Abstract
BackgroundAsymptomatic low-density gametocyte carriers represent the majority of malaria-infected individuals. However, the impact of recommended treatment with single low dose of primaquine and an artemisinin-based combination therapy to reduce transmission in this group is unknown. MethodsThis was a four-arm, open label, randomized controlled trial comparing the effect of dihydroartemisinin-piperaquine (DHAP) alone or combined with single dose of primaquine (PQ) at 0.20mg/kg, 0.40mg/kg, or 0.75mg/kg on Plasmodium falciparum gametocytaemia, infectiousness to mosquitoes and hemoglobin change in asymptomatic, malaria-infected, glucose-6-phosphate dehydrogenase (G6PD) normal individuals. Randomization was done using a computer-generated sequence of uneven block sizes with codes concealed in sequentially numbered opaque envelopes. The primary endpoint was the prevalence of P. falciparum gametocytemia at day 7 of follow-up determined by quantitative nucleic acid sequence based assay and analysis was by intention to treat. The trial has been concluded (registration number: NCT01838902; https://clinicaltrials.gov/ct2/show/NCT01838902). ResultsA total of 694 asymptomatic, malaria-infected individuals were enrolled. Gametocyte prevalence at day 7 was 37.0% (54/146; 95% CI 29.2–45.4), 19.0% (27/142; 95% CI 12.9–26.4), 17.2% (25/145; 95% CI 11.0–23.5) and 10.6% (15/141; 95% CI 6.1–16.9) in the DHAP alone, 0.20mg/kg, 0.40mg/kg, and 0.75mg/kg PQ arms, respectively. The main adverse events reported include headache (130/471, 27.6%), cough (73/471, 15.5%), history of fever (61/471, 13.0%) and abdominal pain (57/471, 12.1%). There were five serious adverse events however, none was related to the interventions. InterpretationA single course of PQ significantly reduces gametocyte carriage in malaria-infected asymptomatic, G6PD-normal individuals without increasing the risk of clinical anemia. The limited number of successful mosquito infections suggests that post-treatment transmission potential in this asymptomatic population is low.
Highlights
Asymptomatic, low-density infections constitute over 60% of the human reservoir of malaria parasite (Laishram et al, 2012) and this combined with long periods of carriage without progression to clinical disease (Bereczky et al, 2004), even in low transmission settings, suggests that asymptomatically infected individuals may contribute substantially to malaria transmission (Alves et al, 2005; Mwesigwa et al, 2015)
The impact of recommended treatment with single low dose of primaquine and an artemisininbased combination therapy to reduce transmission in this group is unknown. This was a four-arm, open label, randomized controlled trial comparing the effect of dihydroartemisinin-piperaquine (DHAP) alone or combined with single dose of primaquine (PQ) at 0.20 mg/kg, 0.40 mg/kg, or 0.75 mg/kg on Plasmodium falciparum gametocytaemia, infectiousness to mosquitoes and hemoglobin change in asymptomatic, malaria-infected, glucose-6-phosphate dehydrogenase (G6PD) normal individuals
Our study is the first to determine the effect of single low dose PQ on gametocytemia and infectivity to mosquitoes after treatment with a currently available artemisinin-based combination therapy (ACT) in asymptomatic, low-density infections
Summary
Asymptomatic, low-density infections constitute over 60% of the human reservoir of malaria parasite (Laishram et al, 2012) and this combined with long periods of carriage without progression to clinical disease (Bereczky et al, 2004), even in low transmission settings, suggests that asymptomatically infected individuals may contribute substantially to malaria transmission (Alves et al, 2005; Mwesigwa et al, 2015). Primaquine (PQ), an 8-aminoquinoline, is recommended in combination with an artemisinin-based combination therapy (ACT) in low Plasmodium falciparum transmission settings to further reduce transmission (World Health Organization, 2010) These drugs act complimentarily: ACTs rapidly clear the P. falciparum asexual parasite biomass as well as early gametocyte stages (Chotivanich et al, 2006), considerably reducing post-treatment gametocyte carriage (WWARN Gametocyte Study Group, 2016) while PQ clears mature gametocytes (White, 2008). Methods: This was a four-arm, open label, randomized controlled trial comparing the effect of dihydroartemisinin-piperaquine (DHAP) alone or combined with single dose of primaquine (PQ) at 0.20 mg/kg, 0.40 mg/kg, or 0.75 mg/kg on Plasmodium falciparum gametocytaemia, infectiousness to mosquitoes and hemoglobin change in asymptomatic, malaria-infected, glucose-6-phosphate dehydrogenase (G6PD) normal individuals. The limited number of successful mosquito infections suggests that post-treatment transmission potential in this asymptomatic population is low
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