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Antimicrobial Agents and Chemotherapy, November 2004, p. 4271-4280, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4271-4280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up

Faculty of Tropical Medicine, Mahidol University, Bangkok,¹ Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand,¹⁰ Tropical Diseases Research, World Health Organization, Geneva, Switzerland,³ Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration, Vientiane, Lao People's Democratic Republic,⁴ Medecins sans Frontières-Holland, Yangon, Myanmar,⁵ Epicentre, Paris, France,⁶ Department of Pharmacology, University of Cape Town, Cape Town, South Africa,⁷ Oxford University Clinical Research Unit,⁹ Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam,⁸ Centre for Tropical Medicine and Vaccinology, Churchill Hospital, Oxford, United Kingdom²

Received 2 February 2004/ Returned for modification 5 February 2004/ Accepted 8 May 2004

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r² = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.

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