Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis

HIV; Adolescent; Perinatally acquiredVIH; Adolescent; Adquirit perinatalmentVIH; Adolescente; Adquirida perinatalmenteIntroduction Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. Methods Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10–17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. Results A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from 7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3. Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3. This decline was observed across all regions, in males and females. Conclusions Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood.This work was supported by the International AIDS Society – Collaborative Initiative for Paediatric HIV Education & Research (IAS-CIPHER, http://www.iasociety.org/CIPHER), which is made possible through funding from CIPHER Founding Sponsor ViiV Healthcare (https://www.viivhealthcare.com) and Janssen (http://www.janssen.com)

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes

Global variations in pubertal growth spurts in adolescents living with perinatal HIV

Objective: To describe pubertal growth spurts among adolescents living with perinatally-acquired HIV (ALWPHIV) on antiretroviral therapy (ART)./ Design: Observational data collected from 1994–2015 in the CIPHER global cohort collaboration./ Methods: ALWPHIV who initiated ART age <10 years with ≥4 height measurements age ≥8 were included. Super Imposition by Translation And Rotation (SITAR) models, with parameters representing timing and intensity of the growth spurt, were used to describe growth, separately by sex. Associations between region, ART regimen, age, height-for-age (HAZ), and BMI-for-age z-scores (BMIz) at ART initiation (baseline) and age 10 years and SITAR parameters were explored./ Results: 4,723 ALWPHIV were included: 51% from East and Southern Africa (excluding Botswana and South Africa), 17% Botswana and South Africa, 6% West and Central Africa, 11% Europe and North America, 11% Asia-Pacific, and 4% Central, South America, and Caribbean. Growth spurts were later and least intense in sub-Saharan regions. In females, older baseline age and lower BMIz at baseline were associated with later and more intense growth spurts; lower HAZ was associated with later growth spurts. In males, older baseline age and lower HAZ were associated with later and less intense growth spurts; however, associations between baseline HAZ and timing varied by age. Lower HAZ and BMIz at 10 years were associated with later and less intense growth spurts in both sexes./ Conclusions: ALWPHIV who started ART at older ages or already stunted were more likely to have delayed pubertal growth spurts. Longer-term follow-up is important to understand the impact of delayed growth.

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

Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this ‘may be difficult for cell-based medicinal products’. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates

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 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

Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis.

INTRODUCTION Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. METHODS Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10-17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. RESULTS A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from 7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3 . Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3 . This decline was observed across all regions, in males and females. CONCLUSIONS Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood

Malnutrition et infection pédiatrique par le VIH en Afrique de l'Ouest

HIV-infected children in sub-Saharan Africa are exposed to high risk of malnutrition duringtheir life. However, data on the nutrition of HIV-infected children are still limited in West Africa.Thus, the main objective of this thesis is to better investigate the link between nutrition and HIVinfection among HIV-infected children in West Africa. More specifically, it is aimed to estimate theprevalence of malnutrition, to describe growth evolution after antiretroviral treatment initiation, andto assess proposed nutritional interventions to integrate to pediatric HIV care. The main results showa high prevalence of malnutrition among these children, around 50% before antiretroviral treatmentinitiation. This initiation had positive effects on growth evolution; all the more important whenantiretroviral treatment is early initiated. Weight deficiency is easier to recover than heightdeficiency, but a substantial part of children stay malnourished even after two years of treatment. Inaddition to antiretroviral treatment, nutritional support interventions are needed to fight againstmalnutrition among these children. Those assessed were efficient for acute malnourished children,but not for those with chronic malnutrition. Furthermore, growth could be a useful marker of HIVprogression. Integration of nutritional care into global pediatric HIV care is possible in West Africa,but further studies and advocacy work have to be developed to better adapt it.Les enfants infectés par le VIH en Afrique subsaharienne sont exposés à un risque de malnutrition élevé au cours de leur vie. Or, les données sur la nutrition chez ces enfants sont encore limitées en Afrique de l’Ouest. L’objectif global de cette thèse est d’étudier la relation entre nutrition et infection par le VIH, chez les enfants infectés vivant en Afrique de l’Ouest. Plus spécifiquement, il s’agit d’estimer la prévalence de la malnutrition, de décrire l’évolution de la croissance après l’initiation du traitement antirétroviral, et d’évaluer des interventions nutritionnelles à intégrer au sein de la prise en charge pédiatrique du VIH. Les principaux résultats montrent une prévalence élevée de la malnutrition chez ces enfants, proche de 50 % avant la mise sous traitement antirétroviral. L’initiation du traitement a des effets positifs sur la croissance, d’autant plus important que l’initiation se fait de façon précoce. Un déficit pondéral est plus facilement corrigeable qu’un déficit statural, mais une part non négligeable d’enfants continue d’être malnutrie même après deux ans de traitement. En complément du traitement antirétroviral, des interventions de soutien nutritionnel sont donc nécessaires pour lutter contre la malnutrition chez ces enfants. Celles évaluées sont efficaces pour ceux malnutris aigues, mais pas pour ceux avec une malnutrition chronique. De plus, la croissance peut être un marqueur utile de la progression du VIH pédiatrique.L’intégration de la prise en charge nutritionnelle au sein de la prise en charge globale du VIH pédiatrique est possible en Afrique de l’Ouest, mais d’autres études et des actions de plaidoyer sont à développer pour l’adapter au mieux

Malnutrition and HIV pediatric infection in West Africa

Les enfants infectés par le VIH en Afrique subsaharienne sont exposés à un risque de malnutrition élevé au cours de leur vie. Or, les données sur la nutrition chez ces enfants sont encore limitées en Afrique de l’Ouest. L’objectif global de cette thèse est d’étudier la relation entre nutrition et infection par le VIH, chez les enfants infectés vivant en Afrique de l’Ouest. Plus spécifiquement, il s’agit d’estimer la prévalence de la malnutrition, de décrire l’évolution de la croissance après l’initiation du traitement antirétroviral, et d’évaluer des interventions nutritionnelles à intégrer au sein de la prise en charge pédiatrique du VIH. Les principaux résultats montrent une prévalence élevée de la malnutrition chez ces enfants, proche de 50 % avant la mise sous traitement antirétroviral. L’initiation du traitement a des effets positifs sur la croissance, d’autant plus important que l’initiation se fait de façon précoce. Un déficit pondéral est plus facilement corrigeable qu’un déficit statural, mais une part non négligeable d’enfants continue d’être malnutrie même après deux ans de traitement. En complément du traitement antirétroviral, des interventions de soutien nutritionnel sont donc nécessaires pour lutter contre la malnutrition chez ces enfants. Celles évaluées sont efficaces pour ceux malnutris aigues, mais pas pour ceux avec une malnutrition chronique. De plus, la croissance peut être un marqueur utile de la progression du VIH pédiatrique.L’intégration de la prise en charge nutritionnelle au sein de la prise en charge globale du VIH pédiatrique est possible en Afrique de l’Ouest, mais d’autres études et des actions de plaidoyer sont à développer pour l’adapter au mieux.HIV-infected children in sub-Saharan Africa are exposed to high risk of malnutrition duringtheir life. However, data on the nutrition of HIV-infected children are still limited in West Africa.Thus, the main objective of this thesis is to better investigate the link between nutrition and HIVinfection among HIV-infected children in West Africa. More specifically, it is aimed to estimate theprevalence of malnutrition, to describe growth evolution after antiretroviral treatment initiation, andto assess proposed nutritional interventions to integrate to pediatric HIV care. The main results showa high prevalence of malnutrition among these children, around 50% before antiretroviral treatmentinitiation. This initiation had positive effects on growth evolution; all the more important whenantiretroviral treatment is early initiated. Weight deficiency is easier to recover than heightdeficiency, but a substantial part of children stay malnourished even after two years of treatment. Inaddition to antiretroviral treatment, nutritional support interventions are needed to fight againstmalnutrition among these children. Those assessed were efficient for acute malnourished children,but not for those with chronic malnutrition. Furthermore, growth could be a useful marker of HIVprogression. Integration of nutritional care into global pediatric HIV care is possible in West Africa,but further studies and advocacy work have to be developed to better adapt it

Malnutrition and HIV pediatric infection in West Africa

Les enfants infectés par le VIH en Afrique subsaharienne sont exposés à un risque de malnutrition élevé au cours de leur vie. Or, les données sur la nutrition chez ces enfants sont encore limitées en Afrique de l’Ouest. L’objectif global de cette thèse est d’étudier la relation entre nutrition et infection par le VIH, chez les enfants infectés vivant en Afrique de l’Ouest. Plus spécifiquement, il s’agit d’estimer la prévalence de la malnutrition, de décrire l’évolution de la croissance après l’initiation du traitement antirétroviral, et d’évaluer des interventions nutritionnelles à intégrer au sein de la prise en charge pédiatrique du VIH. Les principaux résultats montrent une prévalence élevée de la malnutrition chez ces enfants, proche de 50 % avant la mise sous traitement antirétroviral. L’initiation du traitement a des effets positifs sur la croissance, d’autant plus important que l’initiation se fait de façon précoce. Un déficit pondéral est plus facilement corrigeable qu’un déficit statural, mais une part non négligeable d’enfants continue d’être malnutrie même après deux ans de traitement. En complément du traitement antirétroviral, des interventions de soutien nutritionnel sont donc nécessaires pour lutter contre la malnutrition chez ces enfants. Celles évaluées sont efficaces pour ceux malnutris aigues, mais pas pour ceux avec une malnutrition chronique. De plus, la croissance peut être un marqueur utile de la progression du VIH pédiatrique.L’intégration de la prise en charge nutritionnelle au sein de la prise en charge globale du VIH pédiatrique est possible en Afrique de l’Ouest, mais d’autres études et des actions de plaidoyer sont à développer pour l’adapter au mieux.HIV-infected children in sub-Saharan Africa are exposed to high risk of malnutrition duringtheir life. However, data on the nutrition of HIV-infected children are still limited in West Africa.Thus, the main objective of this thesis is to better investigate the link between nutrition and HIVinfection among HIV-infected children in West Africa. More specifically, it is aimed to estimate theprevalence of malnutrition, to describe growth evolution after antiretroviral treatment initiation, andto assess proposed nutritional interventions to integrate to pediatric HIV care. The main results showa high prevalence of malnutrition among these children, around 50% before antiretroviral treatmentinitiation. This initiation had positive effects on growth evolution; all the more important whenantiretroviral treatment is early initiated. Weight deficiency is easier to recover than heightdeficiency, but a substantial part of children stay malnourished even after two years of treatment. Inaddition to antiretroviral treatment, nutritional support interventions are needed to fight againstmalnutrition among these children. Those assessed were efficient for acute malnourished children,but not for those with chronic malnutrition. Furthermore, growth could be a useful marker of HIVprogression. Integration of nutritional care into global pediatric HIV care is possible in West Africa,but further studies and advocacy work have to be developed to better adapt it