Nonrandomized controlled trial of artesunate plus sulfadoxine-pyrimethamine with or without primaquine for preventing posttreatment circulation of Plasmodium falciparum gametocytes

Abstract

Artemisinin combination therapies eliminate immature Plasmodium falciparum gametocytes but not mature gametocytes, which may persist for up to 1 month posttreatment. A single dose of primaquine, which is inexpensive and effective against mature gametocytes, could be added to further reduce the potential for posttreatment parasite transmission. Currently, we have few data regarding the effectiveness or safety of doing so. We collected data from 21 therapeutic efficacy trials of the National Antimalarial Drug Resistance Monitoring System of India conducted during 2009 to 2010, wherein 9 sites used single-dose primaquine (0.75 mg/kg of body weight) administered on day 2 along with artesunate plus sulfadoxine-pyrimethamine (AS+SP) while 12 did not. We estimated the effect of primaquine on posttreatment gametocyte clearance and the total number of gametocyte-weeks as determined by microscopy. We compared the median area under the curve for gametocyte density and reported adverse events. One thousand three hundred thirty-five patients completed the antimalarial drug treatment. Adjusting for region, primaquine increased the rate of gametocyte clearance (hazard ratio, 1.9; 95% confidence interval [CI], 1.1 to 3.3), prevented 45% (95% CI, 19 to 62) of posttreatment gametocyte-weeks, and decreased the area under the gametocyte density curve over the 28-day follow-up compared to AS+SP alone (P value = 0.01). The results were robust to other adjustment sets, and the estimated effect of primaquine increased during sensitivity analysis on the measurement of exposure time. No serious adverse events were detected. In conclusion, the addition of primaquine to AS+SP was effective in reducing the posttreatment presence of P. falciparum gametocytes. Primaquine was well tolerated and could be administered along with an artemisinin combination therapy as the first-line therapy.

Fig 1

Flowchart of patients eligible for treatment with primaquine from the National Antimalarial Drug Resistance Monitoring System, India, 2009 to 2010. QC, quality control; RDT, rapid diagnostic test; D0, day zero.

Fig 2

Prevalence of gametocytemia by treatment arm at each study visit among patients from the National Antimalarial Drug Resistance Monitoring System, India, 2009 to 2010. PQ, primaquine; arrow, administration of primaquine.

Fig 3

Clearance of gametocytes by treatment arm among patients with pretreatment gametocytemia from the National Antimalarial Drug Resistance Monitoring System, India, 2009 to 2010. PQ, primaquine.

Fig 4

Area under the curve for the mean gametocyte density by treatment arm at each study visit among patients from the National Antimalarial Drug Resistance Monitoring System, India, 2009 to 2010. PQ, primaquine; arrow, administration of primaquine.