Defining the optimal management of Plasmodium falciparum malaria on a background of emerging artemisinin combination therapy resistance

Drug resistant falciparum malaria has emerged twice from the Thai-Cambodian border and spread to the rest of the globe with disastrous consequences. The deployment of artemisinin-based combination therapy (ACT) as first-line treatment for P. falciparum malaria has reduced the burden of malaria dramatically worldwide and reignited the interest in the goal of malaria elimination. However, slow-clearing parasites resistant to artemisinin are emerging across the Greater Mekong Sub-region eventually leading to the failure of the ACTs. One objective of this thesis was to determine the association between therapeutic efficacy of one of the first line ACTs (mefloquine-artesunate) and the drug-resistant molecular markers for the constituent drugs (Pfmdr-1 and K-13 mutations). Between 2003 and 2013, the adequate clinical and parasitological response to mefloquine-artesunate declined from 100% to 81.1% as the proportions of isolates with multiple Pfmdr-1 copies doubled from 32.4% to 64.7% and those with K-13 mutations increased from 6.7% to 83.4%. Detailed investigations of the various K-13 polymorphisms revealed that along the ThailandâMyanmar border, the fittest alleles (C580Y) are taking over from less resistant or less fit ones. The second objective of this thesis was to evaluate new antimalarials (OZ439, a synthetic peroxide structurally related to artemisinin; KAE609, a spironindolone; and KAF156, an imidazolopiperazine, both are structurally novel molecules) in Phase 2a proof-of-concept studies. Parasitological efficacy was evaluated by measuring parasite clearance half-life. In all trialled doses of OZ439, KAE609 and KAF156 parasite clearance half-lives were not different in patients with artemisinin-sensitive and artemisinin-resistant parasites. No serious drug-related adverse effects were reported and these compounds will move into Phase 2b studies in late 2016.