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Previous Volume 344:257-263 January 25, 2001 Number 4 Next

	Full Text PDF Editorial by Warhurst, D. C. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively.

Methods To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine.

Results The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P< 0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine (Y86) for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1).

Conclusions This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.

Source Information

From the Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore (A. Djimdé, J.F.C., A. Dicko, C.V.P.); the Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Mali, Bamako, Mali (A. Djimdé, O.K.D., K.K., S.D., Y.D., A. Dicko); and the Malaria Genetics Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (A. Djimdé, A. Dicko, X.S., T.N., D.A.F., T.E.W.). Drissa Coulibaly, M.D., Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Mali, Bamako, Mali, was also an author.Yacouba Diourte, Pharm.D., is deceased.

Address reprint requests to Dr. Plowe at the Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore St., HSF 480, Baltimore, MD 21201, or at cplowe{at}medicine.umaryland.edu.

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