Predicting mortality within 1 year of ART initiation in children and adolescents living with HIV in sub-Saharan Africa: a retrospective observational cohort study.

BACKGROUND: Differentiated service delivery (DSD) for children and adolescents living with HIV can improve targeted resource use. We derived a mortality prediction score to guide clinical decision making for children and adolescents living with HIV. METHODS: Data for this retrospective observational cohort study were evaluated for all children and adolescents living with HIV and initiating antiretroviral therapy (ART); aged 0-19 years; and enrolled at Baylor clinics in Eswatini, Malawi, Lesotho, Tanzania, and Uganda between 2005 and 2020. Data for clinical prediction, including anthropometric values, physical examination, ART, WHO stage, and laboratory tests were captured at ART initiation. Backward stepwise variable selection and logistic regression were performed to develop predictive models for mortality within 1 year of ART initiation. Probabilities of mortality were generated, compared with true outcomes, internally validated, and evaluated against WHO advanced HIV criteria. FINDINGS: The study population included 16 958 children and adolescents living with HIV and initiated on ART between May 18, 2005, and Dec 18, 2020. Predictive variables for the most accurate model included: age, CD4 percentage, white blood cell count, haemoglobin concentration, platelet count, and BMI Z score as continuous variables, and WHO clinical stage and oedema, abnormal muscle tone and respiratory distress on examination as categorical variables. The area under the curve (AUC) of the predictive model was 0·851 (95% CI 0·839-0·863) in the training set and 0·822 (0·800-0·845) in the test set, compared with 0·606 (0·595-0·617) for the WHO advanced HIV criteria (p<0·0001). INTERPRETATION: This study evaluated a large, multinational population to derive a mortality prediction tool for children and adolescents living with HIV. The model more accurately predicted clinical outcomes than the WHO advanced HIV criteria and has the potential to improve DSD for children and adolescents living with HIV in high-burden settings. FUNDING: National Institute of Health Fogarty International Center.

D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa.

Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed-effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one-compartment model with first-order absorption (incorporating a lag-time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation-predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.

HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study.

BACKGROUND: Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission. METHODS: IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m2 and lopinavir 300 mg/m2 from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255. FINDINGS: Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2. INTERPRETATION: Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Long-term non-progression and risk factors for disease progression among children living with HIV in Botswana and Uganda: A retrospective cohort study.

OBJECTIVES: We utilize a large retrospective study cohort derived from electronic medical records to estimate the prevalence of long-term non-progression (LTNP) and determine the factors associated with progression among children infected with HIV in Botswana and Uganda. METHODS: Electronic medical records from large tertiary HIV clinical centers in Botswana and Uganda were queried to identify LTNP children 0-18 years enrolled between June 2003 and May 2014 and extract demographic and nutritional parameters. Multivariate subdistribution hazard analyses were used to examine demographic factors and nutritional status in progression in the pre-antiretroviral therapy era. RESULTS: Between the two countries, 14,246 antiretroviral therapy-naïve children infected with HIV were enrolled into clinical care. The overall proportion of LTNP was 6.3% (9.5% in Botswana vs 5.9% in Uganda). The median progression-free survival for the cohort was 6.3 years, although this was lower in Botswana than in Uganda (6.6 vs 8.8 years; P <0.001). At baseline, the adjusted subdistribution hazard ratio (aHRsd) of progression was increased among underweight children (aHRsd 1.42; 95% confidence interval [CI]: 1.32-1.53), enrolled after 2010 (aHRsd 1.32; 95% CI 1.22-1.42), and those from Botswana (aHRsd 2; 95% CI 1.91-2.10). CONCLUSIONS: In our study, the prevalence of pediatric LTNP was lower than that observed among adult populations, but progression-free survival was higher than expected. Underweight, year of enrollment into care, and country of origin are independent predictors of progression among children.

High prevalence of low high-density lipoprotein cholesterol and insulin resistance among children and adolescents living with HIV in Uganda: harbinger for metabolic syndrome?

BACKGROUND: Antiretroviral therapy-associated adverse effects and comorbidities are still pervasive in people living with HIV, especially metabolic syndrome (MetS). We investigated the age-dependent prevalence of components of MetS and insulin resistance in children and adolescents living with HIV (CALWH). METHODS: A cross-sectional pilot study of CALWH treated at the Baylor Uganda Clinical Centre of Excellence in Kampala, Uganda, May to August 2021. The primary outcome of MetS was defined by both the International Diabetes Federation (IDF) and the Adult Treatment Panel (ATP III) criteria. We estimated the prevalence of MetS and its components for all participants and by the stratification factors. RESULTS: We enrolled 90 children and adolescents, aged 6 to <10 years (n = 30), 10 to <16 years (n = 30), and ≥ 16 to <19 years (n = 30). Fifty-one percent were females. The estimated prevalence of MetS was 1.11% (1 of 90) using either IDF or ATPIII criteria for all participants, and 3.33% in the oldest age group. Notably, while only one among study participants met the criterion based on having central obesity or blood pressure, over 55% of participants had one or more IDF component, with 47% having low high-density lipoprotein (HDL) cholesterol. Two participants (6.67%) in the group aged 10 to <16 years met one of the definitions for insulin resistance (IR) using the Homeostatic Model Assessment (HOMA-IR) index. For every 1-year increase in age, HOMA-IR index increased by 0.04 (95% confidence interval: 0.01-0.08; p = 0.02). CONCLUSIONS: With increasing survival of CALWH into adulthood, lifetime exposure to ART, the frequency of MetS in this population may rise, increasing the lifetime risk for associated health problems. There is a need to study the natural history of MetS in CALWH to inform preventative and treatment interventions as needed.

Abacavir Drug Exposures in African Children Under 14 kg Using Pediatric Solid Fixed Dose Combinations According to World Health Organization Weight Bands.

BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: a sub-study of the ODYSSEY randomized controlled trial.

INTRODUCTION: Dolutegravir-based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre-conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub-study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development. METHODS: We conducted the sub-study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir-based ART (DTG) and non-dolutegravir-based standard-of-care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24-weekly in all ODYSSEY participants. Samples analysed in the sub-study were collected between September 2016 and October 2020. RESULTS: A total of 229 children aged ≥6 years were included in the sub-study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG-SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p<0.001), and this difference persisted to week ≥96 (2.7 ng/ml, 95% CI 1.7, 3.7; p<0.001). Mean RBC folate at ≥96 weeks was also higher in the DTG arm (difference 73 ng/ml, 95% CI 3, 143; p = 0.041). There was no difference in the treatment arms for vitamin B12 levels at ≥96 weeks or change in MCV through trial follow-up. CONCLUSIONS: Plasma and RBC folate levels were higher in children and adolescents receiving dolutegravir-based ART than on other ART regimens. Further studies are needed to clarify the mechanisms of these interactions and the clinical implications of increased blood folate levels.

Prevalence and factors associated with sexual and reproductive health literacy among youth living with HIV in Uganda: a cross-sectional study.

BACKGROUND: Adequate sexual and reproductive health literacy (SRHL) among young people has been linked to informed sexual behaviours. Studies on SRHL have largely been conducted among the general adolescent population. Little is known about youth aged 15-24 years living with human immunodeficiency virus (YLHIV). There is a possible lack of SRHL in this population, considering the high rate of teenage pregnancies and unprotected sex reported by YLHIV. This study aimed to assess the prevalence and associated personal and environmental factors for SRHL among YLHIV at a high-volume urban HIV Clinic in Uganda. METHODS: Through a cross-sectional survey, YLHIV receiving routine HIV care services at Baylor-Uganda HIV Clinic were interviewed using an adapted European Health Literacy Survey (HLS-EU). Using simple random sampling, eligible youth who received HIV care services between August and November 2019 were enrolled in the study. SRHL scores were computed using the HLS-EU index method; and individuals whose scores ranged from 34 to 50 were considered health literate. We used descriptive statistics to determine the prevalence. Potential associated personal and environmental factors (p<0.05) were identified by performing two-step inferential statistics, bivariate analysis and binary logistic regression. Odds ratios were calculated to estimate the likelihood of youth being health literate on sexual and reproductive health (SRH) issues in comparison with the reference categories, and 95% confidence intervals were determined to establish whether the relationships were statistically significant. RESULTS: Of the 267 YLHIV interviewed at Baylor-Uganda HIV Clinic, 167 (62.5%) were female with a mean age of 18.9 years (SD± 2.8), and the majority (242; 90.6%) were vertically infected with HIV. Only 52 (19.5%) were health literate on SRH issues. At the multivariate level, YLHIV who never had difficulty accessing SRH information were 0.391 times less likely to be health literate on SRH issues than their counterparts with challenges in accessing SRH information (Adjusted Odds Ratio [AOR] = 0.391, 95% CI =0.178 to 0.860; p= 0.019). YLHIV who did not find it easy to access SRH care service points were 2.929 times more likely to be literate in SRH than those who found it easy to access such services (Adjusted Odds Ratio [AOR] = 2.929, 95% CI =1.241 to 6.917; p=0.014). Additionally, YLHIV who did not listen to radio health talks were 2.406 times more likely to be health literate on SRH issues than those who did (AOR = 2.406, 95% CI =1.133 to 5.112; p=0.022). CONCLUSIONS: SRHL is an unmet need among YLHIV; only 19.5% were health literate on SRH issues. This could complicate the achievement of the UNAIDS sustainable development goal (SDG) of an HIV/AIDS-free generation by 2030 because low health literacy (HL) skills can affect the efficacy of almost all HIV disease prevention and health promotion efforts. Inaccessible SRH care service points and not listening to radio health talks were positively associated with SRHL, while having access to SRH information was negatively associated with SRHL.

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial.

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124-159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir. FUNDING: Penta Foundation, ViiV Healthcare, and UK Medical Research Council.

Biochemical Markers of Calcium and Bone Metabolism during and after Lactation in Ugandan Women with HIV on Universal Maternal Antiretroviral Therapy.

We reported accentuated lactational decreases in areal bone mineral density and only partial skeletal recovery after lactation in Ugandan women with HIV (WWH) initiated on tenofovir disoproxil fumarate-based antiretroviral therapy (TDF-based ART) during pregnancy compared to women without HIV (REF). WWH also had higher breast milk calcium in the first months of lactation. To investigate the mechanisms, we measured bone turnover markers (bone resorption: C-terminal telopeptide [CTX]; bone formation: procollagen type 1 N-terminal propeptide [P1NP], bone-specific and total alkaline phosphatase [BALP, TALP]), hormones (parathyroid hormone [PTH], intact fibroblast growth factor 23 [FGF23], 1,25-dihydroxyvitamin D [1,25(OH)2 D]), vitamin D status (25-hydroxyvitamin D [25OHD]), and indices of mineral metabolism and renal function. Blood and urine samples collected at 36 weeks of gestation, 14 and 26 weeks of lactation, and 3-6 months after lactation were analyzed. Mean 25OHD was >50 nmol/L throughout. Both groups experienced similar biochemical changes during pregnancy and lactation to women in other settings, but within these patterns, the two groups differed significantly. Notably, WWH had higher PTH (+31%) and lower 1,25(OH)2 D (-9%) and TmP/GFR (-9%) throughout, lower P1NP (-27%) and plasma phosphate (-10%) in pregnancy, higher CTX (+15%) and BALP (+19%), and lower eGFR (-4%) during and after lactation. P1NP/CTX ratio was lower in WWH than REF in pregnancy (-21%), less so in lactation (-15%), and similar after lactation. Additionally, WWH had lower plasma calcium (-5%), lower FGF23 (-16%) and fasting urinary calcium (-34%) at one or both lactation timepoints, and higher fasting urinary phosphate (+22%) at 26 weeks of lactation and after lactation. These differences resemble reported TDF effects, especially raised PTH, increased bone resorption, decreased bone formation, and decreased renal function, and may explain the observed differences in bone mineral density and breast milk calcium. Further studies are needed to determine whether HIV and TDF-based ART have long-term consequences for maternal bone health and offspring growth. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)]. Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Acceptability of a new 4-in-1 Abacavir/Lamivudine/Lopinavir/Ritonavir paediatric fixed-dose combination: the caregiver-child dyads' perspective.

Background: Worldwide, 1.7 million children younger than 15 years were living with HIV in 2021. Only 52% of them had access to antiretrovirals (ARVs). Lack of age-appropriate ARV formulations (i.e. easy to swallow for young infants, acceptable taste) remains the main obstacle to the access to ARVs. Therefore, a strawberry-flavoured Abacavir/Lamivudine/Lopinavir/Ritonavir (30/15/40/10 mg) fixed-dose combination of granules in a capsule (4-in-1) for children living with HIV weighing 3-25 kg was developed. Objective: We assessed caregivers' perceived acceptability of the 4-in-1 compared with previous paediatric ARV formulations and factors influencing acceptability. Methods: This exploratory qualitative case study embedded in a phase I/II, open-label, randomized cross-over pharmacokinetic, safety and acceptability study (LOLIPOP) was conducted in three sites in Uganda (May 2019-October 2020). Thirty-six children weighing between 3 and 19.9 kg participated in the main study. We purposively sampled caregiver-child dyads according to weight bands, and conducted 20 semi-structured interviews with caregivers and 5 with healthcare providers. We triangulated these results with a quantitative acceptability questionnaire. We analysed interviews inductively using NVivo12 adopting a thematic analysis approach and acceptability questionnaires descriptively to assess concordance between them. Results: All caregivers found the 4-in-1 formulation highly acceptable and easier to use than previous formulations (i.e. pellets/tables/syrup). Appealing taste, ease of administration, easy storage and children's acceptance contributed to acceptability despite structural challenges of food shortage and HIV stigma. Visible improvements in children's health and comprehensive and tailored healthcare provider support to overcome initial difficulties such as vomiting increased caregivers' acceptance. Concordant results from questionnaire- and interview-data confirmed high acceptability. Conclusion: Caregivers of children in all weight bands in this sample found the 4-in-1 granules highly acceptable compared with the pellets/tablets combination. Healthcare providers' support to caregivers allowed for individual tailoring of drug administration despite challenges such as food shortage. This enabled short-term adherence. These findings informed further practical recommendations. Registration: Clinical trial number: NCT03836833.

Milk Calcium and Phosphorus in Ugandan Women with HIV on Tenofovir-Based Antiretroviral Therapy.

BACKGROUND: Breastfed infants depend on human milk calcium and phosphorus for bone mineral accretion and growth. We reported greater mobilization of bone mineral and delayed skeletal recovery in lactating Ugandan women with HIV initiated on tenofovir-based antiretroviral therapy during pregnancy compared to HIV-uninfected counterparts in the Gumba Study. However, it is unknown if these disruptions in maternal bone metabolism affect milk mineral concentrations. RESEARCH AIM: To compare concentrations and patterns of change in milk calcium and phosphorus between lactating women with and without HIV. METHODS: A longitudinal observational study was conducted to compare milk mineral concentrations between women with HIV receiving tenofovir-based ART and uninfected women in the Gumba Study. Milk collected at 2, 14, 26, and 52 weeks lactation was analyzed for calcium and phosphorus. Sodium and potassium were measured at 2 and 14 weeks to detect sub-clinical mastitis. Differences in milk composition between 84 women with HIV and 81 uninfected women were investigated. RESULTS: Women with HIV had higher milk calcium than uninfected women at 14 weeks. The percent difference was +10.2% (SE = 3.0, p = .008) and there was a tendency to greater values at 2 and 26 weeks. Milk calcium decreased in both groups during lactation (p ≤ .001) but was more pronounced in women with HIV. The magnitude of change within individuals in the 1st year of lactation from 2 to 52 weeks was -28.3% (SE 3.9) versus -16.5% (SE 3.5), p for interaction = .05. Differences in milk phosphorus and calcium-to-phosphorus ratio were smaller and mostly not significant. CONCLUSIONS: Participants with HIV on tenofovir-based antiretroviral therapy had altered milk mineral composition. Studies are needed to investigate mechanisms and health implications for the woman and infant.

Risk factors and prognostic significance of platelet count abnormalities in children with HIV infection on antiretroviral therapy.

OBJECTIVES: To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH). DESIGN: A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004-2014. METHODS: Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with selected clinical variables. We constructed Kaplan-Meier curves and a Cox proportional hazards model to evaluate the impact of T/T on survival. RESULTS: Two thousand, one hundred and nine children were sampled. The incidence density of thrombocytopenia was 1 per 57.9 (95% confidence interval [CI] 50.3-66.8) CWH-years. Thrombocytopenia was higher in children with WHO Stage III/IV, lower in children on zidovudine, and had no association with use of lamivudine or nevirapine, CD4 + suppression, age, and nutrition status. Thrombocytopenia was independently associated with 2.2-fold higher mortality (95% CI 1.62-3.08). The incidence density of thrombocytosis was 1 per 11.4 (95% CI 10.7-12.1) CWH-years. Thrombocytosis was associated with higher CD4 + cell count, younger age, and use of lamivudine or nevirapine, and did not impact survival. CONCLUSIONS: Platelet count is a clinically valuable biomarker of HIV clinical progression and mortality. Laboratory studies are necessary to elucidate the mechanisms of T/T.

Optimal Timing of Antiretroviral Therapy Initiation in Children and Adolescents With Human Immunodeficiency Virus-Associated Pulmonary Tuberculosis.

BACKGROUND: There is insufficient evidence in children and adolescents with human immunodeficiency virus (CAHIV) to guide the timing of antiretroviral treatment (ART) initiation after starting treatment for pulmonary tuberculosis (pTB). To address this knowledge gap, we evaluated the risk of mortality associated with timing of ART initiation in ART-naive CAHIV treated for pTB. METHODS: Data were extracted from electronic medical records of ART-naive patients, aged 0-19 years, who were treated for HIV-associated pTB at Baylor Centers of Excellence in Botswana, Eswatini, Malawi, Lesotho, Tanzania, or Uganda between 2013 and 2020. Data were analyzed against a primary outcome of all-cause mortality with unadjusted Kaplan-Meier curves and Cox proportional hazard models. RESULTS: The study population included 774 CAHIV with variable intervals to ART initiation after starting TB treatment: <2 weeks (n = 266), 2 weeks to 2 months (n = 398), >2 months (n = 66), and no ART initiated (n = 44). Adjusted Cox proportional hazards models demonstrated increased mortality 1 year from TB treatment initiation in children never starting ART (adjusted HR [aHR]: 2.67; 95% CI: 1.03, 6.94) versus children initiating ART between 2 weeks and 2 months from TB treatment initiation. Mortality risk did not differ for the <2-weeks group (aHR: 1.02; 95% CI: .55, 1.89) versus the group initiating ART between 2 weeks and 2 months. CONCLUSIONS: This retrospective study demonstrated no increase in mortality among CAHIV initiating ART <2 weeks from TB treatment initiation. Given the broad health benefits of ART, this evidence supports the recent WHO recommendation for CAHIV to initiate ART within 2 weeks of initiating TB treatment.

Risk factors and prognostic significance of anemia in children with HIV infection on antiretroviral therapy.

OBJECTIVES: To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH). DESIGN: Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014. METHODS: Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival. RESULTS: Two thousand, one hundred and thirty-seven children were sampled. The incidence density of anemia was 1 per 6.6 CLWH-years. Anemia was moderate in 31.8% and severe in 17.3% of anemia cases, which had 10-year mortality hazards of 3.4 and 4.5, respectively. Microcytic anemia (36% cases) was associated with 2.3-fold hazard of 10-year mortality, and with malnutrition and CD4 + suppression. Normocytic anemia (50.5% cases) was associated with 2.6-fold hazards of 10-year mortality, and with more severe malnutrition, CD4 + suppression, and WHO stage, but inversely associated with lamivudine and nevirapine therapy. Macrocytic anemia (13.5% cases) was neither associated with higher 10-year mortality nor with severe malnutrition or CD4 + suppression but was associated with WHO stage II/III and negatively associated with lamivudine therapy. CONCLUSION: This large multicountry study of CLWH found a high incidence density of anemia. Higher severity, normocytic and microcytic types of anemia were independently associated with long-term mortality. Laboratory studies are needed to decipher the mechanisms of anemia and how it impacts mortality in CLWH.

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial.

BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127. FINDINGS: Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir. INTERPRETATION: Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial.

BACKGROUND: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0-24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014-002632-14), and the ISRCTN registry (ISRCTN91737921). FINDINGS: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4-17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08-2·11) for Ctrough, 1·23 (0·99-1·53) for AUC0-24 h, and 0·94 (0·76-1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30-40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. INTERPRETATION: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB. FUNDING: Penta Foundation, ViiV Healthcare, UK Medical Research Council.

Dolutegravir dosing for children with HIV weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority ODYSSEY trial.

BACKGROUND: Dolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial. METHODS: We did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (Ctrough). Pharmacokinetic targets were based on adult dolutegravir Ctrough and the 90% effective concentration (EC90; ie, 0·32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies. FINDINGS: Between May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean Ctrough in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0·53-0·87 mg/L, comparable to the adult geometric mean Ctrough of 0·83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. Ctrough below EC90 was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean Ctrough of 0·44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film-coated tablets. Exposures were 1·7-2·0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir. INTERPRETATION: Weight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council.