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).