Resistance to dihydroartemisinin.

To the Editor: The title of the letter by Cojean et al. (1) 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 ([IC.sub.50]) for dhART. The S769N PfATPase6 mutation associated with in vitro resistance to artemether (2) was observed in 1 isolate. This mutant isolate had a low [IC.sub.50] for dhART, but its [IC.sub.50] for artemether has not been tested. Since the relationship between in vitro susceptibility to artemether and dhART is still uncertain (3), these data do not disprove the association of a PfATPase6 S769N polymorphism with elevated [IC.sub.50] for artemether that was observed in isolates from French Guiana (2).

Worth noting is that the association of the S769N PfATPase6 polymorphism with elevated [IC.sub.50] for artemether was confirmed in an isolate collected in French Guiana in 2005; that isolate had an ICs0 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 [IC.sub.50] 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 (4,5).

References

(1.) Cojean S, Hubert V, Le Bras J, Durand R. Resistance to dihydroartemisinin. Emerg Infect Dis. 2006; 12:1798-9.

(2.) Jambou R, Legrand E, Niang M, Ing NK, Lim P, Volney B, et al. In vitro artemether resistance of Plasmodium falciparum field isolates and point mutations pf the SERCA-type PfATPase6. Lancet. 2005;366:1960-3.

(3.) Brockman A, Price RN, van Vugt M, Heppner DG, Walsh D, Sookto P, et al. Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine. Trans R Soc Trop Meg Hyg. 2000;94:537-44.

(4.) Grandesso F, Hagerman A, Kamara S, Lam E, Checchi F, Balkan S, et al. Low efficacy of the combination artesunate plus amodiaquine for uncomplicated falciparum malaria among children under 5 in Kailahun, Sierra Leone. Trop Med Int Health. 2006; 11: 1017-21.

(5.) Bukirwa H, Yeka A, Kamya MR, Talisuna A, Banek K, Bakyaita N, et al. Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda. PLoS Clin Trials. 2006;1:e7

Address for correspondence: Eric Legrand, Institut Pasteur-CNRCP, 23 Ave Pasteur, PO Box 6010, Cayenne, French Guiana 97306;email: [e-mail]

Eric Legrand,* Beatrice Volney, * Jean-Baptiste Meynard, * Philippe Esterre, * and Odile Mercereau-Puijalon ([dagger])

* Institut Pasteur de la Guyane, Cayenne, French Guiana; and ([dagger])Institut Pasteur, Paris, France