Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.

BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m-<1 y, n = 12), 582.8 (1-5 y, n = 126), 871.1 (6-9 y, n = 80), and 931.0 (10-11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8-5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.

PARIST study protocol: a phase I/II randomised, controlled clinical trial to assess the feasibility, safety and effectiveness of paracetamol in resolving acute kidney injury in children with severe malaria.

BACKGROUND: Acute kidney injury (AKI) has in the past been considered a rare complication of malaria in children living in high-transmission settings. More recently, however, a growing number of paediatric case series of AKI in severe malaria studies in African children have been published (Artesunate vs Quinine in the Treatment of Severe P. falciparum Malaria in African children and Fluids Expansion as Supportive Therapy trials). The Paracetamol for Acute Renal Injury in Severe Malaria Trial (PARIST) therefore, aims to assess feasibility, safety and determine the effective dose of paracetamol, which attenuates nephrotoxicity of haemoproteins, red-cell free haemoglobin and myoglobin in children with haemoglobinuric severe malaria. METHODS: PARIST is a phase I/II unblinded randomised controlled trial of 40 children aged >6 months and <12 years admitted with confirmed haemoglobinuric severe malaria (blackwater fever), a positive blood smear for P. falciparum malaria and either serum creatinine (Cr) increase by ≥0.3 mg/dL within 48 hours or to ≥1.5 times baseline and elevated blood urea nitrogen (BUN) >20 mg/dL. Children will be randomly allocated on a 1:1 basis to paracetamol intervention dose arm (20 mg/kg orally 6-hourly for 48 hours) or to a control arm to receive standard of care for temperature control (ie, tepid sponging for 30 min if fever persists give rescue treatment). Primary outcome is renal recovery at 48 hours as indicated by stoppage of progression and decrease of Cr level below baseline, BUN (<20 mg/dL). Data analysis will be on the intention-to-treat principle and a per-protocol basis.Results from this phase I/II clinical trial will provide preliminary effectiveness data of this highly potential treatment for AKI in paediatric malaria (in particular for haemoglobinuric severe malaria) for a larger phase III trial. ETHICS AND DISSEMINATION: Ethical and regulatory approvals have been granted by the Mbale Hospital Institutional Ethics Review Committee (MRRH-REC OUT 002/2019), Uganda National Council of Science and Technology (UNCST-HS965ES) and the National drug Authority (NDA-CTC 0166/2021). We will be disseminating results through journals, conferences and policy briefs to policy makers and primary care providers. TRIAL REGISTRATION NUMBER: ISRCTN84974248.

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. METHODS: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. FINDINGS: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97). INTERPRETATION: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. FUNDING: UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.

Perceived roles, benefits and barriers of virtual global health partnership initiatives: a cross-sectional exploratory study.

BACKGROUND: Virtual global health partnership initiatives (VGHPIs) evolved rapidly during the COVID-19 pandemic to ensure partnership continuity. However the current landscape for VGHPI use and preference is unknown. This study aimed to increase understanding of GH partners' perspectives on VGHPIs. METHODS: From 15 October to 30 November 2020, An online, international survey was conducted using snowball sampling to document pandemic-related changes in partnership activities, preferences for VGHPIs, and perceived acceptability and barriers. The survey underwent iterative development within a diverse author group, representing academic and clinical institutions, and the non-profit sector. Participants from their professional global health networks were invited, including focal points for global health partnerships while excluding trainees and respondents from the European Economic Area. Analysis stratified responses by country income classification and partnership type. Authors used descriptive statistics to characterize responses, defining statistical significance as α = 0.05. RESULTS: A total of 128 respondents described 219 partnerships. 152/219 (69%) partnerships were transnational, 157/219 (72%) were of > 5 years duration, and 127/219 (60%) included bidirectional site visits. High-income country (HIC) partners sent significantly more learners to low- to middle-income country (LMIC) partner sites (p < 0.01). Participants commented on pandemic-related disruptions affecting 217/219 (99%) partnerships; 195/217 (90%) were disruption to activities; 122/217 (56%) to communication; 73/217 (34%) to access to professional support; and 72/217 (33%) to funding. Respondents indicated that VGHPIs would be important to 206/219 (94%) of their partnerships moving forward. There were overall differences in resource availability, technological capacity, and VGHPI preferences between LMIC and HIC respondents, with a statistically significant difference in VGHPI acceptability (p < 0.001). There was no significant difference between groups regarding VGHPIs' perceived barriers. CONCLUSIONS: The pandemic disrupted essential partnership elements, compounding differences between LMIC and HIC partners in their resources and preferences for partnership activities. VGHPIs have the potential to bridge new and existing gaps and maximize gains, bi-directionality, and equity in partnerships during and after COVID-19.

Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda.

Background: In Uganda to date, there are neither established registries nor descriptions of facility-based sickle cell disease (SCD) patient characteristics beyond the central region. Here, we summarize data on the baseline clinical characteristics and routine care available to patients at four clinics in Eastern Uganda as a prelude to a clinical trial. Methods: Between February and August 2018, we conducted a cross-sectional survey of patients attending four SCD clinics in Mbale, Soroti, Atutur and Ngora, all in Eastern Uganda, the planned sites for an upcoming clinical trial (H-PRIME:  ISRCTN15724013). Data on socio-demographic characteristics, diagnostic methods, clinic schedules, the use of prophylactic and therapeutic drugs, clinical complications and patient understanding of SCD were collected using a structured questionnaire. Results: Data were collected on 1829 patients. Their ages ranged from 0 to 64 years with a median (IQR) of 6 (3-11) years. 49.1% of participants were male. The majority (1151; 62.9%) reported a positive family history for SCD. Approximately half knew that SCD is inherited from both parents but a substantial proportion did not know how SCD is transmitted and small numbers believed that it is acquired by either transfusion or from other people. Only 118/1819 (6.5%) participants had heard about or were using hydroxyurea while 356/1794 (19.8%) reported stigmatization. Participants reported a median of three (IQR 1-4) hospital admissions during the preceding 12 months; 80.8% had been admitted at least once, while 14.2% had been admitted more than five times. Pain was the most common symptom, while 83.9% of those admitted had received at least one blood transfusion. Conclusion: The majority of patients attending SCD clinics in Eastern Uganda are children and few are currently being treated with hydroxyurea. The data collected through this facility-based survey will provide background data that will be useful in planning for the H-PRIME trial.