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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

Kasia Stepniewska,1,2 Walter R.J. Taylor,3 Mayfong Mayxay,4 Ric Price,1,2 Frank Smithuis,5 Jean-Paul Guthmann,6 Karen Barnes,7 Hla Yin Myint,1 Martin Adjuik,3 Piero Olliaro,3 Sasithon Pukrittayakamee,1 Sornchai Looareesuwan,1 Tran Tinh Hien,8 Jeremy Farrar,9 François Nosten,1,2,10 Nicholas P.J. Day,1,2 and Nicholas J. White1,2*

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.

* Corresponding author. Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: (66) 2 354 9172. Fax: (66) 2 354 9169. E-mail: nickw{at}tropmedres.ac.

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.



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