Misclassification of drug failure in Plasmodium falciparum clinical trials in southeast Asia.
Most trials of antimalarials occur in areas in which reinfections are possible. For Plasmodium falciparum, reinfections are distinguished from recrudescences by polymerase chain reaction analysis of 3 polymorphic genes. However, the validity of this approach has never been rigorously tested. We tested for misclassification in 6 patients from clinical trials in Thailand and Cambodia who were classified as being reinfected by the standard polymerase chain reaction protocol. Using heteroduplex tracking assays and direct DNA sequencing, we found that 5 (83%) of 6 patients were misclassified. Misclassification in this manner overestimates the efficacy of antimalarials and delays the recognition of decreasing therapeutic efficacy, thus delaying potential changes in policy.
Juliano
Jonathan J
JJ
Division of Infectious Diseases, School of Medicine, Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
Ariey
Frederic
F
Sem
Rithy
R
Tangpukdee
Noppadon
N
Krudsood
Srivicha
S
Olson
Carol
C
Looareesuwan
Sornchai
S
Rogers
William O
WO
Wongsrichanalai
Chansuda
C
Meshnick
Steven R
SR
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002160:Cambodia / Q000453:epidemiology; D016054:DNA, Protozoan / Q000235:genetics; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000235:genetics*; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins; D012008:Recurrence; D013785:Thailand / Q000453:epidemiology; D017211:Treatment Failure
D000962:Antimalarials; D016054:DNA, Protozoan; D005819:Genetic Markers; D015800:Protozoan Proteins