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n engl j med 359;24 www.nejm.org december 11, 2008 2619

Evidence of Artemisinin-Resistant Malariain Western Cambodia

To the Editor:Although artemisinins are po-tent and rapidly acting antimalarial drugs, theirwidespread use for treating patients with Plasmo-

dium falciparum malaria raises the question ofemerging drug resistance.1,2Artemisinin mono-therapy should not be used in areas where ma-laria is endemic; it requires an extended admin-istration period and may lead to treatment failure,most frequently because of problems with com-pliance. Recent reports of high failure rates asso-ciated with artemisinin-based combination ther-apy, as well as in vitro drug-susceptibility data,suggest the possibility of clinical artemisinin re-sistance along the ThaiCambodian border.3,4We studied the potential emergence of artemisi-

nin resistance using in vivo, in vitro, molecular,and pharmacokinetic methods specifically de-signed to address the question of potential ar-temisinin resistance.

We randomly assigned, in a ratio of 2:1, 94adults from Battambang Province presenting withuncomplicated P. falciparummalaria (100 to 100,000parasites per microliter) to receive either high-dose artesunate therapy (4 mg per kilogram ofbody weight per day, orally, for 7 days) (60 pa-

tients) or quinine (30 mg per kilogram per day)plus tetracycline (25 mg per kilogram per day) ina split dose every 8 hours for 7 days (34 patients).

The study was approved by ethics review com-mittees in Cambodia and the United States andwas conducted from October 2006 through March2007. Written informed consent was obtainedfrom all study participants.

Patients were admitted for 28 days to rule outreinfection. The clinical outcome was recorded,plasma drug concentrations and in vitro drugsusceptibility were measured, and molecular as-says were performed to investigate genetic resis-tance markers and to rule out reinfection. Onlypatients who met all the following criteria were

classified as having artemisinin-resistant infec-tion: persistence of parasites 7 days after the startof treatment or reemergence of parasites within28 days after the start of treatment; adequateplasma concentrations of dihydroartemisinin, amajor artemisinin metabolite; prolonged time toparasite clearance; and reduced in vitro suscep-tibility to dihydroartemisinin.5

Four of the 60 patients who received artesu-nate had reemergence of parasitemia between

P=0.03

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ParasiteDensity

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fdensityatscreening)

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90

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Treatment failure dueto drug failure

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Cure

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BA

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Parasite-Clearance Time (hr)

Figure 1.Parasite Density, Parasite-Clearance Time, and 50% Inhibitory Concentration (IC50) among Patients Receiving Artesunate,

According to Clinical Outcome.

Panel A shows the parasite-reduction curves for the 56 patients who were cured, the 2 patients classified as having artemisinin-resistant

infections, and the 2 with drug failures (i.e., patients who had recrudescence but who were not classified as having artemisinin-resistantinfection, since the drug level was inadequate). The data points and horizontal Ibars denote the means and standard errors. Panel B

shows the parasite-clearance times in the artesunate group, as compared with the IC 50for dihydroartemisinin (R = 0.31, P = 0.03). Orangecircles indicate patients whose infection was classified as artemisinin-resistant, and blue squares patients in whom treatment failed but

whose infection was not classified as resistant.

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days 21 and 28 after the start of treatment (witha KaplanMeier probability estimate for cure atday 28 of 93.6%; 95% confidence interval [CI], 84.7to 97.7); 2 of these patients (3.3%) were classi-fied as having artemisinin-resistant infection,according to the criteria listed above (Fig. 1A).These two patients had parasite-clearance times

that were prolonged (133 and 95 hours, as com-pared with a median of 52.2 hours for patientswho were cured), and the plasma drug concen-trations after the first dose were classified asadequate (greater than the mean for the curedpatients minus 1 SD) (see the Supplementary Ap-pendix, available with the full text of this letterat www.nejm.org). For these subjects, the 50%inhibitory concentrations for dihydroartemisininwere up to 4 times the geometric mean for curedpatients and almost 10 times that for the refer-ence clone W2. In the artesunate group, 47.9%

(95% CI, 36.1 to 60.0) of the patients still hadparasitemia 48 hours after the start of treat-ment, as did 21.9% (95% CI, 13.1 to 33.1) 72hours after the start of treatment. Clinical andin vitro data suggest that artemisinin resistancemay be more accurately portrayed as the long tailof a single distribution than as the result of asudden change in sensitivity (Fig. 1B). Resistancedid not appear to be mediated by the number ofcopies of the P. falciparummultidrug resistancegenepfmdr1or selected PfATPase6polymorphismstested in this study.

The high overall treatment efficacy seen in pa-tients treated with artesunate indicates that rela-tively few parasite isolates have crossed the thresh-old of artemisinin resistance as defined in ourstudy. Artemisinin resistance does not seem to bea widespread epidemiologic phenomenon at this

time. The prolonged parasite-clearance times andthe two cases meeting our definition of artesu-nate resistance are nonetheless a concern.

Harald Noedl, M.D., Ph.D.Medical University of ViennaA-1090 Vienna, Austriaharald.noedl@meduniwien.ac.at

Youry Se, M.D.Kurt Schaecher, Ph.D.Bryan L. Smith, M.D.Armed Forces Research Institute of Medical SciencesBangkok 10400, Thailand

Duong Socheat, M.D.National Center for Parasitology, Entomology, and Malaria ControlPhnom Penh, Cambodia

Mark M. Fukuda, M.D.Armed Forces Research Institute of Medical SciencesBangkok 10400, Thailand

for the Artemisinin Resistance in Cambodia 1

(ARC1) Study ConsortiumSupported by the U.S. Department of Defense Global Emerg-

ing Infections System Program. The opinions or assertions con-tained herein are the private views of the authors and are not tobe construed as official or as reflecting the views of the Depart-ment of the Army or the Department of Defense.

Duffy PE, Sibley CH. Are we losing artemisinin combination1.therapy already? Lancet 2005;366:1908-9.

Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisi-2.nins: their growing importance in medicine. Trends PharmacolSci 2008;29:520-7.

Jambou R, Legrand E, Niang M, et al. Resistance of Plasmo-3.dium falciparum field isolates to in-vitro artemether and pointmutations of the SERCA-type PfATPase6. Lancet 2005;366:1960-3.

Vijaykadga S, Rojanawatsirivej C, Cholpol S, Phoungmanee4.D, Nakavej A, Wongsrichanalai C. In vivo sensitivit y monitoringof mefloquine monotherapy and artesunate-mefloquine combi-nations for the treatment of uncomplicated falciparum malariain Thailand in 2003. Trop Med Int Health 2006;11:211-9.

Noedl H. Artemisinin resistance: how can we find it? Trends5.Parasitol 2005;21:404-5.Correspondence Copyright 2008 Massachusetts Medical Society.

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