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.