The Gametocytocidal Efficacy of Different Single Doses of Primaquine with Dihydroartemisinin-piperaquine in Asymptomatic Parasite Carriers in The Gambia: A Randomized Controlled Trial.
BACKGROUND
Asymptomatic 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.


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 0.20mg/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).


RESULTS
A 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.


CONCLUSIONS
A 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.
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia; Epidemiology for Global Health Institute, Faculty of Medicine & Health Sciences, University of Antwerp, Antwerp, Belgium. Electronic address: jokebe@mrc.gm.
Joseph
J
Okebe
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: teun.bousema@radboudumc.nl.
Teun
T
Bousema
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: maffara@mrc.gm.
Muna
M
Affara
Pragmatic Clinical Trials Unit, Centre for Primary Care and Public Health, Queen Mary University of London, United Kingdom. Electronic address: g.ditanna@qmul.ac.uk.
Gian Luca
GL
Di Tanna
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: edgardabira@yahoo.fr.
Edgard
E
Dabira
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: abgaye@mrc.gm.
Abdoulaye
A
Gaye
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: sanyaisijolafrank@yahoo.com.
Frank
F
Sanya-Isijola
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: hbadji@mrc.gm.
Henry
H
Badji
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: scorrea@mrc.gm.
Simon
S
Correa
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. Electronic address: dnwakanma@mrc.gm.
Davis
D
Nwakanma
Epidemiology for Global Health Institute, Faculty of Medicine & Health Sciences, University of Antwerp, Antwerp, Belgium. Electronic address: Jean-Pierre.VanGeertruyden@uantwerpen.be.
Jean-Pierre
JP
Van Geertruyden
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom. Electronic address: Chris.Drakeley@lshtm.ac.uk.
Chris
C
Drakeley
Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia; Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium. Electronic address: udalessandro@mrc.gm.
Umberto
U
D'Alessandro
D000293:Adolescent; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058070:Asymptomatic Diseases; D002353:Carrier State; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D005714:Gambia; D006801:Humans; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy* / Q000469:parasitology*; D008297:Male; D010963:Plasmodium falciparum; D011319:Primaquine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D010879:Piperazines
D000962:Antimalarials; D037621:Artemisinins; D011319:Primaquine; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
Asymptomatic infection; Efficacy; Gametocyte carriage; Infectivity; Malaria; Plasmodium falciparum; Primaquine; Randomized trial