Obstacles 2: Artemisinin resistance
Artemisinin resistance was found first near the Thailand-Cambodia border. It manifests by slowing of parasite clearance which reflects reduced “ring stage” killing (1). In falciparum malaria the young ring stage parasites in the first third of the 48 hour asexual life cycle circulate in the blood stream before the infected erythrocytes adhere to vascular endothelium (cytoadherence) – a process called sequestration. This does not occur to a significant extent with the other human malarias. Sequestration is considered central to the potentially lethal pathology of falciparum malaria, and the life saving benefit of the artemisinin derivatives (Figure 1) results from reducing sequestration by killing the ring stage parasites (12). The pharmacodynamic effect is best measured in-vivo from the log-linear decline in parasite densities which follows a variable lag phase. The slope provides the parasite clearance rate and thus a half-life. Parasite clearance half-lives over 5 hours are generally associated with artemisinin resistance (18,20) (Figure 3). When artemisinin resistance was recognised first it was observed there were multiple independent mutations in the Pf kelch gene propeller region but in recent years successful artemisinin resistant parasite lineages have outcompeted the other parasites and spread across large areas (37). In the Eastern GMS a parasite lineage bearing the C580Y mutation has predominated, whereas in Myanmar a lineage bearing the F446I mutation has spread over large distances (41, 42) (Figure 4). The F446I mutation confers a lower degree of resistance (in terms of parasite clearance) than many of the other propeller mutants. This may reflect a lesser fitness cost and thus greater competitive advantage in areas of higher transmission. These artemisinin resistant parasites have then acquired resistance to the ACT partner drugs -piperaquine (in the Eastern GMS) and mefloquine (along the Thailand-Myanmar border). This has resulted in increasing rates of ACT failure (21-23) forcing Governments to change their first-line treatment policies. There is serious concern that these resistant parasites could spread westward, or that artemisinin resistance could emerge de-novo elsewhere, and derail global aspirations to control and eliminate malaria.