To the Editor: Dondorp et al. (July 30 issue)1 describe artemisinin-resistantPlasmodium falciparum, based on a prolonged parasite clearancetime, in Pailin, western Cambodia, as compared with Wang Pha,on the Thai–Burmese border. Paradoxically, post-treatmentrecurrent parasitemia occurred less frequently in Pailin thanin Wang Pha. The authors assert that 12 of the 15 recurrentinfections in Wang Pha were new infections and not the resultof drug failure.
This reinfection rate among the 40 patients enrolled (30%) greatlyexceeds both the rate reported previously by the authors' researchunit2 and the area's attack rate of one case per person peryear.3 Furthermore, the polymerase-chain-reaction assay protocolused to diagnose recurrences commonly misidentifies drug failuresas new infections in Thailand and Cambodia.4 Thus, many of the"new infections" on the Thai–Burmese border may actuallybe recrudescent infections; the true failure rates in Pailinand Wang Pha could be as high as 20.0% and 37.5%, respectively.These data — in conjunction with the absence of an increased50% inhibitory concentration in vitro, molecular evidence ofresistance, or a clear association between the parasite clearancetime and clinical response — suggest that clinically relevantartemisinin resistance has not emerged in Pailin.
Steve M. Taylor, M.D., M.P.H. Duke University Durham, NC steve.taylor{at}duke.edu
Jonathan J. Juliano, M.D., M.S.P.H. Steven R. Meshnick, M.D.,Ph.D. University of North Carolina Chapel Hill, NC
References
Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009;361:455-467. [Free Full Text]
Carrara VI, Zwang J, Ashley EA, et al. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One 2009;4(2):e4551.
Luxemburger C, Thwai KL, White NJ, et al. The epidemiology of malaria in a Karen population on the western border of Thailand. Trans R Soc Trop Med Hyg 1996;90:105-111. [CrossRef][Web of Science][Medline]
Juliano JJ, Ariey F, Sem R, et al. Misclassification of drug failure in Plasmodium falciparum clinical trials in southeast Asia. J Infect Dis 2009;200:624-628. [CrossRef][Web of Science][Medline]
To the Editor: In the study reported on by Dondorp et al., thetwo study groups have significant differences in parasite densityat baseline. Parasite density has a strong effect on treatmentresponse and outcome that statistical adjustment may not properlyaccount for. Clinically, patients with a high parasite countwill have more severe illness, a delayed response to therapy,and a greater chance of the detection of parasites after treatment.Moreover, a slight difference in the peripheral-blood parasitecount may mean a great difference in the parasite biomass (i.e.,the number of parasites sequestered in vital organs, which maybe 40 times as high as the number of the peripheral parasitecount).1,2 Significant differences in other baseline variablessuch as temperature and levels of plasma glucose, creatinine,bilirubin, aspartate aminotransferase, and alkaline phosphatasemake the two populations different clinically. Since 20 patientsrecruited in Wang Pha did not have fever at admission, thesepatients may have had partial immunity to malaria (premunition);this may have affected the treatment response. The results reportedare excellent, with fever clearance at day 2 and parasite clearanceat day 2 to day 3. Is drug resistance really a problem?
Newton CR, Hien TT, White N. Cerebral malaria. J Neurol Neurosurg Psychiatry 2000;69:433-441. [Free Full Text]
Silamut K, Phu NH, Whitty C, et al. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am J Pathol 1999;155:395-410. [Free Full Text]
The authors reply: Taylor et al. and Htut question whether ourdata provide support for the conclusion that artemisinin-resistantfalciparum malaria has emerged in western Cambodia, yet noneof the correspondents dispute the key findings of markedly delayedparasite clearance times with sufficient drug concentrations.Taylor et al. have promoted their alternative to the methodsof parasite genotyping recommended by the World Health Organization(WHO) and used in our study.1 On the basis of the use of thesegenotyping methods recommended by the WHO in a small numberof patients hospitalized outside the area of Thailand wheremalaria is endemic, they suggest that we have significantlymisattributed recrudescences as reinfections. We do not findtheir estimates of misattribution convincing, and we think itis unlikely that the methods of parasite genotyping recommendedby the WHO are seriously flawed. Furthermore, even if recrudescencesin Thailand were underestimated, we do not see how this challengesthe main findings of our study. High reinfection rates in WangPha are probably explained by the recruitment of patients fromMyanmar (formerly known as Burma), because the transmissionof malaria is higher there than in the refugee camps on theThai side, where the data mentioned by Taylor et al. were collected.The lack of in vitro correlates of resistance is probably explainedby the fact that current in vitro susceptibility techniqueswill not detect a stage-specific loss of ring-stage susceptibility.
We also do not agree with Htut that faster parasite clearancetimes on the Thai–Burmese border are caused by acquiredhost immunity, since in our article we described no effect ofage on parasite clearance times in a large data set from thesame region. We do agree that the difference in the levels ofparasitemia on admission is a confounder in the comparison ofparasite clearance times between sites. However, stratificationaccording to the levels of parasitemia on admission and comparisonof clearance rates rather than times, which are much less dependenton levels of parasitemia at admission, still showed a largeand highly significant difference between the two regions. Weare forced reluctantly to conclude that artemisinin resistancein P. falciparum is now established in western Cambodia.
Arjen M. Dondorp, M.D. François Nosten, M.D. Nicholas J. White, F.R.S. Oxford University Oxford, United Kingdom arjen{at}tropmedres.ac
References
Genotyping to identify parasite populations. Geneva: World Health Organization, 2008.
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