In utero/peripartum antiretroviral therapy exposure and mental health outcomes at 8-18 years old: A longitudinal comparative study of children with perinatally acquired HIV, children perinatally HIV exposed but uninfected, and children unexposed uninfected from Uganda.

In utero/peripartum antiretroviral therapy (IPA) exposure type was examined in relationship to mental health symptoms among 577 children with perinatally acquired HIV (CPHIV), children perinatally HIV exposed but uninfected (CHEU), and children HIV unexposed uninfected (CHUU). IPA exposure was categorized for CPHIV and CHEU as none, single-dose nevirapine with or without zidovudine (sdNVP±AZT), sdNVP+AZT+lamivudine (3TC), or combination antiretroviral therapy (cART). Anxiety and depressive symptoms were reported at baseline, 6-, and 12-month follow-up per behavioral assessment system for children. Multivariable linear mixed models were used to estimate differences (b) with 95% confidence intervals (95% CI) for IPA exposure types versus CHEU without IPA exposure. Depressive and anxiety symptoms were lower in CHUU relative to CHEU and CPHIV but did not differ between CPHIV and CHEU. CHEU with sdNVP±AZT exposure had greater anxiety (b = 0.51, 95% CI: [0.06, 0.96]) and depressive symptoms (b = 0.48, 95% CI: [0.07, 0.89]) than CHEU without IPA exposure. CHEU with sdNVP+AZT+3TC exposure had higher anxiety (b = 0.0.45, 95% CI: [0.03, 0.86]) and depressive symptoms (b = 0.72, 95% CI: [0.27, 1.17]) versus CHEU without IPA exposure. Depressive and anxiety symptoms were not different for CHEU and CPHIV exposed to cART (b = 0.12-0.60, 95% CI: [-0.41, 1.30]) and CHEU and CHUU (b = -0.04 to 0.08, 95% CI: [-0.24, 0.29]) without IPA exposure. Among CHEU, peripartum sdNVP±AZT and sdNVP+AZT+3TC but not cART compared to no IPA exposure was associated with clinically important elevations in anxiety and depressive symptoms. Monitoring of mental health trajectory of HIV-affected children considering IPA is needed to inform mental health interventions. Patient Contribution: Caregivers and their dependents provided consent for participation and collaborated with study team to identify mutually convenient times for protocol implementation.

Association of serum PUFA and linear growth over 12 months among 6-10 years old Ugandan children with or without HIV.

OBJECTIVE: To quantify PUFA-associated improvement in linear growth among children aged 6-10 years. DESIGN: Serum fatty acids (FA), including essential FA (EFA) (linoleic acid (LA) and α-linolenic acid (ALA)) were quantified at baseline using GC-MS technology. FA totals by class (n-3, n-6, n-9, PUFA and SFA) and FA ratios were calculated. Height-for-age Z-score (HAZ) relative to WHO population reference values were calculated longitudinally at baseline, 6 and 12 months. Linear regression models estimated PUFA, HIV status and their interaction-associated standardised mean difference (SMD) and 95 % CI in HAZ over 12 months. SETTING: Community controls and children connected to community health centre in Kampala, Uganda, were enrolled. PARTICIPANTS: Children perinatally HIV-infected (CPHIV, n 82), or HIV-exposed but uninfected (CHEU, n 76) and community controls (n 78). RESULTS: Relative to highest FA levels, low SFA (SMD = 0·31, 95 % CI: 0·03, 0·60), low Mead acid (SMD = 0·38, 95 % CI: 0·02, 0·74), low total n-9 (SMD = 0·44, 95 % CI: 0·08, 0·80) and low triene-to-tetraene ratio (SMD = 0·42, 95 % CI: 0·07, 0·77) predicted superior growth over 12 months. Conversely, low LA (SMD = -0·47, 95 % CI: -0·82, -0·12) and low total PUFA (sum of total n-3, total n-6 and Mead acid) (SMD = -0·33 to -0·39, 95 % CI: -0·71, -0·01) predicted growth deficit over 12 months follow-up, regardless of HIV status. CONCLUSION: Low n-3 FA (ALA, EPA and n-3 index) predicted growth deficits among community controls. EFA sufficiency may improve stature in school-aged children regardless of HIV status. Evaluating efficacy of diets low in total SFA, sufficient in EFA and enriched in n-3 FA for improving child growth is warranted.

Toxic Stress and Quality of Life in Early School-Aged Ugandan Children With and Without Perinatal Human Immunodeficiency Virus Infection.

Caregiver's and child's self-reported quality of life (QOL) was defined using standardized questionnaires in a sample (N = 277) of 6-10 years old HIV-infected, HIV-exposed uninfected, and HIV-unexposed uninfected children from Uganda. Psychosocial stress (acute stress and cumulative lifetime adversity) and physiologic stress (dysregulations across 13 biomarkers), perinatal HIV status, and their interaction were related to child QOL via general linear models. Lower child- and caregiver-reported psychosocial stress were dose-dependently associated with higher QOL (acute stress: mean difference coefficient b = 8.1-14.8, effect size [ES] = 0.46-0.83). Lower allostasis was dose-dependently associated with higher QOL (b = 6.1-9.7, ES = 0.34-0.54). Given low caregiver acute stress, QOL for HIV-infected was similar to HIV-uninfected children; however, given high caregiver acute stress, a QOL disadvantage (b = -7.8, 95% CI: -12.8, -2.8; ES = -0.73) was evident for HIV-infected versus uninfected children. Testing of caregiver stress reduction interventions is warranted to increase wellbeing in dependent children.

Psychosocial Adjustment in Ugandan Children: Coping With Human Immunodeficiency Virus Exposure, Lifetime Adversity, and Importance of Social Support.

Cumulative lifetime adversity and social support were investigated as determinants of psychosocial adjustment (esteem, distress, hopefulness, positive outlook/future aspirations, and sense of purpose) over 12 months in 6-10-years-old HIV-infected, HIV-exposed uninfected and HIV-unexposed uninfected children from Uganda. Each determinant and psychosocial adjustment indicator was self-reported using standardized questionnaires administered at baseline, 6, and 12 months. Linear mixed effects models were used to relate time-varying lifetime adversity and social support to psychosocial adjustment over 12 months. Regardless of HIV status, higher adversity predicted lower esteem (coefficient b = -2.98, 95% confidence interval (CI): [-4.62, -1.35]) and increased distress (b =3.96, 95% CI: [1.29, 6.62]) but was not associated with hopefulness, positive outlook or sense of purpose. Low social support predicted higher distress (b =9.05, 95% CI: [7.36, 10.73]), lower positive outlook (b = -10.56, 95% CI: [-2.34, -8.79]) and low sense of purpose (b = -9.90, 95% CI: [-11.44, -8.36]) over 12 months. Pragmatic interventions that enhance coping with adversity and provide emotional/instrumental support should be tested for effectiveness in promoting resilient psychosocial adjustment trajectory in vulnerable children.

Caregiver socioemotional health as a determinant of child well-being in school-aged and adolescent Ugandan children with and without perinatal HIV exposure.

OBJECTIVE: Caregiver socio-emotional attributes are major determinants of child well-being. This investigation in vulnerable school-aged Ugandan children estimates relationships between children's well-being and their caregiver's anxiety, depression and social support. METHODS: Perinatally HIV-infected, HIV-exposed uninfected and HIV-unexposed Ugandan children and their caregivers were enrolled. Perinatal HIV status was determined by 18 months of age using DNA-polymerase chain-reaction test; status was confirmed via HIV rapid diagnostic test when children were 6-18 years old. Five indicators of child well-being (distress, hopelessness, positive future orientation, esteem and quality of life (QOL)) and caregivers' socioemotional status (depressive symptoms, anxiety and social support) were measured using validated, culturally adapted and translated instruments. Categories based on tertiles of each caregiver psychosocial indicator were defined. Linear regression analyses estimated percent differences (ß) and corresponding 95% confidence intervals (CI) for child well-being in relation to caregiver's psychosocial status. RESULTS: As per tertile increment, caregiver anxiety was associated with 2.7% higher distress (95%CI:0.2%, 5.3%) and lower self-esteem/QOL (ß = -1.3%/-2.6%; 95%CI: -5.0%,-0.2%) in their children. Child distress/hopelessness increased (ß = 3.3%/7.6%; 95%CI:0.4%, 14.7%) and self-esteem/QOL decreased 2.3% (ß = -2.3%/-4.4%; 95%CI: -7.2%, -1.3%) as per tertile increment in caregiver depression. Higher caregiver social support was associated with lower distress and higher positive outlook (ß = 3%; 95%CI:1.4%, 4.5%) in their children. HIV-infected/exposed children had most caregiver depression-related QOL deficit (ß = -5.2%/-6.8%; 95%CI: -12.4%, -0.2%) and HIV-unexposed children had most caregiver social support-related enhancements in positive outlook (ß=4.5%; 95%CI:1.9%, 7.1%). CONCLUSIONS: Caregiver anxiety, depressive symptoms and low social support were associated with worse well-being in school-aged and adolescent children. Improvement of caregiver mental health and strengthening caregiver social support systems may be a viable strategy for improving well-being of vulnerable children and adolescents in this setting.

OBJECTIF: Les attributs socio-affectifs des responsables d'enfants sont des déterminants majeurs du bien-être des enfants. Cette investigation menée auprès d'enfants ougandais vulnérables d'âge scolaire a estimé les relations entre le bien-être des enfants et l'anxiété, la dépression et le soutien social de leur responsable. MÉTHODES: Des enfants ougandais infectés par le VIH de manière périnatale, exposés au VIH mais non infectés, et non exposés au VIH ainsi que leurs responsables ont été inscrits. Le statut VIH périnatal a été déterminé à l'âge de 18 mois à l'aide du test de PCR de l'ADN; le statut a été confirmé par un test de diagnostic rapide du VIH chez les enfants âgés de 6 à 18 ans. Cinq indicateurs du bien-être de l'enfant (détresse, désespoir, orientation future positive, estime et qualité de vie (QV)), et le statut psychosocial des responsables (symptômes dépressifs, anxiété et soutien social) ont été mesurés à l'aide de méthodes validées, adaptées à la culture et respectées et d'outils traduits. Des catégories basées sur les tertiles de chaque indicateur psychosocial du responsable ont été définies. Des analyses de régression linéaire ont estimé les différences en pourcentage (ß) et les intervalles de confiance (IC) à 95% correspondants pour le bien-être de l'enfant par rapport au statut psychosocial de leurs responsables. RÉSULTATS: Par incrément de tertile, l'anxiété des responsables était associé à 2,7% de détresse plus élevé (IC95%: 0,2%, 5,3%) et de faible estime de soi/QV (ß = −1,3%/−2,6%; IC95%: −5,0%, −0,2%) chez leurs enfants. La détresse et le désespoir des enfants augmentaient (ß = 3,3%/7,6%; IC95%: 0,4%, 14,7%) et l'estime de soi/QV diminuait de 2,3% (ß = −2,3%/−4,4%; IC95%: −7,2%, −1,3%) par incrément de tertile de la dépression chez le responsable. Un soutien social plus élevé des responsables était associé à une détresse moindre et à une perspective positive plus élevée (ß = 3%; IC95%: 1,4%, 4,5%) chez leurs enfants. Les enfants infectés/exposés au VIH présentaient pour la plupart un déficit de QV lié à la dépression de leurs responsables (ß = −5,2%/−6,8%; IC95%: −12,4%, −0,2%), et ceux non exposés au VIH présentaient pour la plupart des améliorations en perspective positive liées au soutien social de leurs responsables (ß = 4,5%; IC95%: 1,9%, 7,1%). CONCLUSIONS: L'anxiété, les symptômes dépressifs et un faible soutien social du responsable étaient associés à un bien-être précaire chez les enfants d'âge scolaire et les adolescents. L'amélioration de la santé mentale des responsables et le renforcement des systèmes de soutien social pour les responsables peuvent constituer une stratégie viable pour améliorer le bien-être des enfants et des adolescents vulnérables dans cette région.

Growth differences by school-age and adolescence according to in utero and peripartum antiretroviral therapy exposure among Ugandan children.

In utero/peripartum antiretroviral (IPA) drug exposure in human immunodeficiency virus (HIV)-exposed children has established benefit for prevention of HIV mother-to-child-transmission but its association with height-for-age by adolescence is unknown. Hence we quantify IPA-associated growth differences at 6 to 18 years old among children with perinatally acquired HIV (CPHIV) infection and children HIV exposed but uninfected (CHEU) relative to children HIV unexposed and uninfected (CHUU). Cohort study. Kampala, Uganda. Two hundred thirty eight community controls and 490 children of women living with HIV born between 2000 and 2011 in a community were enrolled at 6 to 18 years of age and followed every 6 months for 1 year. Height-for-age determined at enrollment, 6 and 12 months after enrollment using the World Health Organization reference. IPA exposure was retrospectively determined from medical records and categorized as: no IPA, single-dose nevirapine with/without zidovudine (sdNVP ±â€…AZT), sdNVP + AZT + lamivudine, or combination antiretroviral therapy (cART). Mean differences (ß) with 95% confidence intervals (CIs) in height-for-age over 12 months were evaluated according to IPA exposure for CPHIV and CHEU and relative to CHUU using longitudinal linear mixed effects models adjusted for caregiver factors (sex, age, education, functioning in caregiving role, and lifetime adversity) in Statistical Analysis Software (v.9.4). Regardless of IPA type, CPHIV grew worse than CHUU by school-age/adolescence (ß = -0.30, 95% CI: -0.48, -0.11). Relative to CHUU height-for-age was similar for CHEU exposed to sdNVP ±â€…AZT (ß = -0.16, 95% CI: -0.46, 0.14) and for CHEU exposed to sdNVP + AZT + lamivudine (ß = 0.08, 95% CI: -0.20, 0.35). However, CHEU without any IPA exposure had lower height-for-age (ß = -0.27, 95% CI: -0.52, -0.00) whereas CHEU with cART exposure had greater height-for-age (ß = 0.41, 95% CI: 0.10, 0.71) in comparison with CHUU by 6 to 18 years old. Our findings suggest that CHEU may achieve height-for-age parity with CHUU by school-age and adolescent years- especially if provided benefit of effective cART in the peripartum period. However, CPHIV regardless of IPA exposure type and CHEU without IPA exposure remain at a disadvantage and will benefit from intervention to support their growth.

Serum Vitamin D is Differentially Associated with Socioemotional Adjustment in Early School-Aged Ugandan Children According to Perinatal HIV Status and In Utero/Peripartum Antiretroviral Exposure History.

An impact of vitamin D in neurocognitive function has been theorized but it remains unknown whether vitamin-D insufficiency (VDI) is associated with worse socio-emotional adjustment (SEA) in vulnerable early school-aged children. This study examines the thesis that deficits in SEA are related to VDI using longitudinal data from 254 children that are perinatally HIV-infected (PHIV), exposed-uninfected (HEU), or unexposed-uninfected (HUU). In utero/peripartum antiretroviral (IPA) exposure was established per medical record documentation of biological mother's ART regimen in pregnancy. Four caregiver-reported age- and sex-standardized measures of SEA were obtained at months 0, 6, and 12 for dependent children aged 6-10 years: externalizing problems (EPC), internalizing problems (IPC), behavioral symptoms index (BSI), and adaptive skills index (ASI). VDI was highly prevalent (74%, n = 188), and its association with change in SEA measures over 12 months varied by HIV-status (VDI*HIV, all p-values < 0.03). There was further variation in relationship of vitamin-D to SEA by IPA among PHIV (for ASI, BSI, and EPC, vitamin-D*IPA, p-value ≤ 0.01) and HEU (for BSI and EPC, vitamin-D*IPA, p-value ≤ 0.04). Among HUU, BSI (ß = -0.32, 95% CI: -0.50, -0.13), IPC (ß = -0.28, 95% CI: -0.47, -0.09), and EPC (ß = -0.20, 95% CI: -0.37, -0.02) all declined moderately per quartile increment in VD. Among PHIV, on the one hand higher vitamin D predicted ASI gains (moderate vs. low VD, ß = 0.52, p = 0.002), but this protective association was absent for BSI, EPC, and IPC (ß = 0.36-0.77, p < 0.05). In absence of IPA-exposure, increasing vitamin-D predicted declines in BSI and EPC (moderate vs. low Vitamin D, ß = -0.56 to -0.71, p ≤ 0.02) among HEU. However, given IPA exposure among HEU, higher VDI predicted moderate elevation in BSI (ß = 0.39, 95% CI: 0.00, 0.78) and IPC (ß = 0.48, 95% CI: 0.05, 0.92). Interaction between VD and IPA exposure for SEA outcomes among HEU and PHIV children warrants further investigation. The vitamin-D associated SEA improvement among HUU and HEU without IPA exposure suggests vitamin-D supplementation may remediate behavioral and adaptive deficits in this groups.

Perinatal HIV Status and Executive Function During School-Age and Adolescence: A Comparative Study of Long-Term Cognitive Capacity Among Children From a High HIV Prevalence Setting.

The aim of this study was to determine whether perinatal HIV infection (PHIV), HIV-exposed uninfected (PHEU) versus HIV-unexposed (PHU) status predicted long-term executive function (EF) deficit in school-aged Ugandan children.Perinatal HIV status was determined by 18 months via DNA polymerase chain reaction test and confirmed at cognitive assessment between 6 and 18 years using HIV rapid-diagnostic test. Primary outcome is child EF measured using behavior-rating inventory of executive function questionnaire across 8 subscales summed to derive the global executive composite (GEC). EF was proxy-reported by caregivers and self-reported by children 11 years or older. Descriptive analyses by perinatal HIV status included derivation of mean, standard deviations (SD), number, and percent (%) of children with EF deficits warranting clinical vigilance. Raw scores were internally standardized by age and sex adjustment. EF scores warranting clinical vigilance were defined as ≥ mean + 1.5SD. t Tests for mean score differences by perinatal HIV status and linear-regression models were implemented in SAS version 9.4 to derive HIV status-related EF deficits (ß) and 95% confidence intervals (CIs).Proxy-reported and self-reported EF were assessed in 166 and 82 children, respectively. GEC deficit was highest for PHIV (mean = 121.9, SD = 29.9), intermediate for PHEU (mean = 107.5, SD = 26.8), and lowest for PHU (mean = 103.4, SD = 20.7; P-trend < 0.01). GEC deficit levels warranting clinical vigilance occurred in 9 (15.8%), 5 (9.3%) and 0 (0%) PHIV, PHEU, and PHU children, respectively (P-trend = 0.01). Nineteen percent (n = 32) children had deficits requiring clinical vigilance in ≥2 proxy-reported EF subscales. Of these, multisubscale deficits occurred in 35.1%, 13.0%, and 9.3% of PHIV, PHEU, and PHU respectively (P-trend = 0.001). Multivariable analyses find significantly higher GEC deficits for PHIV compared with PHU and PHEU children regardless of respondent (all P values <0.01). Proxy-reported EF performance was similar for PHEU compared with PHU; however, child self-reported GEC scores were elevated by 12.8 units (95% CI: 5.4-25.5) for PHEU compared with PHU.PHIV had long-term EF deficits compared with other groups. Furthermore, PHEU ≥11 years may have long-term EF deficits compared with PHU, but future studies are needed to clarify this relationship. Cognitive remediation interventions with emphasis on EF may translate to improvements in long-term functional survival in HIV-affected children from sub-Saharan Africa.

Psychosocial adjustment in perinatally human immunodeficiency virus infected or exposed children - a Retrospective Cohort Study.

OBJECTIVE: To determine whether perinatal HIV infection and exposure adversely affected psychosocial adjustment (PA) between 6 and 18 years of life (i.e. during school-age and adolescence). METHODS: We enrolled 58 perinatally HIV-infected, 56 HIV-exposed uninfected and 54 unexposed controls from Kampala, Uganda. Perinatal HIV status was determined by 18 months of age using a DNA-polymerase chain-reaction test and was confirmed via HIV rapid diagnostic test at psychosocial testing when the children were 6 to 18 years old. Five indicators of PA (depressive symptoms, distress, hopelessness, positive future orientation and esteem) were measured using validated, culturally adapted and translated instruments. Multivariable linear regression analyses estimated HIV-status-related percent differences (ß) in PA indicators and corresponding 95% confidence intervals (CIs). RESULTS: During school-age and adolescence, positive outlook (ß=-3.8, 95% CI: -7.2, -0.1) and self-esteem (ß=-4.3, 95% CI: -6.7, -1.8) scores were significantly lower, whereas depressive (ß=11.4, 95% CI: 3.3, 19.5) and distress (ß=12.3, 95% CI: 5.9, 18.7) symptoms were elevated for perinatally HIV-infected, compared to unexposed controls and exposed uninfected children. Similarly, positive outlook (ß=-4.3, 95% CI: -7.3, -1.2) and self-esteem were lower for exposed controls versus HIV-unexposed children. Hopelessness was similar by perinatal HIV status. Likewise, the distress and depressive symptom levels were comparable for HIV-exposed uninfected and HIV-unexposed children. CONCLUSIONS: Perinatal HIV infection predicted higher distress and depressive symptoms, while HIV-affected status (infection/exposure) predicted low self-esteem and diminished positive outlook in the long term. However, HIV-affected status had no impact on hopelessness, suggesting that psychosocial interventions as an integral component of HIV care for infected children or primary care exposed uninfected children may improve PA and quality of life in these vulnerable groups.