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.

Fosmidomycin plus Clindamycin for Treatment of Pediatric Patients Aged 1 to 14 Years with Plasmodium falciparum Malaria

“…The extension of follow-up to 28 days increased the sensitivity of the in vivo test (25), providing more precise estimates of the efficacy of an antimalarial drug. This advantage, however, is at least partly offset by the difficulty in reliably distinguishing recrudescent from new, and hence confounding, infections.…”

Molecular genotyping to distinguish between recrudescents and new infections in treatment trials of Plasmodium falciparum malaria conducted in Sub‐Saharan Africa: adjustment of parasitological outcomes and assessment of genotyping effectiveness

“…The optimal length of follow up for high transmission areas has not yet been established. With good evidence that the previously recommended 14-day protocol underestimates treatment failure rates, an extended period of follow up is needed (White 2002;WHO 2003;Stepniewska et al 2004). The World Health Organization (WHO) now recommends follow up for 28 (for chloroquine and amodiaquine) 42 (for sulfadoxine-pyrimethamine and artemether-lumefantrine) and 63 days (for mefloquine), provided polymerase chain reaction (PCR) is available to reliably distinguish between new and recrudescent infections (WHO 2003).…”

Efficacy of chloroquine, sulfadoxine–pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria among children under five in Bongor and Koumra, Chad

“…Moreover, the 28-day follow-up, combined with PCR analysis, provided more realistic estimates of efficacy than traditional 14-day studies (Stepniewska et al, 2004). The major limitation of our studies was the method of treatment allocation, which was not randomized.…”