Resistance to dihydroartemisinin.

To the Editor

The title of the letter by Cojean et al. () is misleading. The data presented essentially point to an absence of in vitro resistance to dihydroartemisinin (dhART) in the panel of African isolates studied, with 1 of 397 isolates having an elevated 50% inhibitory concentration (IC50) for dhART. The S769N PfATPase6 mutation associated with in vitro resistance to artemether () was observed in 1 isolate. This mutant isolate had a low IC50 for dhART, but its IC50 for artemether has not been tested. Since the relationship between in vitro susceptibility to artemether and dhART is still uncertain (), these data do not disprove the association of a PfATPase6 S769N polymorphism with elevated IC50 for artemether that was observed in isolates from French Guiana ().

Worth noting is that the association of the S769N PfATPase6 polymorphism with elevated IC50 for artemether was confirmed in an isolate collected in French Guiana in 2005; that isolate had an IC50 for artemether of 127 nmol/L. Molecular typing identified 2 clonal types, 1 with a wild-type PfATPase6 allele and 1 with a S769N single mutant. After 3 weeks of in vitro cultivation without drug, the mutant allele was no longer detected and the IC50 for artemether was 8.2 nmol/L. This finding suggests poor fitness of the mutant allele under standard culture conditions.

The observation of an additional case of in vitro resistance to artemether in French Guiana 3 years after the first cases is of concern. Reinforcement of surveillance is needed as is clarification of the relationship of in vitro susceptibility to artemether and artesunate, the derivatives currently included in artemisinin-based combination therapies (ACTs). Surveillance and clarification would be particularly timely since emerging clinical or parasitologic failures to some ACTs have been reported (,).

The original title of our article was “Lack of Plasmodium falciparum in Vitro and Genomic Resistance to Dihydroartemisinin in Travelers Returning to France from Africa.” EID’s shortening of the title () led to the perception that the letter title was misleading, but it was not on purpose. We have recently tested the 50% inhibitory concentration for artemether of the S769N PfATPase6 isolate that we had kept in liquid nitrogen, and it showed susceptibility.

We underline that the previously reported clinical or parasitologic failures to some artemisinin-based combination therapies (,) were not synonymous with the emergence of resistance to artemisinin compounds. In the study by Grandesso et al., a combination of artesunate plus amodiaquine was given to children <5 years of age who lived in an area in which amodiaquine alone was ineffective to adequately treat uncomplicated falciparum malaria in 1 of 3 cases at day 28 (). Such a combination (artesunate plus amodiaquine) was nearly equivalent in 1 of 3 cases to a 3-day artesunate monotherapy, which may fail to completely cure children because of the short half-life of artesunate. In the study by Bukirwa et al., no recrudescence occurred in patients treated with artesunate plus amodiaquine and only 2 of 199 patients treated with artemether plus lumefantrine experienced recrudescence at day 28 (). As Birkiwa et al. themselves acknowledged, artemether plus lumefantrine was not administered with food, and it is known that lumefantrine is absorbed better when it is taken with a small amount of fat. Thus, the clinical failures observed did not necessarily reflect P. falciparum resistance to artemisinin compounds.