Abstract
BackgroundA single low dose (0.25 mg/kg) of primaquine is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness to mosquitoes has not been quantified.MethodsIn this randomised, double-blind, placebo-controlled trial, 360 asymptomatic parasitaemic children aged 2-15 years were enrolled and assigned to receive: artemether-lumefantrine (AL) and a dose of placebo; AL and a 0.25 mg/kg primaquine dose; or AL and a 0.40 mg/kg primaquine dose. On days 0, 2, 3, 7, 10 and 14, gametocytes were detected and quantified by microscopy, Pfs25 mRNA quantitative nucleic acid sequence based amplification (QT-NASBA), and quantitative reverse-transcriptase PCR (qRT-PCR). For a subset of participants, pre- and post-treatment infectiousness was assessed by mosquito feeding assays on days -1, 3, 7, 10 and 14.ResultsBoth primaquine arms had lower gametocyte prevalences after day 3 compared to the placebo arm, regardless of gametocyte detection method. The mean (95 % confidence interval) number of days to gametocyte clearance in children with patent gametocytes on day 0 (N = 150) was 19.7 (14.6 – 24.8), 7.7 (6.3 – 9.1) and 8.2 (6.7 – 9.6) for the AL-placebo, the 0.25 mg/kg primaquine dose and the 0.40 mg/kg primaquine dose arms, respectively. While 38.0 % (30/79) of selected gametocytaemic individuals were infectious before treatment, only 1/251 participant, from the AL-placebo group, infected mosquitoes after treatment.ConclusionsWe observed similar gametocyte clearance rates after 0.25 and 0.40 mg/kg primaquine doses. Infectivity to mosquitoes after AL was very low and absent in primaquine arms.ClinicalTrials.gov RegistrationNCT01935882Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0581-y) contains supplementary material, which is available to authorized users.
Highlights
A single low dose (0.25 mg/kg) of primaquine is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness to mosquitoes has not been quantified
Gametocyte prevalence determined by microscopy was not significantly different between study arms at enrolment, during Study Phase A it was higher in the 0.25 mg/kg primaquine arm (32.0 %) compared to the AL-placebo and the 0.40 mg/kg primaquine arms (17.7 and 20.5 %, respectively)
We showed that individuals receiving a 0.25 mg/kg primaquine dose in combination with AL had similar gametocyte clearance time compared to children in the 0.40 mg/kg primaquine arm
Summary
A single low dose (0.25 mg/kg) of primaquine is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness to mosquitoes has not been quantified. Artemisinin-based combination therapy (ACT) is universally adopted as first-line treatment for clinical falciparum malaria [2], effectively clears asexual parasites and immature gametocytes, and is associated with lower post-treatment infectivity based on membrane feeding assays compared to other antimalarials [3]. The World Health Organization recommends a single low dose (0.25 mg/kg) as a gametocytocide in combination with ACT for Plasmodium falciparum malaria in elimination and artemisinin resistance containment scenarios [8]. The effect of the 0.25 mg/kg dose in clearing gametocytes or preventing transmission after currently used ACT regimens has not been formally assessed. Only mosquito feeding assays can truly determine the lowest efficacious dose of primaquine for preventing transmission [12]
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