Obstacles 1: The emergence and spread of antimalarial drug resistance
There is resistance in Plasmodium falciparum to all currently used antimalarial drugs but there is substantial variation in the geographic distribution and degree of reduced susuceptibility. The most resistant parasites are found in the eastern greater Mekong subregion of Southeast Asia. Multidrug resistant P. falciparum is also prevalent in parts of South America. In general P.falciparum in Africa is more sensitive with higher levels of resistance in East compared with West Africa (37). Resistance is generally less in the other malarias although antifol resistance in P.vivax is widespread and chloroquine resistance in P. vivax is found throughout Indonesia and Papua New Guinea (38). Antifol resistance in both P.falciparum and P.vivax results from stepwise accumulation of mutations in the dhfr gene encoding the drug target dihydrofolate reductase , (S108N, N51I, C59R) and sulphonamide resistance results from accumulation of mutations in the dhpsgene encoding the drug target dihydropteroate synthase (A437G,K540E, A581G). In general, the more of these mutations there are more resistant is the P. falciparum infection (39). The highest level of antifol resistance is conferred by the Pfdhfr I164L mutation (found in Southeast Asia and South America). This renders parasites completely resistant to pyrimethamine. Resistance to chloroquine and the structurally related antimalarials which interfere with haem detoxification results from mutations in the transporter Pfcrt , and to a lesser extent mutations in Pfmdr (notably N86Y, N1042D, S1034C, and D1246Y). Positions 72 to 76 are mutated in the Pfcrtof most P. falciparum (causing 4-aminoquinoline resistance) with K76T being consistently mutant in the five major haplotypes (CVIET, SVMNT, SVIET, CVMNT and CVTNT) (39). Recently downstream mutations from the chloroquine resistance locus have been strongly associated with piperaquine resistance (23,39). Copy number increase in wild typePfmdr is the main identified genetic association with mefloquine and lumefantrine resistance (22). Atovaquone resistance arises readily as a result of mutations in the mitochondrial multicopy cytochrome b gene (usually at position 268; Y268S or Y268N).
From a therapeutic perspective high level resistance precludes use of chloroquine and sulphadoxine-pyrimethamine alone in most areas (1). Amodiaquine alone is also not sufficiently efficacious in many parts of the tropics but still contributes significantly to efficacy in combinations - and artesunate-amodiaquine remains efficacious in Central and West Africa. Significant resistance to mefloquine and piperaquine is prevalent only in the Greater Mekong subregion (GMS) of Southeast Asia. Fortunately in these areas artemether-lumefantrine and artesunate-pyronaridine currently remain highly effective (24, 40). It is an ominous precedent that the eastern GMS is the same area from which resistance to chloroquine and sulphadoxine-pyrimethamine arose and then spread to India and Africa (at a cost of millions of lives), and it is where resistance to the artemisinin drugs has arisen first.