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Antimicrobial Agents and Chemotherapy, December 2002, p. 3947-3953, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3947-3953.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Therapeutic Efficacies of Artesunate-Sulfadoxine-Pyrimethamine and Chloroquine-Sulfadoxine-Pyrimethamine in Vivax Malaria Pilot Studies: Relationship to Plasmodium vivax dhfr Mutations

Emiliana Tjitra,1,2 Joanne Baker,3 Sri Suprianto,4 Qin Cheng,3 and Nicholas M. Anstey2,5*

National Institute of Health Research and Development, Ministry of Health,1 Directorate-General of Communicable Disease Control and Environmental Health, Ministry of Health, Jakarta, Indonesia,4 International Health Program, Division of Infectious Diseases, Menzies School of Health Research,2 Division of Medicine, Flinders University Northern Territory Clinical School, Darwin, Northern Territory,5 Australian Army Malaria Institute, Enoggera, Queensland, Australia3

Received 4 June 2002/ Returned for modification 5 August 2002/ Accepted 5 September 2002

Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T->M mutation at residue 61 linked to an S->T (but not an S->N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.

* Corresponding author. Mailing address: International Health Programme, Division of Infectious Diseases, Menzies School of Health Research, P.O. Box 41096, Casuarina, Darwin, Northern Territory, 0811 Australia. Phone: 61-8-8922 8932. Fax: 61-8-8927 5187. E-mail: anstey{at}menzies.edu.au.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3947-3953, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3947-3953.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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