Determining the degree of infant exposure to primaquine through colostrum and transitional breast milk – opening the gateway to early postpartum radical cure to curb maternal Plasmodium vivax relapse

The malaria parasite Plasmodium vivax forms dormant liver-stage parasites (hypnozoites) that can reactivate to cause recurrent episodes of febrile illness (relapses) after the initial infection. Hypnozoites require radical cure through treatment with primaquine. In endemic settings, women are at high risk of relapse within weeks following birth, yet they are excluded from primaquine as the World Health Organization (WHO) cautions against maternal administration during pregnancy, and in the first six months postpartum, to prevent iatrogenic haemolysis from in utero exposure and via breast milk in a glucose-6-phosphate dehydrogenase (G6PD)-deficient fetus/infant.Reassuringly, infant exposure to primaquine through transfer in mature breast milk was recently found to be equivalent to 0.021 mg/kg/week, i.e., only a fraction of what is given to patients with severe G6PD deficiency (0.75mg/kg/week). The WHO have stated a research priority to assess transfer of primaquine through colostrum and transitional breast milk, i.e., prior to closure of alveolar tight junctions 2 weeks after birth, to determine the degree of neonatal exposure from early maternal primaquine treatment. Minimal transfer raises the possibility that maternal primaquine treatment could be initiated pragmatically before hospital discharge to prevent relapse. Such an approach would facilitate maximizing uptake of the intervention and benefit for maternal health outcomes and malaria control.

Women who have recently delivered at the Alexishafen labour ward will be given an explanation of the study (approached >24 hours post-delivery). Those expressing interest in participation will be screened to determine eligibility for recruitment.

After collection of baseline demographic and clinical details, recruited women will be randomised 2:1 into intervention (0.5 mg/kg primaquine for 14 days) or control (no intervention) groups. Women enrolled into the intervention group will receive daily doses of 0.5 mg/kg primaquine for 14 days, given as directly observed treatment. All doses will be given with water and food, to prevent gastrointestinal discomfort. Timed breast milk (fore- and hind-milk), maternal venous plasma (2 mL), and infant dried blood spot (50μL) pharmacokinetic samples will be collected on days 0, 6, 13, and 15, complemented by measurement of safety parameters haemoglobin, haematocrit, methaemoglobin, and hepatorenal function (also on days 20 and 28). At each scheduled postpartum clinic day visit (day 0, 6, 13, 15 and 28) each mother and infant will be weighed, and a symptom questionnaire (reflecting the mother’s observations of her child) will be completed. The mother will also be asked to report the number of feeds given to the infant during the previous 24-hours, whether they fed on one or both 10 breasts, and her estimation of how long each feed lasted. Breast milk samples will be collected by the mother by manual expression, with a crematocrit being conducted immediately after collection for fat content. Each maternal venous sample will be collected into lithium heparin anticoagulant, which will be promptly centrifuged with the plasma separated. Heel prick sampling will be undertaken to collect 100 μL blood from each infant for preparation of dried blood spots for pharmacokinetic assay (50 μL; Whatman Protein 903 filter paper cards) and 50 μL for determining haemoglobin concentration and assessment of hepatorenal function. Methaemoglobin readings will be conducted in both mother and neonate by pulse oximetry (with SpMet% function), and a manual haematocrit prepared, as a continued safety assessment for oxidative drug pressure and associated cyanosis. All drug assay samples will be stored at -20C until time of shipment to Perth, for pharmacokinetic assay and modelling.

Drug-based Strategies
P. vivax
Vulnerable Populations

Nov 2022 — Oct 2023

$15,000

Papua New Guinea

Australian Centre for Research Excellence in Malaria Elimination (ACREME)