In Vivo Selection ofPlasmodium falciparum pfmdr186N Coding Alleles by Artemether‐Lumefantrine (Coartem)

Abstract

Artemisinin derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa. We have performed an artemether-lumefantrine (Coartem; Novartis) follow-up clinical trial in Zanzibar, in which pfcrt K76T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days. A significant increase in pfmdr1 86N was observed after exposure to the drug. This points to 86N as a potential marker of lumefantrine resistance in vivo, while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial settings.

Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

“…Mutation at positions 86, 184, 1034, 1042, and 1246 in Pfmdr1 mediate and/or modulate CQ, LM and mefloquine resistance ( Ecker et al , 2012; Price et al , 1999; Price et al , 2004; Sisowath et al , 2005). Studies in the rodent malaria Plasmodium chabaudi found no association between crt and CQ resistance ( Afonso et al , 2006; Hunt et al , 2004).…”

Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

“…43 Furthermore, a recent report from Nigeria linked the N86-Y184F-D1246 genotype with artemether-lumefantrine treatment failure, 44 and the N86 haplotype has been suggested as a potential marker of lumefantrine resistance in vivo, because recurrent parasites displayed a significant increase in pfmdr1 N86 after exposure to artemether-lumefantrine in Zanzibar. 45 This polymorphism has also been postulated as the first step in a series of mutation steps leading to the selection of artemether-lumefantrine resistance. 46 However, the N86 polymorphism seems to confer parasite resistance to artemetherlumefantrine in a pfmdr1 multicopy setting, 12 which was still alarming, because multicopy parasites have already been isolated in Suriname.…”

A Comparison of Methods to Detect and Quantify the Markers of Antimalarial Drug Resistance

“…First, Schoepflin and others 19 noted that mutant SNP frequencies may be higher in newly acquired infections and suggested that this may be caused by putative fitness effects associated with the mutations being less deleterious when there are no competing coinfecting clones. Second, low MOI infections may reflect recent drug use; most antimalarial drugs have long half-lives, and the first clones to recolonize treated individuals tend to be those that are more resistant to the drug, [20][21][22] making resistance mutations likely to be overrepresented in infections with low MOI. An important bias arises in analyses counting unambiguous samples, because low-frequency SNPs and haplotypes will be systematically underrepresented.…”