Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria

Abstract

Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4 g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P < 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P < 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivax and multidrug-resistant P. falciparum malaria are endemic.

Fig 1

Kaplan-Meier survival curves for malaria-preventive efficacy in the three groups. Dihydroartemisinin-piperaquine treatment doses (over 3 days) monthly (DPm) or every 2 months (DPalt) or an identical placebo were given with or without 6.4 g of fat for each dose administered.

Fig 2

Plasma piperaquine trough concentrations and incidences of malaria infections. Graphs show individual piperaquine trough concentrations (open circles) with median values and interquartile range (red bars) for DPm (A) and DPalt (B). The solid black horizontal line indicates the piperaquine cutoff concentration of 31 ng/ml above which there were no malaria infections. Five data points in the DPm group (167 ng/ml at week 12, 204 ng/ml at week 24, 167 ng/ml and 180 ng/ml at week 32, 251 ng/ml at week 36) are outside the axis limits. (C and D) Individual piperaquine trough concentrations for subjects that developed a new malaria infection (open circles) are shown on the primary y axis, and the total number of malaria infections for that period (open bars) are shown on the secondary y axis.

Fig 3

Cumulative fraction of total malaria infections versus piperaquine trough concentrations. The solid red line indicates the trough plasma piperaquine cut-off concentration of 31 ng/ml, above which there were no malaria infections.