Jacqueline Hoare

Characterization of HIV-Associated Neurocognitive Disorders among individuals starting antiretroviral therapy in South Africa.

HIV-Associated Neurocognitive Disorders (HAND) exert an impact on everyday functions, including adherence. The prevalence of and risk factors for HAND in patients commencing anti-retroviral therapy in Southern Africa are unknown. Participants from primary care clinics in Cape Town, South Africa underwent detailed neuropsychological, neuropsychiatric, and neuromedical evaluation. Using the updated American Academy of Neurology (AAN) criteria, participants were classified into categories of HAND, and demographic and clinical risk factors for HIV-dementia (HIV-D) were assessed. The prevalence of mild neurocognitive disorder (MND) and HIV-D were 42.4 and 25.4%, respectively. There were significant associations between lower levels of education and older age with HIV-D, and a trend to association with HIV-D and lower CD4 count. In a regression model, a lower level of education and male gender were predictive of HIV-D. These findings suggest that HAND are highly prevalent in primary care settings in South Africa where clade C HIV is predominant.

Validity of the International HIV Dementia Scale in South Africa

HIV-associated neurocognitive disorders (HAND) remain prevalent, especially in regions like South Africa where HIV prevalence is high but access to antiretroviral treatment (ART) is limited. The incidence of HIV dementia (HAD) has been halved with the use of ART, but the prevalence remains high. Appropriate brief screening tools to screen for HAD are needed in order to facilitate treatment initiation. The validity of the International HIV Dementia Scale has not been established in a region where infection with HIV clade C is predominant. The International HIV Dementia Scale (IHDS) was administered together with a detailed neuropsychological test battery to 96 HIV-positive individuals who had not received ART and who were attending primary care HIV clinics. The validity of the IHDS was established using a receiver operating characteristic (ROC) analysis. HIV-positive individuals displayed greater impairment when compared to HIV-negative controls on the IHDS and a range of neuropsychological tests. Neuropsychological tests discriminated well across HAND categories for HIV-positive individuals. In ROC analysis, the IHDS showed an area under the curve of 0.64, with a sensitivity of 45% and specificity of 79% at a cutoff score of 10. Individuals with HAD, who screened negative on the IHDS, performed poorly on some tests of executive function. These data suggest that the IHDS may have limitations as a tool to screen for HAD in South Africans infected with HIV. Variable performance in neuropsychological testing may account for false negative screens. The inclusion of brief tests of executive function in a screening battery should be considered.

Neuropsychological outcomes in adults commencing highly active anti-retroviral treatment in South Africa: a prospective study.

BackgroundInfection with HIV may result in significant neuropsychological impairment, especially in late stage disease. To date, there have been no cohort studies of the impact of highly active anti-retroviral treatment (HAART) in South Africa where clade C HIV is predominant.MethodsParticipants in the current study were recruited from a larger study of HIV-associated neurocognitive disorders (HAND) and included a group of individuals commencing HAART (n = 82). Baseline and one-year neuropsychological function was assessed using a detailed battery, and summary global deficit scores (GDS) obtained. Associations with change in GDS were calculated.ResultsParticipants had a median CD4 cell count of 166 at baseline and 350 at follow-up. There were significant difference across groups of GDS severity at baseline with respect to level of education and GDS change at one year (p = 0.00 and 0.00 respectively). Participants with severe impairment at baseline improved significantly more than those with lesser degrees of impairment. Significant improvements were observed in the domains of attention, verbal fluency, motor function, and executive functions. There were unadjusted associations between GDS change and male gender, lower levels of education, baseline CD4 count and baseline GDS severity. In an adjusted model, only baseline GDS severity (p = 0.00) remained significant, with a lower level of education nearing significance (p = 0.05). The overall model was highly significant (p = 00; r-squared = 0.58).DiscussionIn individuals in late stage HIV commencing HAART in South Africa, those with severe baseline neuropsychological impairment improved significantly more than those less impaired. While improvement across a number of neuropsychological domains was observed, high rates of impairment persisted.ConclusionsThe effects of HAART and participant variables, such as test experience, require clarification. Studies with larger comparison groups, and where HIV disease characteristics are needed to establish whether the trends we identified are clinically meaningful.

Systematic review of neuroimaging studies in vertically transmitted HIV positive children and adolescents

One of the most serious consequences of vertical HIV-infection is its impact on the central nervous system (CNS). Although much work has been done to elucidate the complex mechanism of HIV associated neurotoxicity, several questions remain unanswered. The purpose of this review is to summarise what is already known in the field of neuroimaging in vertically acquired HIV, addressing three aims and to highlight possible future directions in using neuroimaging and neurocognitive testing to understand the spectrum of neurocognitive disorders in HIV positve children. Here we aim to address several clinically relevant questions in pediatric neuroHIV, using the current evidence base by conducting a systematic review. We aim to investigate what is known about the relationship between cognitive impairment and central nervous system damage in HIV as seen in neuroimaging studies, and to search for any evidence in the current literature which suggests a spectrum of neuocognitive disorders in vertically infected HIV. Secondly, we aim to enquire whether children with a clinical diagnosis of encephalopathy are clearly distinguishable from HIV positive children without encephalopathy on neuroimaging and neurocognitive testing. Finally aim to investigate what is known about the effect on the CNS of antiretroviral therapy in paediatric HIV. Three separate databases were searched and two investigators systematically evaluated the titles, abstracts, and keywords associated with each individual article to determine those that may have met the inclusion and exclusion criteria. Following this process 11 studies were included in the review. Thus there was limited available data to address the 3 questions posed.

Association between apolipoprotein E4 genotype and human immunodeficiency virus-associated dementia in younger adults starting antiretroviral therapy in South Africa

It is not known whether the apolipoprotein E (ApoE) ε4 allelic variant is associated with human immunodeficiency virus (HIV)-associated dementia (HAD) in a South African population, where HIV clade C is predominant. ApoE genotyping was performed on 144 participants in a larger study of HIV-associated neurocognitive disorders (HAND). There was a lower frequency of the ε2 and ε3 alleles in the HIV-positive group, compared to a group of 300 community-based newborn infants. There were no differences in ApoE genotype across different categories of HAND. The ε4 allelic variant was less common in individuals with HAD than in those without HAD. These findings suggest that the ε4 allelic variant in HIV-positive individuals is not associated with the development of HAD in Southern Africa.

White-Matter Damage in Clade C HIV-Positive Subjects: A Diffusion Tensor Imaging Study

The relationship between cognitive impairment and white-matter integrity in human immunodeficiency virus (HIV) remains poorly understood, particularly in clade C. The authors utilized diffusion tensor imaging (DTI) and a comprehensive neuropsychological evaluation to investigate the relationship between cognitive impairment and white-matter integrity in HIV-positive subjects with clade C HIV. Forty-four HIV-infected individuals and 10 seronegative subjects were compared, using a whole-brain, voxel-based approach to define fractional anisotropy (FA) and mean diffusion (MD). Compared with healthy-control subjects, the HIV-infected group exhibited decreased FA in the corpus callosum, superior longitudinal fasciculus, and cingulum and sagittal stratum. This study provides evidence that white-matter integrity is compromised in individuals infected with clade C HIV.

White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa.

Objective:To describe the effect of HIV on white matter integrity and neurocognitive function in children vertically infected with HIV, compared to a HIV-negative healthy control group. Design:Cross-sectional. Methods:We compared 75 HIV-infected children aged 6–16 years, including children on antiretroviral therapy (ART) and those who were ART-naive, with 30 controls on diffusion tensor imaging and a neuropsychological battery sensitive to fronto-striatal pathology. In a secondary analysis, we compared ‘slow progressor’ ART-naive children, children on ART without a diagnosis of encephalopathy and children on ART with HIV encephalopathy. Results:Compared to controls (n = 30), HIV-infected children (n = 75) displayed decreased fractional anisotropy and axial diffusion, and increased mean diffusivity and radial diffusion, indicating damaged neuronal microstructure. HIV-infected children performed poorly on the neuropsychological battery (P = <0.001). Within the HIV-infected group, children with HIV encephalopathy (n = 14) had poor white matter integrity when compared to ART-treated children without encephalopathy (n = 41), and there was significant myelin loss in ART-naive children (n = 20), compared with ART-treated children. ART-treated children had significant axonal damage in the corpus callosum (P = 0.009). Conclusion:Children infected with HIV, irrespective of treatment status, displayed significantly poorer white matter integrity and impaired cognition compared to HIV-negative controls. Our findings suggest that despite immune recovery in children on ART, they remain at risk for developing central nervous system disease, and that initiation of ART as early as possible may reduce the risk of developing white matter damage in ART-naive slow progressors.

HIV-Associated Cognitive Impairment in Perinatally Infected Children: A Meta-analysis

CONTEXT: Research shows, conclusively, that perinatal HIV infection has negative effects on cognitive functioning of children and adolescents. However, the extent of these cognitive impairments is unknown. Current literature does not document specific cognitive domains most affected in HIV-infected children and adolescents. OBJECTIVE: To systematically review and meta-analyze the degree of cognitive impairment, and the specific cognitive domains affected, in children and adolescents with perinatally acquired HIV infection. DATA SOURCES: We systematically searched 5 electronic bibliographic databases, namely: PubMed, PsychINFO, Academic Search Premier, Scopus, and WorldCat, by using a search protocol specifically designed for this study. STUDY SELECTION: Studies were selected on the basis of set a priori eligibility criteria. Titles, abstracts, and full texts were assessed by 2 independent reviewers. DATA EXTRACTION: Data from included studies were extracted into Microsoft Excel by 2 independent reviewers. RESULTS: Twenty-two studies were identified for inclusion in the systematic review and of this, 6 studies were included in the meta-analysis. Results from the meta-analysis indicated that working memory and executive function were the domains most affected by the HIV virus. LIMITATIONS: Only 27% of the included studies were suitable to enter into the meta-analysis. There was significant geographic bias in published studies, with only 32% (7/22) of included studies from sub-Saharan Africa. CONCLUSIONS: The evidence supports an association between HIV infection in children and adolescents and cognitive impairment in the domains of working memory, executive function and processing speed, with effect size estimates also providing some support for deficits in visual memory and visual-spatial ability.

Impact of the HIV Tat C30C31S dicysteine substitution on neuropsychological function in patients with clade C disease.

Previous animal studies have identified a C31S residue substitution in the C30C31 dicysteine motif of the Tat protein that is associated with reduced neurovirulence in clade C human immunodeficiency virus (HIV). However, clinical studies of patients infected with clade C HIV have reported significant levels of cognitive impairment. To date, no study has specifically examined cognitive function in clade C-infected patients as a function of the presence or absence of the Tat C31 substitution. The present study investigated the impact of the Tat C30C31S genetic substitution among individuals residing in South Africa infected with clade C HIV that either exhibited the C30C31 motif (n = 128) or the C31S motif (n = 46). A control group of seronegative individuals was included to examine the overall impact of HIV on cognitive performance. All individuals completed a comprehensive neuropsychological battery consisting of tests sensitive to HIV. Results revealed that clade C-infected individuals performed significantly worse across cognitive tests compared to seronegative controls. However, there were no significant differences in cognitive performances between individuals with the C31S motif versus those without the C31S substitution. Proximal CD4 cell count and plasma viral load were unrelated to cognitive performances for either group. Results confirm that the C31S dicysteine motif substitution of the Tat protein does not appreciably moderate neuropsychological outcomes in clade C. Further, these findings highlight the importance of clinical management of cognitive symptoms among individuals infected with this viral clade worldwide.

Applying the HIV-associated neurocognitive disorder diagnostic criteria to HIV-infected youth

Objective: The aim of this study was to apply the HIV-associated neurocognitive disorders (HAND) criteria for diagnosing HAND in HIV-infected adults, in a cohort of HIV-infected youth to thus establish whether this system is able to detect a spectrum of neurocognitive disorders (ND) in HIV-infected youth. Methods: We used a comprehensive pediatric neurocognitive battery, an assessment of functional competence, and the American Academy of Neurology system for diagnosing ND in a cross-sectional study of HIV-infected youth (n = 86) and HIV-negative controls (n = 34) to establish whether this system could detect a spectrum of ND in HIV-infected youth (6–16 years). Results: Compared to a well-matched control group of HIV-negative youth, HIV-infected youth performed significantly more poorly on tests of Verbal IQ, Full Scale IQ, processing speed, finger tapping, verbal memory, expressive language, cognitive flexibility, and inhibition. HIV-infected youth were also more likely to have impaired total competence on the Child Behavior Checklist. Using the criteria for HAND, we found that 45.35% of the 86 HIV-infected youth could be diagnosed with an ND. Furthermore, youth with HIV encephalopathy (HIVE) were 9.4 times more likely to have a diagnosis of a major ND compared to HIV-infected youth without HIVE. Conclusions: The HAND criterion designed for adults was able to identify youth with important functional cognitive impairments who do not fit criteria for HIVE and would therefore not have been identified otherwise. This has major clinical implications regarding the importance of managing HIV-infected youth.