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Antimicrobial Agents and Chemotherapy, September 2007, p. 3096-3103, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00159-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Impact of Transmission Intensity on the Accuracy of Genotyping To Distinguish Recrudescence from New Infection in Antimalarial Clinical Trials{triangledown}

Bryan Greenhouse,1* Christian Dokomajilar,1 Alan Hubbard,2 Philip J. Rosenthal,1 and Grant Dorsey1

Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California,1 Group in Biostatistics, School of Public Health, University of California, Berkeley, California2

Received 2 February 2007/ Returned for modification 3 April 2007/ Accepted 16 June 2007

Antimalarial clinical trials use genotyping techniques to distinguish new infection from recrudescence. In areas of high transmission, the accuracy of genotyping may be compromised due to the high number of infecting parasite strains. We compared the accuracies of genotyping methods, using up to six genotyping markers, to assign outcomes for two large antimalarial trials performed in areas of Africa with different transmission intensities. We then estimated the probability of genotyping misclassification and its effect on trial results. At a moderate-transmission site, three genotyping markers were sufficient to generate accurate estimates of treatment failure. At a high-transmission site, even with six markers, estimates of treatment failure were 20% for amodiaquine plus artesunate and 17% for artemether-lumefantrine, regimens expected to be highly efficacious. Of the observed treatment failures for these two regimens, we estimated that at least 45% and 35%, respectively, were new infections misclassified as recrudescences. Increasing the number of genotyping markers improved the ability to distinguish new infection from recrudescence at a moderate-transmission site, but using six markers appeared inadequate at a high-transmission site. Genotyping-adjusted estimates of treatment failure from high-transmission sites may represent substantial overestimates of the true risk of treatment failure.

* Corresponding author. Mailing address: Department of Medicine, University of California, San Francisco, Box 0811, San Francisco, CA 94143. Phone: (415) 206-8844. Fax: (415) 648-8425. E-mail: bgreenhouse{at}medsfgh.ucsf.edu

{triangledown} Published ahead of print on 25 June 2007.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3096-3103, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00159-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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