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

Joseph Okebe, Teun Bousema, Muna Affara, Gian Luca Di Tanna, Edgard Dabira, Abdoulaye Gaye, Frank Sanya-Isijola, Henry Badji, Simon Correa, Davis Nwakanma, Jean-Pierre Van Geertruyden, Chris Drakeley, Umberto D'Alessandro, Joseph Okebe, Teun Bousema, Muna Affara, Gian Luca Di Tanna, Edgard Dabira, Abdoulaye Gaye, Frank Sanya-Isijola, Henry Badji, Simon Correa, Davis Nwakanma, Jean-Pierre Van Geertruyden, Chris Drakeley, Umberto D'Alessandro

Abstract

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://ichgcp.net/clinical-trials-registry/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.

Interpretation: 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.

Keywords: Asymptomatic infection; Efficacy; Gametocyte carriage; Infectivity; Malaria; Plasmodium falciparum; Primaquine; Randomized trial.

Copyright © 2016 The Author. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Flow diagram of the study. DHAP: dihydroartemisinin-piperaquine, PQ: primaquine, QT-NASBA: quantitative nucleic acid sequence-based assay.
Fig. 2
Fig. 2
Gametocyte prevalence in each trial arms for each analyzed day of follow up. Error bars indicates the upper limit of the 95% confidence interval around the prevalence.
Fig. 3
Fig. 3
Odds ratio of gametocyte prevalence on each of the days of follow-up compared with the control arm adjusted for baseline gametocyte density. Bars indicate the upper and lower limits of the 95% confidence.
Fig. 4
Fig. 4
Kaplan Meier plot for gametocyte clearance in individuals who were gametocyte positive at enrolment.

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