Triple antimalarial drug combinations for the treatment of falciparum malaria

Artemisinin-based Combination Therapies (ACTs), in which an artemisinin component is combined with a slowly eliminated partner drug such as piperaquine, mefloquine, lumefantrine, amodiaquine or sulphadoxine-pyrimethamine, are the recommended first-line treatment for Plasmodium falciparum in all malaria endemic countries. Artemisinin resistance, which was first identified between 2006 and 2009 in western Cambodia, results in a high number of parasites surviving the initial 3 days of artemisinin exposure. As a result, a large number of parasites is exposed to a partner drug with a limited potency for an extended time, providing ideal conditions for the selection of partner drug resistance. The threat of artemisinin and partner drug resistance spreading out of Southeast Asia and the threat of independent emergence in other areas underlines the need for treatments that are effective against multidrug resistant malaria and are less likely to fall to resistance. A potential strategy to prolong the utility of existing antimalarials is combining an artemisinin with two partner drugs in the form of a Triple Artemisinin-based Combination Therapy. This thesis describes the current extent of antimalarial resistance in Plasmodium falciparum malaria and assesses the safety, tolerability and efficacy of Triple Antimalarial Combination Therapies. In addition, this thesis explores potential barriers and outstanding questions that will need to be addressed to enable widescale implementation of Triple Antimalarial Combination Therapies