Single low dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission after artemether-lumefantrine in children with asymptomatic infection: a randomised, double-blind, placebo-controlled trial

Abstract

Background: 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.

Methods: In 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.

Results: Both 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.

Conclusions: We 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 registration: NCT01935882.

Figures

Fig. 1

Clinical trial profile. a Study Phase where the presence of asexual parasites (1,000 - 200,000 parasites/μL) at screening was an inclusion criterion (initial 143 and final 67 participants). b Study Phase where children with patent gametocytes, regardless of their asexual parasite count, at screening were eligible (150 participants). Participants were considered to have a complete follow-up, if they had a total of seven follow-up visits (days 0, 1, 2, 3, 7, 10, 14). AL artemether-lumefantrine, PQ primaquine

Fig. 2

Gametocyte prevalences (a) and densities (b) measured by qRT-PCR in children with patent gametocytes on day 0. 95 % confidence intervals are presented in (a). Samples were considered to be gametocyte negative if assigned levels were lower than 0.02 gametocytes per μL. AL = artemether-lumefantrine; 0.25 mg/kg = 0.25 mg/kg primaquine arm; 0.40 mg/kg = 0.40 mg/kg primaquine arm

Fig. 3

Changes in haemoglobin levels from baseline values. Means and 95 % confidence intervals are presented. Haemoglobin levels determined by Hemocue photometer on day 0 were used as baseline measurement; whenever haemoglobin concentrations on day 0 were not available or were only quantified by full blood count analysis on venous samples, Hemocue results at screening were used: the median (IQR) interval between screening and the day 0 of follow-up was 2 (1 – 2) days. AL artemether-lumefantrine, PQ primaquine, Hb haemoglobin, IQR interquartile range