Cape Town Adolescent Antiretroviral Cohort Research Articles

Persistent accelerated epigenetic ageing in a longitudinal cohort of vertically infected HIV-positive adolescents

We have previously shown accelerated ageing in adolescents perinatally infected with HIV (PHIV +), based on discrepancies between epigenetic and chronological age. The current study examines follow-up longitudinal patterns of epigenetic ageing and the association of epigenetic ageing with cognition as well as whole brain structure changes in PHIV + and healthy controls enrolled in the Cape Town Adolescent Antiretroviral Cohort Study (CTAAC). The Illumina EPIC array was used to generate blood DNA methylation data from 60 PHIV + adolescents and 36 age-matched controls aged 9–12 years old at baseline and again at a 36-month follow-up. Epigenetic clock software estimated two measures of epigenetic age acceleration: extrinsic epigenetic accelerated ageing (EEAA) and age acceleration difference (AAD) at both time points. At follow-up, each participant completed neuropsychological testing, structural magnetic resonance imaging, and diffusion tensor imaging. At follow-up, PHIV infection remains associated with increased EEAA and AAD. Accelerated epigenetic ageing remained positively associated with viral load and negatively associated with CD4 ratio. EEAA was positively associated with whole brain grey matter volume and alterations in whole brain white matter integrity. AAD and EEAA were not associated with cognitive function within the PHIV + group. Measures of epigenetic ageing, as detected in DNA methylation patterns, remain increased in PHIV + adolescents across a 36-month period. Associations between epigenetic ageing measures, viral biomarkers, and alterations in brain micro- and macrostructure also persist at 36-month follow-up. Further study should determine if epigenetic age acceleration is associated with cognitive functional changes due to brain alterations in later life.

Normal values of respiratory oscillometry in South African children and adolescents.

Noninvasive measurement of respiratory impedance by oscillometry can be used in young children aged from 3 years and those unable to perform forced respiratory manoeuvres. It can discriminate between healthy children and those with respiratory disease. However, its clinical application is limited by the lack of reference data for African paediatric populations. The aim of the present study was to develop reference equations for oscillometry outcomes in South African children and adolescents. Healthy subjects, enrolled in the Drakenstein Child Health Study, HIV-uninfected adolescents in the Cape Town Adolescent Antiretroviral Cohort and healthy children attending surgical outpatient clinics at Red Cross War Memorial Children's Hospital were measured with conventional spectral (6-32 Hz) and intra-breath (10 Hz) oscillometry. Stepwise linear regression was used to assess the relationship between respiratory variables and anthropometric predictors (height, sex, ancestry) to generate reference equations. A total of 692 subjects, 48.4% female, median age of 5.2 years (range: 3-17 years) were included. The median (interquartile range (IQR)) for weight for age z-score and height for age z-score was -0.42 (-1.11-0.35) and -0.65 (-1.43-0.35), respectively. Stepwise regression demonstrated that all the variables were significantly dependent on height only. Comparison to previous reference data indicated slightly higher resistance and lower compliance values in the smallest children. We established the first respiratory oscillometry reference equations for African children and adolescents, which will facilitate use in early identification and management of respiratory disease. Our results suggest differences in oscillometry measures by ancestry but also highlight the lack of standardisation in methodology.

A longitudinal and qualitative analysis of caregiver depression and quality of life in the Cape Town adolescent antiretroviral cohort

• Depression in caregivers of adolescents living with perinatal HIV (PHIV) was associated with poor physical health, poor overall quality of life and externalizing and internalizing behaviour problems in PHIV adolescents. • However, depression, physical health and family resources in caregivers of PHIV adolescents improved significantly longitudinally. • Improved quality of life was associated with less depression and improved access to family resources and social support. • Main concerns of caregivers include educational/learning and health problems in PHIV adolescents. This study aimed to investigate depression and quality of life longitudinally in caregivers of adolescents with perinatally acquired HIV (PHIV) enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). Depression, socioeconomic factors and quality of life were assessed in caregivers (n=121) at baseline and 36 months follow-up using the Centers for Epidemiological Studies Depression Scale (CESD), the Family Resources Scale (FRS), Family Support Scale (FSS), and the World Health Organization's Quality of Life Scale (WHOQoL). Internalizing and externalizing behaviors in PHIV adolescents were assessed using the Child Behaviour Checklist (CBCL). Qualitative analysis was conducted to highlight key concerns raised by caregivers in caring for PHIV adolescents. CESD was significantly lower at follow-up compared to baseline (p=0.001), with FRS (p=0.003) and WHOQoL physical health (p=0.038) significantly higher at follow-up. Higher CESD scores were predicted by increased CBCL internalizing (baseline: p=0.002; follow-up: p=0.021) and externalizing behavior (baseline: p=0.010; follow-up: p=0.015) in PHIV adolescents and decreased WHOQoL physical health (baseline: p=0.001; follow-up: p=0.016) and WHOQoL overall quality of life (baseline: p=0.003; follow-up: p=0.019). Higher WHOQoL Total Score was predicted by lower CESD scores (baseline: p<0.001; follow-up: p=0.010) and higher FRS (p<0.001) and FSS (baseline: p<0.001; follow-up: p=0.001). Qualitative analysis indicated that caregivers’ main concerns were PHIV adolescent educational and health problems. Self-report measures and small sample size. This study highlights the need for adequate intervention strategies to provide resources and social support to caregivers of PHIV adolescents in order to improve their mental health.

Alcohol use is associated with mental health problems and brain structural alterations in adolescents with perinatally acquired HIV infection on ART.

Alcohol use, presents unique challenges for HIV-1 treatment in adolescents with perinatally acquired infection. The effects of alcohol on host-virus interaction in the brain and the immune system remains understudied in this population. Adolescents with perinatally acquired HIV infection (PHIV) well established on ART, from the Cape Town Adolescent Antiretroviral Cohort who self-reported alcohol use (PHIV+alcohol) (n=26) were compared to age matched 26 PHIV (PHIV-alcohol) and 26 healthy controls (HC) who reported no use of alcohol. Participants completed clinical investigations including highly-sensitive CRP (hs-CRP), a comprehensive neurocognitive test battery and mental health measures. In addition, we investigated the relationship between alcohol use in PHIV and diffusion tensor imaging (DTI) and structural brain magnetic resonance imaging (MRI) to determine fractional anisotropy (FA), mean diffusivity (MD), grey and white matter volumes and cortical thickness. PHIV (mean age 12,5 years; mean age of ART initiation 3.15 years) reported an occasional weekend drinking pattern of alcohol use. hs-CRP was significantly different between groups, with PHIV+alcohol higher than PHIV-alcohol and HC. General intelligence, attention, working memory, processing speed and executive function were more impaired in the PHIV+alcohol than PHIV alone, with HC having the highest scores. In addition, self-concept was significantly lower in PHIV+alcohol. The Child Behavior Checklist (CBCL) Externalizing behaviour, internalising behaviour and CBCL Total problems were significantly higher in PHIV+alcohol. FA of the superior corona radiata, superior fronto-occipital fasciculus and corpus callosum was significantly lower in PHIV+alcohol compared to PHIV-alcohol and MD of the corona radiata was significantly increased in PHIV+alcohol. The cortical thickness of the lateral orbitofrontal, middle frontal and precentral gyri were significantly lower in PHIV+alcohol compared to PHIV-alcohol and HC. In conclusion PHIV associated impairments in systemic inflammation, cognitive function, mental health and changes in brain structure may be exacerbated by alcohol use, even if only occasional use. However, the study is cross-sectional, which is not able to distinguish between cause and effect.

The association between mental health and metabolic outcomes in youth living with perinatally acquired HIV in the Cape Town Adolescent Antiretroviral Cohort

ABSTRACT Youth living with perinatally acquired HIV (YLPHIV) have been found to have a range of mental disorders. Some adult HIV studies have linked mental health to adverse metabolic outcomes due to dysregulation of the sympathetic nervous system and hypothalamic–pituitary–adrenal axis, but this association has not previously been explored in YLPHIV. We investigated the association of mental health measures with metabolic outcomes in YLPHIV and HIV-uninfected youth (HIV-U) and linear regression was used to assess the adjusted associations. Overall, 203 YLPHIV (median age = 10.7years; 52% female; mean duration on ART 8 years, 12% CD4 count <500 cells/µL, 18% viral load >50 copies/mL) and 44 HIV-U (median age = 10.3 years; 55% female) were enrolled. YLPHIV had higher median total cholesterol (4.2 vs 3.9 mmol/L, p = 0.049) and triglyceride (0.9 vs 0.7 mmol/L, p < 0.001) compared to HIV-U. We found higher percentage of poor functional competence (40% vs 25%, p = 0.02) and self-concept (23% vs 9%, p = 0.03) and higher depression (6% vs 2%, p < 0.01), anger (6% vs 2%, p = 0.04) and disruptive behaviour (4% vs 0%, p < 0.01) in YLPHIV as compared to HIV-U. Among YLPHIV, higher scores of anger were associated with higher total cholesterol and higher low-density lipoprotein (ß = 0.010, p = 0.041 and ß = 0.012, p = 0.048 respectively) and disruptive behaviour with higher low-density lipoprotein (ß = 0.010, p = 0.043) after adjusting for age, sex and BMIZ. This is the one of first study to investigate the association of mental health with metabolic outcomes among YLPHIV. The association of increased anger and disruptive behaviour with increased lipid concentration is a novel finding. Further longitudinal studies are needed to evaluate the causal relationships between mental health and metabolic outcomes.

Childhood Trauma and Mental Health in the Cape Town Adolescent Antiretroviral Cohort.

This study aimed to assess the association of childhood trauma, stressful life events and HIV stigma with mental health in South African adolescents from the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Childhood Trauma Questionnaire, Life Events Questionnaire and the HIV Stigma Scale for South African Adolescents Living with HIV was used to assess childhood trauma, stressful life events and stigma in adolescents living with perinatally acquired HIV and healthy controls enrolled in the CTAAC. These measures were associated with mental health outcomes including the Beck-Youth Inventories, Child Behaviour Checklist, Columbian Impairment Scale, Childrens Motivation Scale, Conners Scale for Attention Deficit Hyperactivity Disorder using Pearson correlations and self-reported alcohol use, using Spearman-rank correlation. 63.7% of adolescents reported at least one childhood trauma on the CTQ. Significant associations were reported between CTQ measures and Beck-Youth Inventories. Emotional abuse was associated with anxiety, anger, depression and disruptive behaviour. Emotional neglect was associated with poor self-concept and disruptive behaviour. LEQ total score was significantly associated with Beck-Youth Inventories including anxiety, depression, anger and disruptive behaviour scales. HIV stigma was significantly associated with Beck-Youth Inventories including depression, anger and disruptive behaviour. Childhood trauma, stressful life events and HIV stigma in South African adolescents are associated with anxiety, depression, anger, disruptive-behaviour and poor self-concept. This study highlights the importance of enquiring about exposure to a variety of traumas, particularly those commonly experienced by South African adolescents. In addition, it is important to understand the impact of trauma exposure on each individuals mental health and functioning.

Tuberculosis infection and disease in South African adolescents with perinatally acquired HIV on antiretroviral therapy: a cohort study.

IntroductionThere are limited data on Tuberculosis (TB) in adolescents with perinatally acquired HIV (APHIV). We examined the incidence and determinants of TB infection and disease in the Cape Town Adolescent Antiretroviral Cohort (CTAAC).MethodsYouth between nine and fourteen years on antiretroviral therapy (ART) for more than six months in public sector care, and age‐matched HIV‐negative adolescents, were enrolled between July 2013 through March 2015 and followed six‐monthly. Data were censored on 31 October 2018. Symptom screening, chest radiograph, viral load, CD4 count, QuantiFERON (QFT) and sputum for Xpert MTB/RIF, microscopy, culture and sensitivity were performed annually. TB infection was defined by a QFT of >0.35 IU/mL. TB diagnosis was defined as confirmed (culture or Xpert MTB/RIF positive) or unconfirmed (clinical diagnosis and started on TB treatment). Analyses examined the incidence and determinants of TB infection and disease.ResultsOverall 496 HIV+ and 103 HIV‐negative participants (median age at enrolment 12 years (interquartile range, IQR 10.6 to 13.3) were followed for a median of 3.1 years (IQR 3.0 to 3.4); 50% (298/599) were male. APHIV initiated ART at median age 4.4 years (IQR 2.1 to 7.6). At enrolment, 376/496 (76%) had HIV viral load <40 copies/mL, median CD4 count was 713 cells/mm3 and 179/559 (32%) were QFT+, with no difference by HIV status (APHIV 154/468, 33%; HIV negative 25/91, 27%; p = 0.31). The cumulative QFT+ prevalence was similar (APHIV 225/492, 46%; 95%CI 41% to 50%; HIV negative 44/98, 45%; 95% CI 35% to 55%; p = 0.88). APHIV had a higher incidence of all TB disease than HIV‐negative adolescents (2.2/100PY, 95% CI 1.6 to 3.1 vs. 0.3/100PY, 95% CI 0.04 to 2.2; IRR 7.36, 95% CI 1.01 to 53.55). The rate of bacteriologically confirmed TB in APHIV was 1.3/100 PY compared to 0.3/100PY for HIV‐negative adolescents, suggesting a fourfold increased risk of developing TB disease in APHIV despite access to ART. In addition, a positive QFT at enrolment was not predictive of TB in this population.ConclusionsHigh incidence rates of TB disease occur in APHIV despite similar QFT conversion rates to HIV‐negative adolescents. Strategies to prevent TB in this vulnerable group must be strengthened.

Accelerated epigenetic aging in adolescents living with HIV is associated with altered development of brain structures.

We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01years) of the participants was higher than their mean chronological age (10.77years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ .

Hospitalization in South African Adolescents With Perinatally Acquired HIV on Antiretroviral Therapy.

Little is known about hospitalization in African adolescents with perinatally acquired HIV (PHIV+ adolescents). We described the incidence and causes of hospitalization in participants enrolled in the Cape Town Adolescent Antiretroviral Cohort in South Africa. Data collected from July 2013 to October 2018 from PHIV+ and HIV- adolescents were analyzed. Participants were assessed every 6 months and data on intercurrent hospitalization were abstracted. Causes of hospitalizations were classified according to ICD-10 codes. Descriptive statistics, time-to-event analysis and Poisson regression were used to describe causes and incidence and to determine incidence rate ratios for factors associated with hospitalization. Five hundred fifteen PHIV+ and 109 HIV- participants had a median follow-up of 4.1 years [interquartile range (IQR): 3.7-4.6]. At enrollment HIV+ participants had a median duration of ART of 7.6 years (IQR: 4.6-9.2), median CD4 count of 713 cells/mm (IQR: 561.0-957.5) and 387 (75%) had a viral load <50 copies/mL. There were 149 hospital admissions over 64 months. Crude incidence rates for hospitalization were 6.6 [95% confidence interval (CI): 5.7-7.8] and 2.2 (95% CI: 1.2-4.3) per 100-person-years (P = <0.01) in HIV + and HIV-, respectively. Ninety of 149 (60%) admissions in HIV+ participants were classified as non-infectious, 36/149 (24%) were infectious and 23/149 (16%) were "other HIV-related" or "unknown." Older age (15-19 years) and maintaining a CD4 >500 cells/cm were associated with decreased risk of hospitalization: adjusted incidence rate ratios of 0.61 (CI: 0.44-0.86, P = <0.01) and 0.68 (CI: 0.49-0.94, P = 0.02), respectively. PHIV+ adolescents had a high incidence of hospitalization despite ART. Strategies addressing infectious and non-infectious morbidity must be strengthened.

Monocyte activation and gut barrier dysfunction in South African youth on antiretroviral therapy and their associations with endothelial dysfunction.

There is evidence for endothelial dysfunction in youth living with perinatally acquired HIV (YLPHIV). However, little data exist on its mechanisms. YLPHIV and age-matched HIV-uninfected (HIV-) youth enrolled in the Cape Town Adolescent Antiretroviral Cohort in South Africa between 9 and 14 years of age were included. YLPHIV were on antiretroviral therapy more than 6 months with viral load less than 400 copies/ml at baseline and 24 months. Serum biomarkers of systemic inflammation, monocyte activation, intestinal integrity, and oxidized LDL-cholesterol were measured at baseline and after 24 months. Endothelial function was measured at 24 months using reactive hyperemic index (RHI); endothelial dysfunction was defined as RHI less than 1.35. Spearman correlation coefficient and quantile regression were used to examine associations between RHI and different biomarkers. We included 266 YLPHIV and 69 HIV- participants. At baseline, median (Q1, Q3) age was 12 (11, 13) years and 53% were females. YLPHIV had poorer endothelial function compared with HIV- youth (RHI = 1.36 vs. 1.52, P < 0.01). At baseline and 24 months, YLPHIV had higher markers of monocyte activation (soluble CD14), gut barrier dysfunction (intestinal fatty acid binding protein) and oxidized LDL-cholesterol (P ≤ 0.04) compared with HIV- youth. Among YLPHIV, soluble CD14 remained associated with endothelial dysfunction after adjusting for age, sex, Tanner stage, and antiretroviral therapy duration (β: -0.05, P = 0.01). Despite viral suppression, South African YLPHIV have poor endothelial function and persistent evidence of monocyte activation and gut barrier dysfunction compared with HIV- youth. The long-term clinical significance of gut integrity and monocyte activation needs to be further assessed in YLPHIV.

Accelerated epigenetic aging in adolescents from low-income households is associated with altered development of brain structures.

The relationship between cognitive performance, macro and microstructural brain anatomy and accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock in healthy adolescents has not been studied. Healthy adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort Study were studied cross sectionally. The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 44 adolescents aged 9 to 12years old. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration residual (AAR) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent neurocognitive testing, T1 structural magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). Correlation tests were run between the two epigenetic aging measures and 10 cognitive functioning domains, to assess for differences in cognitive performance as epigenetic aging increases. In order to investigate the associations of epigenetic age acceleration on brain structure, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, and cortical surface area, as well as DTI measures of white matter microstructural integrity. In addition to negatively affecting two cognitive domains, visual memory (p = .026) and visual spatial acuity (p = .02), epigenetic age acceleration was associated with alterations of brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of regions. Stress was a significant predictor (p = .029) of AAR. Understanding the drivers of epigenetic age acceleration in adolescents could lead to valuable insights into the development of neurocognitive impairment in adolescents.

Cognition, Structural Brain Changes, and Systemic Inflammation in Adolescents Living With HIV on Antiretroviral Therapy.

To investigate the association between neurocognitive impairment, neuroimaging, and systemic inflammation in perinatally infected adolescents living with HIV (PHIV) on antiretroviral therapy (ART). Systemic inflammation may be one mechanism driving neurocognitive impairment despite ART, but this has not been investigated in adolescence when the brain is undergoing rapid development. Cape Town, South Africa. Baseline data were drawn from the Cape Town Adolescent Antiretroviral Cohort. PHIV on ART >6 months completed a comprehensive neurocognitive test battery. Diffusion tensor imaging and structural brain magnetic resonance imaging was done to determine whole brain fractional anisotropy, mean diffusion (MD), grey and white matter volumes, and cortical thickness. We examined how neurocognitive and neurostructural measures were associated with a concurrently measured marker of systemic inflammation, high-sensitive C-reactive protein (hs-CRP). One hundred sixty-eight PHIV ages 9-12 years (mean CD4 980 cells/µL; 85.3% viral load <50 copies/mL) and 43 controls were included in the analysis. PHIV had similar hs-CRP (P = 0.17) to controls, after participants with hs-CRP >10 were excluded from the analysis. Forty-eight percent of the PHIV in this analysis have a neurocognitive disorder. Whole brain grey (P = 0.049) and white matter volumes (P = 0.044) were lowest in PHIV with a major neurocognitive disorder. Higher MD, was found in PHIV with a major neurocognitive disorder (P = 0.002). Among PHIV with a neurocognitive disorder, hs-CRP negatively correlated with general intelligence, visual spatial acuity, and executive function (all P = < 0.05). Whole brain MD correlated with higher hs-CRP values (P = < 0.01) in PHIV. A marker of systemic inflammation was associated with both neurocognitive impairment and MD increases in PHIV.

Quantitative CT analysis for bronchiolitis obliterans in perinatally HIV-infected adolescents-comparison with controls and lung function data.

To compare quantitative chest CT parameters in perinatally HIV-infected adolescents with and without bronchiolitis obliterans compared with HIV-uninfected controls and their association with lung function measurements. Seventy-eight (41 girls) HIV-infected adolescents with a mean age of 13.8 ± 1.65years and abnormal pulmonary function tests in the prospective Cape Town Adolescent Antiretroviral Cohort underwent contrast-enhanced chest CT on inspiration and expiration. Sixteen age-, sex-, and height-matched non-infected controls were identified retrospectively. Fifty-one HIV-infected adolescents (28 girls) displayed mosaic attenuation on expiration suggesting bronchiolitis obliterans. Pulmonary function tests were collected. The following parameters were obtained: low- and high-attenuation areas, mean lung density, kurtosis, skewness, ventilation heterogeneity, lung mass, and volume. HIV-infected adolescents showed a significantly higher mean lung density, ventilation heterogeneity, mass, and high- and low-attenuation areas compared with non-infected individuals. Kurtosis and skewness were significantly lower as well. HIV-infected adolescents with bronchiolitis obliterans had a significantly lower kurtosis and skewness compared with those without bronchiolitis obliterans. Lung mass and volume showed the strongest correlations with forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and alveolar volume. Low-attenuation areas below -950HU and ventilation heterogeneity showed the strongest correlation with FEV1/FVC (range, - 0.51 to - 0.34) and forced expiratory flow between 25 and 75% of FVC (range, - 0.50 to - 0.35). Quantitative chest CT on inspiration is a feasible technique to differentiate perinatally HIV-infected adolescents with and without bronchiolitis obliterans. Quantitative CT parameters correlate with spirometric measurements of small-airway disease. • Perinatally HIV-infected adolescents showed a more heterogeneous attenuation of the lung parenchyma with a higher percentage of low- and high-attenuation areas compared with non-infected patients. • Kurtosis and skewness are able to differentiate between HIV-infected adolescents with and without bronchiolitis obliterans using an inspiratory chest CT. • Quantitative CT parameters of the chest correlate significantly with pulmonary function test. Low-attenuation areas and ventilation heterogeneity are particularly associated with spirometric parameters related to airway obstruction.

Echocardiographic Findings in a Cohort of Perinatally HIV-Infected Adolescents Compared with Uninfected Peers from the Cape Town Adolescent Antiretroviral Cohort

Little is known about the cardiac health of perinatally HIV-infected (PHIV+) adolescents on antiretroviral therapy (ART) in sub-Saharan Africa. The authors examined cardiac structure and function in PHIV+adolescents on ART compared with HIV-uninfected (HIV-) adolescents. Echocardiography was performed on PHIV+ and age- and sex-frequency-matched HIV- adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort. Participants were eligible if they were 9 to 14years of age and had been on ART for ≥6months. Overall, 474 PHIV+adolescents (median age, 12years; 51% boys; mean age at ART initiation, 5years) and 109 HIV- adolescents (median age, 11.8years; 45% boys) were included. The mean duration on ART was 7years, with 37% starting treatment before 2years of age. Compared with HIV- adolescents, PHIV+adolescents had higher median Z scores for left ventricular (LV) internal end-diastolic dimension, LV end-systolic posterior wall thickness, and end-systolic interventricular septal thickness. PHIV+adolescents had a lower median Z score for right ventricular internal end-diastolic dimension as compared with HIV- adolescents. There was no difference in ejection fraction or diastolic function between groups. Later initiation of ART (after 6years) was associated with increased risk for LV hypertrophy (odds ratio, 2.9; 95% CI, 1.3-6.6; P=.01) compared with those who started ART earlier. PHIV+adolescents with World Health Organization stage IV HIV infection were at increased risk (odds ratio, 2.2; 95% CI, 1.0-4.6; P=.05) of having LV diastolic dysfunction compared with those with less advanced clinical disease. This study revealed subtle differences in echocardiographic parameters between PHIV+ and HIV- adolescents. Although these were not clinically significant, starting ART at an older age was a significant risk factor for LV hypertrophy, while more advanced clinical disease was associated with LV diastolic dysfunction.

Mental Health and Functional Competence in the Cape Town Adolescent Antiretroviral Cohort.

The impact of HIV and antiretrovirals (ART) on long-term mental health in perinatally infected children has not been well studied in sub-Saharan Africa where HIV is most prevalent. Cape Town, South Africa. We investigated mental health measures, including depression, anxiety, attention-deficit hyperactivity disorder, motivation, disruptive behavior, and functioning in perinatally infected adolescents (PHIV+) stable on ART within the Cape Town Adolescent Antiretroviral Cohort. Two hundred four adolescents living with HIV (median age 10 years; mean CD4 953) and a sample of 44 uninfected adolescents were enrolled. The Beck Youth Inventories, Children's Motivation Scale, Conner's Parent's Rating Scale, and Child Behavior Checklist were administered. Among PHIV+, we explored independent associations between HIV-related stigma, recent life stressors, sociodemographic, clinical, and caregiver-related variables, and mental health measures. PHIV+ had poorer functional competence, self-concept and motivation, higher levels of disruptive behavior, depression and attention-deficit hyperactivity disorder symptoms and clinically significant anger and disruptive behavior. Within the PHIV+ group, the loss of both biological parents was associated with higher levels of disruptive behavior. Within the PHIV+, factors associated with mental health symptoms and poorer functioning were mostly sociodemographic factors, HIV-related stigma, and life stressors. Age of initiation of ART was associated with self-concept, and failing first-line ART with internalizing and externalizing behavior problems. PHIV+ are likely to face future physical and psychological health consequences related to the functional competence challenges they face if mental health care is not made a priority in the fight against HIV.

Cardiopulmonary dysfunction in perinatally HIV-infected South African adolescents on antiretroviral therapy: baseline findings from the Cape Town Adolescent Antiretroviral Cohort.

IntroductionAntiretroviral therapy (ART) has reduced morbidity and mortality in sub‐Saharan Africa, but the burden of coexistent cardiopulmonary disease in perinatally HIV‐positive adolescents on antiretroviral therapy (ART) has not been well described. The aim of this study was to investigate the prevalence and associations of cardiopulmonary dysfunction in adolescents with perinatally acquired HIV on ART.MethodsFor this cross‐sectional analysis, 515 perinatally HIV‐positive adolescents ages 9 to 14 years on ART for at least six months, and a comparator group of 110 age‐matched HIV‐uninfected adolescents were tested between August 2013 and April 2015 using echocardiography, six‐minute walk test (6MWT) and spirometry. Those with either abnormal spirometry or abnormal 6MWT and any right or left systolic or diastolic dysfunction or abnormal mean pulmonary arterial pressure were considered as having impaired cardiopulmonary function. Logistic regression was used to investigate determinants of impaired cardiopulmonary function.ResultsOverall, 474 adolescents with perinatally acquired HIV (mean [SD] age, 12 [1.6] years; median [IQR] ART duration, 7 [4.6 to 9.3] years; median [IQR] CD4 count, 712 [571 to 959] cell/mm3) and 109 HIV‐uninfected adolescents mean (SD) age 11.8 (1.8) years, had successful cardiac and lung function testing. Impaired cardiopulmonary function was detected in 13% of adolescents with perinatally acquired HIV and 8% of HIV‐uninfected adolescents, p = 0.136. Among adolescents with perinatally acquired HIV, those with low tricuspid annular plane systolic excursion (TAPSE) had significantly lower mean FEV1, 1.5 L versus 1.6 L, p = 0.011. Height (OR 0.7, 95%CI 0.5 to 0.9), body mass index (OR 0.7, 95%CI 0.5 to 0.9) and past pulmonary tuberculosis (OR 2.3, 95%CI 1.2 to 4.4) were significantly associated with a low cardiopulmonary function.ConclusionsDespite being on ART, cardiopulmonary dysfunction occurs in an appreciable proportion of perinatally HIV‐infected adolescents but no significant difference to uninfected controls. This finding requires further exploration. Factors associated with dysfunction may be amenable to public health interventions to reduce cardiopulmonary disease in this population.

Longitudinal Changes in Spirometry in South African Adolescents Perinatally Infected With Human Immunodeficiency Virus Who Are Receiving Antiretroviral Therapy.

Despite increased access to highly active antiretroviral therapy (HAART), lung disease remains common in human immunodeficiency virus (HIV)-infected (HIV+) adolescents. There is limited information on changes in lung function over time in perinatally HIV+ adolescents on HAART. The objective was to investigate the progression of spirometry findings over 2 years in HIV+ adolescents on HAART in a prospective cohort, the Cape Town Adolescent Antiretroviral Cohort (CTAAC). HIV+ adolescents aged 9-14 years, with at least 6 months of HAART, and a comparator group of healthy HIV-uninfected (HIV-), age-matched controls were enrolled in CTAAC. Spirometry and bronchodilator testing were done at baseline, 12 months, and 24 months. Mixed-effect models were used to compute longitudinal changes in lung function. Five hundred fifteen HIV+ adolescents, mean age 12 (standard deviation [SD], 1.6) years, 50.4% male, and 110 HIV- adolescents, mean age 11.8 (SD, 1.8) years, 45.6% male, were tested at baseline; 477 (93%) HIV+ and 102 (93%) HIV- adolescents at 12 months; and 473 (92%) HIV+ and 97 (88%) HIV- adolescents at 24 months. Only 5.4% of the HIV+ adolescents had HIV viral load >10 000 copies/mL at baseline. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were lower in the HIV+ compared to the HIV- adolescents and tracked with no deterioration or catch-up over 2 years. Previous pulmonary tuberculosis (PTB) or lower respiratory tract infection (LRTI) was significantly associated with reduced FEV1 and FVC (P < .05 for both). HIV+ adolescents had lower lung function over 2 years than HIV- adolescents. This study highlights the need for lung function surveillance and prevention of LRTIs and PTB in HIV+ adolescents.

Screening for HIV-associated neurocognitive disorders in perinatally infected adolescents: youth-International HIV Dementia Scale validation.

Perinatal HIV infection has adverse cognitive consequences into adolescence. However, there are no screening tools that assess risk for HIV-associated neurocognitive disorders in adolescent populations. Such screening tools are needed urgently for clinical care in resource-poor settings with a high prevalence of HIV. To investigate the performance of the International HIV Dementia Scale (IHDS) as a screening tool for HIV-associated neurocognitive disorders in perinatally adolescents. The current study is a quantitative, quasiexperimental design. Perinatally HIV-infected adolescents aged 9-12 years were recruited from community health clinics into the Cape Town Adolescent Antiretroviral Cohort; matched HIV-negative controls from the same communities were enrolled. Each participant completed the IHDS and a comprehensive neuropsychological battery. The adult version of the IHDS was performed, except for two minor modifications. We evaluated the diagnostic validity of this modified instrument, the youth-IHDS (y-IHDS), using a four-step process that included sensitivity and specificity calculations, and generating receiver operating characteristic curves. Validity was measured against the youth HIV-associated diagnostic criteria. At a cut-off score of 10 or less, the y-IHDS demonstrated good sensitivity (94%) but poor specificity (24%) for detecting all forms of neurocognitive disorders, with an acceptable area under the curve value of 0.695. The y-IHDS requires minimal resources and is based on a screening tool for adult HIV-associated cognitive disorders that is already widely used globally. Hence, this brief, cost-efficient, and valid screening tool may be a useful addition for clinicians working in resource-poor contexts in which adolescent HIV is highly prevalent.

Initiation of antiretroviral therapy after the critical neuronal developmental period of the second postnatal year affects white matter microstructure in adolescents living with HIV.

Rapid maturation of major white matter pathways occurs in the first 2years of life, indicating a critical neuronal developmental period. The impact of initiating antiretroviral therapy (ART) in children perinatally infected with HIV-1, after the age of 2years on neurocognitive functioning and white matter development in adolescence has not been studied. Forty-six adolescents who initiated ART during the first 2years of life (< 2years) and 79 adolescents who initiated ART after 2years of age (> 2years), with perinatally acquired HIV were enrolled in the Cape Town Adolescent Antiretroviral Cohort. Adolescents completed a comprehensive neurocognitive battery testing a number of cognitive domains. Diffusion tensor imaging (DTI) was done to determine fractional anisotropy (FA), mean diffusivity (MD), axial diffusion (AD), and radial diffusion (RD) in a region of interest analysis. Neurocognitive performance was similar between adolescents who initiated ART < 2years or > 2years. There was a trend towards attention (p= .07) and working memory (p= .05) being poorer in the group who initiated ART > 2years. FA was lower in the > 2-year group in the superior corona radiata (p= .03), and the external capsule (p= .04). MD was higher in the > 2-year group in the cerebral peduncle (p= .02), the superior corona radiata (p= .01), and the superior fronto-occipital fasciculus (p= .03). RD was higher in the > 2-year group in the superior corona radiata (p= .02), the cerebral peduncle (p= .01), and the superior fronto-occipital fasciculus (p= .01). However, the higher AD in the > 2-year group in the superior corona radiata was not in the expected direction (p= .01). Initiation of ART after the neuronal development period of the second postnatal year is associated with white matter alterations on neuroimaging.

Structural brain changes in perinatally HIV-infected young adolescents in South Africa

To describe the structural brain changes, neurocognitive and mental health associations in adolescents perinatally infected with HIV-1 infection. Cross-sectional. Two hundred and four adolescents with perinatally acquired HIV and 44 uninfected frequency-matched controls aged 9-11 years were enrolled within the Cape Town Adolescent Antiretroviral Cohort. Diffusion tensor imaging and structural brain MRI was done to determine fractional anisotropy, mean diffusivity, grey and white matter volumes, cortical thickness and cortical surfractional anisotropy area. Correlation coefficients were calculated between total grey and white matter volume, cortical surface area, cortical thickness, whole brain fractional anisotropy and whole brain mean diffusivity and clinical and laboratory parameters including general intellectual functioning, Becks Youth Inventory, Child Motivation Scale and Child Behaviour Checklist. HIV-infected adolescents performed worse than controls on the Wechsler Abbreviated Scale of Intelligence (WASI; P < 0.01). HIV-infected adolescents had significant fractional anisotropy decreases, mean diffusivity increases and decreases in cerebral grey matter volumes, cortical surface area and decreased gyrification. Whole-brain mean fractional anisotropy was significantly reduced in the HIV-infected group (P = 0.031). There were significant correlation coefficients between greater total grey (P = 0.008) and white matter volume (P = 0.004) with the WASI and the Becks self-concept subscale (P = 0.038). Lower whole brain fractional anisotropy was associated with higher scores on the Becks anger (P = 0.018) and disruptive behaviour subscales (P = 0.031). Higher whole brain mean diffusivity was associated with apathy (P = 0.046). The pattern of increased risk of white matter microstructure alterations, smaller grey matter volumes, reduced cortical surface area and decreased gyrification, suggests abnormal neurodevelopment in perinatally infected younger adolescents.