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Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number

Price, Ric N., Uhlemann, A. C., Brockman, Alan, McGready, R., Ashley, E., Phaipun, L., Patel, R., Laing, K., Looareesuwan, S., White, Nicholas J., Nosten, F. and Krishna, S. (2004). Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. The Lancet,364(9432):438-447.

Document type: Journal Article
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Title Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number
Author Price, Ric N.
Uhlemann, A. C.
Brockman, Alan
McGready, R.
Ashley, E.
Phaipun, L.
Patel, R.
Laing, K.
Looareesuwan, S.
White, Nicholas J.
Nosten, F.
Krishna, S.
Journal Name The Lancet
Publication Date 2004
Volume Number 364
Issue Number 9432
ISSN 0140-6736   (check CDU catalogue open catalogue search in new window)
Start Page 438
End Page 447
Total Pages 10
Place of Publication London, UK
Publisher The Lancet Publishing Group
Field of Research 0604 - Genetics
1115 - Pharmacology and Pharmaceutical Sciences
HERDC Category C1 - Journal Article (DEST)
Abstract Background The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. Methods The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Findings Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Interpretation Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Relevance to practice Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine. Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days' artesunate. Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum, and potentially for predicting treatment failure in individual patients.
Keywords western border
chloroquine resistance
increased sensitivity
drug susceptibility
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