Effects of the Covid-19 pandemic on ART initiation and access to HIV viral load monitoring in adults living with HIV in West Africa: a regression discontinuity analysis.

OBJECTIVES: Efforts to control the COVID-19 pandemic have potentially compromised the availability and/or quality of HIV services. We aimed to assess the pandemic's impact on ART initiation and HIV viral load (VL) monitoring in three West African countries. METHODS: We used routinely collected data from five clinics contributing to the IeDEA collaboration in Burkina Faso, Côte d'Ivoire and Nigeria. We included ART-naïve adults living with HIV (ALWH) initiating ART from 01/01/2018. We conducted regression discontinuity analysis to estimate changes in the number of ART initiations and VL measures per week, before and during the pandemic period in each country. RESULTS: In clinics in Burkina Faso and Côte d'Ivoire, ART initiations per week remained constant throughout the studied periods (-0.24 points (p) of ART initiations/week 95%CI -5.5, 5.9, -0.9 p 95%CI -8.5,8.6, respectively), whereas in Nigeria's clinic, they decreased significantly (-6.3 p, 95% CI -10.8, -1.7) after the beginning of the pandemic. The volume of VL tests performed decreased significantly in all three countries (-17.0 p 95%CI -25.3, -8.6 in Burkina Faso, -118.4 p 95%CI -171.1, -65.8 in Côte d'Ivoire and -169.1p 95%CI-282.6, -55.6 in Nigeria). CONCLUSIONS: Access to ART was maintained for newly diagnosed ALWH despite pandemic-related physical/social distancing measures. However, VL monitoring was severely disrupted and did not return to pre-pandemic levels approximately one year after the beginning of the pandemic. While HIV services in West Africa appear rather resilient, the impact of disruptions in VL monitoring on virological and clinical outcomes should continue to be monitored.

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.

Delayed presentation of HIV among older individuals: a growing problem.

Late presentation for care is a major impediment to the prevention and effective treatment of HIV infection. Older individuals are at increased risk of late presentation, represent a growing proportion of people with late presentation, and might require interventions tailored to their age group. We provide a summary of the literature published globally between 2016-21 (reporting data from 1984-2018) and quantify the association of age with delayed presentation. Using the most common definitions of late presentation and older age from these earlier studies, we update this work with data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium, focusing on data from 2000-19, encompassing four continents. Finally, we consider how late presentation among older individuals might be more effectively addressed as electronic medical records become widely adopted.

Assessment of dietary diversity and nutritional support for children living with HIV in the IeDEA pediatric West African cohort: a non-comparative, feasibility study.

BACKGROUND: Nutritional care is not optimally integrated into pediatric HIV care in sub-Saharan Africa. We assessed the 6-month effect of a nutritional support provided to children living with HIV, followed in a multicentric cohort in West Africa. METHODS: In 2014-2016, a nutritional intervention was carried out for children living with HIV, aged under 10 years, receiving antiretroviral therapy (ART) or not, in five HIV pediatric cohorts, in Benin, Togo and Côte d'Ivoire. Weight deficiency was assessed using two definitions: wasting (Weight for Height Z-score [WHZ] for children<5 years old or Body-Mass-Index for Age [BAZ] for ≥5 years) and underweight (Weight for Age Z-score [WAZ]) (WHO child growth standards). Combining these indicators, three categories of nutritional support were defined: 1/ children with severe malnutrition (WAZ and/or WHZ/BAZ <-3 Standard Deviations [SD]) were supported with Ready-To-Use Therapeutic Food (RUTF), 2/ those with moderate malnutrition (WAZ and/or WHZ/BAZ = [-3;-2[ SD) were supported with fortified blended flours produced locally in each country, 3/ those non malnourished (WAZ and WHZ/BAZ ≥-2 SD) received nutritional counselling only. Children were followed monthly over 6 months. Dietary Diversity Score (DDS) using a 24h recall was measured at the first and last visit of the intervention. RESULTS: Overall, 326 children were included, 48% were girls. At baseline, 66% were aged 5-10 years, 91% were on ART, and 17% were severely immunodeficient (CD4 <250 cells/mL or CD4%<15). Twenty-nine (9%) were severely malnourished, 63 (19%) moderately malnourished and 234 (72%) non-malnourished. After 6 months, 9/29 (31%) and 31/63 (48%) recovered from severe and moderate malnutrition respectively. The median DDS was 8 (IQR 7-9) in Côte d'Ivoire and Togo, 6 (IQR 6-7) in Benin. Mean DDS was 4.3/9 (sd 1.2) at first visit, with a lower score in Benin, but with no difference between first and last visit (p=0.907), nor by intervention groups (p-value=0.767). CONCLUSIONS: This intervention had a limited effect on nutritional recovery and dietary diversity improvement. Questions remain on determining appropriate nutritional products, in terms of adherence, proper use for families and adequate energy needs coverage for children living with HIV. TRIAL REGISTRATION: PACTR202001816232398 , June 01, 2020, retrospectively registered.

24-Month Clinical, Immuno-Virological Outcomes, and HIV Status Disclosure in Adolescents Living With Perinatally-Acquired HIV in the IeDEA-COHADO Cohort in Togo and Côte d'Ivoire, 2015-2017.

Background: Adolescents living with perinatally-acquired HIV (APHIV) face challenges including HIV serostatus disclosure. We assessed their 24-month outcomes in relation to the disclosure of their own HIV serostatus. Methods: Nested within the International epidemiologic Database to Evaluate AIDS pediatric West African prospective cohort (IeDEA pWADA), the COHADO cohort included antiretroviral (ART)-treated APHIV aged 10-19 years, enrolled in HIV care before the age of 10 years, in Abidjan (Côte d'Ivoire) and Lomé (Togo) in 2015. We measured the HIV serostatus disclosure at baseline and after 24 months and analyzed its association with a favorable combined 24-month outcome using logistic regression. The 24-month combined clinical immuno-virological outcome was defined as unfavorable when either death, loss to follow-up, progression to WHO-AIDS stage, a decrease of CD4 count >10% compared to baseline, or a detectable viral load (VL > 50 copies/mL) occurred at 24 months. Results: Overall, 209 APHIV were included (51.6% = Abidjan, 54.5% = females). At inclusion, the median CD4 cell count was 521/mm 3 [IQR (281-757)]; 29.6% had a VL measurement, of whom, 3.2% were virologically suppressed. APHIV were younger in Lomé {median age: 12 years [interquartile range (IQR): 11-15]} compared to Abidjan [14 years (IQR: 12-15, p = 0.01)]. Full HIV-disclosure increased from 41.6% at inclusion to 74.1% after 24 months. After 24 months of follow-up, six (2.9%) died, eight (3.8%) were lost to follow-up, and four (1.9%) were transferred out. Overall, 73.7% did not progress to the WHO-AIDS stage, and 62.7% had a CD4 count above (±10%) of the baseline value (48.6% in Abidjan vs. 69.0% in Lomé, p < 0.001). Among the 83.7% with VL measurement, 48.8% were virologically suppressed (Abidjan: 45.4%, Lomé: 52.5%, p <0.01). The 24-month combined outcome was favorable for 45% (29.6% in Abidjan and 61.4% in Lomé, p < 0.01). Adjusted for baseline variables, the 24-month outcome was worse in Lomé in those who had been disclosed for >2 years compared to those who had not been disclosed to [aOR = 0.21, 95% CI (0.05-0.84), p = 0.03]. Conclusions: The frequency of HIV-disclosure improved over time and differed across countries but remained low among West African APHIV. Overall, the 24-month outcomes were poor. Disclosure before the study was a marker of a poor 24-month outcome in Lomé. Context-specific responses are urgently needed to improve adolescent care and reach the UNAIDS 90% target of virological success.

Age-specific mortality rate ratios in adolescents and youth aged 10-24 years living with perinatally versus nonperinatally acquired HIV.

OBJECTIVE: To measure mortality incidence rates and incidence rate ratios (IRR) in adolescents and youth living with perinatally acquired HIV (YPHIV) compared with those living with nonperinatally acquired HIV (YNPHIV), by region, by sex, and during the ages of 10-14, 15-19, and 20-24 years in IeDEA. DESIGN AND METHODS: All those with a confirmed HIV diagnosis, antiretroviral therapy (ART)-naive at enrollment, and who have post-ART follow-up while aged 10-24 years between 2004 and 2016 were included. We estimated post-ART mortality incidence rates and 95% confidence intervals (95% CI) per 100 person-years for YPHIV (enrolled into care <10 years of age) and YNPHIV (enrolled ≥10 years and <25 years). We estimate mortality IRRs in a negative binomial regression model, adjusted for sex, region time-varying age, CD4+ cell count at ART initiation (<350 cells/µl, ≥350 cells/µl, unknown), and time on ART (<12 and ≥12 months). RESULTS: Overall, 104 846 adolescents and youth were included: 21 340 (20%) YPHIV (50% women) and 83 506 YNPHIV (80% women). Overall mortality incidence ratios were higher among YNPHIV (incidence ratio: 2.3/100 person-years; 95% CI: 2.2-2.4) compared with YPHIV (incidence ratio: 0.7/100 person-years; 95% CI: 0.7-0.8). Among adolescents aged 10-19 years, mortality was lower among YPHIV compared with YNPHIV (all IRRs <1, ranging from 0.26, 95% CI: 0.13-0.49 in 10-14-year-old boys in the Asia-Pacific to 0.51, 95% CI: 0.30-0.87 in 15-19-year-old boys in West Africa). CONCLUSION: We report substantial amount of deaths occurring during adolescence. Mortality was significantly higher among YNPHIV compared to YPHIV. Specific interventions including HIV testing and early engagement in care are urgently needed to improve survival among YNPHIV.

Comparison of three galenic forms of lamivudine in young West African children living with Human Immunodeficiency Virus.

BACKGROUND: Few pharmacokinetic data were reported on dispersible tablets despite their increasing use. One hundred fifty HIV-infected children receiving lamivudine were enrolled in the MONOD ANRS 12,206 trial. Three galenic forms were administered: liquid formulation, tablet form and dispersible scored tablet. METHOD: HIV-infected children <4 years old were enrolled in the MONOD ANRS 12,206 trial designed to assess the simplification of a successful 12-months lopinavir-based antiretroviral treatment with efavirenz. Lamivudine plasma concentrations were analysed using nonlinear mixed effects modelling approach. RESULTS: One hundred and fifty children (age: 2.5 years (1.9-3.2), weight 11.1 (9.5-12.5) kg (median (IQR)) were included in this study. Over the study period, 79 received only the syrup form, 29 children switched from syrup form to tablet 3TC/AZT form, 36 from syrup to the orodispersible ABC/3TC form and two from the 3TC/AZT form to the orodispersible ABC/3TC form. The 630 lamivudine concentrations were best described by a two-compartment model allometrically scaled. Galenic form had no significant effect on 3TC pharmacokinetic. CONCLUSION: This trial provided an opportunity to compare three galenic forms (liquid formulation, tablet form and dispersible scored tablet) of lamivudine in the target population of young HIV-1-infected children. Galenic form had no significant effect on lamivudine pharmacokinetics.

Time-varying age- and CD4-stratified rates of mortality and WHO stage 3 and stage 4 events in children, adolescents and youth 0 to 24 years living with perinatally acquired HIV, before and after antiretroviral therapy initiation in the paediatric IeDEA Global Cohort Consortium.

INTRODUCTION: Evaluating outcomes of paediatric patients with HIV provides crucial data for clinicians and policymakers. We analysed mortality and clinical events rates among children, adolescents, and youth with perinatally acquired HIV (PHIV) aged 0 to 24 years stratified by time-varying age and CD4, before and after antiretroviral therapy (ART), in the paediatric IeDEA multiregional collaboration (East, West, Central and Southern Africa, Asia-Pacific, and Central/South America and the Caribbean). METHODS: ART-naïve children with HIV enrolled before age 10 (proxy for perinatal infection) at IeDEA sites between 2004 and 2016, with ≥1 CD4 measurement during follow-up were included. We estimated incidence rates (IR) and 95% confidence intervals (95% CI) of mortality and first occurrence of WHO-4 and WHO-3 events, excluding tuberculosis, during person-years (PY) spent within different age (<2, 2 to 4, 5 to 9, 10 to 14, 15 to 19, 20 to 24) and CD4 (percent when <5 years [<15%, 15% to 24%, ≥25%]; count when ≥5 years [<200, 200 to 499, ≥500 cells/µL]) strata. We used linear mixed models to predict CD4 evolution, with trends modelled by region. RESULTS: In the pre-ART period, 49 137 participants contributed 51 966 PY of follow-up (median enrolment age: 3.9 years). The overall pre-ART IRs were 2.8/100 PY (95% CI: 2.7 to 2.9) for mortality, 3.3/100 PY (95% CI: 3.0 to 3.5) for first occurrence of a WHO-4 event, and 7.0/100 PY (95% CI: 6.7 to 7.4) for first occurrence of a WHO-3 event. Lower CD4 and younger age strata were associated with increased rates of both mortality and first occurrence of a clinical event. In the post-ART period, 52 147 PHIVY contributed 207 945 PY (ART initiation median age: 4.5 years). Overall mortality IR was 1.4/100 PY (95% CI: 1.4 to 1.5) and higher in low CD4 strata; patients at each end of the age spectrum (<2 and >19) had increased mortality post-ART. IRs for first occurrence of WHO-4 and WHO-3 events were 1.3/100 PY (95% CI: 1.2 to 1.4) and 2.1/100 PY (95% CI: 2.0 to 2.2) respectively. These were also associated with lower CD4 and younger age strata. CONCLUSIONS: Mortality and incidence of clinical events were highest in both younger (<2 years) and older (>19 years) youth with PHIV. Scaling-up services for <2 years (early access to HIV diagnosis and care) and >19 years (adolescent- and youth-focused health services) is critical to improve outcomes among PHIVY.

International epidemiology databases to evaluate AIDS (IeDEA) in sub-Saharan Africa, 2012-2019.

PURPOSE: The objectives of the International epidemiology databases to evaluate AIDS (IeDEA) are to (i) evaluate the delivery of combination antiretroviral therapy (ART) in children, adolescents and adults in sub-Saharan Africa, (ii) to describe ART regimen effectiveness, durability and tolerability, (iii) to examine HIV-related comorbidities and coinfections and (iv) to examine the pregnancy-related and HIV-related outcomes of women on ART and their infants exposed to HIV or ART in utero or via breast milk. PARTICIPANTS: IeDEA is organised in four regions (Central, East, Southern and West Africa), with 240 treatment and care sites, six data centres at African, European and US universities, and almost 1.4 million children, adolescents and adult people living with HIV (PLWHIV) enrolled. FINDINGS TO DATE: The data include socio-demographic characteristics, clinical outcomes, opportunistic events, treatment regimens, clinic visits and laboratory measurements. They have been used to analyse outcomes in PLWHIV-1 or PLWHIV-2 who initiate ART, including determinants of mortality, of switching to second-line and third-line ART, drug resistance, loss to follow-up and the immunological and virological response to different ART regimens. Programme-level estimates of mortality have been corrected for loss to follow-up. We examined the impact of coinfection with hepatitis B and C, and the epidemiology of different cancers and of (multidrug resistant) tuberculosis, renal disease and of mental illness. The adoption of 'Treat All', making ART available to all PLWHIV regardless of CD4+ cell count or clinical stage was another important research topic. FUTURE PLANS: IeDEA has formulated several research priorities for the 'Treat All' era in sub-Saharan Africa. It recently obtained funding to set up sentinel sites where additional data are prospectively collected on cardiometabolic risks factors as well as mental health and liver diseases, and is planning to create a drug resistance database.

Weight-for-age distributions among children with HIV on antiretroviral therapy in the International epidemiology Databases to Evaluate AIDS (IeDEA) multiregional consortium.

OBJECTIVE: Pediatric antiretroviral therapy (ART) for children with HIV (CHIV) must be dosed appropriately for children's changing weights as they grow. To inform accurate estimates of ART formulations and doses needed, we described weight-for-age distributions among CHIV on ART in the IeDEA global pediatric collaboration between 2004 and 2016, using data from six regions (East, West, Central, and Southern Africa, Asia-Pacific, and Central/South America and the Caribbean). RESULTS: Overall, 59,862 children contributed to the analysis. Age and weight data were available from 530,080 clinical encounters for girls and 537,894 for boys. For each one-year age stratum from 0 to 15 years, we calculated the proportion of children in each of the weight bands designated by the World Health Organization as relevant to pediatric ART formulations: 0 to < 3 kg, 3 to < 6 kg, 6 to < 10 kg, 10 to < 14 kg, 14 to < 20 kg, 20 to < 25 kg, 25 to < 30 kg, 30 to < 35 kg, 35 to < 40 kg, 40 to < 45 kg, 45 to < 50 kg, 50 to < 55 kg, 55 to < 60 kg, and ≥ 60 kg. Data are reported for the entire cohort, as well as stratified by sex and IeDEA region, calendar year of ART use, and duration on ART at time of assessment (< 12 or ≥ 12 months), provided in data tables. These data are critical to improve the accuracy of forecasting and procurement of pediatric ART formulations as the pediatric HIV epidemic and pediatric HIV treatment strategies evolve.

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.

Mortality and losses to follow-up among adolescents living with HIV in the IeDEA global cohort collaboration.

INTRODUCTION: We assessed mortality and losses to follow-up (LTFU) during adolescence in routine care settings in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS: Cohorts in the Asia-Pacific, the Caribbean, Central, and South America, and sub-Saharan Africa (Central, East, Southern, West) contributed data, and included adolescents living with HIV (ALHIV) enrolled from January 2003 and aged 10 to 19 years (period of adolescence) while under care up to database closure (June 2016). Follow-up started at age 10 years or the first clinic visit, whichever was later. Entering care at <15 years was a proxy for perinatal infection, while entering care ≥15 years represented infection acquired during adolescence. Competing risk regression was used to assess associations with death and LTFU among those ever receiving triple-drug antiretroviral therapy (triple-ART). RESULTS: Of the 61,242 ALHIV from 270 clinics in 34 countries included in the analysis, 69% (n = 42,138) entered care <15 years of age (53% female), and 31% (n = 19,104) entered care ≥15 years (81% female). During adolescence, 3.9% died, 30% were LTFU and 8.1% were transferred. For those with infection acquired perinatally versus during adolescence, the four-year cumulative incidences of mortality were 3.9% versus 5.4% and of LTFU were 26% versus 69% respectively (both p < 0.001). Overall, there were higher hazards of death for females (adjusted sub-hazard ratio (asHR) 1.19, 95% confidence interval (CI) 1.07 to 1.33), and those starting treatment at ≥5 years of age (highest asHR for age ≥15: 8.72, 95% CI 5.85 to 13.02), and in care in mostly urban (asHR 1.40, 95% CI 1.13 to 1.75) and mostly rural settings (asHR 1.39, 95% CI 1.03 to 1.87) compared to urban settings. Overall, higher hazards of LTFU were observed among females (asHR 1.12, 95% CI 1.07 to 1.17), and those starting treatment at age ≥5 years (highest asHR for age ≥15: 11.11, 95% CI 9.86 to 12.53), in care at district hospitals (asHR 1.27, 95% CI 1.18 to 1.37) or in rural settings (asHR 1.21, 95% CI 1.13 to 1.29), and starting triple-ART after 2006 (highest asHR for 2011 to 2016 1.84, 95% CI 1.71 to 1.99). CONCLUSIONS: Both mortality and LTFU were worse among those entering care at ≥15 years. ALHIV should be evaluated apart from younger children and adults to identify population-specific reasons for death and LTFU.

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.

Malnutrition, Growth Response and Metabolic Changes Within the First 24 Months After ART Initiation in HIV-infected Children Treated Before the Age of 2 Years in West Africa.

BACKGROUND: There is limited information about malnutrition, growth evolution and metabolic changes among children initiated early on lopinavir-based antiretroviral therapy (ART) in Africa. METHODS: HIV-1-infected children, age <2 years were initiated on ART, as part of the MONOD ANRS 12206 project, conducted in Burkina Faso and Côte d'Ivoire. Weight-for-age, height-for-age and weight-for-height Z scores defined malnutrition [Z score less than -2 standard deviations (SDs)] using World Health Organization growth references. Biologic data were collected every 6 months. Factors associated with baseline malnutrition were evaluated using multivariate logistic regression, and with growth evolution in the first 24 months on ART using linear mixed models. RESULTS: Between 2011 and 2013, 161 children were enrolled: 64% were from Abidjan, 54% were girls. At ART initiation, median age was 13.7 months (interquartile range 7.7; 18.4), 52% were underweight (weight-for-age), 52% were stunted (height-for-age) and 36% were wasted (weight-for-height). Overall, baseline malnutrition was more likely for children living in Burkina Faso, with low birth weight, never breastfed and older age (12-24 months). Growth improved on ART, mainly within the first 6 months for weight, and was greater for the most severely malnourished children at baseline, but 8%-32% remained malnourished after 24 months. Over the 24-month period of ART, there was a significant increase of hypercholesterolemia and decrease of anemia and hypoalbuminemia. CONCLUSIONS: Prevalence of malnutrition was high before ART initiation. Even though growth improved on ART, some children remained malnourished even after 2 years of ART, highlighting the need for more active nutritional support.

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.

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.).

Virological response and resistances over 12 months among HIV-infected children less than two years receiving first-line lopinavir/ritonavir-based antiretroviral therapy in Cote d'Ivoire and Burkina Faso: the MONOD ANRS 12206 cohort.

INTRODUCTION: Lopinavir/ritonavir-based antiretroviral therapy (ART) is recommended for all HIV-infected children less than three years. However, little is known about its field implementation and effectiveness in West Africa. We assessed the 12-month response to lopinavir/ritonavir-based antiretroviral therapy in a cohort of West African children treated before the age of two years. METHODS: HIV-1-infected, ART-naive except for a prevention of mother-to-child transmission (PMTCT), tuberculosis-free, and less than two years of age children with parent's consent were enrolled in a 12-month prospective therapeutic cohort with lopinavir/ritonavir ART and cotrimoxazole prophylaxis in Ouagadougou and Abidjan. Virological suppression (VS) at 12 months (viral load [VL] <500 copies/mL) and its correlates were assessed. RESULTS: Between May 2011 and January 2013, 156 children initiated ART at a median age of 13.9 months (interquartile range: 7.8-18.4); 63% were from Abidjan; 53% were girls; 37% were not exposed to any PMTCT intervention or maternal ART; mother was the main caregiver in 81%; 61% were classified World Health Organization Stage 3 to 4. After 12 months on ART, 11 children had died (7%), 5 were lost-to-follow-up/withdrew (3%), and VS was achieved in 109: 70% of children enrolled and 78% of those followed-up. When adjusting for country and gender, the access to tap water at home versus none (adjusted odds ratio (aOR): 2.75, 95% confidence interval (CI): 1.09-6.94), the mother as the main caregiver versus the father (aOR: 2.82, 95% CI: 1.03-7.71), and the increase of CD4 percentage greater than 10% between inclusion and 6 months versus <10% (aOR: 2.55, 95% CI: 1.05-6.18) were significantly associated with a higher rate of VS. At 12 months, 28 out of 29 children with VL ≥1000 copies/mL had a resistance genotype test: 21 (75%) had ≥1 antiretroviral (ARV) resistance (61% to lamivudine, 29% to efavirenz, and 4% to zidovudine and lopinavir/ritonavir), of which 11 (52%) existed before ART initiation. CONCLUSION: Twelve-month VS rate on lopinavir/ritonavir-based ART was high, comparable to those in Africa or high-income countries. The father as the main child caregiver and lack of access to tap water are risk factors for viral failure and justify a special caution to improve adherence in these easy-to-identify situations before ART initiation. Public health challenges remain to optimize outcomes in children with earlier ART initiation in West Africa.

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.

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%.