such, study of older HIV-infected patients, including study of the psychiatric and neurocognitive aspects of the disease, appears highly indicated. Epidemiological studies have demonstrated that HIV infection is associated with higher rates of several psychological/psychiatric disorders when compared to general population base rates. There is also a rich literature that has documented the adverse neurocognitive effects of HIV infection, ranging from subtle cognitive complaints to frank dementia, among younger adults. Although it has been hypothesized that older age may potentiate the deleterious effects of HIV infection, little is actually known, however, regarding the incidence, prevalence, course, and clinical features of HIV-associated psychiatric and cognitive dysfunction among older adults. This article provides an overview of the epidemiology and clinical manifestations of HIV-associated cognitive and psychiatric disorder across the age spectrum, with particular focus on what is known regarding the interaction of advancing age and HIV infection. Future directions for research are suggested, including basic epidemiologic study of incidence and prevalence rates of neurodisease among older HIV-infected adults as well as investigations designed to determine whether the nature, severity, course, or treatment of such disorders differs among older versus younger patients.

Objectives: This study investigates the potential impact of a bereavement support group on plasma viral load., Methods: A randomly selected subsample of human immunodeficiency virus type 1 (HIV-1)-positive homosexual men participating in a controlled clinical trial of a bereavement support group intervention was studied. The intervention consisted of one 90-minute group session per week for 10 weeks. The plasma HIV-1 RNA copy number was measured at baseline and after intervention (10 weeks) by the Roche AMPLICOR assay., Results: There was a significant effect of the intervention on the change on the plasma HIV-1 RNA copy number (limited control model, beta = -0.49, p = 0.02; extended control model, beta = -0.37, p = 0.01), independent of antiretroviral therapies; prophylactic therapies against potentially lethal HIV-1 associated conditions; CD4 cell count; viral load; and Centers for Disease Control and Prevention clinical disease stage at baseline., Conclusions: Bereavement support group interventions may prove to be not only a primary therapy for psychologic distress after bereavement but also an adjunctive therapy for sustained control of plasma viral load in conjunction with highly active antiretroviral therapy in this population.

Reduced level of serotonin (5-hydroxytryptamine, 5-HT) in humans has been associated with a number of mental health and behavioral problems including depression, aggression, violence, sexual dysfunctions, sleep and eating disorders. Even though among HIV-1-infected individuals, prevalence of mental health and behavioral problems are common, their relationship with central nervous system serotonin functions is not clearly understood. This investigation was carried out to study the status of CSF 5-HT in HIV-1+ subjects (n = 21), in the early stage of infection, and HIV-1- control subjects (n = 24). Samples of CSF were obtained by lumbar puncture and were analyzed for 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), using high-performance liquid chromatography equipped with electrochemical detector. Levels of CSF 5-HT were significantly lower in the HIV-1+ group compared to the HIV-1- group. There was no significant difference in the CSF 5-HIAA levels between the two groups. In both groups, however, there was a significant correlation between CSF 5-HT and 5-HIAA. In the HIV-1 + group, although CSF 5-HT level was significantly negatively correlated with serostatus, there was no correlation between either CSF 5-HT or 5-HIAA levels and CD4 cell number or any behavioral measures evaluated in this study, including Beck's Depression Inventory and state/trait anxiety scores. These data suggest that HIV-1 infection affects the CNS 5-HT status with no significant association with measures of depression and anxiety, at least in the early stage of infection., (Copyright 2001 S. Karger AG, Basel.)

HIV-1-associated brain pathology exhibits regional variability and we therefore studied the genetic differences in the V1-V5 domains of the HIV env gene in up to four regions of brain (frontal lobe, basal ganglia, medial temporal lobe, and nonmedial temporal lobe) from three patients. We found that in each separate brain region HIV-1 forms different quasispecies and that there is little gene flow among these regions. In further support of brain region-specific evolution of HIV-1, we analyzed amino acid signatures in these clones. In addition to known amino acid signatures associated with macrophage tropism and the lack of syncytium formation, we found 15 majority amino acid signature patterns from the V1-V5 env sequences associated with the neuroanatomical regions analyzed from the three individuals. Furthermore, on average, intrabrain genetic distances for the HIV-1 env were estimated to be much smaller than genetic distances between brain regions. Specific strains of HIV-1 may be neurotropic or neuroinvasive (replication preference in brain tissue) and may contribute to pathology, cognitive loss, and neuropsychiatric disease.

Patients infected with human immunodeficiency virus, type 1, may present with neuropsychiatric manifestations across all stages of disease. Frequently, these patients may present with more than one neuropsychiatric disorder concomitantly. The case presented highlights the utility of detailed clinical observation, careful use of medical terminology, and a neuropsychiatric organizing paradigm in the diagnosis and treatment of a patient presenting over time with delirium, aphasia, mania, and a complex partial seizure disorder.

Objective: Altered levels of serum cholesterol, which are prevalent in early HIV-1 infection, have been associated with disturbances in mood state and behavior. The objective of this study was to evaluate the relationship of serum cholesterol status and psychological distress in HIV-1 seropositive and seronegative men., Method: The association between serum cholesterol level and psychological distress, measured with the Profile of Mood States (POMS), was examined in 169 individuals (117 HIV-1 seropositive and 52 seronegative homosexual men), controlling for negative life events, social support, coping style, and HIV-1 serostatus., Results: Individuals with hypocholesterolemia (serum cholesterol levels < 150 mg/dL), exhibited significantly higher levels of distress, relative to individuals with values of cholesterol > 150 mg/dL (p = 0.01). HIV-1 seropositive men had significantly lower cholesterol levels (p = 0.0001) and higher levels of distress than the seronegative men (p = 0.03). A significant interaction between negative life events and cholesterol status was demonstrated as well (p = 0.04)., Conclusions: Hypocholesterolemia appears to be associated with increased psychological distress. Whereas the causal direction of the cholesterol-distress association cannot be specified, our results suggest that HIV-1 infected men with low cholesterol levels may benefit from being monitored for changes in distress level, so that appropriate psychosocial intervention can be instituted, as necessary.

Mild manifestations (HIV-1 associated minor cognitive/motor disorder), severe manifestations (HIV-1 associated dementia complex and HIV-1 associated myelopathy), and sensory neuropathy are consequences of HIV-1 infection. Our goal is to elucidate the role of HIV-1 in the complications of AIDS including cytokine immunopathology and HIV-1 DNA sequence variants. We have examined the brain and sensory ganglia from 60 AIDS patients and 20 seronegative controls using PCR, DNA sequencing of the HIV-1 envelope protein (env), in situ hybridization (ISH), and immunohistochemistry (IHC). Using our combined ISH-IHC technique, we could identify different types of cells and HIV-1 simultaneously in cryostat and paraffin sections. We found HIV-1 predominantly in macrophage/microglia in brain. In dorsal root ganglia (DRG) we found rare macrophages infected with HIV-1 and neurons and interstitial cells (including macrophages) which were apoptotic. Cytokines were detected in mononuclear and endothelial cells near neurons. We achieved single copy sensitivity detecting HIV-1 in nervous tissue using nested PCR. We sequenced HIV-1, DNA from 3 intravenous drug users (IDUs): from brain, CSF, and blood. PCR amplification was followed by cloning and then sequencing the HIV-1 insert: V1-V5 regions of the envelope (env) gene. We found that the env genes had increased sequence variation compared to the literature, cDNA sequences derived from RNA were less heterogeneous than clones derived from DNA from the same specimens, clones derived from brain are more closely related (show restricted heterogeneity) compared to clones from blood and CSF from the same patients. Patient 149 clones we examined to date did not correspond to any of the designated subtypes (A-F) of HIV-1 based on the DNA sequences of the C2-V3 regions. Finally, the HIV-1 RNA produced in these tissues is derived from a minority of DNA clones. Although HIV-1 infected macrophages are not entirely responsible for pathology in the brain and less so in sensory ganglia, some of the products of infection, cytokines, are more widespread in these tissues. Furthermore, HIV-1 strains infecting the brain appear to exhibit restricted heterogeneity compared to autologous CSF and blood and these strains may be associated with cytokines and pathology. HIV-1 strains that infect nervous tissue and cytokines produced in this tissue may effect neuropathogenesis, in vivo, in spite of low levels of local HIV-1 infection. We attempt to delineate, here, common sequence variations in HIV-1 isolates in the hope of developing future therapeutic strategies.

Objective: Inadequate vitamin B6 status has been associated with altered neuropsychiatric function, possibly through its effect on the metabolism of neurotransmitters, including serotonin (5-HT). The present eighteen month longitudinal study evaluated the relationship between vitamin B6 status and psychological distress in HIV-1 infected individuals, controlling for the influence of negative life events, social support and coping style., Method: Biochemical measurements of nutritional status, and dietary intake evaluations were obtained in HIV-1 seropositive homosexual men, (at baseline: CDC Stages II and III, n = 70; Stage IVA, IVC2 n = 18) at six month intervals. Alterations in nutrient status (e.g., vitamin B6 adequate to inadequate; inadequate to adequate), were compared with changes in psychological distress, measured by the Profile of Mood States, using a multiple regression analysis., Results: A significant decline in psychological distress was demonstrated with normalization of vitamin B6 status from inadequate to adequate status (p < 0.02). A decrease in psychological distress was also observed with increased tryptophan intake in subjects who were vitamin B6 adequate (p < 0.02)., Conclusions: Significant effects for the nutritional variables remained even when negative life event stressors, social support, and coping style were controlled, suggesting that vitamin B6 status may be an important co-factor in determining level of psychological distress over time in HIV-1 infected individuals.

Objective: Psychosocial associations have been observed with level of cervical dysplasia or "pre-cancer" and invasive cervical cancer [related to human papillomavirus (HPV) infection]. Psychoneuroimmunological relationships have been observed in human immunodeficiency virus type 1 (HIV-1) infection, which is being described in an increasing number of women. Our objective was to review these relationships regarding effects that might be expected in HIV-1 and HPV co-infected women., Method: This review was based on a Medline literature search supplemented by a manual search of selected journals unrepresented in that database., Results: Relationships of psychosocial factors and level of cervical dysplasia were similarly observed with reference to immunological and health status in asymptomatic and early symptomatic HIV-1 infected homosexual men, suggesting that a potentiating effect may occur in HIV-1 and HPV co-infected women. Consistency of relationships across studies appeared to be enhanced by the use of a biopsychosocial model integrating the effects of life stressors, social support and coping style as well as psychiatric disorders., Conclusions: Research is indicated on the relationships between psychosocial factors, immunological status and clinical health status in this group of women. Because of the high prevalence of psychosocial risk factors for chronic psychological distress in these women and the known immunological and health status decrements occurring with progression of these two infections, a clinical screening program based on the biopsychosocial model is recommended as a means of secondary prevention. If effective in generating treatment referrals, such a program would likely improve quality of life and could aid in the determination of relationships with immunological and health status as well.

A stress moderator framework was employed to investigate the relationship of negative life events, hardiness and social support to psychological distress among 67 asymptomatic HIV-1 seropositive gay males. Both main effects and stress moderator (interaction) models were evaluated. Main effects were found for negative life events and social support but not hardiness (either as commitment or overall hardiness); no moderator effects emerged. Results were the same whether events were quantified as negative impact or as number of events, and were in the predicted direction--life events associated with greater distress, social support with less distress. The present study replicates for early HIV-1 infection findings obtained in non-HIV-infected samples about the influence on psychological distress of negative life events and social support. Methodological limitations, possible explanations for the absence of stress moderator effects, and clinical implications of the findings are discussed.

Progressive multifocal leukoencephalopathy (PML) affects about 1 in 20 individuals with the acquired immunodeficiency syndrome (AIDS) and has been associated with poor survival. This report describes the results of a phase II clinical trial using the drug topotecan, a semisynthetic analogue of camptothecan, administered to a cohort of subjects with AIDS-related PML. Data were evaluated on 11 of 12 subjects enrolled in the study. Three responded to therapy. Additionally, one patient was treated off-protocol and showed a response to treatment. Progression occurred after the first course; however, a partial response was noted after five courses. One study patient died from accidental overdose of topotecan. Overall, responders had higher pretreatment Karnofsky and lower Kurtzke expanded disability status scale scores than nonresponders. The most frequent toxicities were hematologic (anemia, neutropenia, and thrombocytopenia). Five patients had dose delays; all delays were due to hematologic adverse events. This study demonstrates that topotecan treatment may be associated with decreased lesion size and prolonged survival from the infection. Because of the small number of subjects in the study, further studies are required to evaluate the efficacy of topotecan in treating this disease. [ABSTRACT FROM AUTHOR]

Focuses on the clinical trial examining the safety, tolerability and potential efficacy of topotecan in patients with AIDS-related progressive multifocal leukoencephalopathy. Creation of nicks in DNA during replication; Suppression of JC virus replication; Eligibility for the study.