The IeDEA harmonist data toolkit: A data quality and data sharing solution for a global HIV research consortium.

We describe the design, implementation, and impact of a data harmonization, data quality checking, and dynamic report generation application in an international observational HIV research network. The IeDEA Harmonist Data Toolkit is a web-based application written in the open source programming language R, employs the R/Shiny and RMarkdown packages, and leverages the REDCap data collection platform for data model definition and user authentication. The Toolkit performs data quality checks on uploaded datasets, checks for conformance with the network's common data model, displays the results both interactively and in downloadable reports, and stores approved datasets in secure cloud storage for retrieval by the requesting investigator. Including stakeholders and users in the design process was key to the successful adoption of the application. A survey of regional data managers as well as initial usage metrics indicate that the Toolkit saves time and results in improved data quality, with a 61% mean reduction in the number of error records in a dataset. The generalized application design allows the Toolkit to be easily adapted to other research networks.

Growth in the first 5 years after antiretroviral therapy initiation among HIV-infected children in the IeDEA West African Pediatric Cohort.

OBJECTIVE: To describe growth evolution and its correlates in the first 5 years of antiretroviral therapy (ART) initiation among HIV-infected children followed up in West Africa. METHODS: All HIV-infected children younger than 10 years followed in the IeDEA pWADA cohort while initiating ART, with at least one anthropometric measurement within the first 5 years of treatment were included in the study. Growth was described according to the WHO child growth standards, using Weight-for-age Z-score (WAZ), Height-for-age Z-score (HAZ) and Weight-for-Height/BMI-for-age Z-score (WHZ/BAZ). Growth evolution and its correlates, measured at ART initiation, were modelled in individual linear mixed models for each anthropometric indicator, with a spline term added at the 12-, 24- and 9-month time point for WAZ, HAZ and WHZ/BAZ, respectively. RESULTS: Among the 4156 children selected (45% girls, median age at ART initiation 3.9 years [IQR interquartile range 1.9-6.6], and overall 68% malnourished at ART initiation), important gains were observed in the first 12, 24 and 9 months on ART for WAZ, HAZ and WHZ/BAZ, respectively. Correlates at ART initiation of a better growth evolution overtime were early age (<2 years of age), severe immunodeficiency for age, and severity of malnutrition. CONCLUSIONS: Growth evolution is particularly strong within the first 2 years on ART but slows down after this period. Weight and height gains help to recover from pre-ART growth deficiency but are insufficient for the most severely malnourished. The first year on ART could be the best period for nutritional interventions to optimize growth among HIV-infected children in the long-term.

OBJECTIF: Décrire l'évolution de la croissance et ses corrélats au cours des cinq premières années d'initiation du traitement antirétroviral (ART) chez les enfants infectés par le VIH, suivis en Afrique de l'Ouest. MÉTHODES: Tous les enfants infectés par le VIH âgés de moins de 10 ans suivis dans la cohorte IeDEA pWADA au début de l'ART, avec au moins une mesure anthropométrique au cours des cinq premières années de traitement, ont été inclus dans l'étude. La croissance a été décrite selon les normes de croissance de l'enfant de l'OMS, en utilisant le Z-score Poids pour l'âge (WAZ), le Z-score Taille pour l'âge (HAZ) et le Z-score Poids-pour-Taille/IMC pour l'âge (WHZ/BAZ). L'évolution de la croissance et ses corrélats, mesurés au début de l'ART, ont été modélisés dans des modèles mixtes linéaires individuels pour chaque indicateur anthropométrique, avec un terme spline ajouté aux points 12, 24 et 9 mois pour WAZ, HAZ et WHZ/BAZ respectivement. RÉSULTATS: Parmi les 4.156 enfants sélectionnés (45% de filles, âge médian au début l'ART 3,9 ans [intervalle interquartile IQR de 1,9 à 6,6] et au total 68% de malnutrition au début de l'ART), des gains importants ont été observés dans les 12, 24 et 9 premiers mois sous ART pour WAZ, HAZ et WHZ/BAZ respectivement. Les corrélats au début de l'ART pour une meilleure évolution de la croissance au cours du temps étaient: l'âge précoce (<2 ans), un déficit immunitaire sévère pour l'âge et la sévérité de la malnutrition. CONCLUSIONS: L'évolution de la croissance est particulièrement forte au cours des deux premières années sous ART, mais ralentit après cette période. Les gains de poids et de taille aident à récupérer du retard de croissance pré-ART mais sont insuffisants pour les plus sévèrement malnutris. La première année sous ART pourrait être la meilleure période pour les interventions nutritionnelles visant à optimiser la croissance à long terme des enfants infectés par le VIH.

Access to antiretroviral therapy in HIV-infected children aged 0-19 years in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium, 2004-2015: A prospective cohort study.

INTRODUCTION: Access to antiretroviral therapy (ART) is a global priority. However, the attrition across the continuum of care for HIV-infected children between their HIV diagnosis and ART initiation is not well known. We analyzed the time from enrollment into HIV care to ART initiation in HIV-infected children within the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium. METHODS AND FINDINGS: We included 135,479 HIV-1-infected children, aged 0-19 years and ART-naïve at enrollment, between 1 January 2004 and 31 December 2015, in IeDEA cohorts from Central Africa (3 countries; n = 4,948), East Africa (3 countries; n = 22,827), West Africa (7 countries; n = 7,372), Southern Africa (6 countries; n = 93,799), Asia-Pacific (6 countries; n = 4,045), and Latin America (7 countries; n = 2,488). Follow-up in these cohorts is typically every 3-6 months. We described time to ART initiation and missed opportunities (death or loss to follow-up [LTFU]: last clinical visit >6 months) since baseline (the date of HIV diagnosis or, if unavailable, date of enrollment). Cumulative incidence functions (CIFs) for and determinants of ART initiation were computed, with death and LTFU as competing risks. Among the 135,479 children included, 99,404 (73.4%) initiated ART, 1.9% died, 1.4% were transferred out, and 20.4% were lost to follow-up before ART initiation. The 24-month CIF for ART initiation was 68.2% (95% CI: 67.9%-68.4%); it was lower in sub-Saharan Africa-ranging from 49.8% (95% CI: 48.4%-51.2%) in Central Africa to 72.5% (95% CI: 71.5%-73.5%) in West Africa-compared to Latin America (71.0%, 95% CI: 69.1%-72.7%) and the Asia-Pacific (78.3%, 95% CI: 76.9%-79.6%). Adolescents aged 15-19 years and infants <1 year had the lowest cumulative incidence of ART initiation compared to other ages: 62.2% (95% CI: 61.6%-62.8%) and 66.4% (95% CI: 65.7%-67.0%), respectively. Overall, 49.1% were ART-eligible per local guidelines at baseline, of whom 80.6% initiated ART. The following children had lower cumulative incidence of ART initiation: female children (p < 0.01); those aged <1 year, 2-4 years, 5-9 years, and 15-19 years (versus those aged 10-14 years, p < 0.01); those who became eligible during follow-up (versus eligible at enrollment, p < 0.01); and those receiving care in low-income or lower-middle-income countries (p < 0.01). The main limitations of our study include left truncation and survivor bias, caused by deaths of children prior to enrollment, and use of enrollment date as a proxy for missing data on date of HIV diagnosis, which could have led to underestimation of the time between HIV diagnosis and ART initiation. CONCLUSIONS: In this study, 68% of HIV-infected children initiated ART by 24 months. However, there was a substantial risk of LTFU before ART initiation, which may also represent undocumented mortality. In 2015, many obstacles to ART initiation remained, with substantial inequities. More effective and targeted interventions to improve access are needed to reach the target of treating 90% of HIV-infected children with ART.

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old.

The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C12 h) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority of C12 h values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), with C12 h values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but his C12 h value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.).

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Côte d'Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial.

BACKGROUND: The 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years. METHODS: The MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12-15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test). RESULTS: Between May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12-15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), -11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, -13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation. CONCLUSIONS: At the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored. TRIAL REGISTRATION: ClinicalTrial.gov registry n° NCT01127204 , 19 May 2010.

Suboptimal cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines.

AIMS: A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole [sulfamethoxazole (SMX) and trimethoprim (TMP)] advised by the WHO. METHODS: Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/40 mg of TMP once daily). A nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Factors that could impact the pharmacokinetic profile were investigated. The model was subsequently used to simulate individual exposure and evaluate different administration schemes. RESULTS: The cohort comprised 136 children [average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3])]. A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetics. SMX and TPM clearance were estimated at 0.49 l h-1 /9.5 kg and 3.06 l h-1 /9.5 kg, respectively. The simulated exposures obtained after administration of oral dosing recommended by the WHO for children from 10 to 15 kg were significantly lower than in adults for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg kg-1 of SMX and 6 mg kg-1 of TMP in the 5-10 kg group and 25 mg kg-1 of SMX and 5 mg kg-1 of TMP in the 10-15 kg group are more suitable doses. CONCLUSIONS: In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed.

Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children Ages 1-5 Years: A Causal Modeling Analysis.

BACKGROUND: There is limited evidence regarding the optimal timing of initiating antiretroviral therapy (ART) in children. We conducted a causal modeling analysis in children ages 1-5 years from the International Epidemiologic Databases to Evaluate AIDS West/Southern-Africa collaboration to determine growth and mortality differences related to different CD4-based treatment initiation criteria, age groups, and regions. METHODS: ART-naïve children of ages 12-59 months at enrollment with at least one visit before ART initiation and one follow-up visit were included. We estimated 3-year growth and cumulative mortality from the start of follow-up for different CD4 criteria using g-computation. RESULTS: About one quarter of the 5,826 included children was from West Africa (24.6%).The median (first; third quartile) CD4% at the first visit was 16% (11%; 23%), the median weight-for-age z-scores and height-for-age z-scores were -1.5 (-2.7; -0.6) and -2.5 (-3.5; -1.5), respectively. Estimated cumulative mortality was higher overall, and growth was slower, when initiating ART at lower CD4 thresholds. After 3 years of follow-up, the estimated mortality difference between starting ART routinely irrespective of CD4 count and starting ART if either CD4 count <750 cells/mm³ or CD4% <25% was 0.2% (95% CI = -0.2%; 0.3%), and the difference in the mean height-for-age z-scores of those who survived was -0.02 (95% CI = -0.04; 0.01). Younger children ages 1-2 and children in West Africa had worse outcomes. CONCLUSIONS: Our results demonstrate that earlier treatment initiation yields overall better growth and mortality outcomes, although we could not show any differences in outcomes between immediate ART and delaying until CD4 count/% falls below 750/25%.

Effect of cotrimoxazole prophylaxis on the incidence of malaria in HIV-infected children in 2012, in Abidjan, Côte d'Ivoire: a prospective cohort study.

BACKGROUND: Cotrimoxazole prophylaxis has an antimalarial effect which could have an additional protective effect against malaria in HIV-infected children on antiretroviral therapy (ART). We measured the incidence and associated factors of malaria in HIV-infected children on ART and/or cotrimoxazole in Abidjan, Côte d'Ivoire. METHODS: All HIV-infected children <16 years, followed-up in the IeDEA West-African paediatric cohort (pWADA) in Abidjan, were prospectively included from May to August 2012, the rainy season. Children presenting signs suggesting malaria had a thick blood smear and were classified as confirmed or probable malaria. We calculated incidence density rates (IR) per 100 child-years (CY). Risk factors were assessed using a Poisson regression model. RESULTS: Overall, 1117 children were included, of whom 89 % were ART-treated and 67 % received cotrimoxazole. Overall, there were 51 malaria events occurring in 48 children: 28 confirmed and 23 probable; 94 % were uncomplicated malaria. The overall IR of malaria (confirmed and probable) was 18.3/100 CY (95 % CI: 13.3-23.4), varying from 4.2/100 CY (95 % CI: 1.1-7.3) in children on ART and cotrimoxazole to 57.3/100 CY (95 % CI: 7.1-107.6) for those receiving no treatment at all. In univariate analysis, age < 5 years was significantly associated with a 2-fold IR of malaria compared to age >10 years (incidence rate ratio [IRR] = 2.18, 95 % CI: 1.04-4.58). Adjusted for severe immunodeficiency, cotrimoxazole reduced significantly the IR of first malarial episode (adjusted IRR [aIRR] = 0.13, 95 % CI: 0.02-0.69 and aIRR = 0.05, 95 % CI:0.02-0.18 in those off and on ART respectively). Severe immunodeficiency increased significantly the malaria IR (aIRR = 4.03, 95 % CI: 1.55-10.47). When considering the IR of confirmed malaria only, this varied from 2.4/100 CY (95 % CI: 0.0-4.8) in children on ART and cotrimoxazole to 34.4/100 CY (95 % CI: 0.0-73.3) for those receiving no treatment at all. In adjusted analyses, the IR of malaria in children on both cotrimoxazole and ART was significantly reduced (aIRR = 0.05, 95 % CI: 0.01-0.24) compared to those receiving no treatment at all. CONCLUSIONS: Cotrimoxazole prophylaxis was strongly protective against the incidence of malaria when associated with ART in HIV-infected children. Thus, these drugs should be provided as widely and durably as possible in all HIV-infected children <5 years of age.

Sex-Based Disparities in the Transition to Dolutegravir-Based Antiretroviral Therapy in West African HIV Cohorts.

Transition to dolutegravir among 21 167 individuals experienced in antiretroviral therapy in West Africa showed heterogeneous timelines and patterns. Initially reported sex disparities tended to catch up over time with persisting disparities, according to contributing HIV clinics. Key factors facilitating dolutegravir switch were male sex, age <50 years, viral suppression, and regimens not based on protease inhibitors.

Disparities in access to Dolutegravir in West African children, adolescents and young adults aged 0-24 years living with HIV. A IeDEA Pediatric West African cohort analysis.

Introduction: We describe the 24-month incidence of Dolutegravir (DTG)-containing antiretroviral treatment (ART) initiation since its introduction in 2019 in the pediatric West African IeDEA cohorts. Methods: We included all patients aged 0-24 years on ART, from nine clinics in Côte d'Ivoire (n=4), Ghana, Nigeria, Mali, Benin, and Burkina Faso. Baseline varied by clinic and was defined as date of first DTG prescription; patients were followed-up until database closure/death/loss to follow-up (LTFU, no visit ≥ 7 months), whichever came first. We computed the cumulative incidence function for DTG initiation; associated factors were explored in a shared frailty model, accounting for clinic heterogeneity. Results: Since 2019, 3,350 patients were included; 49% were female;79% had been on ART ≥ 12 months. Median baseline age was 12.9 years (IQR: 9-17). Median follow-up was 14 months (IQR: 7-22). The overall cumulative incidence of DTG initiation reached 35.5% (95% CI: 33.7-37.2) and 56.4% (95% CI: 54.4-58.4) at 12 and 24 months, respectively. In univariate analyses, those aged <5 years and females were overall less likely to switch. Adjusted on ART line and available viral load (VL) at baseline, females >10 years were less likely to initiate DTG compared to males of the same age (aHR among 10-14 years: 0.62, 95% CI: 0.54-0.72; among ≥15 years: 0.43, 95% CI: 0.36-0.50), as were those with detectable VL (> 50 copies/mL) compared to those in viral suppression (aHR: 0.86, 95% CI: 0.77-0.97) and those on PIs compared to those on NNRTIs (aHR after 12 months of roll-out: 0.75, 95% CI: 0.65-0.86). Conclusion: Access to paediatric DTG was incomplete and unequitable in West African settings: children <5years, females ≥ 10 years and those with detectable viral load were least likely to access DTG. Maintained monitoring and support of treatment practices is required to better ensure universal and equal access. Key messages: What is already known on this topic?: Dolutegravir (DTG)-based ART regimens are recommended as the preferred first-line ART regimens recommended by the World Health Organisation in all people living with HIV since 2018, with a note of caution for pregnant women, then confirmed in all children with approved DTG dosing and adolescents since 2019.Deployment of universal DTG access in adults in West Africa has faced challenges such as infrastructure challenges, and healthcare system disparities, and was hindered by initial perinatal safety concerns affecting greatly women of childbearing age.Specific data on access to DTG in children, adolescents and young adults in West Africa is limited.What this study adds ?: This study describes the dynamic of the DTG roll-out over the first 24 months and its correlates since 2019 in a large West African multicentric cohort of children, adolescents and youth.We observed a rapid scale-up of DTG among children, adolescents and young adults living with HIV in West Africa, despite the COVID-19 pandemic.However, DTG access after 24 months was incomplete and unequitable, with adolescent girls and young women being less likely to initiate DTG compared to males, as were those with a detectable viral load (> 50 copies/mL) compared to those in success.Younger children < 5 years were also less likely to initiate DTG, explained by the later approval of paediatric formulations and their low availability.How this study might affect research, practice or policy?: Maintained monitoring, training and updating guidance for healthcare workers is essential to ensure universal access to DTG, especially for females, for whom inequity begins age 10 years.Efforts to improve access to universal DTG in West Africa require multifaceted interventions including healthcare infrastructure improvement and facilitation of paediatric antiretroviral forecasting and planification.