The world has seen an impressive reduction in the burden of falciparum malaria over the last decade which can to a large extent be attributed to the wide deployment of insecticide treated bed nets and the introduction of highly effective artemisinin combination therapies (ACTs). However, resistance of P. falciparum to artemisinins has emerged in Western Cambodia and has spread to all 5 countries of the Greater Mekong Subregion (GMS). Potency loss of the artemisinin component has facilitated the selection for resistance against ACT partner drugs, and consequently high ACT treatment failure rates are now observed in Cambodian, S-Viet Nam, and on the Thai-Myanmar border.
Much progress has been made in understanding the molecular genetic and biological basis of artemisinin and partner drug resistance, and molecular markers for artemisinin resistance (“PfKelch13”) and piperaquine resistance (Plasmepsin-2 amplification) have been identified. Over the last 15 years, soft selective sweeps of multiple different PfKelch13 mutations in the GMS have evolved into a hard selective sweep with a single lineage containing PfKelch13 C580Y. Recent genetic epidemiological studies show that this single lineage of artemisinin resistant P. falciparum has spread from its origin in W-Cambodia to NE-Thailand, S-Laos, and S-Viet Nam, picking up piperaquine resistance in its course. Further spread of multidrug resistant (MDR) malaria in the region and beyond, in particular to Sub-Saharan Africa harboring >90% of malaria cases, would have disastrous consequences.
New antimalarials are not expected within this decade. A promising strategy to treat MDR falciparum malaria using existing antimalarials is with triple artemisinin combination therapies, combining two partner drugs with potentially counteracting resistance mechanisms, and matching pharmacokinetic profiles. DHA-pipeaquine-mefloquine and artemether-lumefantrine-amodiaquine are currently being trialed.
Containment of artemisinin and partner drug resistance falciparum malaria implies the elimination of falciparum malaria in areas of artemisinin resistance, since with continued drug pressure the remaining parasite populations will be the most resistant. Accelerated elimination will need to include the parasite reservoir in asymptomatic carriers, which was shown to be considerable even in these low malaria transmission settings. A malaria elimination strategy has been endorsed by all countries of the GMS.