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.

FIG. 1.

Summary of trial arms and patient numbers.

FIG. 2.

Underestimation of the true treatment failure rate. Box plots show the median percentage (25 to 75% interquartile range; range) of true treatment failures not detected by day 14 (black box) and corresponding proportions of failures not detected by day 28 (white box) for antimalarial drugs with short (A), medium (B) and long (C) elimination half-lives. The true failure rate was considered the PCR genotype-confirmed failure rate at day 63.

FIG. 3.

Relationship of malaria transmission intensity to underestimation of failure rate. Index plots of day 14 (•) and the corresponding day 28 failure rates (○) for the malaria transmission categories in order, from left to right, of increasing day 14 failure rates. PCR genotype-corrected results are shown. Each pair of dots corresponds to one trial arm. (A) Low transmission intensity. Estimated EIR, <2 infectious bites/person/year. (B) Medium transmission intensity. EIR, 2 to 10 infectious bites/person/year. (C) High transmission intensity. EIR, >10 infectious bites/person/year.

FIG. 4.

The relationship between the day 14 parasitological assessment and the failure rate at the maximum period of follow-up (maximum observed failure rate). Each circle represents a trial result in which the PCR genotype-corrected maximum failure rate was known at the end of follow-up. Black circles (•) denote results for trial arms with 63 or 42 days of follow-up, and the hollow circles (○) correspond to arm trials with 28 days of follow-up. Note that a failure rate at day 14 cannot exceed the maximum failure rate (lower triangle). A day 14 failure rate (vertical dotted line) of 25% has been recommended as the threshold for antimalarial drug policy change.

FIG. 5.

Relationship between the proportion of antimalarial treatment failures detected and the duration of follow-up for (A) short half-life, (B) medium half-life, and (C) long half-life antimalarial drugs. PCR genotype-corrected results are shown.

FIG. 6.

Relative utility of (A) day 14 assessment and (B) day 28 assessment in predicting true failure rate. PCR genotype-corrected results are shown.

FIG. 7.

Relationship between the proportion of recurrent infections during a 63-day follow-up period which are true recrudescences and the overall true failure rate in low-transmission settings. PCR genotype-corrected data are shown.