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Prior to the 2001 malarial treatment policy change in Tanzania, we conducted trials to assess the efficacy of sulfadoxine-pyrimethamine (SP) and the usefulness of molecular markers in monitoring resistance. A total of 383 uncomplicated Plasmodium falciparum malaria patients (between 6 and 59 months old) were treated with SP and their responses were assessed. Mutations in the P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes in admission day blood samples were analyzed. Results indicated that 85.6% of the patients showed an adequate clinical response, 9.7% an early treatment failure, and 4.7% a late treatment failure. The quintuple mutant genotype (pfdhfr 51 Ile, 59 Arg, and 108 Asn and pfdhps 437 Gly and 540 Glu) showed an association with treatment outcome (odds ratio = 2.1; 95% confidence interval = 0.94–4.48, P = 0.045). The prevalence of the triple pfdhfr mutant genotype (51 Ile, 59 Arg, and 108 Asn) at a site of high SP resistance (23.6%) was four times higher compared with that observed at sites of moderate SP resistance (6.8–14.4%) (P = 0.000001). The genotype failure index calculated by using this marker was invariable (1.96–2.1) at sites with moderate SP resistance, but varied (3.4) at a site of high SP resistance. In conclusion, our clinical and molecular findings suggest that SP may have a short useful therapeutic life in Tanzania; thus, its adoption as an interim first-line antimalarial drug. The findings also point to the potential of the triple pfdhfr mutant genotype as an early warning tool for increasing SP resistance. These data form the baseline SP efficacy and molecular markers profile in Tanzania prior to the policy change.
Received November 17, 2003. Accepted for publication June 16, 2004.
Acknowledgments: We thank the Tanzania Ministry of Health, the NMCP, and the East African Network for Monitoring Antimalarial Treatment (EANMAT) for coordinating the study in the sentinel sites. The sample collection exercise in some sites was also part of EANMAT activities of antimalarial sensitivity testing. We are grateful to the Swiss Tropical Institute for facilitating acquisition of molecular biological reagents and chemicals. We also thank the laboratory team at the IHRDC, including John Malugu, Magdalena Kiulugo, and Selina Churu for their hard working spirit. Lastly, we thank the individual clinical and field officers who performed the on site duties and the parents/guardians of all children who volunteered and consented to participate.
Financial support: These studies were supported by Multilateral Initiative on Malaria-United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases (TDR). The IHRDC receives core financial support from Swiss Agency for Development and Cooperation. The International Atomic Energy Agency and the Swiss Tropical Institute provided laboratory equipment and personnel training. The PhD program of Kefas Mugittu was supported by the TDR.
Authors’ addresses: Kefas Mugittu, Ifakara Health Research and Development Centre, Box 53, Ifakara, Tanzania, Telephone: 255-23-2625164, Fax: 255-23-2625312, E-mail: Kmugittu{at}ifakara.mimcom.net and Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland, E-mail: Kefas.Mugittu{at}unibas.ch. Modesta Ndejembi, Allen Malisa, Salim Abdulla, and Hassan Mshinda, Ifakara Health Research and Development Centre, Box 53, Ifakara, Tanzania, Telephone: 255-23-2625164, Fax: 255-23-2625312, E-mails: mndejembi{at}ifakara.mimcom.net, amalisa{at}ifakara.mimcom.net, sabdulla{at}ifakara.mimcom.net, and hmshinda{at}ifakara.mimcom.net. Martha Lemnge, National Institute for Medical Research Box 4, Amani, Tanga, Tanzania, Telephone: 255-27-2640303, Fax: 255-27-2643869, E-mail: mlemnge{at}amani.mimcom.net. Zulfikar Premji, Muhimbili College of Health Sciences, PO Box 65011, Dar es Salaam, Tanzania, Telephone: 255-22-2153419, Fax: 255-22-2150563, E-mail: zpremji{at}muchs.ac.tz. Alex Mwita, National Malaria Control Program, PO Box 9083, Dar es Salaam, Tanzania, E-mail: mwitanmcp{at}raha.com. Watoky Nkya, Kilimanjaro Christian Medical Centre, Box 3010, Moshi, Tanzania, Telephone: 255-27-54377-83, Fax: 255-27-53826, E-mail: wnkya{at}kcmc.tz. Johannes Kataraihya, Bugando Medical Centre, PO Box 1370, Mwanza, Tanzania, Telephone: 255-28-2500513, Fax: 255-28-2500799, E-mail: jbkataraihya{at}hotmail.com. Hans-Peter Beck, Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland, Telephone: 41-61-284 8116, Fax: 41-61-271 8654, E-mail: Hans-Peter.Beck{at}unibas.ch.
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