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.