title: In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up.
abstract: 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 (r(2) = 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.
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand.
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.forename: Ric
authors.initials: R
authors.lastname: Price
authors.forename: Frank
authors.initials: F
authors.lastname: Smithuis
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Guthmann
authors.forename: Karen
authors.initials: K
authors.lastname: Barnes
authors.forename: Hla Yin
authors.initials: HY
authors.lastname: Myint
authors.forename: Martin
authors.initials: M
authors.lastname: Adjuik
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Sasithon
authors.initials: S
authors.lastname: Pukrittayakamee
authors.forename: Sornchai
authors.initials: S
authors.lastname: Looareesuwan
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
mesh_terms: D000465:Algorithms; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004351:Drug Resistance; D023381:Endpoint Determination; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D000962:Antimalarials