title: Distinguishing recrudescences from new infections in antimalarial clinical trials: major impact of interpretation of genotyping results on estimates of drug efficacy.
abstract: The use of molecular genotyping to distinguish recrudescence from new infections has become common in antimalarial clinical trials. However, methods used to interpret genotyping results have not been standardized. We analyzed data from 3,000 patients enrolled in clinical trials at seven sites in Uganda. Late treatment failure requiring genotyping occurred in 51% of the patients. Among samples successfully genotyped, 21% were definitive new infections (no recrudescent strains present on day of failure), 35% were definitive recrudescences (only recrudescent strains present), and 44% were mixed (new and recrudescent strains present). The probability of having a mixed genotyping result increased as transmission intensity increased. At the highest transmission site, the estimated risk of treatment failure increased from 34% to 84% for chloroquine plus sulfadoxine-pyrimethamine, from 18% to 45% for amodiaquine plus sulfadoxine-pyrimethamine, and from 12% to 57% for amodiaquine plus artesunate, depending on whether mixed genotyping results were classified as new infections or recrudescences, respectively. The method used to classify treatment outcomes can have a major impact on estimates of drug efficacy, especially in areas of high transmission intensity.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Madeline
authors.initials: M
authors.lastname: Slater
authors.forename: Moses
authors.initials: M
authors.lastname: Kiggundu
authors.forename: Chris
authors.initials: C
authors.lastname: Dokomajilar
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.forename: Nathan
authors.initials: N
authors.lastname: Bakyaita
authors.forename: Ambrose
authors.initials: A
authors.lastname: Talisuna
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000145:classification* / Q000235:genetics* / Q000472:pathogenicity; D012008:Recurrence; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D000962:Antimalarials