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Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. Methods: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. Results: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. Conclusions: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. Trial registration: NCT, NCT02259127, registered 7th October 2014; EUDRACT, 2014–002632-14, registered 18th June 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES); ISRCTN, ISRCTN91737921, registered 4th October 2014. [ABSTRACT FROM AUTHOR]

Background: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg., Methods: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUC tau ) and concentration at the end of the dosing interval (C tau ) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320., Findings: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUC tau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); C tau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48., Interpretation: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg., Funding: Gilead Sciences., Competing Interests: Declaration of interests CAR received grant support to their institution from Gilead, GSK, and ViiV Healthcare during the study and outside the submitted work; and support for meeting travel from Gilead outside the submitted work. RS reports grant support to their institution from Gilead, GSK, Merck, and Penta outside the submitted work; and support for meeting travel from Gilead outside the submitted work. CKC and PK report grant support to their institution from Gilead for the conduct of this study. MK, RL, JTH, VAV, and KK are employed by Gilead and hold stocks in Gilead. MFC reports grant support to their institution from Gilead for the conduct of this study. AHG reports clinical trial agreement to their institution from Gilead for the conduct of this study; and is Chair of the Data Safety and Monitoring Board for a study sponsored by the National Institute of Dental and Craniofacial Research. All other authors declare no competing interests., (© 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART)., Methods: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables., Results: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF., Conclusions: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Intensified tuberculosis (TB) case finding and isoniazid preventive therapy (IPT) are strongly recommended for children who are HIV infected. Data are needed to assess the feasibility of the WHO 2011 intensified tuberculosis case finding/IPT clinical algorithm., Methods: Children who are HIV infected and attending Nsambya Home Care at Nsambya Hospital, Uganda, were screened for TB following WHO recommendations. IPT was given for 6 months after excluding TB. Factors associated with time to IPT initiation were investigated by multivariate Cox proportional hazard regression. Health care workers were interviewed on reasons for delay in IPT initiation., Results: Among the 899 (49% male) children with HIV, 529 (58.8%) were screened for TB from January 2011 to February 2013. Children with active TB were 36/529 (6.8%), 24 (4.5%) were lost to follow-ups and 280 (52.9%) started IPT, 86/280 (30.7%) within 3 months of TB screening and 194/280 (69.3%) thereafter. Among the 529 children screened for TB, longer time to IPT initiation was independently associated with cough at TB screening (hazard ratio 0.62, P = 0.02, 95% confidence interval: 0.41 to 0.94). Four children (1% of those starting treatments) interrupted IPT because of a 5-fold increase in liver function measurements. In the survey, Health care workers reported poor adherence to antiretroviral therapy, poor attendance to periodic HIV follow-ups, and pill burden as the 3 main reasons to delay IPT., Conclusion: In resource-constrained settings, considerable delays in IPT initiation may occur, particularly in children with HIV who are presenting with cough at TB screening. The good safety profile of isoniazid in antiretroviral-therapy-experienced children provides further support to IPT implementation in this population.

After witnessing an episode of poor injection safety in large numbers of children in a rural under-resourced hospital in Uganda, we briefly review our own experience and that of others in investigating HIV infection in children considered unlikely to be through commonly identified routes such as vertical transmission, sexual abuse or blood transfusion. In the majority of cases, parents are HIV uninfected. The cumulative experience suggests that the problem is real, but with relatively low frequency. Vertical transmission is the major route for HIV to children. However, factors such as poor injection safety, undocumented surrogate breast feeding, an HIV-infected adult feeding premasticated food to a weaning toddler, poor hygienic practice in the home and using unsterilised equipment for minor surgical or traditional procedures are of cumulative concern.