Advance 2: Better treatments for uncomplicated falciparum
malaria
The main advance in the treatment of falciparum malaria has been the
replacement of the failing monotherapies chloroquine and
sulfadoxine-pyrimethamine by artemisinin combination therapies (ACTs)
(1). These three-day regimens combine an artemisinin derivative with a
more slowly eliminated partner drug (Figure 2A). Four ACTs were
recommended originally; artesunate combined with
sulfadoxine-pyrimethamine (SP), amodiaquine or mefloquine, and
artemether combined with lumefantrine. More recently
dihydroartemisinin-piperaquine and artesunate-pyronaridine have been
introduced (1,15). All except artesunate-SP are available in combined
formulations and all but artemether-lumefantrine are taken once daily.
These drugs are all rapidly effective and generally well tolerated (1,
10, 16). Early concerns over potential neurotoxicity and teratogenicity
have receded with increasing evidence of safety (12). Worries over
piperaquine cardiotoxicity (QT prolongation - risk of Torsade de
Pointes) have also declined with large meta-analyses showing no increase
in the rate of sudden death (17). ACTs are now recommended as first line
treatment for all patients with falciparum malaria, including in
pregnancy (1). Costs have been reduced, and generics developed. Hundreds
of millions of treatments are dispensed annually.
The main current concern is ensuring access to diagnosis and effective
treatment and emerging resistance in Plasmodium falciparum to the
artemisinin derivatives. Artemisinin resistance manifests as slowing of
parasite clearance because of reduced ring stage (the younger asexual
forms) parasite susceptibility (18). The discovery of a parasite
molecular marker, mutations in the propeller region of the kelch gene on
chromosome 13, has greatly facilitated characterization and
epidemiological assessments. (19, 20) Reduced parasite killing in
artemisinin resistant malaria infections places greater selective
“pressure” on the ACT partner drug, This is because the number of
parasites which remain after the artemisinin component in an ACT has
been eliminated is many orders of magnitude greater - and the
probability of selecting resistant mutants is correspondingly higher
(Figure 2A). Indeed ACT partner drug resistance has followed artemisinin
resistance in the Greater Mekong subregion of Southeast Asia (21-24).
Fortunately artemisinin resistant P. falciparum are still largely
confined to this one region (25), although there are increasing reports
that clusters of kelch mutant parasites have been identified elsewhere
(27,27). One potential solution is to deploy triple artemisinin
combination treatments (TACTs) which combine an artemisinin derivative
with two slowly eliminated antimalarials (23). This solves the
pharmacokinetic mismatch whereby the rapidly eliminated artemisinin
component leaves the slowly eliminated partner drug “unprotected” for
days or weeks after the second post-treatment asexual parasite cycle
(i.e. >3 days after starting the ACT). With TACTs there are
now two slowly eliminated partner drugs providing mutual protection
against the selection of resistance (Figure 2B). The two TACTs under
current development artemether-lumefantrine -amodiaquine and
dihydroartemisinin-piperaquine-mefloquine exploit reciprocal
susceptibilities whereby resistance to one of the slowly eliminated
components is associated with increased susceptibility to the other. In
large scale trials TACTs have proved well tolerated, safe and highly
effective (24).