Reply to van der Pluijm et al., “Antimalarial Resistance Unlikely To Explain U.K. Artemether-Lumefantrine Failures”

REPLY

I thank van der Pluijm et al. for drawing attention to the potential pitfalls of interpreting a handful of case reports of antimalarial treatment failure as indicative of developing resistance in the parasite populations from which the observed infections originate (1). As stated in my recent paper describing four such cases in the United Kingdom: “Treatment failure cannot be unequivocally ascribed to parasite resistance in these four patients, …” (2). I am delighted that these authors have endorsed our call for ongoing studies of resistance in Africa and agree with the need to explore alternative artemisinin-based combination treatment (ACT)-based regimens, such as our proposal for sequential double ACT administered over 6 days (3).

However, van der Pluijm and coauthors make two errors in discussing the genotyping data presented in reference 2. First, they fail to notice that three of the four cases discussed harbored chloroquine-resistant parasites with the CVIET haplotype of pfcrt, and so their arguments regarding lumefantrine being less effective against parasites of the CVMNK haplotype do not hold. Second, they erroneously state that: “Of the molecular markers described, only K13 (no mutations), pfmdr1, and pfcrt have been validated by transfection and/or independent association studies.” In fact, the pfap2mu Ser160Asn mutation harbored by patient 1 has been verified in vitro by transfection studies and by association studies in vivo in Kenyan children and can be considered a validated candidate modulator of susceptibility to dihydroartemisinin (4, 5).