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Efficacy, Safety, and Selection of Molecular Markers of Drug Resistance by Two ACTs in Mali

We conducted a randomized single-blinded trial comparing the efficacy and safety of artesunate (AS) + amodiaquine (AQ, 3 days) versus AS (3 days) + sulfadoxine–pyrimethamine (SP, single dose) versus AS monotherapy (5 days) in Southern Mali. Uncomplicated malaria cases were followed for 28 days. Molecular markers of drug resistance were determined. After identification of recrudescences by genotyping, both artemisinin-based combination therapies (ACTs) reached nearly 100% efficacy at Day 14 and Day 28 versus 98.3% and 96.5% for AS, respectively (P > 0.05). AS + SP significantly selected DHFR and DHPS mutations associated with sulfadoxine and pyrimethamine resistance (P < 0.001), and AS + AQ equally selected PfCRT and PfMDR1 point mutations associated with chloroquine and AQ resistance (P < 0.001). No significant adverse event attributable to any of the study drugs was found. The ACTs were efficacious and safe, but the selection of markers for resistance to the partner drugs raises concerns over their lifespan in areas of intense malaria transmission.

Received August 7, 2007. Accepted for publication December 10, 2007.

Acknowledgments: The authors thank the local guides of Bougoula-Hameau (Chiaka Traore, Bourama Diarra, and Karim Traore), the Village council, the entire population of Bougoula-Hameau, and Health and Administrative authorities of Sikasso for their help and support during the study. The authors thank Mr. Ousmane Toure for help with graphics. We are grateful to Dr. Valerie Lameyre for her help and support for this study. This work was supported by Access to Medicines, Sanofi-Aventis, and by the International Atomic Energy Agency (grant RAF/6025). A.A.D. is supported by European and Developing Countries Clinical Trial Partnership Senior Fellowship (grant 2004.2.C.f1) and Howard Hughes Medical Institution International Scholarship (grant 55005502).

^* Address correspondence to Abdoulaye A. Djimdé, Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of Bamako, PO Box 1805, Point G, Bamako, Mali (West Africa). E-mail: adjimde{at}mrtcbko.org

Authors’ addresses: Abdoulaye A. Djimdé, Bakary Fofana, Issaka Sagara, Bakary Sidibe, Sekou Toure, Demba Dembele, Souleymane Dama, Dinkorma Ouologuem, Alassane Dicko, and Ogobara K. Doumbo, Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology (DEAP/FMPOS), University of Bamako, PO Box 1805, Point G, Bamako, Mali (West Africa), Telephone/Fax: + 223-222-81-09, E-mail: adjimde{at}mrtcbko.org.

Reprint requests: Abdoulaye A. Djimdé, MRTC/FMPOS, Point G, Bamako, Mali (West Africa), Telephone: + 223-222-8109, E-mail: adjimde{at}mrtcbko.org.