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A Randomized Controlled Trial

Toby Leslie, MSc; M. Ismail Mayan, MD; M. Anwar Hasan, MD; M. Hanif Safi; Eveline Klinkenberg, PhD; Christopher J. M. Whitty, FRCP; Mark Rowland, PhD

JAMA. 2007;297(20):2201-2209.

Context  In areas where Plasmodium falciparum and Plasmodium vivax coexist and treatments for the 2 species differ, misdiagnosis can lead to poor outcomes in either disease. A unified therapy effective against both species would reduce reliance on species-specific diagnosis, which in many areas is difficult to maintain. The antifolates are an important and affordable antimalarial class to which it is often assumed P vivax malaria is intrinsically resistant.

Objective  To test the relative efficacy and safety of 2 antifolate drugs against P vivax malaria and compare each with chloroquine.

Design, Setting, and Patients  An open-label randomized controlled trial comparing chloroquine, sulfadoxine-pyrimethamine, and chlorproguanil-dapsone for the treatment of P vivax malaria was conducted in eastern Afghanistan and northwestern Pakistan, areas in which P vivax malaria predominates. A total of 20 410 patients older than 3 years were screened; 767 patients (315 in Pakistan and 452 in Afghanistan) with confirmed P vivax malaria were enrolled and followed up daily for 4 days, then weekly for 28 days, between March 2004 and June 2006.

Main Outcome Measures  Complete clearance of parasites with no recrudescence by day 14. Secondary outcomes included being parasite-free by day 28, clinical failure, and anemia.

Results  By day 14, only 1 patient in the sulfadoxine-pyrimethamine group had parasites. By day 28, failure rates were found in 2 of 153 patients (1.3%) in the chloroquine group, 5 of 290 patients (1.7%) in the sulfadoxine-pyrimethamine group, and 27 of 272 patients (9.9%) in the chlorproguanil-dapsone group. Chlorproguanil-dapsone was less effective than sulfadoxine-pyrimethamine (adjusted odds ratio [OR], 6.4; 95% confidence interval [CI], 2.4-17.0; P<.001) and chloroquine (adjusted OR, 8.4; 95% CI, 2.0-36.5; P = .004). Chloroquine and sulfadoxine-pyrimethamine were equivalent in efficacy at day 28 (adjusted OR, 1.3; 95% CI, 0.3-7.0; P = .73). Chloroquine cleared gametocytes and asexual parasites more rapidly than sulfadoxine-pyrimethamine or chlorproguanil-dapsone did. All drugs were well tolerated.

Conclusions  Although chloroquine remains the drug of choice, antifolates are effective against P vivax malaria in South Asia. These drugs may be appropriate for unified treatment where species-specific diagnosis is unavailable, most likely in combination with other drugs.

Trial Registration  clinicaltrials.gov Identifier: NCT00158561

Author Affiliations: HealthNet TPO Malaria and Leishmaniasis Control Programme, Peshawar, Northwest Frontier Province, Pakistan (Drs Mayan, Hasan, and Klinkenberg, and Messrs Leslie and Safi); Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, England (Drs Whitty and Rowland, and Mr Leslie).

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