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.