Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria

Abstract

Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages. These combinations increase the rates of clinical and parasitological cures and decrease the selection pressure for the emergence of antimalarial resistance. This Review article discusses our current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance.

Figures

Figure 1. The worldwide incidence of malaria and the rapid adoption of artemisinin-based combination therapies across sub-Saharan Africa

a | The estimated incidence of malaria worldwide in 2006, stratified per 1, 000 population. Cases in Africa constituted 86% of the global total, Southeast Asia accounted for 9% and the eastern Mediterranean region had 3%. Plasmodium falciparum was found to be responsible for over 75% of the cases in most sub-Saharan African countries but was second to Plasmodium vivax in most countries outside Africa. b | The official first-line antimalarial policy in Africa in 2003 and 2007, demonstrating the dramatic shift from a diversity of first-line antimalarials (typically chloroquine or sulphadoxine–pyrimethamine) towards the adoption of artemisinin-based combination therapies. Part a image is modified, with permission, from REF. © (2008) WHO. Part b image is modified, with permission, from REF. © (2007) UNICEF.

Figure 2. Site of action of antimalarial drugs

Depiction of an intra-erythrocytic Plasmodium falciparum parasite and the proposed target sites of several key antimalarials.

Figure 3. Recent trends in malaria cases and deaths

The graphs show the recent trends in malaria cases and deaths in six African countries following the implementation of malaria control programmes based on the use of: indoor residual spraying (IRS); insecticide-treated bed nets (ITN), including the more recent long-lasting insecticide-treated bed nets (LLIN); and an artemisinin-based combination therapy (ACT), typically artesunate–amodiaquine or artemether–lumefantrine. Figure is modified, with permission, from REF. © (2008) WHO.