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Differential Effect of Regional Drug Pressure on Dihydrofolate Reductase and Dihydropteroate Synthetase Mutations in Southern Mozambique

Jaishree Raman^*, Brian Sharp, Immo Kleinschmidt, Cally Roper, Elizabeth Streat, Val Kelly, AND Karen I. Barnes

The prevalence and frequency of the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) mutations associated with sulfadoxine–pyrimethamine (SP) resistance at 13 sentinel surveillance sites in southern Mozambique were examined regularly between 1999 and 2004. Frequency of the dhfr triple mutation increased from 0.26 in 1999 to 0.96 in 2003, remaining high in 2004. The dhps double mutation frequency peaked in 2001 (0.22) but declined to baseline levels (0.07) by 2004. Similarly, parasites with both dhfr triple and dhps double mutations had increased in 2001 (0.18) but decreased by 2004 (0.05). The peaking of SP resistance markers in 2001 coincided with a SP–resistant malaria epidemic in neighboring KwaZulu-Natal, South Africa. The decline in dhps (but not dhfr) mutations corresponded with replacement of SP with artemether–lumefantrine as malaria treatment policy in KwaZulu-Natal. Our results show that drug pressure can exert its influence at a regional level rather than merely at a national level.

Received May 15, 2007. Accepted for publication September 21, 2007.

Acknowledgments: The authors thank the Global Fund for AIDS, Tuberculosis and Malaria, The South African Business Trust, and South African Department of Health for financial support without which this project would not have been possible, Ms. Natashia Morris for GIS support, members of the Database section of the Malaria Lead Programme, particularly Mr. Dayalan Govender, for assistance with database management, and 2 anonymous reviewers for their constructive comments.

Financial support: The Global Fund for Aids, Tuberculosis and Malaria (grants MAF-202-GO1-M-00 and MAF-202-GO2-M-00); The South African Business Trust; and The South African Department of Health.

^* Address correspondence to Jaishree Raman, Malaria Lead Programme, Medical Research Council, 491 Ridge Road, Overport, Durban, KZN, 4067 South Africa. E-mail: jaishree.raman{at}mrc.ac.za

Deceased.

Authors’ addresses: Jaishree Raman and Val Kelly, Malaria Lead Programme, Medical Research Council, 491 Ridge Road, Durban, 4067, KwaZulu-Natal, South Africa, Telephone: +27 31 203 4782, Fax: +27 31 203 4704, E-mails: jaishree.raman{at}mrc.ac.za and val.kelly{at}mrc.ac.za. Immo Kleinschmidt, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, England, Telephone: +44 207 927 2103, Fax: +44 207 636 8739, E-mail: immo.kleinschmidt{at}lshtm.ac.uk. Cally Roper, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, England, Telephone: +44 207 927 2331, Fax: +44 207 636 8739; E-mail: cally.roper{at}lshtm.ac.uk. Elizabeth Streat, Maputo Province Directorate of Health, Av. Gov. Raimundo Bila 438, Matola City, Maputo Province, Mozambique, Telephone: +258 2172 2929, Fax: +258 2172 2929, E-mail: lsdi_coord{at}tvcabo.co.mz. Karen I. Barnes, Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Groote Schuur Hospital, Old Main Road, Cape Town, 7707, Western Cape, South Africa, Telephone: +27 21 406 6294, Fax: +27 21 406 6759, E-mail: karen.barnes{at}uct.ac.za.