Abstract
BackgroundAnti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure.MethodsChildren were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored.ResultsThe incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39–66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6–49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54–76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89–99 %, P < 0.001).ConclusionsThe protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.Trial Registration: Current Controlled Trials Identifier NCT00948896Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0908-8) contains supplementary material, which is available to authorized users.
Highlights
Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure
Baseline characteristics independently associated with malaria risk in this setting, including location of residence, maternal age, housing construction type, and primary caregiver education [16], were similar between the two groups (Table 1)
In multivariate analysis controlling for factors associated with malaria risk in this setting, the results were nearly identical (Table 3). These findings suggest that the protective efficacy of DHA/PQ chemoprevention in young children is directly related to adequate drug exposure, and that in children with the highest drug exposure, monthly DHA/PQ is nearly 100 % protective against malaria
Summary
Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure. Despite widespread use of insecticide-treated bednets and case management using artemisinin-based combination therapy (ACT), the incidence of malaria among children continues to be very high in many parts of Africa [1, 2]. Malaria control centers on vector management and effective use of anti-malarial drugs [3]. ACT is the standard therapy for uncomplicated falciparum malaria in most areas, due to widespread resistance to chloroquine and sulfadoxine-pyrimethamine (SP) [5]. In Africa, IPT is standard practice during pregnancy, with doses of sulfadoxinepyrimethamine (SP) each trimester in endemic areas, this strategy is seriously limited by resistance to SP [7]. IPT is recommended in children in some settings (with SP or SP + AQ), but only when resistance to SP is uncommon, which limits this practice principally to the Sahel subregion [8, 9]
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