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Abstract Background Despite efforts to promote optimal breastfeeding practices, the practice of exclusive breastfeeding is low in South Africa. We conducted a trial to determine whether text messaging plus motivational interviewing prolonged exclusive breastfeeding during the first six months of life and improved child health outcomes. Methods We conducted a randomized parallel group-controlled trial between July 2022 and May 2024, at a secondary-level healthcare facility. Mothers living with HIV, 18 years or older, initiating breastfeeding, on combination antiretroviral therapy (cART) and their infants were enrolled. The primary endpoint was exclusive breastfeeding from birth through week 24, based on the consecutive 24-hour food recall interviews. We compared differences in exclusive breastfeeding rates using a proportion test. Mothers who completely stopped breastfeeding were asked an open-ended question on reasons for stopping breastfeeding. Results Using block randomization mother-child pairs (n = 276) were randomly allocated to receive intervention (n = 138) or standard infant feeding counselling (n = 138), of whom 105 and 101 mother-child pairs in the intervention group and standard care group, respectively, completed all four study visits. Exclusive breastfeeding rate at 24 weeks in the intervention group was 6% (6/105) and 7% (7/101) in the standard care group, rate difference − 1% (95% CI -6–4%). Sixty-two of 276 mothers completely stopped breastfeeding, of whom 25% (34/138) and 20% (28) were in the intervention group and standard care group, respectively. The most common reasons for stopping breastfeeding were the mother needing to return to work or look for work, 66% (n = 41). We also found that early breastfeeding cessation increased risk of child hospitalization or death compared to any form of breastfeeding to week 24, 10% (5/48) versus 3% (5/158), p = 0.055. Conclusions We found no effect of the intervention on exclusive breastfeeding rates. Early cessation of breastfeeding was prevalent and maternal employment characteristics are important social determinants of breastfeeding behaviour. There is need for further research evaluating the effect of interventions that include financial incentives on breastfeeding practices among socioeconomically disadvantaged mothers. HIV services should reliably offer cART, consistently monitor viral load, and support mothers cART adherence, in settings where mixed feeding is common. Trial registration The trial was registered on ClinicalTrials.gov (NCT05063240) and Pan African Clinical Trial Registries (PACTR202110870407786) before recruitment of the first subject.

Abstract In this work our aim was to identify early biomarkers in plasma samples associated with mortality in children with perinatal HIV treated early in life, to potentially inform early intervention targeting this vulnerable group. 20/215 children (9.3%) with perinatal HIV, enrolled within 3 months of age died prematurely within the first year of the study, despite early ART initiation. Using a propensity score, we selected 40 alive study participants having similar clinical and virological records compared to the deceased group. 13 HIV unexposed (HU) healthy children were additionally used as controls. Baseline plasma samples were analyzed using a targeted proteomic approach, and to assess pathogen-associated and damage-associated molecular patterns (PAMPs, DAMPs) levels. Data from deceased participants were compared to both control groups, with multivariate logistic regression models used to evaluate the association between mortality and plasma proteins. We developed a machine learning model to predict mortality risk, finding that IL-6 and CXCL11 not only were higher in deceased children than Matched-children with HIV (p

Abstract Background Many infants in low-resourced settings at high risk of infectious disease morbidity and death are deprived of the immunological and nutritional benefits of breast milk, through an attenuated duration of breast milk exposure. South Africa has one of the lowest exclusive breastfeeding rates in Africa, with 8% of infants under 6 months of age. We assume that breastfeeding is sustained among women living with HIV receiving weekly text messages and motivational interviewing and that this contributes to improved infant health outcomes. Objectives (1) To evaluate the effectiveness of a combined intervention of mobile phone text messaging and motivational interviewing in promoting (a) exclusive breastfeeding and (b) any form of breastfeeding, until 6 months of child age, compared to usual care, among mothers living with HIV. (2) To evaluate the effectiveness of a combined intervention on (a) reduction in all-cause hospitalization and mortality rates and (b) improvements in infant linear growth, compared to usual care, among HIV-exposed infants aged 0–6 months. Methods We are conducting a clinical trial to determine whether text messaging plus motivational interviewing prolongs breastfeeding and improves infant health outcomes. We are recruiting 275 women living with HIV and their HIV-exposed infants at birth and randomly assign study interventions for 6 months. Statistical methods Breastfeeding rates are compared between the study groups using a standard proportion test and binomial regression. Survival endpoints are presented using Kaplan–Meier survival curves and compared between the study groups using the Cox proportional-hazards regression model. The count endpoint is analysed using the Poisson random-effects model and mean cumulative function. We use mixed linear regression models to assess the evolution of infant growth over time. The maximum likelihood method will be used to handle missing data. Discussion The study findings may facilitate decision-making on (1) whether implementation of the breastfeeding policy achieved the desired outcomes, (2) interventions needed to sustain breastfeeding, and (3) whether the interventions do have an impact on child health. Trial registration ClinicalTrials.gov NCT05063240. Pan African Clinical Trial Registry PACTR202110870407786. Oct. 1, 2021.

Abstract Background Transient elastography (TE) is a rapid noninvasive ultrasound-based technology that measures liver stiffness as a surrogate for liver fibrosis and controlled attenuation parameter (CAP) as a measure of liver steatosis. However, normal ranges in children are not well defined in all populations. The aim of this study was to determine transient elastography values in healthy South African children. Methods From April 2019 to December 2021, children were recruited from the HIV negative control group of a cohort study. Only children neither overweight nor obese, without evidence of liver disease, no medical condition or medication associated with hepatic steatosis or fibrosis and normal metabolic profile were included in this cross-sectional analysis. Clinical data, anthropometry and blood samples were collected on the same day as transient elastography with controlled attenuation parameter was performed. Results 104 children (median age 12.8 years [IQR 11.4–14.8, range 7.9–17.7 years]; 59 [57%] boys) were included. Liver stiffness was positively correlated with age (Pearson’s r = 0.39, p

Abstract Background Life-long early ART (started before age 2 years), often with periods of treatment interruption, is now the standard of care in pediatric HIV infection. Although cross-sectional studies have investigated HIV-related differences in cortical morphology in the setting of early ART and ART interruption, the long-term impact on cortical developmental trajectories is unclear. This study compares the longitudinal trajectories of cortical thickness and folding (gyrification) from age 5 to 9 years in a subset of children perinatally infected with HIV (CPHIV) from the Children with HIV Early antiRetroviral therapy (CHER) trial to age-matched children without HIV infection. Methods 75 CHER participants in follow-up care at FAMCRU (Family Centre for Research with Ubuntu), as well as 66 age-matched controls, received magnetic resonance imaging (MRI) on a 3 T Siemens Allegra at ages 5, 7 and/or 9 years. MR images were processed, and cortical surfaces reconstructed using the FreeSurfer longitudinal processing stream. Vertex-wise linear mixed effects (LME) analyses were performed across the whole brain to compare the means and linear rates of change of cortical thickness and gyrification from 5 to 9 years between CPHIV and controls, as well as to examine effects of ART interruption. Results Children without HIV demonstrated generalized cortical thinning from 5 to 9 years, with the rate of thinning varying by region, as well as regional age-related gyrification increases. Overall, the means and developmental trajectories of cortical thickness and gyrification were similar in CPHIV. However, at an uncorrected p

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ABSTRACT Combination antiretroviral therapy (cART) suppresses viral replication but does not cure HIV infection because a reservoir of infectious (intact) HIV proviruses persists in long-lived CD4+T cells. However, a large majority (>95%) of HIV-infected cells that persist on effective cART carry defective (non-infectious) proviruses. Defective proviruses consisting of only a single LTR (solo long terminal repeat) are commonly found as endogenous retroviruses in many animal species, but the frequency of solo-LTR HIV proviruses has not been well defined. Here we show that, in five pediatric donors whose viremia was suppressed on cART for at least 5 years, the proviruses in the nine largest clones of HIV-infected cells were solo LTRs. The sizes of five of these clones were assayed longitudinally by integration site-specific quantitative PCR. Minor waxing and waning of the clones was observed, suggesting that these clones are generally stable over time. Our findings show that solo LTRs comprise a large fraction of the proviruses in infected cell clones that persist in children on long-term cART. IMPORTANCE This work highlights that severely deleted HIV-1 proviruses comprise a significant proportion of the proviral landscape and are often overlooked.

Abstract Background The World Health Organization (WHO) risk assessment algorithm for vertical transmission of HIV (VT) assumes the availability of maternal viral load (VL) result at delivery and early viral control 4 weeks after initiating antiretroviral treatment (ART). However, in many low-and-middle-income countries, VL is often unavailable and mothers’ ART adherence may be suboptimal. We evaluate the inclusion of the mothers’ self-reported adherence into the established WHO-algorithm to identify infants eligible for enhanced post-natal prophylaxis when mothers’ VL result is not available at delivery. Methods We used data from infants with perinatal HIV infection and their mothers enrolled from May-2018 to May-2020 in Mozambique, South Africa, and Mali. We retrospectively compared the performance of the WHO-algorithm with a modified algorithm which included mothers’ adherence as an additional factor. Infants were considered at high risk if born from mothers without a VL result in the 4 weeks before delivery and with adherence

Abstract Background Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. Methods We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. Results The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing

IntroductionSuccessful programmes for prevention of vertical HIV transmission have reduced the risk of infant HIV infection in South Africa from 8% in 2008 to below 1% in 2018/2019, resulting in an increasing population of children exposed to HIV perinatally but who are uninfected (HEU). However, the long-term effects of HIV and antiretroviral treatment (ART) exposure on the developing brain are not well understood. Whereas children who are HEU perform better than their HIV-infected counterparts, they demonstrate greater neurodevelopmental delay than children who are HIV unexposed and uninfected (HUU), especially in resource-poor settings. Here we investigate subcortical volumetric differences related to HIV and ART exposure in neonates.MethodsWe included 120 infants (59 girls; 79 HEU) born to healthy women with and without HIV infection in Cape Town, South Africa, where HIV sero-prevalence approaches 30%. Of the 79 HEU infants, 40 were exposed to ART throughout gestation (i.e., mothers initiated ART pre conception; HEU-pre), and 39 were exposed to ART for part of gestation (i.e., mothers initiated ART post conception; HEU-post). Post-conception mothers had a mean (± SD) gestational age (GA) of 15.4 (± 5.7) weeks at ART initiation. Mothers with HIV received standard care fixed drug combination ART (Tenofovir/Efavirenz/Emtricitabine). Infants were imaged unsedated on a 3T Skyra (Siemens, Erlangen, Germany) at mean GA equivalent of 41.5 (± 1.0) weeks. Selected regions (caudate, putamen, pallidum, thalamus, cerebellar hemispheres and vermis, and corpus callosum) were manually traced on T1-weighted images using Freeview.ResultsHEU neonates had smaller left putamen volumes than HUU [β (SE) = −90.3 (45.3), p = 0.05] and caudate volume reductions that depended on ART exposure duration in utero. While the HEU-pre group demonstrated no caudate volume reductions compared to HUU, the HEU-post group had smaller caudate volumes bilaterally [β (SE) = −145.5 (45.1), p = 0.002, and −135.7 (49.7), p = 0.008 for left and right caudate, respectively].DiscussionThese findings from the first postnatal month suggest that maternal ART throughout gestation is protective to the caudate nuclei. In contrast, left putamens were smaller across all HEU newborns, despite maternal ART.

Abstract Background Reduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial. Methods Infants with HIV < 12 weeks old with CD4% ≥ 25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40 W, ART-96 W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40 W/ART-96 W, ART was started/re-started for clinical progression or CD4%

ART interruption in children can occur especially in resource-limited settings for reasons including poor adherence, stock-outs, ART intolerance of non-pediatric formulas and pill size, as well as ultimately to test for HIV remission. Although early ART initiation is now standard of care in pediatric HIV management, very little is known on the effect of early ART initiation or subsequent interruption on brain development. This study aimed to investigate the effect of ART interruption on brain cortical thickness (CT) and folding in a subset of children from the Children with HIV Early antiRetroviral therapy (CHER) trial cohort who all started ART before 18 months of age. CHER participants in the neuroimaging follow-up study had magnetic resonance (MRI) scans on a 3T Siemens Allegra brain scanner at age 5.44 ± 0.37 years. MR images were processed using the automated cross-sectional stream in FreeSurfer v6.0 and vertex wise comparisons of CT and local gyrification indices (LGIs) were performed between HIV+ children and HIV- controls, as well as between HIV+ children on interrupted or continuous ART and controls. HIV+ children (n = 46) showed thicker cortex than HIV- children (n = 29) in bilateral frontal and left temporo-insular regions but lower LGIs in left superior and bilateral medial orbitofrontal cortex extending into rostral anterior cingulate. Children on interrupted ART (n = 21) had thicker cortex than HIV- controls in left frontal and right insular regions, but children on continuous treatment (n = 25) showed no difference from controls. Children on both interrupted and continuous ART showed region-specific alterations in LGI relative to controls. Cortical folding appears more sensitive than CT to early life events including early ART and interruption. However, immune health resilience in children can translate to long term preservation of morphometric brain development, especially for those on early and continuous treatment.

BackgroundThe International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1104s study evaluated neuropsychological outcomes over 96 weeks in children living with HIV (CLHIV) aged 5–11 years at 6 Sub-Saharan African sites to explore associations between HIV-illness related biomarkers and neuropsychological outcomes.MethodsChildren living with HIV had participated in IMPAACT P1060, which compared efficacy of nevirapine versus lopinavir/ritonavir in children initiating ART at

Abstract Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children

Abstract Background Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. Methods DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. Results 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study.

ObjectivesWe evaluated the prevalence and risk factors for hepatic steatosis in South African children with perinatally acquired HIV (PHIV) who started treatment early and remain on long-term antiretroviral therapy (ART) compared to HIV-uninfected children.DesignA cross-sectional study from April 2019 to October 2021. PHIV, HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled from an ongoing cohort study.MethodsAll children had transient elastography (TE) with controlled attenuation parameter (CAP). Liver enzymes, lipogram, insulin and glucose were sent after an overnight fast. Multivariable linear regression analyses identified predictors of CAP. Hepatic steatosis was defined as CAP>248kPa.Results215 children (111 [52%] male; median age 14.1 years; IQR 12.7–14.9) participated in the study, 110 PHIV, 105 HIV-uninfected (36 HEU, 69 HU). PHIV initiated ART at a median age of 2.7 months (IQR 1.8–8.5). Hepatic steatosis prevalence was 9% in PHIV, 3% in HEU and 1% in HU children (p = 0.08). However, 8% of lean (body mass index z-score ≤ +1) PHIV had hepatic steatosis compared to zero lean HEU or HU children (p = 0.03). In multivariable linear regression analysis of all PHIV, body mass index (BMI) z-score was positively associated with CAP (p = 0.001) while CD4 count (p = 0.02) and duration of suppression of HIV viraemia (p = 0.009) were negatively associated with CAP, adjusting for age, sex and ethnicity.ConclusionsHepatic steatosis prevalence was higher in lean PHIV than lean HIV-uninfected South African children. Longer suppression of HIV viraemia and higher CD4 count were associated with lower CAP and might be protective factors for hepatic steatosis in PHIV children.

Despite the introduction of antiretroviral therapy (ART), HIV-associated pulmonary complications remain prevalent in children following perinatal HIV infection. In the post-ART era the incidence of opportunistic infections has decreased; however, non-infectious complications including diminished lung function are common. It is unclear whether early initiation of ART influences lung function later in life. We performed a cross-sectional study examining pulmonary function tests (PFT) (spirometry, plethysmography, carbon monoxide diffusing capacity) in HIV-unexposed (HU), HIV-exposed-uninfected (HEU) and perinatally HIV-infected children on early ART (HIV+) recruited from the Cape Town arms of the CHER and IMPAACT 1060 trials. PFT was performed once children could participate (October 2013 to January 2020). Global Lung Initiative reference software was used for Z-standardisation of lung function by sex, age and height. In total 394 children (HU n=90, HEU n=162, HIV+ n=142) underwent PFT, median age 8.7 (IQR 7.7–9.8) years. HIV+ had ART initiated at a median age of 17.6 (8.0–36.7) weeks. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC Z-scores were similar in all groups. Plethysmography demonstrated air-trapping with increased total lung capacity (TLC), functional residual capacity, residual volume (RV) and RV/TLC Z-scores in HIV+. There were no differences in alveolar volume; however, diffusing capacity was increased in HIV+. Our findings indicate that following perinatal HIV infection, early ART may attenuate HIV-associated lung disease and is associated with normal childhood spirometry. However plethysmography demonstrates that small airway dysfunction is more pronounced in HIV+. Longitudinal follow-up is required to assess if these children are at risk of obstructive airway disease later in life.

Background Despite the reduction of HIV mother-to-child transmission, there are concerns regarding transmission rate in the breastfeeding period. We describe the routine uptake of 6 or 10 (6/10) weeks, 9 months and 18 months testing, with and without tracing, in a cohort of infants who received HIV PCR testing at birth (birth PCR) (with and without point of care (POC) testing) in a peri-urban primary health care setting in Khayelitsha, South Africa. Methods In this cohort study conducted between November 2014 and February 2018, HIV-positive mothers and their HIV-exposed babies were recruited at birth and all babies were tested with birth PCR. Results of routine 6/10 weeks PCR, 9 months and 18 months testing were followed up by a patient tracer. We compared testing at 6/10 weeks with a subgroup from historical cohort who was not tested with birth PCR. Results We found that the uptake of 6/10 weeks testing was 77%, compared to 82% with tracing. When including all infants in the cascade and comparing to a historical cohort without birth testing, we found that infants who tested a birth were 22% more likely to have a 6/10 weeks test compared to those not tested at birth. There was no significant difference between the uptake of 6/10 weeks testing after birth PCR POC versus birth PCR testing without POC. Uptake of 9 months and 18 months testing was 39% and 24% respectively. With intense tracing efforts, uptake increased to 45% and 34% respectively. Conclusion Uptake of HIV testing for HIV-exposed uninfected infants in the first 18 months of life shows good completion of the 6/10 weeks PCR but suboptimal uptake of HIV testing at 9 months and 18 months, despite tracing efforts. Birth PCR testing did not negatively affect uptake of the 6/10 weeks HIV test compared to no birth PCR testing.

Background: Hand hygiene (HH) is a cornerstone of programmes to prevent healthcare associated infections (HAI) globally, but HH interventions are seldom reported from African neonatal units. Methods: We conducted a quasi-experimental study evaluating the impact of a multi-modal intervention (SafeHANDS) on HH compliance rates, alcohol-based handrub (ABHR) usage, the Hand Hygiene Self-Assessment Framework (HHSAF) score, and healthcare-associated bloodstream infection (HA-BSI) rates at a 132-bed South African neonatal unit (4 wards and 1 neonatal intensive care unit [NICU]). The intervention included a campaign logo, HH training, maternal education leaflets, ABHR bottles for staff, and the setting of HH performance targets with feedback. Three 5-month study phases were completed in July 2020 (baseline), December 2020 (early) and May 2021 (intensive). Results: A total of 2430 HH opportunities were observed: 1002 (41.3%) at baseline, 630 (25.9%) at early and 798 (32.8%) at intensive study phases. At baseline, the overall neonatal unit HH compliance rate was 61.6%, ABHR use was 70 mL/patient day, and the baseline HHSAF score was ‘basic’ (165). The overall neonatal unit HH compliance rate was unchanged from baseline to intensive phases (617/1002 [61.6%] vs. 497/798 [62.3%]; p = 0.797). The ABHR use remained similar between phases (70 versus 73 mL/patient day). The HHSAF score improved to ‘intermediate’ level (262). There was no change in the neonatal unit HA-BSI rate. Conclusion: Despite improvement in the HHSAF score, no improvement in overall HH compliance rates, ABHR usage, or HA-BSI rates was observed. Future HH interventions in resource-limited neonatal units should incorporate implementation science and behaviour modification strategies to better understand the barriers and facilitators of HH best practice.

Treatment guidelines recommend that children with perinatal HIV infection (PHIV) initiate antiretroviral therapy (ART) early in life and remain on it lifelong. As part of a longitudinal study examining the long-term consequences of PHIV and early ART on the developing brain, 89 PHIV children and a control group of 85 HIV uninfected children (HIV-) received neuroimaging at ages 5, 7, 9 and 11 years, including single voxel magnetic resonance spectroscopy (MRS) in three brain regions, namely the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM). We analysed age-related changes in absolute metabolite concentrations using a multivariate approach traditionally applied to ecological data, the Correlated Response Model (CRM) and compared these to results obtained from a multilevel mixed effect modelling (MMEM) approach. Both approaches produce similar outcomes in relation to HIV status and age effects on longitudinal trajectories. Both methods found similar age-related increases in both PHIV and HIV- children in almost all metabolites across regions. We found significantly elevated GPC+PCh across regions (95% CI=[0.033; 0.105] in BG; 95% CI=[0.021; 0.099] in PWM; 95% CI=[0.059; 0.137] in MFGM) and elevated mI in MFGM (95% CI=[0.131; 0.407]) among children living with PHIV compared to HIV- children; additionally the CRM model also indicated elevated mI in BG (95% CI=[0.008; 0.248]). These findings suggest persistent inflammation across the brain in young children living with HIV despite early ART initiation.

Background: Chlorhexidine gluconate (CHG) body washes and emollient application may modulate bacterial pathogen colonization and prevent neonatal hospital-acquired infections. Methods: This pilot, non-randomized, open-label trial, enrolled preterm neonates (1000-1500g; day 1-3 of life) at a tertiary hospital in Cape Town, South Africa. Participants were sequentially allocated to 4 trial arms (n=20 each): 1% aqueous CHG (CHG), 1% CHG plus emollient (CHG+EM), emollient only (EM) and standard of care (SOC: no antiseptic/emollient). Trial treatment/s were applied daily for 10 days (d) post-enrolment, documenting neonatal skin condition score. Anterior nose, neck, umbilical and perianal swabs for bacterial culture were collected at d1, d3, d10 and d16 post-enrolment, (±1 day), reporting pathogen acquisition rates and semi-quantitative bacterial colony counts. (ClinicalTrials.gov identifier: NCT03896893; trial status: closed). Findings: Eighty preterm neonates (mean gestational age 30 weeks [SD 2]) were enrolled between 4 March and 26 August 2019. The bacterial pathogen acquisition rate (comparing d1 and d16 swabs) varied from 33·9% [95%CI 22·9-47·0] at the umbilicus, 39·3% [95%CI 27·6-52·4] at the neck, to 71·4% [95%CI 58·5-81·7] at both the nose and perianal region. At d10, CHG babies had reduced bacterial density detected from neck, umbilicus, and perianal swabs compared to other groups (see Table 3). Following intervention cessation, colonization density was similar across all trial arms, but S. aureus colonization was more prevalent among EM and CHG+EM babies. Neonatal skin condition score improved in babies receiving emollient application (EM: -0·87 [95%CI 0·69-1·06] and CHG+EM: -0·73 [0·45-0·99]), compared to the SOC and CHG arms (Table 2); no CHG-related skin reactions occurred. Interpretation: Bacterial colonization density was significantly reduced in babies receiving 1% CHG washes but colonization levels rebounded rapidly post-intervention. Emollient application improved skin condition but was associated with higher rates of S. aureus colonization. Funding: South African Medical Research Council; National Institutes of Health (TW010682).

HIV-1 integrates its genome into the DNA of host cells. Consequently, HIV-1 genomes are copied with the host cell DNA during cellular division.

Some perinatally HIV infected children who have received early antiretroviral therapy (ART) show long-term sustained virological control after ART cessation. Here the authors describe a case who, at age 9.5 years, shows normal CD4:CD8 T cell ratios and has no detectable levels of replication-competent virus.

Objectives: We evaluated memory responses and antibody persistence to diphtheria-toxoid, tetanus-toxoid, whole-cell-pertussis (DTwP), and Hepatitis-B vaccines in HIV-unexposed, HIV-exposed-uninfected and HIV-infected children previously randomized to initiate time-limited ART at 6–10 weeks (ART-Immed) or when clinically/immunologically indicated (ART-Def). Methods: All children received DTwP booster at 15–18 months. Antibodies were measured for pertussis-toxoid, filamentous haemagglutinin (FHA), diphtheria-toxoid, tetanus-toxoid, and hepatitis-B prior to booster, 1–2 weeks post-booster and at 24 months of age. Results: Pre-booster antibody GMC were lower in HIV-infected groups than HIV-unexposed children for all epitopes. Post-booster and at 24 months of age, the ART-Def group had lower GMCs and antibody proportion ≥0.1 IU/ml for tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. At 24 months of age, the ART-Immed group had higher GMCs, and more likely to maintain antibody titres ≥1.0 IU/ml to tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. Compared to HIV-unexposed children, at 15 and 24 months of age, persistence of antibody to HBsAg of ≥10 mIU/ml was similar in the ART-Immed group but lower among the ART-Def group. Antibody kinetics indicated more robust memory responses in HIV-exposed-uninfected than HIV-unexposed children to diphtheria-toxoid and wP. Conclusion: HIV-infected children not on ART at primary vaccination had poorer memory responses, whereas HIV-exposed-uninfected children mounted robust memory responses.

Objectives:Rapid human immunodeficiency virus (HIV) antibody tests, routinely used for diagnosis in adults and older children in resource-limited settings (RLS), do not detect early HIV infections prior to seroconversion or when antibody levels are still low. Nucleic acid amplification to detect HIV-1 RNA is the most sensitive method for acute HIV infection diagnosis, but is costly. We therefore investigated HIV- 1 RNA testing of pooled dried blood spots (DBS) to diagnose acute HIV infection. Design:Laboratory-based investigation. Methods:DBS were collected from HIV-1 Voluntary Counselling and Testing (HVCT) clients who tested negative on the Advanced QualityTM HIV antibody rapid test. DBS samples from five participants were pooled and tested on the COBAS AmpliPrep/COBAS TaqMan HIV-1 (CAP/CTM) Test v2. Individual DBS were tested when pools tested positive ( 200 RNA copies/ml). Acute infection was confirmed by HIV viral load testing, two fourth-generation HIV serological assays, and Geenius™ HIV 1/2 Assay for antibody band identification. Results:Of 482 participants who were tested, one (0.2%) had acute. HIV infection: Fourth generation serology was low-level positive, the plasma HIV viral load was 15 929 HIV-1 RNA copies/ml, gp160 and gp41 antibody bands were positive and the p31 band was negative, indicating a Fiebig Stage 5 infection. Conclusions: Pooled DBS HIV-1 RNA testing is efficient compared to individual testing for acute HIV infection diagnosis. Early identification of participants with acute HIV infection facilitates immediate initiation of antiretroviral therapy to improve immune recovery and prevent transmission to others.

Abstract Background The successful implementation of maternal vaccination relies on results of clinical trials, considering the prenatal and postnatal attendance at selected healthcare institutions. This study evaluated factors influencing maternal/infant access to healthcare facilities to identify potential barriers to participation in future clinical trials on maternal vaccination. Methods In this prospective, multi-centre, observational study, pregnant women (N = 3243) were enrolled at ten sites across Panama, the Dominican Republic, South Africa, and Mozambique between 2012 and 2014. They completed questionnaires at enrolment, delivery, and infant follow-up (90 days post-partum) visits, including questions on transportation, phone accessibility, alternative childcare, gestational age at enrolment, delivery location, and health status of their infant. Logistic regression was used to identify factors significantly associated with return to study site for delivery or infant follow-up visits. Results Among 3229 enrolled women with delivery information, 63.6% (range across sites: 25.3–91.5%) returned to study site for delivery. Older women and those at later gestational age at enrolment were more likely to deliver at the study site. While heterogeneities were observed at site level, shorter travel time at delivery and increased transportation costs at enrolment were associated with increased likelihood of women returning to study site for delivery. Among 3145 women with live-born infants, 3077 (95.3%) provided 90-day follow-up information; of these, 68.9% (range across sites: 25.6–98.9%) returned to study site for follow-up visits. Women with other children and with lower transportation costs at delivery were more likely to return to study site for follow-up visits. Among 666 infants reported sick, 94.3% were taken to a healthcare facility, with only 41.9% (range across sites: 4.9–77.3%) to the study site. Conclusion Although high retention was observed from enrolment through 90 days after delivery, post-partum surveillance should be broadened beyond the study sites and additional follow-up visits should be planned within the neonatal period. The factors influencing maternal/infant access to healthcare facilities and the issues identified in this study should be taken into consideration in planning future clinical studies on maternal immunisation in low- and middle-income countries. Trial registration The study was registered at ClinicalTrial.gov ( NCT01734434 ) on November 22, 2012.

Children and adolescents living with HIV continue to be impacted disproportionately by tuberculosis as compared to peers without HIV. HIV can impact TB screening and diagnosis by altering screening and diagnostic test performance and can complicate prevention and treatment strategies due to drug–drug interactions. Post-tuberculosis lung disease is an underappreciated phenomenon in children and adolescents, but is more commonly observed in children and adolescents with HIV-associated tuberculosis. This review presents new data related to HIV-associated TB in children and adolescents. Data on the epidemiology of HIV-associated TB suggests that an elevated risk of TB in children and adolescents with HIV persists even with broad implementation of ART. Recent guidance also indicates the need for new screening strategies for HIV-associated TB. There have been major advances in the availability of new antiretroviral medications and also TB prevention options for children, but these advances have come with additional questions surrounding drug–drug interactions and dosing in younger age groups. Finally, we review new approaches to manage post-TB lung disease in children living with HIV. Collectively, we present data on the rapidly evolving field of HIV-associated child tuberculosis. This evolution offers new management opportunities for children and adolescents living with HIV while also generating new questions for additional research.

Abstract Background South Africa recently phased out access to free formula milk in the public sector in support of breastfeeding for women living with HIV. Few women living with HIV in South Africa choose breastfeeding and among those who do, many stop breastfeeding early. We sought to explore the feasibility of using mobile phone text messaging coupled with motivational interviewing to enhance adherence to breastfeeding practices. Methods and design A randomized, parallel group, single-center pilot trial. Electronic sequence generation and random allocation will be done centrally. Women of low socioeconomic status, from Cape Town, South Africa will be randomly assigned within 24 h of giving birth at a primary healthcare clinic to a structured weekly text message plus motivational interviewing and usual standard of care, using a permutation of different block sizes. Criteria for feasibility success will include: five participants recruited per week (over 12 weeks), about 75% of all eligible participants consent for study participation, complete evaluation of outcomes in at least 70% of all recruited participants, breastfeeding adherence rates of at least 70% in the intervention group, six months after delivery. Participants will be evaluated soon after giving birth and post-delivery at weeks 2, 6, 10, and 24. Primary analysis will follow the “intention-to-treat” principle. Sub-group analysis will be used to assess sub-group effects. Discussion This pilot trial will evaluate the feasibility of conducting a larger trial on communication and support approaches to improve adherence to breastfeeding by HIV-infected women. Text messaging and motivational interviewing are simple interventions which may allow participants to access personalized adherence advice and support. Trial registration ClinicalTrials.gov: NCT02949713 . Registered on 26 October 2016; Pan African Clinical Trial Registry PACTR201611001855404 . Registered on 8 November 2016.

The neurological changes in children living with perinatal HIV (PHIV) on antiretroviral therapy (ART) can be studied at a metabolic level through proton magnetic resonance spectroscopy. While previous studies in children have largely focused on individual metabolite changes, investigating patterns within and across regions of interest can aid in identifying metabolic markers of HIV infection.In this study 76 children with PHIV from the Children with HIV Early AntiRetroviral (CHER) trial, 30 children who were HIV-exposed-uninfected (HEU) and 30 children who were HIV-unexposed (HU), were scanned at the age of 11.6 (sd = 0.3) years using a 3 T Skyra scanner. Metabolite concentrations were quantified within the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM), comparing levels between HIV status groups using linear regression. Factor analysis and logistic regression were performed to identify metabolic patterns characteristic of HIV infection within and across the regions of interest.In the BG region we observed restored metabolic activity in children with PHIV and children who were HEU, despite differences being previously observed at younger ages, suggesting that treatment may effectively reduce the effects of HIV infection and exposure. Elevated MFGM choline levels in children with PHIV are indicative of inflammation. Further, we observed reduced N-acetyl-aspartate (NAA) in the PWM of children with PHIV and children who were HEU, indicating possible axonal damage. Lower levels of PWM creatine in children with PHIV suggest that this may not be a valid reference metabolite in HIV studies. Finally, factor scores for a cross-regional inflammatory factor and a PWM axonal factor, driven by PWM NAA and creatine levels, distinguished children with PHIV from children without HIV (HEU and HU) at 11 years. Therefore, the effects of perinatal HIV infection and exposure continue to be seen at 11 years despite early treatment.

Background: Antiretroviral therapy (ART) started between 7 and 12 weeks of age improves neurodevelopmental outcomes in HIV-infected (HIV+) infants, but the impact of even earlier initiation is not yet described. Objective: We assessed the early neurodevelopment of HIV+ infants who started ART within 21 days of life. Methods: Participants were enrolled from the public sector birth HIV-diagnosis program. Inclusion criteria included: birth weight 2000g, infant commencing ART 6 weeks and no infant Cytomegalovirus disease. ART included Zidovudine/Lamivudine/Nevirapine for the first 2 weeks, the latter then replaced by Lopinavir/Ritonavir. Once body weight 3kg and gestational age 44 weeks, Abacavir replaced Zidovudine. The Griffiths Mental Development Scales (GMDS) were administered at 10-12 months. Results: Of 29 infants assessed, 23 (79%) were girls. Mean birth weight was 3002 ± 501g. Twenty-four mothers (83%) received ART during pregnancy. Seven (24%) infants were diagnosed HIV+ within 48 hours of birth. Median [IQR] viral load (VL) at diagnosis was 3904 [259;16922] copies/ml, age starting ART was 6.0 [3;10] days and age at VL suppression was 19.1 [15; 36] weeks. At the GMDS assessment nine (31%) participants had detectable VL and 26 (90%) had WHO clinical stage I disease. GMDS was performed at a mean age of 11.5±0.8 months. Mean quotients were within the average range: Global Griffiths score was 103.6±10.9 and mean quotients on the subscales ranged from lowest 95.9±13.4 for Locomotor to highest 112.8±11.3 for Hearing-and-language. Conclusion: Preliminary findings in this small group suggest that early neurodevelopmental scores are within the normal range in infants with perinatal HIV-infection who started ART at a median of 6 days.

Background: The extent of disclosure of HIV status to children and adolescents and the context facilitating their disclosure process have received little attention. Objectives: To assess disclosure and provide a comprehensive analysis of characteristics associated with disclosure to children (3–14 years) receiving antiretroviral treatment in a South African semi-urban clinic. Methods: This cross-sectional study used structured interview administered questionnaires which were supplemented with medical record data. Predictors included child, caregiver, clinical and socio-economic characteristics, viral suppression, immune response, adherence, health-related quality of life and family functioning. Results: We included 190 children of whom 45 (23.7%) received disclosure about their HIV status, of whom 28 (14.7%) were partially disclosed and 17 (8.9%) were fully disclosed. Older age of the child and higher education of the caregiver were strongly associated with disclosure. Female caregivers, detectable viral load, syrup formulation, protease inhibitor (PI) regimens with stavudine and didanosine, and self-reported non-adherence were strongly associated with non-disclosure. Conclusion: When children do well on treatment, caregivers feel less stringent need to disclose. Well-functioning families, higher educated caregivers and better socio-economic status enabled and promoted disclosure. Non-disclosure can indicate a sub-optimal social structure which could negatively affect adherence and viral suppression. There is an urgent need to address disclosure thoughtfully and proactively in the long-term disease management. For the disclosure process to be beneficial, an enabling supportive context is important, which will provide a great opportunity for future interventions.

HIV and tuberculosis (TB) often occur together with each exacerbating the other. Improvements in vertical transmission prevention has reduced the number of HIV-infected children being born and early antiretroviral therapy (ART) protects against tuberculosis. However, with delayed HIV diagnosis, HIV-infected infants often present with tuberculosis co-infection. The number of HIV exposed uninfected children has increased and these infants have high exposure to TB and may be more immunologically vulnerable due to HIV exposure in utero. Bacillus Calmette-Guérin (BCG) immunization shortly after birth is essential for preventing severe TB in infancy. With early infant HIV diagnosis and ART, disseminated BCG is no longer an issue. TB prevention therapy should be implemented for contacts of a source case and for all HIV-infected individuals over a year of age. Although infection can be identified through skin tests or interferon gamma release assays, the non-availability of these tests should not preclude prevention therapy, once active TB has been excluded. Therapeutic options have moved from isoniazid only for 6–9 months to shorter regimens. Prevention therapy after exposure to a source case with resistant TB should also be implemented, but should not prevent pivotal prevention trials already under way. A microbiological diagnosis for TB remains the gold standard because of increasing drug resistance. Antiretroviral therapy for rifampicin co-treatment requires adaptation for those on lopinavir-ritonavir, which requires super-boosting with additional ritonavir. For those with drug resistant TB, the main problems are identification and overlapping toxicity between antiretroviral and anti-TB therapy. In spite of renewed focus and improved interventions, infants are still vulnerable to TB.

There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure.

BackgroundThe immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India.Methods and findingsWe conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children ConclusionsIRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.

Abnormalities of the basal ganglia are frequently seen in HIV-infected (HIV+) children despite antiretroviral treatment (ART) initiation during childhood. Assessment of metabolites associated with neuronal integrity or with glial proliferation can present a sensitive description of metabolic events underlying basal ganglia structural changes. We used magnetic resonance spectroscopy to examine differences in creatine, choline, N-acetylaspartate (NAA), glutamate, and myo-inositol between HIV+ children and HIV-unexposed controls, as well as between HIV-exposed uninfected (HEU) children and HIV-unexposed controls at age 7 and at age 9. No differences in metabolites relative to the HIV-unexposed control group were found at age 7. However, at 9 years, both HIV+ and HEU had lower NAA and glutamate than unexposed control children. HEU children also had lower creatine and choline than control children. At age 7, lower CD4/CD8 ratio at enrollment was associated with lower choline levels. At age 9 lower CD4/CD8 at enrollment was associated with lower myo-inositol. Low NAA and glutamate at age 9, but not 7, suggest that basal ganglia neurons may be particularly affected by perinatal HIV/ART and that neuronal damage may be ongoing despite early ART and viral suppression. Reduced basal ganglia metabolite levels in HEU children suggest an effect of HIV exposure on childhood brain development that merits further investigation using neuroimaging and neurocognitive testing.