How robust are malaria parasite clearance rates as indicators of drug effectiveness and resistance?

Artemisinin combination therapies (ACTs) are currently the first line drugs for treating uncomplicated falciparum malaria, the most deadly of the human malarias. Malaria parasite clearance rates estimated from patients' blood following ACT treatment have been widely adopted as a measure of drug effectiveness and as surveillance tools for detecting the presence of potential artemisinin drug resistance. This metric has not been investigated in detail, nor have its properties or potential shortcomings been identified. Herein, the pharmacology of drug treatment, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following ACT treatment. This approach parsimoniously recovers the principal clinical features and dynamics of clearance. Human immunity is the primary determinant of clearance rates unless, or until, artemisinin killing has fallen to near-ineffective levels. Clearance rates are therefore highly insensitive metrics for surveillance that may lead to over-confidence as even quite substantial reductions in drug sensitivity may not be detected as slower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regime changes as this strategy will plausibly miss even very substantial increases in drug effectiveness. In particular, the malaria community may be missing the opportunity to dramatically increase ACT effectiveness through changes in regimen, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears over reliant on a single metric of drug effectiveness, parasite clearance rate that has significant and serious shortcomings.