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ASSOCIATION BETWEEN MUTATIONS IN PLASMODIUM FALCIPARUM CHLOROQUINE RESISTANCE TRANSPORTER AND P. FALCIPARUM MULTIDRUG RESISTANCE 1 GENES AND IN VIVO AMODIAQUINE RESISTANCE IN P. FALCIPARUM MALARIA–INFECTED CHILDREN IN NIGERIA

This study investigated the association between Plasmodium falciparum chloroquine resistance transporter (pfcrt) T76 and P. falciparum multidrug resistance gene 1 (pfmdr1) Y86 alleles and in vivo amodiaquine (AQ) resistance, as well as the clearance of parasites harboring these two alleles in children treated with AQ in southwest Nigeria. One hundred one children with acute uncomplicated P. falciparum malaria infections were treated with the standard dosage of AQ and followed-up for 28 days. Blood samples were collected on filter paper samples at enrollment and during follow-up for identification of parasite genotypes and pfcrt and pfmdr1 mutations using polymerase chain reaction and restriction fragment length polymorphism approaches. Parasitologic assessment of response to treatment showed that 87% and 13% (RI) of patients were cured and failed treatment, respectively. Although infections in patients were polyclonal (as determined by merozoite surface protein 2 genotyping), the presence of both mutants pfcrtT76 and pfmdr1Y86 alleles in parasites is associated with in vivo AQ resistance (odds ratio = 7.58, 95% confidence interval = 1.58–36.25, P = 0.006) and is selected by the drug in children who failed AQ treatment. Treatment failure with the combination of mutant pfcrtT76 and pfmdr1Y86 alleles as well as the ability of patients to clear these resistant parasites is dependent on age, suggesting a critical role of host immunity in clearing AQ-resistant P. falciparum. The combination of mutant pfcrtT76 and pfmdr1Y86 alleles may be useful markers for monitoring the development and spread of AQ resistance, when combining this drug with other antimalarials for treatment of malaria in Africa.

Received January 4, 2006. Accepted for publication February 3, 2006.

Acknowledgments: We thank all patients and their parents or guardians for volunteering to participate in the study, and the Malaria Research and Reference Reagent Resource Centre for providing all genomic DNA used as controls for the PCR and RFLP experiments. We also thank Dr. Dan Milner (Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA) for helpful comments on the manuscript.

Financial support: This study was supported by a grant from the Fogarty International Center, Multilateral Initiative for Malaria in Africa/TDR, project ID A20239, UNICEF/UNDP/World Bank/WHO/TDR grant project ID A50337, Harvard Malaria Initiative, and International Atomic Energy Agency (IAEA) project RAF/0625. C. T. Happi is supported by a Fogarty International Research Collaboration Award (FIRCA) no. NIH RO3TW006298-01A1, the IAEA project RAF/0625, and the UNICEF/UNDP/World Bank/WHO/TDR/PAG/South-South Initiative project ID A50337.

^* Address correspondence to C. T. Happi, Malaria Research Laboratories IMRAT, College of Medicine, University of Ibadan, Nigeria. E-mail: christianhappi{at}hotmail.com or chappi{at}hsph.harvard.edu

Authors’ addresses: C. T. Happi, Malaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115. G. O. Gbotosho, O. A. Folarin, O. M. Bolaji, and A. Sowunmi, Malaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria. D. E. Kyle and W. Milhous, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Springs, MD 20910. D. F. Wirth, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115. A. M. J. Oduola, Special Program for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland.

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