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The extensive data on the relationship between parasite genotype and susceptibility to antifolate drugs can now be coupled with pharmacokinetic information to allow construction of models of the selection and spread of antifolate-resistant Plasmodium falciparum. In this report, we have modeled the effect on resistance selection processes of combinations of antifolate antimalarial drugs with artesunate and with amodiaquine under a variety of conditions that can be defined by the user. The model is intended to assist policymakers in forecasting the useful therapeutic life (UTL) for a range of potential combination treatments. The model is especially designed for use by African malaria programs so that the interactions of key variables can be explored and appropriate combinations of drugs can be chosen for field testing. The model provides some important general conclusions: 1) for optimal extension of UTL, combination therapy must be deployed before either constituent drug is used as monotherapy; 2) even short periods of monotherapy can severely limit the usefulness of subsequent combination therapy; and 3) that adding a second drug to rescue an antifolate antimalarial that is overtly failing is an inappropriate and ultimately wasteful exercise.
Received February 19, 2004. Accepted for publication July 26, 2004.
Acknowledgments: We are grateful to professors S. A. Ward and P. A. Winstanley (University of Liverpool) for their comments and suggestions.
Financial support: Ian M. Hastings is grateful to the Department for International Development-funded Malaria Knowledge Program of the Liverpool School of Tropical Medicine. This work was partly supported by National Institutes of Health grant AI-55604 to Carol Hopkins Sibley. William M. Watkins is grateful to the Wellcome Trust of Great Britain for research and personal support (grant no. 056305).
Disclaimer: The Department for International Development accepts no responsibility for any information or views expressed.
Authors’ addresses: William M. Watkins, 1 Forge Cottages, Mudford, Somerset BA21 5TJ, United Kingdom, E-mail: bwatkins{at}btinternet.com. Carol Hopkins Sibley, Department of Genome Sciences, Box 357730, University of Washington,, Seattle, WA 98195-7730, E-mail: sibley{at}gs.washington.edu. Ian M. Hastings, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L69 3BX, United Kingdom, E-mail: hastings{at}liverpool.ac.uk.
* The Global Fund for AIDS, Tuberculosis and Malaria (GFATM): www.globalfundatm.org.
SP-total failure is defined as the sum of early and late treatment failures in the World Health Organization in vivo test.21
Dapsone (4 mg/kg) plus chlorproguanil (1.4 mg/day) for a three-day period was used in the Thai study.
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