Kevin R. Robertson

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.

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. 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. 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. 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. NCT00096824.

Objective: The objective was to determine whether maraviroc (MVC) has unique neurocognitive benefits in the context of initial antiretroviral therapy (ART). Design: Randomized, double-blind, placebo-controlled, 48-week trial. Setting: Participants were enrolled in US AIDS Clinical Trials Group clinical trial sites. Participants: Total 262 ART-naive, chemokine coreceptor 5 tropic HIV, and HIV RNA greater than 1000 copies/ml participants were randomized, 230 participants completed the study. Intervention: Participants received MVC 150 mg or tenofovir disoproxil fumarate (TDF) 300 mg on a background of ritonavir-boosted darunavir and emtricitabine. Main outcome measure(s): The neuropsychological battery of 15 tests done at baseline, week 24 and week 48 assessed seven domains, and were standardized into z-scores then converted into deficit scores and a global deficit score. The 48-week changes from baseline in the neuropsychological scores and the global deficit score were compared by Wilcoxon or Kruskal–Wallis test between arms, and among baseline impairment groups [classified as normal, mild (2 deficit scores ≥1) and moderate (2 deficit scores ≥2)]. It was hypothesized that the MVC arm would have improved neuropsychological performance over TDF. Results: In this double-blind, randomized, placebo-controlled trial, there were no differences in neuropsychological performance between MVC and TDF. Those with moderate neuropsychological impairment at baseline experienced greater ART-mediated neuropsychological improvement than those with mild or no neuropsychological impairment. Conclusion: Improvement in neurocognitive functioning was greater with more baseline impairment but was comparable with MVC or TDF.

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 (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.

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.

Combination antiretroviral therapy has significantly reduced morbidity and mortality with HIV infection. However, HIV-associated neurocognitive disorders persist at a relatively high prevalence rate despite successful systemic treatment. This paper reviews the current issues related to the neurocognitive impact of antiretroviral treatment.

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.

Among patients with HIV infection, depression is the most frequently observed psychiatric disorder. The presence of depressive symptoms and cognitive dysfunction among HIV patients has not been well studied in Sub-Saharan Africa. Initiation of highly active antiretroviral therapy (HAART) may have an effect on the prevalence and the change over time of depression symptoms and cognitive impairment among HIV-positive individuals. We recruited 102 HIV-positive individuals at risk of cognitive impairment who were initiating HAART and 25 HIV-negative individuals matched for age and education. Depression was assessed using the Centre for Epidemiologic Studies Depression Scale (CES-D). Neurocognitive assessment included the International HIV Dementia Scale (IHDS), an 8 test neuropsychological battery and the Memorial Sloan Kettering scale. Assessments were carried out at 0, 3 and 6 months. The HIV-positive group had more respondents with CES-D score > 16 than the HIV-negative group at all 3 clinic visits (54%Vs 28%; 36% Vs 13%; and 30% Vs 24% respectively; all p < 0.050 OR 2.86, 95% CI: 1.03, 7.95, p = 0.044). The HIV positive group had higher likelihood for cognitive impairment (OR 8.88, 95% CI 2.64, 29.89, p < 0.001). A significant decrease in the mean scores on the CES-D (p = 0.002) and IHDS (p = 0.001) occurred more in the HIV-positive group when compared to the HIV-negative group. There was no association between clinical Memorial Sloan Kettering score and depression symptoms (p = 0.310) at baseline. Depression symptomatology is distinct and common among cognitively impaired HIV patients. Therefore individuals in HIV care should be screened and treated for depression.

In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting “NeuroAIDS in Africa.” This meeting was held in Cape Town,...