Dihydroartemisinin-piperaquine administered at monthly intervals, but not that dosed once a school term, is a remarkably effective measure for the prevention of incidence of malaria, prevalence of parasitemia, and prevalence of anemia in schoolchildren living in a high-transmission setting.
A lack of capacity to diagnose tuberculosis (TB) in children at peripheral health facilities and limited contact screening and management contribute to low case finding in TB-endemic settings. O B J E C T I V E : To evaluate the implementation of a pilot project that strengthened diagnosis, treatment and prevention of child TB at peripheral health facilities in Uganda. M E T H O D S : In June 2015, health care workers at peripheral health facilities were trained to diagnose and treat child TB. Community health care workers were trained to screen household TB contacts. Beforeand-after analysis as well as comparisons with nonintervention districts were used to evaluate impact on caseload and treatment outcomes.
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.
Summary Background Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. Methods We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial ( NCT02259127 ) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (C trough ) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. Findings Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) C trough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM C trough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM C trough was 0·39 mg/L (48%), which was 54% lower than the GM C trough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM C trough was 0·46 mg/L (63%), which was 45% lower than the GM C trough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, C trough was close to the adult reference (with similar estimates on the two formulation...
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