The salience of structural barriers and behavioral health problems to ART adherence in people receiving HIV primary care in South Africa.

Multilevel factors (individual and structural) influence adherence to antiretroviral therapy, particularly in high HIV prevalence areas such as South Africa. The present study examined the relative importance of structural barriers to HIV care and behavioral health factors, depression and alcohol use, in Khayelitsha, Cape Town, South Africa. People receiving HIV care in six primary care clinics in Khayelitsha (N = 194) completed the Center for Epidemiologic Studies Depression Scale, the Alcohol Use Disorders Identification Test, the Structural Barriers to Medication Taking questionnaire, and a qualitative rating of past-two-week adherence. Correlations were employed to examine associations among these variables, and hierarchical regression analysis was used to examine the unique effects of structural barriers over and above depression and alcohol use as predictors of adherence. Participants were primarily Black South African (99%) women (83%), and 41 years old on average. All four variables were significantly correlated. The hierarchical regression analysis showed that among behavioral health predictors, alcohol use alone significantly predicted ART adherence (b = -.032, p = .002). When structural barriers was added to the model, it was the only significant unique predictor of ART adherence (b = -1.58, p < .001). Findings highlight the need to consider structural vulnerabilities in HIV care in South Africa when developing behavioral health interventions.

Comparing dedicated and designated approaches to integrating task-shared psychological interventions into chronic disease care in South Africa: a three-arm, cluster randomised, multicentre, open-label trial.

BACKGROUND: Community health workers (CHWs) are increasingly providing task-shared psychological interventions for depression and alcohol use in primary health care in low-income and middle-income countries. We aimed to compare the effectiveness of CHWs dedicated to deliver care with CHWs designated to deliver care over and above their existing responsibilities and with treatment as usual for patients with a chronic physical disease. METHODS: We did a three-arm, cluster randomised, multicentre, open-label trial done in 24 primary health-care clinics (clusters) within the Western Cape province of South Africa. Clinics were randomly assigned (1:1:1) to implement dedicated care, designated care, or treatment as usual, stratified by urban-rural status. Patients with HIV or type 1 or type 2 diabetes were eligible if they were 18 years old or older, taking antiretroviral therapy for HIV or medication to manage their diabetes, had an Alcohol Use Disorders Identification Test (AUDIT) score of eight or more or a Center for Epidemiologic Studies Depression Scale score of 16 or more, and were not receiving mental health treatment. In the intervention arms, all participants were offered three sessions of an evidence-based psychological intervention, based on motivational interviewing and problem-solving therapy, delivered by CHWs. Our primary outcomes were depression symptom severity and alcohol use severity, which we assessed separately for the intention-to-treat populations of people with HIV and people with diabetes cohorts and in a pooled cohort, at 12 months after enrolment. The Benjamini-Hochberg procedure was used to adjust for multiple testing. The trial was prospectively registered with the Pan African Clinical Trials Registry, PACTR201610001825403. FINDINGS: Between May 1, 2017, and March 31, 2019, 1340 participants were recruited: 457 (34·1%) assigned to the dedicated group, 438 (32·7%) assigned to the designated group, and 445 (33·2%) assigned to the treatment as usual group. 1174 (87·6%) participants completed the 12 month assessment. Compared with treatment as usual, the dedicated group (people with HIV adjusted mean difference -5·02 [95% CI -7·51 to -2·54], p<0·0001; people with diabetes -4·20 [-6·68 to -1·72], p<0·0001) and designated group (people with HIV -6·38 [-8·89 to -3·88], p<0·0001; people with diabetes -4·80 [-7·21 to -2·39], p<0·0001) showed greater improvement on depression scores at 12 months. By contrast, reductions in AUDIT scores were similar across study groups, with no intervention effects noted. INTERPRETATION: The dedicated and designated approaches to delivering CHW-led psychological interventions were equally effective for reducing depression, but enhancements are required to support alcohol reduction. This trial extends evidence for CHW-delivered psychological interventions, offering insights into how different delivery approaches affect patient outcomes. FUNDING: British Medical Research Council, Wellcome Trust, UK Department for International Development, the Economic and Social Research Council, and the Global Challenges Research Fund.

Intersecting Relationships of Psychosocial and Structural Syndemic Problems Among People with HIV in South Africa: Using Network Analysis to Identify Influential Problems.

In South Africa, little is known about interrelationships between syndemic problems among people with HIV (PWH). A better understanding of syndemic problems may yield important information regarding factors amenable to mitigation. We surveyed 194 PWH in Khayelitsha, outside of Cape Town, South Africa. We used network analysis to examine the frequency of 10 syndemic problems and their interrelationships. Syndemic problems among PWH in South Africa were common; 159 (82.8%) participants reported at least 2 co-occurring syndemic problems and 90 (46.9%) endorsed 4 or more. Network analysis revealed seven statistically significant associations. The most central problems were depression, substance use, and food insecurity. Three clusters of syndemics were identified: mood and violence; structural factors; and behavioral factors. Depression, substance use, and food insecurity commonly co-occur among PWH in sub-Saharan Africa and interfere with HIV outcomes. Network analysis can identify intervention targets to potentially improve HIV treatment outcomes.

RESUMEN: En Sudáfrica, poco se sabe sobre interrelaciones entre problemas sindémicos entre personas con VIH (PCV). Un major entendimiento de los problemas sindémicos puede arrojar información importante sobre los factores susceptibles de mitigación. Utilizamos el análisis de redes para examinar la frecuencia de 10 problemas sindémicos y sus interrelaciones. Problemas sindémicos entre PCV en Sudáfrica eran communes; 159 (82.8%) participantes presentaron al menos 2 problemas sindémicos concurrentes y 90 (46.9%) presentaron 4 o más. El análisis de red reveló siete asociaciones estadísticamente significativas. Los problemas más centrales fueron la depresión, el uso de sustancias y la inseguridad alimentaria. Se indetificaron tres grupos de sindemias: estado de ánimo y violencia; factores estructurales; y factores de comportamiento. La depresión, el uso de sustancias y la inseguridad alimentaria comúnmente ocurren simultáneamente entre las PCV en el África subsahariana e interfieren con los resultados del VIH. El análisis de redes puede identificar objetivos de intervención para potencialmente mejorar los resultados del tratamiento del VIH.

Mental Health, ART Adherence, and Viral Suppression Among Adolescents and Adults Living with HIV in South Africa: A Cohort Study.

We followed adolescents and adults living with HIV aged older than 15 years who enrolled in a South African private-sector HIV programme to examine adherence and viral non-suppression (viral load > 400 copies/mL) of participants with (20,743, 38%) and without (33,635, 62%) mental health diagnoses. Mental health diagnoses were associated with unfavourable adherence patterns. The risk of viral non-suppression was higher among patients with organic mental disorders [adjusted risk ratio (aRR) 1.55, 95% confidence interval (CI) 1.22-1.96], substance use disorders (aRR 1.53, 95% CI 1.19-1.97), serious mental disorders (aRR 1.30, 95% CI 1.09-1.54), and depression (aRR 1.19, 95% CI 1.10-1.28) when compared with patients without mental health diagnoses. The risk of viral non-suppression was also higher among males, adolescents (15-19 years), and young adults (20-24 years). Our study highlights the need for psychosocial interventions to improve HIV treatment outcomes-particularly of adolescents and young adults-and supports strengthening mental health services in HIV treatment programmes.

RESUMEN: Monitoreamos adolescentes y adultos mayores de 15 años que viven con VIH y que están registrados en un programa privado Surafricano para el tratamiento del VIH. Nuestro propósito fue examinar adherencia a los medicamentos y supresión viral (carga viral < 400 copias/mL) en los participantes con (20,743, 38%) y sin (33,635, 62%) diagnósticos de salud mental. Los diagnósticos de salud mental estuvieron asociados con patrones de adherencia desfavorables. Comparados con pacientes sin diagnósticos de salud mental, el riesgo de no supresión viral fue más alto entre pacientes con desórdenes mentales orgánicos [riesgo relativo ajustado (aRR) 1.55, 95% intervalo de confidencia (CI) 1.22­1.96], desórdenes en el uso de sustancias (aRR 1.53, 95% CI 1.19­1.97), desórdenes mentales serios (aRR 1.30, 95% CI 1.09­1.54), y depresión (aRR 1.19, 95% CI 1.10­1.28). El riesgo de no supresión viral también fue más alto en hombres que en mujeres, en adolescentes (15­19 años), y en adultos jóvenes. Nuestro estudio resalta la necesidad de intervenciones psicosociales para mejorar los resultados del tratamiento contra el VIH ­particularmente en adolescentes y adultos jóvenes­, y respalda el fortalecimiento de servicios de salud mental como parte de los programas para el tratamiento del VIH.

Mental and cognitive healthcare training targeting primary healthcare workers providing HIV services in Africa: a scoping review.

Mental health and neurocognitive functioning remain a concern among people living with HIV. Symptomatic neurocognitive impairment (NCI) and mental illness can cause difficulties in daily functioning, including problems adhering to treatment. However, many healthcare workers in resource-limited settings have limited knowledge about the relationship between HIV and NCI. A synthesis of available literature on mental health and NCI training provided to healthcare workers delivering HIV services in Africa, is lacking. We conducted a scoping review of published literature to identify training interventions which targeted healthcare workers providing careto people with HIV in Africa. Ten studies met the inclusion criteria. One study focused on NCI, two studies mentioned HIV-associated dementia and seven studies were centred on common mental health disorders. Most studies used a multi-method training approach, with pre-and post-testing as the main evaluation technique. This review highlights the gap in training interventions addressing NCI in Africa. Although there is some commitment to building capacity for mental health and NCI assessment among healthcare workers in this setting, this review suggests that there is a need for research to develop and evaluate training interventions for healthcare workers delivering HIV services in Africa.

South Africa's Psychiatric training capacity in 2008 and in 2018. Has training capacity improved?

Background: There is a deficit of psychiatrists in South Africa, and to our knowledge, there is no situational analysis of training posts for psychiatrists in the country. Aim: To compare the number of specialists and subspecialists in training and training posts available in 2008 and 2018. Setting: South African medical schools with departments of psychiatry. Methods: A situational analysis involving data collection through a survey completed by eight heads of academic psychiatric departments followed by a comparative analysis of the two aforementioned years. Results: Data shows an 11% increase in funded and unfunded posts combined and a 9.3% increase in funded posts. The occupancy of funded posts decreased (92% in 2008 to 82% in 2018). When considering both funded and unfunded posts, only three more psychiatrists were being trained in 2018. Supernumeraries appointed in unfunded posts can be expected to return to their countries of origin. As such, a decrease in filled funded posts likely reflects a decrease in training psychiatrists destined to work in South Africa. While child and adolescent psychiatry was the only sub-speciality with accredited training posts in 2008, all sub-specialities included on the questionnaire had accredited training posts in 2018, and the number of accredited training posts in child and adolescent psychiatry doubled. That said, many of the posts were unfunded and vacant. Conclusion: While there was an increase in posts from 2008 to 2018, many posts remained unfilled. As such, not only are additional funded training posts required but also strategies to increase post-occupancy and successful completion of training. Contribution: This study is the first situational analysis of specialist and subspecialist training posts in Psychiatry in South Africa, at two time points over a 10 year period, that draws on academic heads of departments of psychiatry as respondents. The study highlights the nominal increase in funded training posts over this period, especially subspecialist training posts. The majority of Health Professions Council of South Africa (HPCSA) accredited subspecialities in Psychiatry have no funded training posts which is particularly concerning.

HIV-1 subtype C Tat exon-1 amino acid residue 24K is a signature for neurocognitive impairment.

Variation and differential selection pressures on Tat genes have been shown to alter the biological function of the protein, resulting in pathological consequences in a number of organs including the brain. We evaluated the impact of genetic variation and selection pressure on 147 HIV-1 subtype C Tat exon 1 sequences from monocyte-depleted peripheral lymphocytes on clinical diagnosis of neurocognitive impairment. Genetic analyses identified two signature amino acid residues, lysine at codon 24 (24K) with a frequency of 43.4% and arginine at codon 29 (29R) with a frequency of 34.0% in individuals with HIV-associated neurocognitive impairment. The analyses also revealed two signature residues, asparagine, 24 N (31.9%), and histidine, 29H (21.3%), in individuals without neurocognitive impairment. Both codons, 24 and 29, were associated with high entropy but only codon 29 was under positive selection. The presence of signature K24 increased by 2.08 times the risk of neurocognitive impairment, 3.15 times higher proviral load, and 69% lower absolute CD4 T-cell count compared to those without the signature. The results support a linkage between HIV-1 C Tat N24K polymorphism, proviral load, immunosuppression, and neurocognitive impairment. The signature may induce more neurotoxic effects, which contributes to establishment and severity of HIV-associated neurocognitive impairment.

Gender Moderates Results of a Randomized Clinical Trial for the Khanya Intervention for Substance Use and ART Adherence in HIV Care in South Africa.

Little is known about gender effects of alcohol and drug use (AOD) among people living with HIV (PLWH) in resource-limited settings. Using multilevel models, we tested whether gender moderated the effect of Khanya, a cognitive-behavioral therapy-based intervention addressing antiretroviral (ART) adherence and AOD reduction. We enrolled 61 participants from HIV care and examined outcomes at 3- and 6-months compared to enhanced treatment as usual (ETAU). Gender significantly moderated the effect of Khanya on ART adherence (measured using electronically-monitored and biomarker-confirmed adherence), such that women in Khanya had significantly lower ART adherence compared to men in Khanya; no gender differences were found for AOD outcomes. Exploratory trajectory analyses showed men in Khanya and both genders in ETAU had significant reductions in at least one AOD outcome; women in Khanya did not. More research is needed to understand whether a gender lens can support behavioral interventions for PLWH with AOD.Trial registry ClinicalTrials.gov identifier: NCT03529409. Trial registered on May 18, 2018.

The Relationship Between Harmful Alcohol Use and Antiretroviral Non-adherence in People Accessing HIV Treatment in Cape Town, South Africa: An Event-Level Analysis.

Harmful alcohol consumption can significantly compromise adherence to antiretroviral therapy (ART). Prior research has identified aggregate relationships between alcohol use and ART non-adherence, largely relying on concurrent assessment of these domains. There is relatively limited evidence on more nuanced day-level associations between alcohol use and ART non-adherence, despite potentially important clinical implications. We recruited adults with HIV treatment adherence challenges and harmful alcohol use (n = 53) from HIV care in South Africa. We examined relationships between alcohol use and same and next day ART adherence, accounting for the role of weekends/holidays and participant demographics, including gender. Results demonstrated that ART adherence was significantly worse on weekend/holiday days. Next day adherence was significantly worse in the context of weekend alcohol use and among men. These results suggest the importance of tailoring intervention strategies to support ART adherence during weekend drinking and for men engaged in heavy episodic drinking.

Exploring HIV-Associated Neurocognitive Impairment in the Era of Effective Antiretroviral Therapy: A Primary Healthcare Perspective.

The prevalence of HIV-associated neurocognitive impairment (H-NCI) is concerning. Individuals on effective antiretroviral therapy (ART) may still be at risk for H-NCI as they experience longer life expectancies. There are, however, few professionals with knowledge and skills to identify H-NCI, in low- and middle-income countries. We explored qualitatively, primary healthcare workers' knowledge and views of H-NCI, in the era of effective ART, particularly their views toward task-sharing of H-NCI screening from specialists to mid-level or lay healthcare providers. The first phase of data collection involved two focus group discussions (FGDs) 23 primary healthcare workers from two facilities in the Western Cape participated in the FGDs. In the second phase of data collection12 individual, in-depth interviews were conducted in KwaZulu-Natal. Using thematic analysis, several key themes emerged. Although healthcare providers were unable to specifically identify H-NCI, they described several HIV disease and treatment related or mental health comorbidities that could be responsible for the symptoms. Despite healthcare workers reporting low frequencies of H-NCI, they favoured receiving training to screen for H-NCI with a view toward providing holistic care.

Adapting a Behavioral Intervention for Alcohol Use and HIV Medication Adherence for Lay Counselor Delivery in Cape Town, South Africa: A Case Series.

Human immunodeficiency virus (HIV) and problematic alcohol use are two ongoing and interconnected epidemics in South Africa, with untreated problematic alcohol use associated with poorer HIV treatment outcomes and disease progression. A lack of trained mental health providers is a primary barrier to increasing access to evidence-based treatment in this setting. To address this gap, we integrated evidence-based intervention components for problematic alcohol use and antiretroviral therapy (ART) adherence, adapted for lay provider delivery in an HIV primary care setting in Cape Town, South Africa. The intervention, locally termed "Khanya" in isiXhosa, which means glow, direction, or light, comprises Life Steps adherence counseling, motivational interviewing, behavioral activation, and relapse prevention, including mindfulness-based relapse prevention components. In this case series, we present a detailed description of the intervention and provide three clinical cases of individuals who received the Khanya intervention to showcase necessary clinical adaptations and the supervision needed for optimal treatment delivery, flexibility in intervention delivery, and overall successes and challenges. We present descriptive data on alcohol use and ART adherence outcomes for the cases to supplement the narrative discussion. Successes of intervention delivery included participant uptake of mindfulness skills, reductions in alcohol use despite varying levels of motivation, and interventionist mastery over various clinical skills. Challenges included delivering the intervention within the allotted time and the strong influence of substance-using social networks. Overall, a pragmatic approach to intervention delivery was necessary, as was ongoing support for the interventionist to promote fidelity to both treatment components and therapeutic skills. Trial registration: ClinicalTrials.gov identifier: NCT03529409. Trial registered on May 18, 2018.

Moving on From HAND: Why We Need New Criteria for Cognitive Impairment in Persons Living With Human Immunodeficiency Virus and a Proposed Way Forward.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) criteria are frequently used to describe cognitive impairment in persons living with HIV (PLWH) across diverse populations globally. These criteria typically find 20-60% of PLWH meet criteria for HAND, which does not tally with clinical observations in the modern era that cognitive disorders present relatively infrequently. Most with HAND have asymptomatic neurocognitive impairment; however, the significance of low cognitive test performance without symptoms is uncertain. Methods underlying HAND criteria carry a false-positive rate that can exceed 20%. Comorbidities, education, and complex socioeconomic factors can influence cognitive test performance, further increasing the potential for misclassification. We propose a new framework to characterize cognitive impairment in PLWH that requires a clinical history and acknowledges the multifactorial nature of low cognitive test performance. This framework is intended to be applicable across diverse populations globally, be more aligned with clinical observations, and more closely represent HIV brain pathology.

Rates of cognitive impairment in a South African cohort of people with HIV: variation by definitional criteria and lack of association with neuroimaging biomarkers.

There is wide variation in the reported prevalence of cognitive impairment in people with HIV (PWH). Part of this variation may be attributable to different studies using different methods of combining neuropsychological test scores to classify participants as either cognitively impaired or unimpaired. Our aim was to determine, in a South African cohort of PWH (N = 148), (a) how much variation in reported rates was due to method used to define cognitive impairment and (b) which method correlated best with MRI biomarkers of HIV-related brain pathology. Participants completed detailed neuropsychological assessment and underwent 3 T structural MRI and diffusion tensor imaging (DTI). We used the neuropsychological data to investigate 20 different methods of determining HIV-associated cognitive impairment. We used the neuroimaging data to obtain volumes for cortical and subcortical grey matter and total white matter and DTI metrics for several white matter tracts. Applying each of the 20 methods to the cognitive dataset resulted in a wide variation (20-97%) in estimated rates of impairment. Logistic regression models showed no method was associated with HIV-related neuroimaging abnormalities as measured by structural volumes or DTI metrics. We conclude that for the population from which this sample was drawn, much of the variation in reported rates of cognitive impairment in PWH is due to the method of classification used, and that none of these methods accurately reflects biological effects of HIV in the brain. We suggest that defining HIV-associated cognitive impairment using neuropsychological test performance only is insufficient; pre-morbid functioning, co-morbidities, cognitive symptoms, and functional impairment should always be considered.

Improving Detection of Depression in People Living with HIV: Psychometric Properties of the South African Depression Scale (SADS).

Most measures developed in high income countries to screen for major depressive disorder (MDD) among people living with HIV (PWH) demonstrate suboptimal psychometric properties when utilized in non-western, resource limited settings due to their high false positive rates. For standardized MDD screening to be implementable in local settings, a measure is needed that reduces diagnostic burden by being highly sensitive while limiting false positives. This study sought to evaluate the ability of the locally developed South African Depression Scale (SADS) to screen for MDD in PWH in Cape Town. The SADS was administered along with the SCID-5-RV as gold standard to 236 PWH. It demonstrated good discriminating ability in detecting MDD with an area under the curve of 0.85. A cut-off of 27 yielded 78.2% sensitivity and 54.4% PPV. Given its robust psychometric properties, routine use of the SADS in community clinics to screen at-risk PWH, combined with evidence-based depression treatment, could improve the health outcomes and well-being of PWH in South Africa.ResumenLa mayoría de las medidas desarrolladas en países de ingresos altos para detectar el trastorno depresivo mayor (TDM) entre las personas que viven con el VIH (PVV) demuestran propiedades psicométricas subóptimas cuando se utilizan en entornos no occidentales de recursos limitados debido a sus altas tasas de falsos positivos. Para que la detección de TDM estandarizada sea implementable en entornos locales, se necesita una medida que reduzca la carga diagnóstica al ser altamente sensible mientras limita los falsos positivos. Este estudio trató de evaluar la capacidad de la Escala de Depresión Sudafricana (SADS, por sus siglas en inglés) desarrollada localmente para detectar TDM en PVV en Ciudad del Cabo. El SADS se administró junto con el SCID-5-RV como el test de referencia a 236 PWH. Demostró una buena capacidad discriminatoria en la detección de TDM con un área bajo la curva de 0,85. Un corte de 27 produjo un 78,2% de sensibilidad y un 54,4% de VPP. Dadas sus sólidas propiedades psicométricas, el uso rutinario del SADS en clínicas comunitarias para detectar las PVV en riesgo, combinado con un tratamiento de depresión basado en la evidencia, podría mejorar los resultados de salud y el bienestar de las PVV en Sudáfrica.

Improving the measurement of food insecurity among people with HIV in South Africa: a psychometric examination.

OBJECTIVE: Food insecurity is a structural barrier to HIV care in peri-urban areas in South Africa (SA), where approximately 80 % of households are moderately or severely food insecure. For people with HIV (PWH), food insecurity is associated with poor antiretroviral therapy adherence and survival rates. Yet, measurement of food insecurity among PWH remains a challenge. DESIGN: The current study examines the factor structure of the nine-item Household Food Insecurity Access Scale (HFIAS, isiXhosa-translated) among PWH in SA using a restrictive bifactor model. SETTING: Primary care clinics in Khayelitsha, a peri-urban settlement in Cape Town, SA. PARTICIPANTS: Participants (n 440) were PWH who received HIV care in Khayelitsha screening for a clinical trial. Most were categorised as severely (n 250, 56·82 %) or moderately (n 107, 24·32 %) food insecure in the past 30 d. RESULTS: Revised parallel analysis suggested a three-factor structure, which was inadmissible. A two-factor structure was examined but did not adequately fit the data. A two-factor restrictive bifactor model was examined, such that all items loaded on a general factor (food insecurity) and all but two items loaded on one of two specific additional factors, which adequately fit the data (comparative fit index = 0·995, standardised root mean square residual = 0·019). The two specific factors identified were: anxiety/insufficient quality and no food intake. Reliability was adequate (ω = 0·82). CONCLUSIONS: Results supported the use of a total score, and identified two specific factors of the HFIAS, which may be utilised in future research and intervention development. These findings help identify aspects of food insecurity that may drive relationships between the construct and important HIV-related variables.

HIV-Associated Neurocognitive Impairment Knowledge and Current Practices: A Survey of Frontline Healthcare Workers in South Africa.

Neurocognitive impairment (NCI) associated with the human immunodeficiency virus (HIV) remains prevalent amongst people living with HIV. Testing for HIV-associated NCI in routine clinical care is limited in South Africa and reasons for this are unclear. We conducted an online survey amongst healthcare workers (HCW) to assess HIV-associated NCI knowledge and current practices. The final sample included four hundred surveys (n=400). Chi-square analyses were used to explore HCW knowledge of HIV-associated NCI and screening tools. One-way ANOVA was used to compare mean responses between HCW categories. We observed low awareness of HIV-associated NCI terminology and screening tools. HCW seldom suspected NCI among patients and screening practices were uncommon. Referrals for further NCI investigations were never requested. HCW expressed a desire to receive further training to identify HIV associated NCI. The current study highlights the context of HIV-associated NCI knowledge and practices among front-line HIV HCW in resource-limited settings.

Signatures of HIV-1 subtype B and C Tat proteins and their effects in the neuropathogenesis of HIV-associated neurocognitive impairments.

HIV-associated neurocognitive impairments (HANI) are a spectrum of neurological disorders due to the effects of HIV-1 on the central nervous system (CNS). The HIV-1 subtypes; HIV-1 subtype B (HIV-1B) and HIV-1 subtype C (HIV-1C) are responsible for the highest prevalence of HANI and HIV infections respectively. The HIV transactivator of transcription (Tat) protein is a major contributor to the neuropathogenesis of HIV. The effects of the Tat protein on cells of the CNS is determined by the subtype-associated amino acid sequence variations. The extent to which the sequence variation between Tat-subtypes contribute to underlying mechanisms and neurological outcomes are not clear. In this review of the literature, we discuss how amino acid variations between HIV-1B Tat (TatB) and HIV-1C Tat (TatC) proteins contribute to the potential underlying neurobiological mechanisms of HANI. Tat-C is considered to be a more effective transactivator, whereas Tat-B may exert increased neurovirulence, including neuronal apoptosis, monocyte infiltration into the brain, (neuro)inflammation, oxidative stress and blood-brain barrier damage. These findings support the premise that Tat variants from different HIV-1 subtypes may direct neurovirulence and neurological outcomes in HANI.

Peripheral blood lymphocyte proviral DNA predicts neurocognitive impairment in clade C HIV.

It is not known if proviral DNA in the periphery corresponds to cognitive status in clade C as it does in clade B and recombinant forms. A cross-sectional study was conducted on participants investigated for HIV-associated neurocognitive impairment in South Africa. HIV-1 proviral DNA was quantified using a PCR assay targeting a highly conserved HIV-1 LTR-gag region. Fifty-four (36.7%) participants were cognitively impaired and 93 (63.3%) were not impaired. Forty-three (79.6%) of the cognitively impaired participants were female and 11 (20.4%) were male. There was no significant age difference between cognitively impaired and unimpaired participants (p = 0.42). HIV-1 DNA in cognitively impaired PLWH was significantly higher than in cognitively normal individuals (p = .016). Considering impaired participants, lymphocyte HIV-1 DNA was significantly higher in males than females (p = 0.02). There was a modest positive correlation between lymphocyte HIV-1 DNA and global deficit scores (GDS) r = 0.176; p = 0.03). The two measures of viral load, lymphocyte HIV-1 DNA copies/million and plasma RNA copies/ml, were positively correlated (r = 0.39; p < .001). After adjusting for other covariates, age, sex, treatment status, and the interactions between impairment and treatment, the multivariate regression showed association between proviral load and neurocognitive impairment; omega effect size was 0.04, p value = 0.010. The burden of HIV-1 peripheral blood lymphocyte proviral DNA corresponds to neurocognitive impairment among individuals infected with clade C disease. Therefore, therapeutic strategies to reduce the HIV-1 proviral DNA reservoir in lymphocytes may improve neurocognitive outcomes in PLWH.

The association of peripheral immune markers with brain cortical thickness and surface area in South African people living with HIV.

A spectrum of cognitive impairments known as HIV-associated neurocognitive disorders (HAND) are consequences of the effects of HIV-1 within the central nervous system. Regardless of treatment status, an aberrant chronic neuro-immune regulation is a crucial contributor to the development of HAND. However, the extent to which inflammation affects brain structures critical for cognitive status remains unclear. The present study aimed to determine associations of peripheral immune markers with cortical thickness and surface area. Participants included 65 treatment-naïve HIV-positive individuals and 26 HIV-negative controls. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3 T. Peripheral immune markers included C-C motif ligand 2 (CCL2), matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), thymidine phosphorylase (TYMP), transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF), which were measured using enzyme-linked immunosorbent assays. Associations of these markers with thickness and surface area of cortical regions were evaluated. A mediation analysis examined whether associations of inflammatory markers with cognitive functioning were mediated by brain cortical thickness and surface area. After controlling for multiple comparisons, higher NGAL was associated with reduced thickness of the bilateral orbitofrontal cortex in HIV-positive participants. The association of NGAL with worse motor function was mediated by cortical thickness of the bilateral orbitofrontal region. Taken together, this study suggests that NGAL plays a potential role in the neuropathophysiology of neurocognitive impairments of HIV.

Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites.

BACKGROUND: There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. OBJECTIVES: We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. METHODS: We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. RESULTS: We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (ß = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (ß = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (ß = -0.31, P = 1.8 × 10-04) and CSF efavirenz (ß = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (ß = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (ß = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (ß = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (ß = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. CONCLUSIONS: We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.