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

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Malaria is a parasitic disease transmitted by mosquitoes of the species Anopheles. The parasite can be found in the human host in two forms, asexual and sexual. The latter does not cause disease but is responsible for the transmission of the infection from the human host to the vector mosquito. Therefore, interventions reducing the transfer of parasite sexual forms, called also gametocytes, from man to mosquito may have a major impact on malaria transmission and hence on the burden of disease. The only available treatment against gametocytes is primaquine, an old drug that has not been extensively used in sub-Saharan Africa because it can cause the destruction of reb blood cells in people with a genetic conditions called glucose-6-phosphate dehydrogenase deficiency, resulting sometimes in life-threathening anemia. However, the risk for anaemia is dose-dependent, i.e. the risk increases with increasing dose. The amount of primaquine needed to eliminate gametocyte has been established in the 60s in a small number of experimentally challenged volunteers. It is unknown if lower dosages of primaquine, which are probably associated with a lower risk for anaemia, could have the same effect than the recommended one. The use of primaquine at lower dosages would open the possibility of using it on a large scale in sub-Saharan Africa, where the prevalence of glucose-6-phosphate dehydrogenase deficiency can be as high as 15%. The general objective of this proposal is to determine the lowest possible dose of primaquine having similar activity against gametocytes than the recommended one. This will be done by carring out a clinical trial in two rural sites in The Gambia. In the study area, the population will be screened for malaria infection. Those positive, i.e. with a malaria infection but without symptoms, will be given an artemisinin-based combination treatment (dihydroartemisinin-piperaquine) and randomized to receive only this treatment or to have in addition the recommended or two lower dosages of primaquine. The treatment will be given over 3 days, with primaquine given, when required, in association with the last dose of dihydroartemisinin-piperaquine. Study subject will be actively followed up for more than a month, with blood sampling at regular intervals. The blood collected will be used to determine the difference in gametocyte carriage between the different treatment groups. Gametocytes will be searched with molecular methods, which are more sensitive than microscopy. In a subgroup of study subject we will check what is the actual difference in transmission to mosquitoes between individuals having received different treatments. We will collect a blood sample one week after the beginning of the treatment and we will feed laboratory-reared mosquitoes that will be dissected one week after, to check if the have become infected. The results of this study will be used to determine the feasibility of deploying primaquine on a large scale in sub-Saharan Africa, where the malaria burden is the highest, and may contribute to the drive towards malaria pre-elimination/elimination in this continent.