Primaquine’s gametocytocidal efficacy in malaria asymptomatic carriers treated with dihydroartemisinin-piperaquine

Lead Research Organisation: MRC Unit, The Gambia

Abstract

A single dose of primaquine (PQ) can be added to an antimalarial treatment to eliminate gametocytes and decrease transmission of malaria parasites from humans to mosquitoes. However, PQ use has been and is still limited by the risk of destroying red blood cells in individuals with a genetic condition known as with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Such an effect is dose dependent and may be much lower with decreasing doses. We aim at establishing the lowest possible dose of PQ able to clear gametocytes in asymptomatic malaria carriers. The study is being carried out in 2 rural sites in the Gambia. In each site, individuals with an asymptomatic malaria infection are identified and randomized to 4 different groups, one without PQ and the three others with the recommended or decreasing doses of PQ. Study subjects are followed up for 42 days after treatment and the presence of gametocytes in the blood monitored.

Technical Summary

To date, primaquine (PQ), an 8-aminoquinoline, is the only currently registered product able to clear Plasmodium falciparum mature gametocytes. However, its use has been and is still limited by its haematological toxicity (haemolytic anaemia), particularly but not exclusively in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), in whom haemolysis can occur after a single PQ dose. Such an effect is dose-dependent. Considering that the current recommended dose was established several decades ago on a small number of experimentally challenged volunteers, it may be possible to obtain the same effect with a lower dose and hence decrease the risk of haemolysis. This is a four-arm, open label, randomized, controlled trial. G6PD-normal asymptomatic P. falciparum infected individuals identified through population screening are randomized to receive either a complete course of dihydroartemisinin-piperaquine (DHA-PPQ) alone (control arm) or a complete course of DHA-PPQ plus a single dose of PQ at 3 differing dose strengths (intervention arms), i.e. 0.75mg/kg, the standard dose, 0.4mg base/kg and 0.2mg base/kg. Enrolled individuals are treated and followed up until day 42 after initiation of treatment. The primary end point is the prevalence of P. falciparum gametocyte carriers at day 7, determined by quantitative nucleic acid sequence-based amplification assay (QT-NASBA).

Planned Impact

The proposed research program has the potential of having a large impact on the way malaria control and elimination are tackled in sub-Saharan Africa. It will provide the necessary data for the potential use of a lower-than-recommended dose of primaquine to eliminate gametocytes from malaria infected individuals, hence the potential of reducing transmission. When considering that, despite being recommended as a component of pre-elimination or an elimination program, primaquine is not used in sub-Saharan Africa, for fears of haematological toxicity, providing data on the gametocytocidal activity of lower doses can open the door for its large scale use. The assumption is the risk for haemolysis will be significantly lower with lower doses. This needs to be verified with an additional study in which glucose-6-phospate dehydrogenase deficient individuals will be treated with the new dose. Therefore, beneficiaries will be the populations living in malaria endemic countries, particularly those having achieved a good level of control, e.g. The Gambia, Zanzibar, and Sao Tome. It would be possible to administer primaquine to malaria patients attending health facilities, to asymptomatic carriers identified by systematic screening or to the whole population as a component of a mass drug administration program. The major benefit for subjects treated with primaquine at a lower dose will be the lower risk for serious adverse events, i.e. haemolytic anaemia. Assuming primaquine is deployed on a large scale, its impact on gametocytes and hence transmission will be beneficial for the whole population as it will reduce the risk of malaria.
 
Description PRINOGAM 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Malaria Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Coordination for a grant obtained fromt he Global Health Trials Scheme
Collaborator Contribution Support of the direct membrane feeding assay within the PRINOGAM trial.
Impact No output so far, the trial has just started
Start Year 2012
 
Description PRINOGAM 
Organisation Radboud University Nijmegen Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Coordination for a grant obtained fromt he Global Health Trials Scheme
Collaborator Contribution Support of the direct membrane feeding assay within the PRINOGAM trial.
Impact No output so far, the trial has just started
Start Year 2012