The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread

Abstract

Artemisinins are the most rapidly acting of currently available antimalarial drugs. Artesunate has become the treatment of choice for severe malaria, and artemisinin-based combination therapies (ACTs) are the foundation of modern falciparum malaria treatment globally. Their safety and tolerability profile is excellent. Unfortunately, Plasmodium falciparum infections with mutations in the ‘K13’ gene, with reduced ring-stage susceptibility to artemisinins, and slow parasite clearance in patients treated with ACTs, are now widespread in Southeast Asia. We review clinical efficacy data from the region (2000–2015) that provides strong evidence that the loss of first-line ACTs in western Cambodia, first artesunate-mefloquine and then DHA-piperaquine, can be attributed primarily to K13 mutated parasites. The ring-stage activity of artemisinins is therefore critical for the sustained efficacy of ACTs; once it is lost, rapid selection of partner drug resistance and ACT failure are inevitable consequences. Consensus methods for monitoring artemisinin resistance are now available. Despite increased investment in regional control activities, ACTs are failing across an expanding area of the Greater Mekong subregion. Although multiple K13 mutations have arisen independently, successful multidrug-resistant parasite genotypes are taking over and threaten to spread to India and Africa. Stronger containment efforts and new approaches to sustaining long-term efficacy of antimalarial regimens are needed to prevent a global malaria emergency.

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

“…There is considerable concern that, faced with the spread of pfk13 variants to the wider GMS, the proportion of slow-clearing phenotypes is increasing, thus posing an immediate threat to ACT efficacy within the region and more globally in the future [17][18][19][20]. In fact, some authors have called on the WHO to declare artemisinin 'resistance' to be a ''public health emergency of international concern' [18].…”

“…In fact, some authors have called on the WHO to declare artemisinin 'resistance' to be a ''public health emergency of international concern' [18]. However, a careful overview of data from the GMS and beyond provides several arguments against this emotive response.…”

“…It is widely considered that the endoperoxide bridge in artemisinin is strongly activated by haem metabolism in the food vacuole, leading to parasite killing [29], a process that barely occurs during the first few hours of the life cycle, so it is unclear how activation of artemisinin, so lethal to parasites in these first few hours, occurs [18,26]. One plausible hypothesis is that a specific parasite cellular process in the first few hours post-invasion provides a finite burst of activated artemisinin; variant K13 renders ERT resistant to artemisinin simply by preventing this specific event.…”

Antimalarial Resistance Unlikely To Explain U.K. Artemether-Lumefantrine Failures

“…Such parasites respond well to artesunate-amodiaquine, but the best way to use these two ACTs providing opposing selective forces over an extended period remains ill defined, particularly in areas with falling transmission. Potential options include multiple firstline therapies, which modeling predicts will delay the emergence of resistance to both artemisinins and their partner drugs (14), or ACTs containing two partner drugs ("triples") (15,16). Despite the evidence that ACTs remain highly efficacious across Africa, experience tells us we need to stay ahead of the game.…”

Combining traditional medicine and modern chemistry to fight malaria

“…This decrease is in no small part the result of the widespread use of the antimalarial drug artemisinin (and derivatives thereof), used in combination with a second antimalarial. However, these gains are now under threat by the emergence of parasites resistant against artemisinin (3). Hence, development of new antimalarial drugs is of great importance.…”