Legends to Figures
Figure 1: Mortality by treatment arm in randomized comparative controlled trials in strictly defined severe falciparum malaria (which together enrolled 2874 adults and 7424 children). The size of the circle is approximately proportional to the size of the trial and the error bars are 95% confidence intervals. The adults were enrolled mainly in Southeast Asia and the children in Africa (4,5,7,8).
Figure 2: In artemisinin combination treatments (2A: left panel) the three day artemisinin regimen in sensitive infections (AS) results in rapid parasite killing and consequent decline in parasitaemia. The logarithmic scale vertical axis shows the total number of parasites in the body of an adult with approximately 2% parasitaemia. The ACT partner drug has only approximately 1000 parasites to remove in this example (green triangle). In contrast in an artemisinin resistant infection (AR) there is much less parasite killing initially and the ACT partner drug now has approximately 100 million parasites to remove with a substantially greater risk of treatment failure (recrudescence) and thus selective pressure to the emergence of partner drug resistance. In the right panel (2B) with TACTs there are now two slowly eliminated drugs providing a potentially greater antimalarial effect in resistant infections and ensuring mutual protection against the emergence of resistance. The detection limit (dashed line) is the limit for microscopy to identify a malaria infection.
Figure 3: The parasite clearance half-lives associated withPf kelch mutations in patients with acute falciparum malaria studied in the TRAC1 study (20). WT= wild type (note parasite clearance half-lives can still be much longer than 5 hours in Pf kelch wild-type infections). Mutations in the “propeller “region are usually associated with slow parasite clearance, the phenotypic hallmark of artemisinin resistance, although there is substantial inter-individual variation and some mutations (A578S: pink arrow) are clearly not associated with artemisinin resistance. In the GMS parasite lineages associated with the F446I mutation have spread widely in Myanmar, and a lineages associated with C580Y was common along the Thailand-Myanmar border before targeted elimination activities. In the Eastern GMS lineages associated with R539T and C580Y both spread but in recent years the C580Y lineage (termed Pf Pailin) has dominated. Modified from Ashley et al (20) with permission.