Background. Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. Methods. PLWH with a CD4+ count <300 cells/mm(3) underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once. Associations between covariates with DSPN at entry were assessed using the chi(2) test, and virally suppressed PLWH were assessed using generalized estimating equations. Results. Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; chi(2)(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [chi(2)(df = 1) = 10.6; P = .001] and depression [chi(2)(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. Conclusions. Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

Background. AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)-infected participants in resource-limited settings treated with 3 World Health Organization-recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. Methods. Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. Results. Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/mu L; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P<.001) and fingertapping nondominant hand (P<.01). TB was associated with diffuse CNS disease (P<.05). Furthermore, those with TB had 9.27 times (P<.001) higher odds of reporting decreased quality of life, and had 8.02 times (P=.0005) higher odds of loss of productivity. Conclusions. TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. Clinical Trials Registration. NCT00096824.

BACKGROUND:Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment. METHODS:The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations. RESULTS:Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168. CONCLUSIONS:Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments. CLINICAL TRIALS REGISTRATION:NCT00096824.

BACKGROUND AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings. METHODS Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations. RESULTS The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01). CONCLUSIONS The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization -recommended first-line antiretroviral regimens in resource-limited settings will improve neuropsychological functioning and reduce neurological dysfunction. CLINICAL TRIALS REGISTRATION NCT00096824.

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.

To begin to unravel the complexity of HIV-associated changes in the brain, broader, multifaceted analyses of cerebrospinal fluid (CSF) are needed that examine a wide range of proteins reflecting different functions. To provide the first broad profiles of protein changes in the CSF of HIV-infected patients, we used antibody arrays to measure 120 cytokines, chemokines, growth factors, and other proteins. CSF from HIV-infected patients with a range of cognitive deficits was compared to CSF from uninfected, cognitively normal patients to begin to identify protein changes associated with HIV infection and neurological disease progression. Uninfected patients showed relatively consistent patterns of protein expression. Highly expressed proteins in CSF included monocyte chemotactic protein-1, tissue inhibitors of metalloproteases, granulocyte colony-stimulating factor, adiponectin, soluble tumor necrosis factor receptor-1, urokinase-type plasminogen activator receptor, and insulin-like growth factor binding protein-2. Inflammatory and anti-inflammatory cytokines were expressed at low levels. HIV-infected patients showed increases in inflammatory proteins (interferon-gamma, tumor necrosis factor-alpha), anti-inflammatory proteins (IL-13), and chemokines but these correlated poorly with neurological status. The strongest correlation with increasing severity of neurological disease was a decline in growth factors, particularly, brain-derived neurotrophic factor and NT-3. These studies illustrate that HIV infection is associated with parallel changes in both inflammatory and neuroprotective proteins in the CSF. The inverse relationship between growth factors and neurological disease severity suggests that a loss of growth factor neuroprotection may contribute to the development of neural damage and may provide useful markers of disease progression.

Diffusion tensor image (DTI) is a powerful tool for quantitatively assessing the integrity of anatomical connectivity in white matter in clinical populations. The prevalent methods for group-level analysis of DTI are statistical analyses of invariant measures (e.g., fractional anisotropy) and principal directions across groups. The invariant measures and principal directions, however, do not capture all information in full diffusion tensor, which can decrease the statistical power of DTI in detecting subtle changes of white matters. Thus, it is very desirable to develop new statistical methods for analyzing full diffusion tensors. In this paper, we develop a set of toolbox, called RADTI, for the analysis of the full diffusion tensors as responses and establish their association with a set of covariates. The key idea is to use the recent development of log-Euclidean metric and then transform diffusion tensors in a nonlinear space into their matrix logarithms in a Euclidean space. Our regression model is a semiparametric model, which avoids any specific parametric assumptions. We develop an estimation procedure and a test procedure based on score statistics and a resampling method to simultaneously assess the statistical significance of linear hypotheses across a large region of interest. Monte Carlo simulations are used to examine the finite sample performance of the test procedure for controlling the family-wise error rate. We apply our methods to the detection of statistical significance of diagnostic and age effects on the integrity of white matter in a diffusion tensor study of human immunodeficiency virus.

Objectives: To characterize HIV-1 env compartmentalization between cerebrospinal fluid (CSF) and peripheral blood plasma over all stages of the HIV-1 disease course, and to determine the relationship between the extent of CSF HIV-1 env compartmentalization and clinical neurologic disease status. Design: Paired blood plasma and CSF specimens were collected from 66 HIV-infected patients cross-sectionally representing all major clinical stages relating to HIV-associated neurologic disease, including primary infection, asymptomatic chronic infection, chronic infection with minor global impairment, and immune deficiency with HIV-associated dementia. Methods: Heteroduplex tracking assays and bulk sequence analysis targeting the V1/V2, C2-V3, and V4/V5 regions of env were performed to characterize the genetic makeup of complex HIV-1 populations in the cross-sectional blood plasma and CSF specimens. The levels of blood plasma/CSF env compartmentalization were quantified and compared across the different clinical stages of HIV-1 neurologic disease. Results: Blood plasma/CSF env compartmentalization levels varied considerably by disease stage and were generally consistent across all three regions of env characterized. Little or no compartmentalization was observed in non-impaired individuals with primary HIV-1 infection. Compartmentalization levels were elevated in chronically infected patients, but were not significantly different between mildly impaired and non-impaired patients. Patients with HIV-associated dementia showed significantly greater blood plasma/CSF env compartmentalization relative to other groups. Conclusion: Increased CSF compartmentalization of the HIV-1 env gene, which may reflect independent HIV-1 replication and evolution within the central nervous system, is specifically associated with HIV-associated dementia and not the less severe forms of HIV-1 neurologic disease.

The aim of this paper is to develop an intrinsic regression model for the analysis of positive-definite matrices as responses in a Riemannian manifold and their association with a set of covariates, such as age and gender, in a Euclidean space. The primary motivation and application of the proposed methodology is in medical imaging. Because the set of positive-definite matrices do not form a vector space, directly applying classical multivariate regression may be inadequate in establishing the relationship between positive-definite matrices and covariates of interest, such as age and gender, in real applications. Our intrinsic regression model, which is a semiparametric model, uses a link function to map from the Euclidean space of covariates to the Riemannian manifold of positive-definite matrices. We develop an estimation procedure to calculate parameter estimates and establish their limiting distributions. We develop score statistics to test linear hypotheses on unknown parameters and develop a test procedure based on a resampling method to simultaneously assess the statistical significance of linear hypotheses across a large region of interest. Simulation studies are used to demonstrate the methodology and examine the finite sample performance of the test procedure for controlling the family-wise error rate. We apply our methods to the detection of statistical significance of diagnostic effects on the integrity of white matter in a diffusion tensor study of human immunodeficiency virus. Supplemental materials for this article are available online.

HIV associated dementia (HAD) is the most advanced stage of central nervous system disease caused by HIV infection. Previous studies have demonstrated that patients with HAD exhibit greater cerebral and basal ganglia atrophy than non-demented HIV+ (HND) patients. However, the extent to which white matter is affected in HAD patients compared to HND patients remains elusive. This study is designed to address the potential white matter abnormalities through the utilization of diffusion tensor imaging (DTI) in both HND and HAD patients. DTI and T1-weighted images were acquired from 18 healthy controls, 21 HND and 8 HAD patients. T1 image-based registration was performed to 1) parcellate the whole brain white matter into major white matter regions, including frontal, parietal, temporal and occipital white matter, corpus callosum and internal capsule for statistical comparisons of the mean DTI values, and 2) warp all DTI parametric images towards the common template space for voxel-based analysis. The statistical comparisons were performed with four DTI parameters including fractional anisotropy (FA), mean (MD), axial (AD), and radial (RD) diffusivities. With Whitney U tests on the mean DTI values, both HND and HAD demonstrated significant differences from the healthy control in multiple white matter regions. In addition, HAD patients exhibited significantly elevated MD and RD in the parietal white matter when compared to HND patients. In the voxel-based analysis, widespread abnormal regions were identified for both HND and HAD patients, although a much larger abnormal volume was observed in HAD patients for all four DTI parameters. Furthermore, both region of interest (ROI) based and voxel-based analyses revealed that RD was affected to a much greater extent than AD by HIV infection, which may suggest that demyelination is the prominent disease progression in white matter.

In July of 2006, the National Institute of Mental Health (NIMH) Center for Mental Health Research on AIDS (CMHRA) sponsored the second conference on the Assessment of NeuroAIDS in Africa, which was held in Arusha, Tanzania. The conference mission was to address the regional variations in epidemiology of HIV-related neurological disorders as well as the assessment and diagnosis of these disorders. Participants discussed and presented data regarding the relevance and translation of neuroAIDS assessment measures developed in resource intensive settings and the challenges of neuro-assessment in Africa, including the applicability of current tools, higher prevalence of confounding diseases, and the complexity of diverse cultural settings. The conference presentations summarized here highlight the need for further research on neuroAIDS in Africa and methods for assessing HIV-related neurological disorders.

Since the introduction of combination antiretroviral therapy, the manifestations of HIV-associated central nervous system (CNS) involvement have generally become less severe and more manageable. Patients initiating antiretroviral therapy have demonstrated improvement in cognitive functioning. Reduction of viral burden has been correlated with improved CNS functioning. Recent studies have focused on the importance of CNS-penetrating antiretroviral regimens to target active replication in this protected compartment. There were initial conflicting reports of whether CNS-penetrating antiretrovirals improved cognitive functioning, with more evidence supporting the importance of CNS penetration in reducing viral burden and improving cognitive outcomes. Cognitive loss remains a feature of HIV infection, and some patients still suffer from incident or progressing cognitive and motor dysfunction even on combination therapy. Because the virus enters the CNS within days of initial infection, latent infection may be chipping away at the brain during the long asymptomatic period in HIV. When to start antiretrovirals for the maximum cognitive benefit remains to be determined.

HIV is a prevalent health problem in Kenya as an estimated 6.1% of the adult population is currently HIV positive. Intimate partner violence has been associated with increased HIV risk in both women and in men in other settings. Using nationally-representative data from 2003 Kenya Demographic and Health Survey that includes information on both HIV serostatus and intimate partner violence to explore whether there is a correlation between physical sexual or emotional violence and HIV in currently married Kenyan men and women. Although I find that men whose wives report emotional abuse are more likely to be HIV positive this association is otherwise not significant. Rather among women HIV infection is significantly associated with being in a polygamous marriage as well as the number of years of exposure to premarital sexual activity. Among men being in a polygamous marriage is associated with a higher rate of HIV while being circumcised is associated with a lower probability of infection. In both genders being of Luo ethnicity is also often positively associated with HIV infection. (authors)

The global burden of the HIV epidemic is staggering, but in the short term, it is largely unfelt in the developed world. Almost one million people have been infected with HIV in North America, and the results of effective antiretroviral therapy have dramatically improved survival and quality of life. However, there are 25 million infected in sub-Saharan Africa alone, and antiretroviral treatment is scarce. Ninety-five percent of new infections occur in the developing world where resources are limited. Very little is known about NeuroAIDS in the developing world where few studies have been conducted on the neurologic and neurocognitive effects of antiretroviral treatment. HIV Clade differences and other factors could have dramatic effects on treatment effectiveness. There are a number of barriers in the assessment of neurological and neurocognitive effects in resource limited settings and some of these will be addressed.

Among the many variables affecting transmission and pathogenesis of the human immunodeficiency virus type 1(HIV-1), the effects of HIV subtypes, or clades, on disease progression remain unclear. Although debated, some studies have found that the variable env and pol sequences of different subtypes of HIV-1 may endow some subtypes with greater degrees of cell tropism, virulence, and drug resistance, which may lead to differences in overall disease progression. HIV-associated dementia (HAD) appears to be associated with viral diversity and markers of immune activation. Africa has the highest prevalence of HIV, largest viral diversity, and is where clade recombination occurs most frequently. All of these factors would suggest that HAD would pose the largest threat in this region of the world. Although investigations into the effects of different subtypes on overall disease progression are well documented, few have looked into the effects of subtypes on neurological disease progression. This review highlights the need for more international research involving the neurological effects and especially the clinical presentation of dementia for the entire range of the group M HIV-1 subtypes.

Objectives: To determine the efficacy of adding abacavir (Ziagen, ABC) to optimal stable background antiretroviral therapy (SBG) to AIDS dementia complex (ADC) patients and address trial design. Design: Phase III randomized, double-blind placebo-controlled trial. Setting: Tertiary outpatient clinics. Participants: ADC patients on SBG for ≥8 wk. Interventions: Participants were randomized to ABC or matched placebo for 12 wk. Outcome Measures: The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were HIV RNA and the immune activation markers β-2 microglobulin, soluble tumor necrosis factor (TNF) receptor 2, and quinolinic acid. Results: 105 participants were enrolled. The median change in NPZ at week 12 was +0.76 for the ABC + SBG and +0.63 for the SBG groups (p = 0.735). The lack of efficacy was unlikely related to possible limited antiviral efficacy of ABC: at week 12 more ABC than placebo participants had plasma HIV RNA ≤400 copies/mL (p = 0.002). There were, however, other factors. Two thirds of patients were subsequently found to have had baseline resistance to ABC. Second, there was an unanticipated beneficial effect of SBG that extended beyond 8 wk to 5 mo, thereby rendering some of the patients at baseline unstable. Third, there was an unexpectedly large variability in neuropsychological performance that underpowered the study. Fourth, there was a relative lack of activity of ADC: 56% of all patients had baseline cerebrospinal fluid (CSF) HIV-1 RNA <100 copies/mL and 83% had CSF β-2 microglobulin <3 nmol/L at baseline. Conclusions: The addition of ABC to SBG for ADC patients was not efficacious, possibly because of the inefficacy of ABC per se, baseline drug resistance, prolonged benefit from existing therapy, difficulties with sample size calculations, and lack of disease activity. Assessment of these trial design factors is critical in the design of future ADC trials.

Several studies were undertaken to assess the psychometric properties (reliability and initial convergent and discriminant construct validity) of the Neurological Quality of Life Questionnaire (NeuroQOL). The NeuroQOL contains 114 items answered in self report Likert format, with higher scores reflecting better quality of life. Study one compared the questionnaire with existing quality of life measures (Symptom Distress Scale, Sickness Impact Profile) and a significant (p < 0.05) correlation was found. Studies two through five evaluated the relationship between the NeuroQOL and disease stage, psychological, neuropsychological and neurological measures, and a significant correlation was also found with each domain. The internal consistency reliability (alpha = 0.96), split half reliability (r12 = 0.97), and test-retest reliability (coefficients were 0.78 for 6 months and 0.67 for one year intervals between test and retest) were all found to be high and adequately stable. Overall, these results indicate acceptable reliability and initial construct validity for the NeuroQOL.

The Timed Gait test is a standardized procedure assessing motor dysfunction of lower extremities and gait abnormalities associated with AIDS dementia complex. Heretofore, interpretations of Timed Gait results have been hampered by the lack of normative data. We provide results on this test derived from 1,549 subjects (HIV−seronegatives (HIV−) and seropositives (HIV+) classified according to ADC stage). Timed Gait was found to be a useful screening and assessment tool for evaluating ADC and correlated with clinical ADC staging as well as more extensive structured neurological and neuropsychological evaluations. Analysis of covariance results (with age and education as covariates) revealed symptomatic HIV+(SX) and AIDS groups having significantly slower Timed Gait scores than those in the HIV− and asymptomatic HIV+(ASX) groups. The SX group obtained significantly slower timed gait scores than those in the AIDS group. There was a significant increase in Timed Gait scores with each increase in dementia staging with the HIV− subjects having the fastest mean Timed Gait scores and the HIV+ dementia stage 2+ having the slowest. These normative data should prove useful in both recognition of ADC and treatment response. Given its minimal training requirements, the Timed Gait would have utility in resource limited settings.