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OBJECTIVE: Vitamin D insufficiency occurs commonly in HIV-infected youth in the United States. In light of the importance of vitamin D for skeletal and nonskeletal health, including innate immunity, developing methods for improving vitamin D status in HIV-infected children and adolescents is an important area of clinical research. The objective of this study was to evaluate the effect of administration of oral cholecalciferol, 100,000 IU every 2 months, and 1 g/day calcium on serum 25-hydroxyvitamin D concentrations, serum and urine calcium, and HIV disease progression during a 12-month period. METHODS: HIV-infected children and adolescents who were aged 6 to 16 years were randomly assigned to receive vitamin D (100,000 IU bimonthly) and calcium (1 g/day; n = 29) or double placebo (n = 27). Serum 25-hydroxyvitamin D concentrations as measured by radioimmunoassay, albumin-corrected calcium concentrations, and spot urinary calcium-creatinine ratios were determined monthly. RESULTS: No abnormalities in serum calcium concentration were observed. One participant who received placebo developed hypercalciuria. No group differences were seen in the change in CD4 count or CD4% or viral load during 12 months. The overall mean monthly serum 25-hydroxyvitamin D concentrations were higher in the group that received vitamin D and calcium than in the placebo group, as was the monthly serum 25-hydroxyvitamin D area under the curve. After completing 12 months of study, 2 (6.7%) participants in the group that received vitamin D and calcium had a trough serum 25-hydroxyvitamin D concentration <20 ng/mL compared with 14 (50%) in the placebo group. Twelve (44.4%) in the group that received vitamin D and calcium had a trough serum 25-hydroxyvitamin D concentration of > or =30 ng/mL compared with 3 (11.1%) in the placebo group. CONCLUSIONS: Administration of oral cholecalciferol to HIV-infected children and adolescents at a dosage of 100,000 IU every 2 months, together with 1 g/day calcium, is safe and results in significant increases in serum 25-hydroxyvitamin D concentrations. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of early antiretroviral therapy (ART) on growth trajectories of infants with human immunodeficiency virus (IHIV) in the first year of life., Study Design: As part of a clinical trial of early ART in Johannesburg, South Africa (2015-2018), 116 IHIV diagnosed within 48 hours of birth were started on ART as soon as possible, and 80 uninfected infants born to mothers living with HIV (IHEU) were enrolled. Both groups were followed prospectively from birth through 48 weeks and growth parameters collected. The groups were compared and risk factors for poor growth investigated, in the full cohort and among IHIV separately., Results: IHIV had lower mean weight-for-age Z-scores (WAZ) than IHEU at 4 and 8 weeks (-1.17 [SE:0.14] vs -0.72 [0.14], P = .035 and -1.23 [0.15] vs -0.67 [0.14], P = .012). Although there was some closing of the gap over time, means remained lower in IHIV through 48 weeks. In length-for-age Z-scores (LAZ), differences widened over time and IHIV had lower Z-scores by 48 weeks (-1.41 [0.15] vs -0.80 [0.18], P = .011). Deficits in WAZ and LAZ in IHIV vs IHEU were most marked among girls. IHIV with pre-ART viral load ≥1000 copies/ml had significantly lower weight-for-length and mid-upper arm circumference Z-scores across all time points through 48 weeks., Conclusions: IHIV on early ART had deficits in WAZ over the first 8 weeks of life and lower LAZ at 48 weeks than IHEU. Among IHIV, higher pre-ART viral load was associated with worse anthropometric indicators through 48 weeks., Competing Interests: Declaration of Competing Interest Funding: The Latency and Early Neonatal Provision of Antiretroviral Drugs (LEOPARD) study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Disease, National Institutes of Health (U01HD080441), the South African National HIV Programme, and South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (84177)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Infancy is an important developmental period when the microbiome is shaped. We hypothesized that earlier antiretroviral therapy (ART) initiation would attenuate HIV effects on microbiota in the mouth., Methods: Oral swabs were collected from 477 children with HIV (CWH) and 123 children without (controls) at two sites in Johannesburg, South Africa. CWH had started ART less than 3 years of age; 63% less than 6 months of age. Most were well controlled on ART at median age 11 years when the swab was collected. Controls were age-matched and recruited from the same communities. Sequencing of V4 amplicon of 16S rRNA was done. Differences in microbial diversity and relative abundances of taxa were compared between the groups., Results: CWH had lower alpha diversity than controls. Genus-level abundances of Granulicatella, Streptococcus, and Gemella were greater and Neisseria and Haemophilus less abundant among CWH than controls. Associations were stronger among boys. Associations were not attenuated with earlier ART initiation. Shifts in genus-level taxa abundances in CWH relative to controls were most marked in children on lopinavir/ritonavir regimens, with fewer shifts seen if on efavirenz ART regimens., Conclusion: A distinct profile of less diverse oral bacterial taxa was observed in school-aged CWH on ART compared with uninfected controls suggesting modulation of microbiota in the mouth by HIV and/or its treatments. Earlier ART initiation was not associated with microbiota profile. Proximal factors, including current ART regimen, were associated with contemporaneous profile of oral microbiota and may have masked associations with distal factors such as age at ART initiation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Children living with HIV (CLHIV) have decreased bone mineral content (BMC) and density (BMD), increasing risk for fracture and future osteoporosis. While DXA is the gold-standard for bone assessments, it lacks availability in resource-constrained settings (RCS). Quantitative ultrasound (QUS) offers an alternative owing to its portability, low cost, ease of handling, and lack of ionizing radiation. While QUS has detected reduced bone quality in CLHIV, the relationship between QUS and DXA in this population remains unexplored. At baseline and 12 months, BMC and BMD of the whole body, lumbar spine, and radius were measured by DXA in a longitudinal cohort of CLHIV in Johannesburg, South Africa. Calcaneal speed of sound (SOS) and broadband ultrasound attenuation (BUA) and radius SOS were obtained by QUS, and calcaneal stiffness index (SI) was calculated. Spearman correlations, with and without HIV stratification, were performed between QUS and DXA measurements at each visit and for absolute difference in measurements between visits. At baseline and 12-months, calcaneal BUA and SI displayed strong positive correlations with DXA, with only modest correlations between radial QUS and DXA at baseline. Longitudinal measures of QUS did not correlate with DXA. At both baseline and 12-months, individuals with DXA whole-body BMD z-score < -1 displayed significantly lower calcaneal BUA and SI. Cross-sectionally, calcaneal QUS correlates strongly with whole body DXA and may represent a viable diagnostic alternative in RCS. Longitudinally, the two methods do not correlate well, possibly reflecting that each method assesses distinct aspects of bone architecture., Competing Interests: The authors have declared that no competing interests exist.

HIV viral load (VL) monitoring can reinforce antiretroviral therapy (ART) adherence. Standard VL testing requires high laboratory capacity and coordination between clinic and laboratory which can delay results. A randomized trial comparing point-of-care (POC) VL testing to standard VL testing among 150 adolescents and young adults, ages 10-24 years, living with HIV in Haiti determined if POC VL testing could return faster results and improve ART adherence and viral suppression. Participants received a POC VL test with same-day result (POC arm) or a standard VL test with result given 1 month later (SOC arm). POC arm participants were more likely to receive a test result within 6 weeks than SOC arm participants (94.7% vs. 80.1%; p1000 copies/ml and low self-reported ART adherence was stronger in the POC arm (OR: 6.57; 95%CI: 2.12-25.21) than the SOC arm (OR: 2.62; 95%CI: 0.97-7.44) suggesting more accurate self-report in the POC arm. POC VL testing was effectively implemented in this low-resource setting with faster results and is a pragmatic intervention that may enable clinicians to identify those with high VL to provide enhanced counseling or regimen changes sooner. Trial registration: ClinicalTrials.gov identifier: NCT03288246.

Background: Accelerated epigenetic aging using DNA methylation (DNAm)-based biomarkers has been reported in people with human immunodeficiency virus (HIV, PWH), but limited data are available among African Americans (AA), women, and older PWH., Methods: DNAm was measured using Illumina EPIC Arrays for 107 (69 PWH and 38 HIV-seronegative controls) AA adults ≥60 years in New York City. Six DNAm-based biomarkers of aging were estimated: (1) epigenetic age acceleration (EAA), (2) extrinsic epigenetic age acceleration (EEAA), (3) intrinsic epigenetic age acceleration (IEAA), (4) GrimAge, (5) PhenoAge, and (6) DNAm-estimated telomere length (DNAm-TL). The National Institutes of Health (NIH) Toolbox Cognition Battery (domains: executive function, attention, working memory, processing speed, and language) and Montreal Cognitive Assessment (MoCA) were administered. Participants were assessed for frailty by the Fried criteria., Results: The PWH and control groups did not differ by sex, chronological age, or ethnicity. In total, 83% of PWH had a viral load <50 copies/mL, and 94% had a recent CD4 ≥200 cells/µL. The PWH group had a higher EAA, EEAA, GrimAge, and PhenoAge, and a lower DNAm-TL compared to the controls. IEAA was not different between groups. For PWH, there were significant negative correlations between IEAA and executive function, attention, and working memory and PhenoAge and attention. No associations between biomarkers and frailty were detected., Conclusions: Evidence of epigenetic age acceleration was observed in AA older PWH using DNAm-based biomarkers of aging. There was no evidence of age acceleration independent of cell type National Institutes of Health composition (IEAA) associated with HIV, but this measure was associated with decreased cognitive function among PWH., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: We evaluated longitudinal trends and associations between bone mass, bone turnover and inflammatory markers among South African children living with HIV (CLHIV) and controls., Design: We previously reported decreased bone mass among CLHIV independent of marked inflammation and increased bone turnover. The goal of this study was to evaluate longitudinal changes in bone mass, bone turnover and inflammation over 2 years., Methods: Longitudinal analyses were conducted among 220 CLHIV and 220 controls. Anthropometric measurements, physical activity, antiretroviral regimen, virologic and immunologic status, whole body (WB) and lumbar spine (LS) bone mineral content (BMC) and bone mineral density (BMD) were collected (enrollment, 12 and 24 months). Bone turnover markers including C-telopeptide of type I collagen (CTx) and procollagen type I N-terminal propeptide (P1NP) and inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble CD14 and high-sensitivity C-reactive protein (hsCRP) were collected at enrollment and 24 months., Results: Compared with controls, CLHIV had significantly lower mean WB-BMC, WB-BMD, WB-BMC z scores, LS-BMC and LS-BMD as well as lower bone formation (P1NP) and resorption (CTx), and higher hsCRP and soluble CD14 over 24 months. CLHIV on efavirenz (EFV) had consistently lower TNF-alpha and IL-6 compared with those on ritonavir-boosted lopinavir (LPV/r) at all time points., Conclusion: Over 2 years of follow-up, South African CLHIV had persistently lower bone mass, bone turnover, and macrophage activation. Lower bone mass and higher pro-inflammatory cytokine profiles were consistently observed among those on LPV/r-based compared with EFV-based regimens., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Prior studies have measured accelerated aging in people with HIV using a DNA methylation (DNAm)-based biomarker of aging, "epigenetic age," but data are limited in African American (AA) young adults with perinatally acquired HIV infection (PHIV)., Methods: We performed a cross-sectional study of AA young adults aged 20-35 years with PHIV (N = 31) and seronegative controls (N = 30) using DNAm measured in whole blood and cognitive function measured by the NIH Toolbox. Illumina EPIC array was used to measure DNAm age and accelerated aging markers including epigenetic age acceleration (EAA), as well as extrinsic (EEAA) and intrinsic (IEAA) EAA., Results: PHIV and controls did not differ by sex (45 vs. 43% male), chronological age (26.2 vs. 28.0 years), or ethnicity. Chronological age and DNAm age were correlated (r = 0.56, P < 0.01). PHIV had a higher mean EAA (2.86 ± 6.5 vs. -2.96 ± 3.9, P < 0.01) and EEAA (4.57 ± 13.0 vs. -4.72 ± 6.0, P < 0.01) than controls; however, IEAA was not different between groups. Among PHIV, EAA and EEAA were higher in those with HIV viral load ≥50 copies/mL than <50 copies/mL (EEA: 8.1 ± 5.2 vs. 0.11 ± 5.5, P = 0 < 0.01 and EEAA: 16.1 ± 10.6 vs. -1.83 ± 9.7, P < 0.01). We observed negative correlations (r = -0.36 to -0.31) between EEAA and executive function, attention, and language scores., Conclusions: In conclusion, EAA in blood was observed in AA young adults with PHIV on ART using 2 measures, including EEAA which upweights the contribution of immunosenescent cell types. However, there was no evidence of age acceleration with a measure independent of cell type composition., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Children with HIV (CHIV) have lifetime exposure to antiretrovirals (ART); therefore, optimizing their regimens to have the least impact on fat redistribution is a priority., Methods: This is a cross-sectional study of 219 perinatally infected CHIV and 219 HIV-uninfected controls from similar socioeconomic backgrounds in Johannesburg, South Africa. We compared total body and regional fat distribution in CHIV on suppressive ART regimens with controls and, among CHIV, between ritonavir-boosted lopinavir (LPV/r)-based and efavirenz (EFV)-based regimens., Results: The mean age of the 219 uninfected children (45% girls) and the 219 CHIV (48% girls) was 7.0 and 6.4 years, respectively. CHIV had lower adjusted total body fat (P = 0.005) and lower percentage fat at the trunk (P = 0.020), arms (P = 0.001), and legs (P < 0.001) than uninfected children. CHIV on LPV/r had similar body composition as those on EFV, except for arm fat mass (P = 0.030). When stratified by sex, girls with HIV on LPV/r had lower adjusted total (P = 0.007), trunk (P = 0.002), arms (P = 0.008), legs (P = 0.048) fat mass; trunk-to-total body fat (P = 0.044); and higher legs-to-total body fat (P = 0.011) than those on EFV., Conclusions: South African CHIV receiving ART had lower global and partial fat mass and percentage fat than healthy controls. In girls with HIV with sustained virologic suppression on ART, switching from LPV/r to EFV could attenuate fat mass loss, indicating that EFV-based regimen may be a better option in this group of individuals., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

This study examined behavioral functioning and quality of life in South African children living with perinatally acquired HIV. Compared with controls, children living with perinatally acquired HIV had a higher mean total difficulties score assessed by the Strengths and Difficulties Questionnaire and lower mean quality of life scores assessed by the Pediatric Quality of Life Inventory., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: We previously found lower bone mass but similar bone turnover in pre-pubertal children living with HIV (CLWH) on a ritonavir-boosted lopinavir (LPV/r)-based vs. efavirenz-based antiretroviral therapy regimen 2 years after switch. Here, we evaluate if bone turnover differed between the groups close to the time of switch., Methods: Samples from 108 children remaining on LPV/r and 104 children switched to efavirenz were available for analysis 8 weeks post-randomization. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx), procollagen type-I N-terminal propeptide (P1NP), and osteocalcin were measured. Markers of immune activation were also measured, including IL-6, TNF-alpha, soluble CD14 and high-sensitivity C-reactive protein (CRP)., Results: Eight weeks post-randomization, we did not detect differences in CTx (1.42 vs. 1.44 ng/mL, p = 0.85) or P1NP concentrations (622 vs. 513 ng/mL, p = 0.68) between treatment groups. At 8 weeks, the treatment groups also had similar levels of IL-6, TNF-alpha, soluble CD14 and high-sensitivity CRP. Osteocalcin (ng/mL) was higher in the LPV/r than efavirenz group both at 8 weeks (88.6 vs. 67.3, p = 0.001) and 2 years (67.6 vs. 49.8, p = 0.001)., Conclusions: Overall, we failed to detect difference in bone turnover by P1NP and CTx in virologically-suppressed CLWH on different regimens at a time point close to the switch. We did observe higher levels of total osteocalcin in children remaining on LPV/r compared to children switched to efavirenz. Future studies should focus on uncovering the mechanism and determining whether perturbation in undercarboxylated osteocalcin could explain some of the bone side effects noted with protease inhibitors., Competing Interests: Declaration of competing interest Stephanie Shiau, Michael T. Yin, Renate Strehlau, Jing Shen, Elaine J. Abrams, Ashraf Coovadia, Louise Kuhn, and Stephen M. Arpadi declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Adolescents living with HIV have poor antiretroviral therapy (ART) adherence and viral suppression outcomes. Viral load (VL) monitoring could reinforce adherence but standard VL testing requires strong laboratory capacity often only available in large central laboratories. Thus, coordinated transport of samples and results between the clinic and laboratory is required, presenting opportunities for delayed or misplaced results. Newly available point-of-care (POC) VL testing systems return test results the same day and could simplify VL monitoring so that adolescents receive test results faster which could strengthen adherence counselling and improve ART adherence and viral suppression., Methods and Analysis: This non-blinded randomised clinical trial is designed to evaluate the implementation and effectiveness of POC VL testing compared with standard laboratory-based VL testing among adolescents and youth living with HIV in Haiti. A total of 150 participants ages 10-24 who have been on ART for >6 months are randomised 1:1 to intervention or standard arms. Intervention arm participants receive a POC VL test (Cepheid Xpert HIV-1 Viral Load system) with same-day result and immediate ART adherence counselling. Standard care participants receive a laboratory-based VL test (Abbott m2000sp/m2000rt) with the result available 1 month later, at which time they receive ART adherence counselling. VL testing is repeated 6 months later for both arms. The primary objective is to describe the implementation of POC VL testing compared with standard laboratory-based VL testing. The secondary objective is to evaluate the effect of POC VL testing on VL suppression at 6 months and participant comprehension of the correlation between VL and ART adherence., Ethics and Dissemination: This study is approved by GHESKIO, Weill Cornell Medicine and Columbia University ethics committees. This trial will provide critical data to understand if and how POC VL testing may impact adolescent ART adherence and viral suppression. If effective, POC VL testing could routinely supplement standard laboratory-based VL testing among high-risk populations living with HIV., Trial Registration Number: NCT03288246., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Perinatal HIV infection is associated with delayed neurocognitive development, but less is known about children perinatally HIV-exposed but uninfected (CHEU). We compared cognitive and language outcomes in 4-6-year old CHEU versus children HIV-unexposed and uninfected (CHUU) and children living with HIV (CLHIV). We enrolled 1,581 children (77% of the child population) in five communities in KwaZulu-Natal, South Africa. Children completed: Grover-Counter Scale of cognitive development, sub-scales of the Kaufman Assessment Battery for Children, Reynell Developmental Language Scales. HIV status of children and primary caregivers was determined by repeated rapid tests or report of prior testing. We conducted a cross-sectional multivariable linear regression on 922 dyads with complete data (257 CHEU, 627 CHUU, 38 CLHIV). On all outcome measures, CHEU and CHUU groups had comparable scores; CLHIV scored significantly lower. Emerging global progress toward the elimination of vertical HIV transmission may not only reduce mortality, but also positively impact child development., (© 2020 Wiley Periodicals, Inc.)

Background: Reduced bone mineral mass by dual x-ray absorptiometry is reported in children living with HIV (CLWH), but few studies of bone microarchitecture, particularly in sub-Saharan Africa, have been conducted. Here, we compare bone architecture and strength in black South African CLWH and uninfected control children by peripheral quantitative computed tomography (pQCT)., Setting and Methods: One hundred seventy-two CLWH on antiretroviral therapy (ART) and 98 controls in the CHANGES Bone Study in Johannesburg, South Africa received pQCT scans of the radius and tibia. Measurements included trabecular and cortical volumetric bone mineral density (vBMD) and bone strength, estimated by the polar strength strain index (SSI), a validated measure of fracture risk., Results: CLWH (51% boys) and controls (63% boys) were an average of age 10.4 years. Mean ART duration for CLWH was 9.5 years, with 70.9% on an efavirenz-based, 28.5% on a lopinavir/ritonavir-based, and 1 child on an atazanavir/ritonavir-based regimen. Male CLWH had lower trabecular vBMD at the radius than controls after adjustment for age, radial length, and Tanner stage (β = -17.3, standard error = 7.2, P = 0.018). Bone strength by polar SSI was lower in CLWH than controls (778 vs. 972 mm, P < 0.01). CLWH on an LPV/r-based regimen had lower trabecular vBMD (199 vs. 222 mg/cm, P < 0.001) and cortical vBMD (1074 vs. 1093 mg/cm, P = 0.004) than those on an efavirenz-based regimen. No difference in bone strength by polar SSI was observed between treatment groups., Conclusion: CLWH initiated on ART early in life with well-controlled HIV have deficits in bone architecture and reductions in bone strength as detected by pQCT.

Little is known about how growing up with HIV impacts educational outcomes in sub-Saharan African children. We evaluated if South African children living with HIV (CLWH) were in the appropriate school grade-for-age compared to uninfected control children. We observed higher rates of not being in the correct grade-for-age in CLWH compared with controls (OR 3.32, 95% CI: 2.07-5.34), adjusted for study site, sex, whether the child's biological father was alive, and caregiver education. Initiation of ART before 6 months of age reduced but did not eliminate this association. Whether these associations are due to biological factors or other social and environmental determinants, and how best to support CLWH to achieve educational goals, warrants further investigation.

Purpose of Review: In the era of modern bone-friendly antiretroviral therapy (ART) regimens for people living with HIV (PLWH), this review discusses the research gaps and management concerns that remain for individuals who have already been exposed to ART with negative effects on bone metabolism, especially children and adolescents who have not acquired peak bone mass, and older adults who have additional risk factors for fracture., Recent Findings: Data now support the use of avoidance of TDF and use of bone-friendly regimens that include integrase strand transfer inhibitors in PLWH with increased risk of fracture for either ART initiation or switch. Despite significant advances in our understanding of ART choice for PLWH with regard to bone health, additional diagnostic tests to determine fracture risk and management strategies beyond ART choice are necessary, especially in vulnerable PLWH populations, such as children and adolescents and older adults.

We evaluated bone quality among South African children with HIV over a 2-year period by quantitative ultrasound (QUS). Children with HIV have persistently lower bone quality compared with controls reflecting increased porosity, reduced strength, and possibly an increased short- and long-term risk of fracture., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Perinatally-acquired HIV has persistent effects on long-term health outcomes, even after early treatment. We hypothesize that epigenetic indicators, such as DNA methylation, may elucidate cellular processes that explain these effects. Here, we compared DNA methylation profiles in whole blood from 120 HIV-infected children on antiretroviral therapy (ART) and 60 frequency age-matched HIV-uninfected children aged 4-9 years in Johannesburg, South Africa. Using an individual CpG site approach, we found 1,309 differentially-methylated (DM) CpG sites between groups, including 1,271 CpG sites that were hyper-methylated in the HIV-infected group and 38 CpG sites that were hypo-methylated in the HIV-infected group. Six hyper-methylated CpG sites were in EBF4, which codes for a transcription factor involved in B-cell maturation. The top hypomethylated site was in the promoter region of NLRC5, encoding a transcription factor that regulates major histocompatibility complex (MHC) class I molecule expression. Using a differentially-methylated region (DMR) approach, we found 315 DMRs between groups, including 28 regions encompassing 686 CpG sites on chromosome 6. A large number of the genes identified in both the CpG site and DMR approaches were located in the MHC region on chromosome 6, which plays an important role in the adaptive immune system. This study provides the first evidence that changes in the epigenome are detectable in children with perinatally-acquired HIV infection on suppressive ART started at an early age.

Background: Data on accelerated aging in HIV-infected children are limited. In this study, we assess 2 biomarkers of aging-telomere length and DNA methylation (DNAm) age-in a cohort of early-treated HIV-infected children and compare these aging biomarkers with HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children., Setting: Cross-sectional study of 120 HIV-infected, 33 HEU, and 25 HUU children enrolled in a cohort study in Johannesburg, South Africa. The mean age of children was 6.4 years at the time of measurement. HIV-infected children initiated ritonavir-boosted lopinavir-based antiretroviral therapy before 2 years of age and had been on continuous antiretroviral therapy until biomarker measurement., Methods: Telomere length was determined using multiplex quantitative polymerase chain reaction. DNAm was measured using the Illumina 450K array and DNAm age was calculated as the acceleration residual from regressing DNAm age on chronological age., Results: Telomere length (ln[Kb/genome]) was shorter in HIV-infected children compared with HUU children (4.14 ± 0.85 vs. 4.53 ± 0.79, P = 0.038) and in HEU children compared with HUU children (4.05 ± 0.74 vs. 4.53 ± 0.79, P = 0.023). Age acceleration residual based on DNAm levels was not different between HIV-infected (-0.003 ± 2.95), HEU (0.038 ± 2.39), and HUU (0.18 ± 2.49) children in unadjusted analysis and after adjustment for cell type proportions., Conclusions: Unlike reports of accelerated DNAm age in HIV-infected adults, there was no evidence of accelerated biological aging by DNAm levels in this cohort of early-treated HIV-infected children. By contrast, absolute telomere length was shorter in HIV-infected and HEU children compared with HUU children, but did not differ between HIV-infected and HEU children.

Background: While neurodevelopmental abnormalities are common in children with HIV infection, their detection can be challenging in settings with limited availability of health professionals. The aim of this study was to assess the ability to identify developmental disability among HIV positive and HIV negative children living in South Africa with an internationally used screen., Methods and Findings: This analysis uses a sample of 1,330 4-6 year old children and 1,231 of their caregivers in KwaZulu-Natal, South Africa, including administration of the Ten Questions (TQ) screen, a standardized medical history and physical examination conducted by a medical doctor, with hearing and vision screening, psychological assessment for cognition and language delay, and voluntary HIV testing. There was a high prevalence of disability among the sample. Compared to HIV negative children, HIV positive children were more likely to screen positive on at least one TQ item (59.3 vs 42.8%, p = 0.01), be delayed in sitting, standing or walking (OR 3.89, 95% CI = 2.1-7.2) and have difficulty walking or weakness in the arms or legs (OR = 2.7, 95%CI = 0.8-9.37). By medical doctor assessment, HIV positive children were more likely to be diagnosed with gross motor disability (OR = 3.5, 95%CI = 1.3-9.2) and hearing disability (OR = 2.5, 95%CI = 1.2-5.3). By independent psychological assessment, HIV positive children were more likely to have cognitive delay (OR = 2.2, 95%CI = 1.2-3.9) and language delay (OR = 4.3, 95%CI = 2.2-8.4). Among HIV positive children, the sensitivity and specificity of the TQ for serious disability (vs. no disability) was 100% and 51.2%, respectively. Among HIV-negative children, the sensitivity and specificity of the TQ for serious disability (vs. no disability) was 90.2% and 63.9%, respectively., Conclusions: In this first report of the use of the TQ screen in the isiZulu language, it was found to have high sensitivity for detecting serious developmental disabilities in children, especially HIV positive children. The performance of the TQ in this sample indicates utility for making best use of limited neurodevelopmental resources by screening HIV positive children., Competing Interests: The authors have declared that no competing interests exist.

Background: Prior research in sub-Saharan Africa reports dyslipidemia in perinatally human immunodeficiency virus (HIV)-infected children receiving ritonavir-boosted lopinavir (LPV/r) compared with efavirenz; however, interpretation of findings is limited by lack of comparison data from HIV-uninfected children., Methods: We conducted a cross-sectional analysis of lipid profiles and growth within a larger longitudinal cohort study of perinatally HIV-infected and HIV-uninfected children aged 4-9 years in Johannesburg, South Africa. At enrollment, anthropometrics, viral load, CD4, total cholesterol (TC), high-density lipoprotein, low-density lipoprotein (LDL), and triglycerides were measured. Weight-for-age Z-score (WAZ), height-for-age Z-score (HAZ), and body mass index-for-age Z-score (BAZ) were calculated. United States pediatric thresholds for dyslipidemia were used., Results: Five hundred fifty-three HIV-infected and 300 HIV-uninfected children (median age 6.9 years) of similar demographic characteristics were enrolled. Of the HIV-infected children, 94.8% were on combination antiretroviral therapy (cART) (65.4% on LPV/r- and 28.6% on efavirenz-based regimens). Among the treated, 94.3% had a viral load <200 copies/mL. Median CD4% was 34.4. The HIV-infected children had lower mean WAZ (-0.7 vs -0.3, P < .01) and HAZ (-1.1 vs -0.7, P < .01) compared with HIV-uninfected children. A lower proportion of HIV-infected children were overweight (BAZ >1) compared with HIV-uninfected children (14.4% vs 21.7%, P = .04). Whether on LPV/r or efavirenz, a higher proportion of HIV-infected children had borderline/elevated TC or abnormal triglycerides than HIV-uninfected children, although a higher proportion of those on LPV/r had borderline/elevated TC, borderline/elevated LDL, or abnormal triglycerides than those on efavirenz., Conclusions: In a South African cohort of HIV-infected children and population-appropriate HIV-uninfected children, unfavorable alterations in lipid profiles were detected in HIV-infected children regardless of treatment regimen compared with HIV-uninfected children. The HIV-infected children were of smaller size than HIV-uninfected children, but there was a high prevalence of overweight in both groups. Strategies for optimizing growth and early life management of lipid alterations may be warranted.

In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D 3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D 3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D 3 was associated with a >50% reduction in the rate of respiratory illness during the second year ( P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728., (© 2018 by The American Society of Hematology.)

Interventions to prevent mother-to-child HIV transmission have been extremely successful, but new HIV infections continue to occur in infants. Strong evidence indicates that combination antiretroviral therapy (ART) for treatment should be started in HIV-infected infants to prevent early morbidity and mortality. In 2013, the report of the Mississippi baby, who was started on ART within 30 h of life and maintained off-treatment remission for 27 months before HIV was once again detectable, generated renewed interest in very early ART initiation. The case stimulated interest in the possibility of HIV remission, which we define as maintenance of plasma viraemia below the threshold of detection in the absence of ART, after early treatment initiation. The possibility of HIV remission elicits much hope, given that children with HIV infection currently face a lifetime of treatment. The potential for early ART to lead to HIV remission in infants can be thought of in terms of six factors: rapidity of viral suppression with very early ART; initial viral suppression rate with early ART; later virological control after early treatment; the effect of early treatment on the viral reservoir size; outcomes of randomised trials of structured treatment interruption; and the likelihood of viral rebound in neonates after ART cessation. Review of existing data suggests that achieving long-term remission off treatment remains elusive, and concentrated attention and commitment of the scientific community is needed to investigate the factors that might help to reach this goal., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this study, we evaluated the relationships between immune activation, bone turnover, and bone mass in virally suppressed HIV-infected children and HIV-uninfected children in South Africa. We found that decreased bone mass may occur or persist independent of immune activation and altered bone turnover., Purpose: HIV-infected children and adolescents have deficits in skeletal growth which include decreases in bone mass and alterations in bone microarchitecture. However, the mechanism by which HIV infection compromises bone accrual in children and adolescents is unclear. The goal of this study was to evaluate the relationships between immune activation, bone turnover, and bone mass in a group of pre-pubertal HIV-infected children randomized to remain on ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy (ART) or switch to efavirenz-based ART in South Africa virally suppressed at the time of this study., Methods: This cross-sectional analysis included 219 HIV-infected and 180 HIV-uninfected children enrolled in the CHANGES Bone Study conducted in Johannesburg, South Africa. Whole body (WB) bone mineral content (BMC) was assessed by dual x-ray absorptiometry and WB BMC Z-scores adjusted for sex, age, and height were generated. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx) and procollagen type I N-terminal propeptide (P1NP), were analyzed. Markers of immune activation were also measured, including cytokines IL-6 and TNF-alpha, as well as soluble CD14 and high-sensitivity C-reactive protein (CRP)., Results: Compared to uninfected controls, HIV-infected children had lower WB BMC Z-scores, similar IL-6 and TNF-alpha, higher soluble CD14 and high-sensitivity CRP, and lower markers of bone resorption (CTX) and bone formation (P1NP). Bone turnover markers were not different in those remaining on LPV/r or switched to efavirenz., Conclusions: Our findings suggest that in HIV-infected children with viral suppression, decreased bone accrual may occur or persist independent of immune activation and altered bone turnover.

Introduction: The objective of this commentary is to review considerations for implementing routine viral load (VL) monitoring programmes for HIV-infected infants and children living in low- and middle-income countries (LMIC). Since 2013, the World Health Organization (WHO) guidelines recommend VL testing as the preferred monitoring approach for all individuals treated with ART in order to assess treatment response, detect treatment failure and determine the need to switch to a second-line regimen in a timely manner. More recently, WHO guidelines from 2016 identify HIV-infected infants and children as a priority group for routine VL monitoring., Discussion: There are a number of reasons why HIV-infected infants and children should be prioritized for routine VL monitoring. Data from national VL monitoring programmes as well as systematic reviews and meta-analyses from LMIC indicate rates of viral suppression are lower for infants and children compared to adults. The number of antiretroviral drugs and palatable formulations suitable for young children are limited. In addition, emotional and developmental issues particular to children can make daily medication administration difficult and pose a challenge to adherence and achievement of sustained viral suppression. VL monitoring can be instrumental for identifying those in need of additional adherence support, reducing regimen switches and preserving treatment options. The needs of infants and children warrant consideration in all aspects of VL monitoring services. If capacity for paediatric venipuncture is not assured, platforms that accept dried blood spot specimens are necessary in order for infants and children to have equitable access. Healthcare systems also need to prepare to manage the substantial number of infants and children identified with elevated VL, including adherence interventions that are appropriate for children. Establishing robust systems to evaluate processes and outcomes of routine VL monitoring services and to support drug forecasting and supply management is essential to determine best practices for infants and children in LMIC., Conclusions: The particular concerns of HIV-infected infants and children warrant attention during all phases of planning and implementation of VL monitoring services. There are a number of key areas, including frequency of monitoring, blood specimen type and adherence challenges, where specific approaches tailored for infants and children may be required., (© 2017 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Objectives: The World Health Organization recommends that human immunodeficiency virus (HIV)-infected children increase energy intake and maintain a balanced macronutrient distribution for optimal growth and nutrition. Few studies have evaluated dietary intake of HIV-infected children in resource-limited settings., Methods: We conducted a cross-sectional analysis of the dietary intake of 220 perinatally HIV-infected children and 220 HIV-uninfected controls ages 5 to 9 years in Johannesburg, South Africa. A standardized 24-hour recall questionnaire and software developed specifically for the South African population were used to estimate intake of energy, macronutrients, and micronutrients. Intake was categorized based on recommendations by the World Health Organization and Acceptable Macronutrient Distribution Ranges established by the IOM., Results: The overall mean age was 6.7 years and 51.8% were boys. Total energy intake was higher in HIV-infected than HIV-uninfected children (1341 vs 1196 kcal/day, P = 0.002), but proportions below the recommended energy requirement were similar in the 2 groups (82.5% vs 85.2%, P = 0.45). Overall, 51.8% of the macronutrient energy intake was from carbohydrates, 13.2% from protein, and 30.8% from fat. The HIV-infected group had a higher percentage of their energy intake from carbohydrates and lower percentage from protein compared with the HIV-uninfected group. Intakes of folate, vitamin A, vitamin D, calcium, iodine, and selenium were suboptimal for both groups., Conclusions: Our findings suggest that the typical diet of HIV-infected children and uninfected children in Johannesburg, South Africa, does not meet energy or micronutrient requirements. There appear to be opportunities for interventions to improve dietary intake for both groups.

Background: Little is known about drug use patterns among people living with HIV in comparison to an uninfected group in the general population. The aim of this study was to investigate the association between legal and illegal drug use and HIV infection in a nationally representative sample of adults in the United States., Methods: Public use data files (2005-2014) from the National Survey on Drug Use and Health (NSDUH) were used. Respondents were asked whether a medical professional had ever told them that they had HIV/AIDS. Ever (lifetime), past-year, and past month use of cigarettes, alcohol, marijuana, cocaine, heroin, hallucinogens, inhalants, and nonmedical use of psychotherapeutics was assessed. Logistic regression was used to estimate adjusted odds ratios (aOR) of the relationship between drug use and HIV infection, adjusting for demographics., Results: Of 377,787 respondents age 18 and older, 548 (0.19%) were categorized as HIV-infected. Ever use of cigarettes, tobacco, marijuana, cocaine, heroin, hallucinogens, inhalants, and psychotherapeutics was higher in HIV-infected individuals compared to HIV-uninfected individuals after adjustment for sex, age, race/ethnicity, education, total family income, and marital status. Past year and past month use was also higher for HIV-infected individuals for all substances aside from alcohol., Conclusions: In a nationally representative sample, there are higher levels of drug use and DSM-IV dependence among the HIV-infected population compared to the HIV-uninfected population. This is of concern because drug use and dependence can impede engagement in HIV care and adherence to antiretroviral therapy., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Research in high-income countries has repeatedly demonstrated that intimate partner violence (IPV) experienced by women negatively affects the health and behavior of children in their care. However, there is little research on the topic in lower- and middle-income countries. The population-based Asenze Study gathered data on children and their caregivers in KwaZulu-Natal, South Africa. This data analysis explores the association of caregiver IPV on child behavior outcomes in children <12 years old and is the first such study in Africa., Methods: This population-based study was set in 5 Zulu tribal areas characterized by poverty, food insecurity, unemployment, and a high HIV prevalence. The Asenze Study interviewed caregivers via validated measures of IPV, alcohol use, caregiver mental health difficulties, and child behavior disorders in their preschool children., Results: Among the 980 caregivers assessed, 37% had experienced IPV from their current partner. Experience of partner violence (any, physical, or sexual) remained strongly associated with overall child behavior problems (odds ratio range: 2.46-3.10) even after age, HIV status, cohabitation with the partner, alcohol use, and posttraumatic stress disorder were accounted for., Conclusions: Childhood behavioral difficulties are associated with their caregiver's experience of IPV in this population, even after other expected causes of child behavior difficulties are adjusted for. There is a need to investigate the longer-term impact of caregiver partner violence, particularly sexual IPV, on the health and well-being of vulnerable children in lower- and middle-income countries. Studies should also investigate whether preventing IPV reduces the occurrence of childhood behavior difficulties., (Copyright © 2017 by the American Academy of Pediatrics.)

Objective: The report of the 'Mississippi baby' who was initiated on antiretroviral therapy (ART) within 30 h of birth and maintained viral suppression off ART for 27 months has increased interest in the timing of ART initiation early in life. We examined associations between age at ART initiation and virologic outcomes in five cohorts of HIV-infected infants and young children who initiated ART before 2 years of age in Johannesburg, South Africa., Methods: We compared those who initiated ART early (<6 months of age) and those who started ART late (6-24 months of age). Two primary outcomes were examined: initial response to ART in three cohorts and later sustained virologic control after achieving suppression on ART in two cohorts., Results: We did not observe consistent differences in initial viral suppression rates by age at ART initiation. Overall, initial viral suppression rates were low. Only 31, 40.1, and 26.5% of early-treated infants (<6 months of age) in the three cohorts, respectively, were suppressed less than 50 copies/ml of HIV RNA 6 months after starting ART. We did observe better sustained virologic control after achieving suppression on ART among infants starting ART early compared with late. Children who started ART early were less likely to experience viral rebound (>50 copies/ml or >1000 copies/ml) than children who started late in both cohorts., Conclusion: These findings provide additional support for early initiation of ART in HIV-infected infants., Competing Interests: The authors have no conflicts of interest to report.

The purpose of this clinical note is to describe the performance of the Lunar Achilles Insight device in assessing bone quality at the calcaneus in 142 children between the ages of 5 and 11 y accessing healthcare in Johannesburg, South Africa. We observed an asymmetric bimodal distribution in speed of sound (SOS). The minor mode consisted of unusually high SOS values (≥1625 m/s), which were primarily observed among children with foot size <19 cm and height <119 cm. Cortical regions of the bone may have been inadvertently included in the region of interest for smaller feet, causing unusually high SOS values. The unusually high SOS values indicate that the validity of SOS in this device, as it is currently used for measuring bone quality in young children, is questionable. Future studies using this device in young children should develop new methodology to account for smaller foot size., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives Alcohol abuse, a significant health problem in South Africa, affects the ability of adults to care for children. Little is known regarding risky alcohol use among child caregivers there. A large population-based study examined the prevalence of, and factors associated with, risky drinking among caregivers of young children in KwaZulu-Natal, South Africa comparing the use of the Alcohol Use Disorders Identification Test (AUDIT) and the AUDIT-C screens for hazardous or harmful drinking (referred to here as risky drinking). Methods 83 % of child caregivers from five tribal areas were interviewed using the 10-question AUDIT to screen for risky drinking. The AUDIT-C screen, a subset of AUDIT questions, targets alcohol consumption and binge drinking. Factors associated with risky drinking were investigated using logistic regression. Results 1434 caregivers participated, 98 % female. Sixteen percent reported ever drinking alcohol. Based on AUDIT criteria for risky drinking, 13 % of the sample scored as moderate drinkers, 2 % as hazardous users, and 1 % as harmful or dependent users (identifying 3 % as risky drinkers). Using AUDIT-C criteria to identify risky drinking significantly increased the proportion of caregivers identified as risky drinkers to 9 %. In multivariate analyses, factors associated with risky drinking were similar in both screens: partner violence, smoking, HIV-infection, caring for a child with disabilities. Conclusions for Practice Since the AUDIT-C identified risky alcohol use not otherwise detected with the full AUDIT, and since resources for screening in health care settings is limited, the AUDIT-C may be a more appropriate screen in populations where binge drinking is common.

Background: We investigate if switching from a ritonavir-boosted lopinavir (LPV/r)-based to an efavirenz-based antiretroviral therapy (ART) regimen is associated with beneficial bone development., Methods: The CHANGES Bone Study follows HIV-infected children who participated in a noninferiority randomized trial in Johannesburg, South Africa evaluating the safety and efficacy of preemptive switching to efavirenz (n = 106) compared with remaining on LPV/r (n = 113). HIV-uninfected children were also recruited. Whole-body and lumbar spine bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry at a cross-sectional visit. BMC Z-scores adjusted for sex, age, and height were generated. Physical activity and dietary intake were assessed. CD4 percentage and viral load were measured. We compared bone indices of HIV-infected with HIV-uninfected children and LPV/r with efavirenz by intent-to-treat., Results: The 219 HIV-infected (52% boys) and 219 HIV-uninfected (55% boys) children were 6.4 and 7.0 years of age, respectively. Mean ART duration for HIV-infected children was 5.7 years. Whole-body BMC Z-score was 0.17 lower for HIV-infected children compared with HIV-uninfected children after adjustment for physical activity, dietary vitamin D and calcium (P = 0.03). Whole-body BMC Z-score was 0.55 higher for HIV-infected children switched to efavirenz compared with those remaining on LPV/r after adjustment for physical activity, dietary vitamin D and calcium, CD4 percentage, and viral load (P < 0.0001)., Conclusion: South African HIV-infected children receiving ART have lower bone mass compared with HIV-uninfected controls. Accrued bone mass is positively associated with switching to efavirenz-based ART compared with remaining on LPV/r, providing additional rationale for limiting LPV/r exposure once viral suppression has been achieved.

Objective: To describe physical activity in South African children with and without HIV., Study Design: Study measurements were obtained in 218 children with perinatal HIV and 180 children without HIV aged 5-9 years in a study conducted in Johannesburg, South Africa. Weight-for-age z-score, height-for-age z-score, frequency and duration of moderate and vigorous physical activity, and sedentary behaviors were obtained. These measurements were compared between children with and without HIV., Results: Weight-for-age z-score and height-for-age z-score were significantly lower for children with HIV compared with those without HIV. Among children who attended school, fewer children with HIV than children without HIV participated in physical education (41% vs 64%; P = .0003) and organized after-school sports (38% vs 64%; P < .001). The proportion of children in both groups meeting World Health Organization recommendations for physical activity was similar (84% overall); however, girls with HIV spent less time in vigorous physical activity than girls without HIV (420 vs 780 minutes/week; P = .001). This difference remained significant even when girls with a medical condition with the potential to limit physical activity were excluded, and after adjusting for age. Time spent in sedentary behaviors did not differ significantly between the two groups., Conclusion: Although children with HIV with well-controlled disease after initiating antiretroviral therapy early in life achieve high levels of physical activity, vigorous physical activity is lower in girls with HIV than in healthy controls. This finding may reflect lower participation in school-based physical education and organized after-school physical activity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Children and adolescents, who either acquire HIV infection perinatally, from contaminated blood products or via sexual transmission early in life, have the greatest cumulative exposure to the negative direct and indirect effects of HIV infection and ART on bone, which may lead to increased lifetime risk for osteoporosis and fracture. We conducted a systematic review to evaluate the literature on bone health in children and adolescents with HIV., Methods: We performed a comprehensive search of the Medline, Scopus, and Cochrane Library databases (up to April 1, 2014) for studies that reported on bone imaging or bone fractures in HIV-infected children, adolescents, or young adults., Results: A total of 32 publications met our inclusion criteria. Seventeen studies were cross-sectional and 15 were longitudinal. The majority of studies were conducted in high-income countries, three in middle-income countries and none in low-income countries. Overall, the studies we reviewed indicate that measures of bone mass are reduced, with increased prevalence of low BMD in children and adolescents with HIV. However, the studies are highly variable with respect to comparison sources, measurement methods, adjustment techniques for body size or growth retardation, and highlighted risk factors, including aspects related to medication exposures as well as the effects of HIV infection per se ., Conclusion: HIV infection appears to be associated with decreased bone accrual throughout childhood and adolescence. Initial studies indicate that sub-optimal bone accrual may be persistent and result in reduced peak bone mass, an important determinant of future risk of osteoporosis and fracture. Important areas for future research include evaluation of bone mass, bone quality and fracture risk across the life course among those with early-life infection with HIV, particularly in resource-limited settings where the majority of children with HIV live.

Background: Caregiver compliance with referrals for child health services is essential to child health outcomes. Many studies in sub-Saharan Africa have examined compliance patterns for children referred for acute, life-threatening conditions but few for children referred for non-acute conditions. The aims of this analysis were to determine the rate of referral compliance and investigate factors associated with referral compliance in KwaZulu Natal, South Africa., Methods: From September 2008-2010, a door-to-door household survey was conducted to identify children aged 4-6 years in outer-west eThekwini District, KwaZulu-Natal, South Africa. Of 2,049 identified, informed consent was obtained for 1787 (89%) children who were then invited for baseline assessments. 1581 children received standardized medical and developmental assessments at the study facility (Phase 1). Children with anemia, suspected disorders of vision, hearing, behavior and/or development and positive HIV testing were referred to local health facilities. Caregiver-reported compliance with referrals was assessed 18-24 months later (Phase 2). Relationships between socio-demographic factors and referral compliance were evaluated using chi-square tests., Results: Of 1581 children, 516 received referrals for ≥1 non-acute conditions. At the time of analysis, 68% (1078 /1581) returned for Phase 2. Analysis was limited to children assessed in Phase 2 who received a referral in Phase 1 (n = 303). Common referral reasons were suspected disorders of hearing/middle ear (22%), visual acuity (12%) and anemia (14%). Additionally, children testing positive for HIV (6.6%) were also referred. Of 303 children referred, only 45% completed referrals. Referral compliance was low for suspected disorders of vision, hearing and development. Referral compliance was significantly lower for children with younger caregivers, those living in households with low educational attainment and for those with unstable caregiving., Conclusions: Compliance with referrals for children with non-acute conditions is low within this population and appears to be influenced by caregiver age, household education level and stability of caregiving. Lack of treatment for hearing, vision and developmental problems can contribute to long-term cognitive difficulties. Further research is underway by this group to examine caregiver knowledge and attitudes about referral conditions and health system characteristics as potential determinants of referral compliance.

Background: While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART., Methods: ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005-2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata., Results: A total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r., Conclusions: Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences., Trial Registration: ClinicalTrials.gov Identifier: NCT00117728.

Introduction: HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood., Methods: We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African-American or Hispanic Tanner stage 5 men aged 20-25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls., Results: HIV-infected men were similar in age and BMI, but were more likely to be African-American (P = 0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4-1.2 lower in HIV-infected men at the spine, hip, and radius (all P < 0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (P <0.05). HIV-infected men had dramatic deficiencies in plate-related parameters by individual trabeculae segmentation (ITS) analyses and 14-17% lower bone stiffness by finite element analysis. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR-pQCT parameters differed between men infected perinatally or during adolescence., Conclusion: At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age.

Treatment 2.0 is an initiative launched by UNAIDS and WHO in 2011 to catalyze the next phase of treatment scale-up for HIV. The initiative defines strategic activities in 5 key areas, drugs, diagnostics, commodity costs, service delivery and community engagement in an effort to simplify treatment, expand access and maximize program efficiency. For adults, many of these activities have already been turned into treatment policies. The recent WHO recommendation to use a universal first line regimen regardless of gender, pregnancy and TB status is a treatment simplification very much in line with Treatment 2.0. But despite that fact that Treatment 2.0 encompasses all people living with HIV, we have not seen the same evolution in policy development for children. In this paper we discuss how Treatment 2.0 principles can be adapted for the pediatric population. There are several intrinsic challenges. The need for distinct treatment regimens in children of different ages makes it hard to define a one size fits all approach. In addition, the fact that many providers are reluctant to treat children without the advice of specialists can hamper decentralization of service delivery. But at the same time, there are opportunities that can be availed now and in the future to scale up pediatric treatment along the lines of Treatment 2.0. We examine each of the five pillars of Treatment 2.0 from a pediatric perspective and present eight specific action points that would result in simplification of pediatric treatment and scale up of HIV services for children.

Objective(s): Some but not all studies indicate that individuals with HIV infection are at an increased risk of fracture. We systematically reviewed the literature to investigate whether incidence of fracture (both overall and fragility) differs between individuals with and without HIV., Design: A systematic review and meta-analysis., Methods: Medline, Scopus and the Cochrane Library databases for all studies ever published up to 28 September 2012 and electronically available conference abstracts from CROI, ASBMR, IAS and AIDS were searched. All studies reporting incidence of all fracture and fragility fracture in HIV-infected adults were included. A random effects model was used to calculate pooled estimates of incidence rate ratios (IRRs) for studies that presented data for HIV-infected and controls. For all studies, incidence rates of fracture and predictors of fracture among HIV-infected individuals were summarized., Results: Thirteen eligible studies were analysed, of which seven included controls. Nine studies reported all incident fractures and 10 presented incident fragility fractures. The pooled IRR was 1.58 [95% confidence interval (CI) 1.25-2.00] for all fracture and 1.35 (95% CI 1.10-1.65) for fragility fracture. Smoking, white race and older age were consistent predictors for fragility fractures., Conclusion: Our results indicate that HIV infection is associated with a modest increase in incident fracture. Future research should focus on clarifying risk factors, designing appropriate interventions and the long-term implications of this increased risk for an ageing HIV-infected population.

Poor nutritional status at initiation of antiretroviral therapy (ART) is predictive of mortality. Decreased dietary intake is a major determinant of weight loss in HIV. Despite a biological rationale to treat undernutrition in adults receiving ART, few studies have provided data on feasibility, safety, effectiveness, and sustainability of specific macronutrient supplements with HIV treatment in adults, especially supplements such as a food basket, a supplement approach seldom evaluated in spite of its wide use. We present the rationale and design for a study of a locally procured macronutrient supplement given to HIV-infected patients initiating ART with a body mass index (BMI) ≤20.0 kg/m(2). The objective was to determine feasibility of procurement, distribution, safety and to obtain preliminary effectiveness data for a locally procured supplement. The design was a comparative study for 200 adult participants at two Kenya government-supported clinics. The primary outcome was BMI at 24 weeks. Supplement duration was 24 weeks, total follow-up was 48 weeks, and the study included a comparison site. Novel aspects of this study include use of a standardized macronutrient supplement to protect the participant against household food sharing, and a complementary micronutrient supplement. Comprehensive data collected included dietary intake, HIV-related quality-of-life, food security, neuropsychiatric assessments, laboratory studies, and household geomapping. Assessments were made at baseline, at 24 weeks, and at 48 weeks post-ART initiation. Challenges included establishing a partnership with local millers, distribution from the HIV clinic, food safety, and tracking of participants. These findings will help inform nutrition support programming in Kenya and similar settings, and provide needed data regarding use of macronutrient supplements as an adjunctive intervention with ART.

Background: Skeletal abnormalities have been reported in HIV-infected children and adolescents. Although the etiology is not well understood, vitamin D deficiency may be involved., Objective: The study objective was to evaluate the effect of vitamin D and calcium supplementation on bone mass accrual in HIV-infected youth., Design: Perinatally HIV-infected children were randomly assigned to receive vitamin D (100,000 IU cholecalciferol given every 2 mo) and calcium (1 g/d) (supplemented group) or double placebo (placebo group) for 2 y. The total-body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), spine bone mineral content (SBMC), and spine bone mineral density (SBMD) were assessed by using dual-energy X-ray absorptiometry at baseline and at 2 annual follow-up visits., Results: Fifty-nine participants, aged 6-16 y, were randomly assigned to either the supplemented (n = 30) or the placebo (n = 29) group. At enrollment, supplemented and placebo groups did not differ with respect to age, sex, dietary intakes of vitamin D and calcium, mean baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, TBBMC, TBBMD, SBMC, or SBMD. Significant increases in serum 25(OH)D were observed in the supplemented group but not in the placebo group. TBBMC, TBBMD, SBMC, and SBMD increased significantly at 1 and 2 y in both groups. No between-group differences were observed at any time before or after adjustment for stage of sexual maturation by mixed linear model analysis., Conclusion: One gram of calcium per day and oral cholecalciferol at a dosage of 100,000 IU every 2 mo administered to HIV-infected children and adolescents did not affect bone mass accrual despite significant increases in serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00724178.

Objectives: To assess the uptake of HIV testing among preschool children with HIV-positive mothers in a peri-urban population-based study in KwaZulu-Natal, South Africa, an area of high HIV prevalence., Methods: All children 4-6 years old and their primary caregivers from the area were invited to participate. All participants were asked about prior HIV testing and were offered counselling and voluntary HIV testing irrespective of previous testing. Twenty-seven HIV-infected mothers were interviewed to identify barriers to testing their children., Results: One thousand five hundred and eighty-three children (88% of eligible children) and their caregivers participated. Of the biological mothers, 86% were previously tested for HIV (27% tested positive). Among the surviving 244 children born to an infected mother, only 41% had been tested for HIV (23% tested positive). Subsequently, 90% of previously untested children of infected mothers underwent HIV testing (9.3% were positive). Overall seroprevalence among study children was 4.9%. All infected mothers interviewed endorsed the belief that children of HIV-infected women should be tested for HIV. Women who missed opportunities for antenatal HIV testing reported no systematic testing of their children at later ages., Conclusions: In this community with high HIV prevalence, HIV testing of children is infrequent despite high testing coverage among caregivers. The low proportion of children tested for HIV, particularly those of infected mothers, is of great concern as they are at high risk for morbidity and mortality associated with untreated childhood HIV infection. HIV testing programs should strengthen protocols to include children, especially for those who missed PMTCT opportunities in infancy., (© 2011 Blackwell Publishing Ltd.)

Background: There are concerns about effects of lactation on postpartum weight changes among HIV-infected women because low weight may increase risks of HIV-related disease progression., Methods: This analysis of postpartum maternal weight change is based on a trial evaluating the effects of shortened breastfeeding on postpartum mother-to-child transmission of HIV in Lusaka, Zambia, in which 958 HIV-infected women were randomized to breastfeed for a short duration (4 months) or for a duration of their own informed choosing (median 16 months). Among 768 women who met inclusion criteria, we compared across the two groups change in weight (kg) and the percent underweight [body mass index (BMI) <18.5] through 24 months. We also examined the effect of breastfeeding in two high-risk groups: those with low BMI and those with low CD4 counts., Results: Overall, women in the long-duration group gained less weight compared with those in the short-duration group from 4-24 months {1.0 kg [95% confidence interval (CI): 0.3-1.7] vs 2.3 kg (95% CI: 1.6-2.9), P = 0.01}. No association was found between longer breastfeeding and being underweight (odds ratio 1.1; 95% CI: 0.8-1.6; P = 0.40). Effects of lactation in underweight women and women with low CD4 counts were similar to the effects in women with higher BMI and higher CD4 counts. Women with low baseline BMI tended to gain more weight from 4 to 24 months than those with higher BMI, regardless of breastfeeding duration (2.1 kg, 95% CI: 1.3-2.9; P < 0.01)., Conclusions: In this study of HIV-infected breastfeeding women in a low-resource setting, the average change in weight from 4 to 24 months postpartum was a net gain rather than loss. Although longer duration breastfeeding was associated with less weight gain, breastfeeding duration was not associated with being underweight (BMI < 18.5). Weight change associated with longer breastfeeding may be metabolically regulated so that women with low BMI and at risk of wasting are protected from excess weight loss.

Background: Alterations in regional fat are often reported in HIV infection. Prior studies have not distinguished between normal changes in regional fat related to sexual maturation and those due to HIV. The study aim was to compare changes in regional fat distribution in HIV-infected (HIV+) and healthy (HIV-) children and adolescents living in the United States., Methods: Serial dual energy X-ray absorptiometry was performed at baseline and two annual follow-up visits in 64 HIV+ and 147 HIV--participants aged 6-16 years. Total, leg, arm, and trunk fat masses (kg) and regional fat distribution as the percentage of total body fat (%) were compared., Results: HIV+ and HIV--participants did not differ in total fat mass, but the HIV+ group had significantly lower leg and greater arm fat and trunk fat percentage at all time points. Over time, decreases in leg fat percentage and increases in arm fat percentage were more marked among the HIV+ group. Differences between HIV+ and HIV--groups in arm and leg fat percentage remained significant when age, sex, race, height, and pubertal stage were accounted for by mixed effect modeling. Apart from prior treatment with stavudine, no differences in fat distribution were observed according to treatment or degree of immunodeficiency or viremia., Conclusion: Although no single pattern of change in regional fat distribution was uniquely associated with HIV, perinatally HIV-infected youth manifest significantly decreased leg fat and increased arm and trunk fat. These differences increase over time and may contribute to cardiovascular disease risk.

Background: Bioelectrical impedance analysis (BIA) is an attractive method of measuring pediatric body composition in the field, but the applicability of existing equations to diverse populations has been questioned., Objective: The objectives were to evaluate the performance of 13 published pediatric BIA-based predictive equations for total body water (TBW) and fat-free mass (FFM) and to refit the best-performing models., Design: We used TBW by deuterium dilution, FFM by dual-energy X-ray absorptiometry, and BIA-derived variables to evaluate BIA models in a cross-sectional study of 1291 pediatric subjects aged 4-18 y, from several ethnic backgrounds, including 54 children with HIV infection and 627 females. The best-performing models were refitted according to criterion values from this population, cross-validated, and assessed for performance. Additional variables were added to improve the predictive accuracy of the equations., Results: The correlation between predicted and criterion values was high for all models tested, but bias and precision improved with the refitted models. The 95% limits of agreement between predicted and criterion values were 16% and 11% for TBW and FFM, respectively. Bias was significant for some subgroups, and there was greater loss of precision in specific age groups and pubertal stages. The models with additional variables eliminated bias, but the limits of agreement and the loss of precision persisted., Conclusion: This study confirms that BIA prediction models may not be appropriate for individual evaluation but are suitable for population studies. Additional variables may be necessary to eliminate bias for specific subgroups.

Total body bone mineral content (TBBMC) was measured by dual energy x-ray absorptiometry in a cross-sectional study of 51 prepubertal HIV-infected children and 262 healthy prepubertal children aged 4.2 to 14.7 years. The mean TBBMC +/- SD was lower in HIV-positive children than in HIV-negative controls (955 +/- 325 vs. 1,106 +/- 273 g, respectively; p =.0006). Reductions in TBBMC remained in the HIV-positive group after adjusting for age, sex, and race by analysis of covariance (p <.001). Differences in TBBMC between HIV-positive and HIV-negative groups persisted when height and weight were also accounted for in the analysis (p =.027). The magnitude of the difference in TBBMC between the groups increased with age. In the HIV-positive group, no associations were observed between TBBMC and use of a protease inhibitor, duration of treatment with antiretroviral medications, viral load, or CD4 cell count. TBBMC is decreased in HIV-infected children. As a result of compromised bone mineral accrual, HIV-infected children may be at increased risk for osteoporosis and related complications.

Alterations in regional fat, often associated with abnormalities in lipid and insulin metabolism, have been reported in HIV-infected adults. To determine whether similar abnormalities occur in children with HIV, patterns of change in regional body fat distribution were determined by dual energy x-ray absorptiometry in 28 prepubertal HIV-infected children. Eight (29%) children experienced lipodystrophy (LD), defined as extremity lipoatrophy together with trunk fat accumulation. Despite a mean body weight increase of 2.9 +/- 2.4 kg, children with LD experienced a mean loss of total fat in contrast to children without LD who increased total fat (-0.151 +/- 0.324 versus 0.981 +/- 1.041 kg; p <.01). Children with LD had significantly higher levels of HIV RNA and lower CD4 count and percentage at baseline. LD was associated with use of protease inhibitors or stavudine, (odds ratio [OR], 7.0, 95% confidence interval [CI], 1.1-45.2, p =.04; OR, 9.0, 95% CI, 1.4-59.8, p =.03, respectively). This observational study suggests that during a time in childhood when accumulation of extremity and trunk fat is expected, some HIV-infected children experience changes in fat distribution that are similar to HIV-associated LD reported in adults. Studies to determine whether HIV-infected children with changes in regional fat also experience increases in "atherogenic" lipids and insulin resistance as described in adults with HIV-associated LD are warranted.