Efficacy, safety and pharmacokinetics of dihydroartemisinin-piperaquine for perennial malaria chemoprevention in infants during routine health facility visits

Banda, Clifford George

Efficacy, safety and pharmacokinetics of dihydroartemisinin-piperaquine for perennial malaria chemoprevention in infants during routine health facility visits

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Medicine

Faculty

Faculty of Health Sciences

Abstract

Monthly dihydroartemisinin-piperaquine for perennial malaria chemoprevention (PMC) has been shown to offer superior malaria prevention compared to three-monthly dosing. However, aligning its administration with routine health facility visits has the potential to enhance adherence. Additionally, rapid physiological changes in infancy may influence drug exposure. We hypothesised that increasing age in infancy would result in a reduction in piperaquine's exposure due to age-related increases in apparent clearance (CL/F) and volume of distribution (Vd). Consequently, this could impact the protective efficacy of dihydroartemisinin-piperaquine for malaria prevention in infants. Methods: We assessed the efficacy and safety of dihydroartemisinin-piperaquine and piperaquine's exposure profile in Malawian infants receiving PMC aligned with routine health facility visits at 10 weeks, 14 weeks, 6 months, and 9 months of age, within a setting where the RTS,S/AS01 malaria vaccine became part of the standard of care. In a randomised, single- blind, placebo-controlled trial, infants were allocated to receive a three-day course of dihydroartemisinin-piperaquine (n = 110) or placebo (n = 110) starting at 10 weeks of age. Malaria incidence and adverse events were tracked until 12 months of age. In the dihydroartemisinin-piperaquine arm, piperaquine capillary blood samples were collected pre- dose and on days 3, 7, 14, and 28 following the 10-week and 6-month or 14-week and 9- month treatment courses. Nonlinear mixed-effects modelling was used to derive piperaquine's pharmacokinetic parameters. Geometric means (GM) and 90% confidence intervals (CI) were compared between 10 weeks and 14 weeks, 6 months or 9 months. Results: Malaria incidence was 1 versus 4 cases per 1,000 person-years (0.001 and 0.004 episodes per person-year) in the DP and placebo arms, respectively, corresponding to a non- significant 77% reduction with dihydroartemisinin-piperaquine (adjusted incidence rate ratio 0.23; 95% CI: 0.03 - 2.11; p = 0.196). All cases occurred within the first seven months, when nearly 50% of infants had received at least one malaria vaccine dose. Additionally, DP was associated with a 31% reduction in the prevalence of moderate–to–severe anaemia (18.3% and 12.5% in the DP and placebo arms, respectively; adjusted risk ratio 0.69, 95% CI 0.52– 0.93, p = 0.013). The frequency of adverse events was similar between groups (149 versus 134). At 9 months versus 10 weeks of age, piperaquine exposure was 58% lower (GM ratio 0.42; 90% CI 0.36-0.49) with corresponding CL/F and Vd that were 2.6 (GM ratio 2.61; 90% CI 2.52 – 2.70) and 3.2-fold (GM ratio 3.24; 90% CI 3.01–3.49) higher, respectively. Conclusion: Dihydroartemisinin-piperaquine administration during routine visits, in the context of ongoing malaria vaccination, was safe and showed a non-significant trend towards reduced malaria incidence in early infancy. However, age-related declines in piperaquine exposure indicate the need for dosage regimen optimisation of this promising antimalarial to ensure effective malaria chemoprevention in older infants.

Keywords

volume of distribution

dihydroartemisinin-piperaquine

Reference:

Collections

PhD / Doctoral

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