title: How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?
abstract: Artemisinin-based 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 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. 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 overconfidence, as even quite substantial reductions in drug sensitivity may not be detected as lower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regimen 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 regimen changes, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears overreliant on a single metric of drug effectiveness, the parasite clearance rate, that has significant and serious shortcomings.
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom Ian.Hastings@LSTMed.ac.uk.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Hastings
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kay
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Eva Maria
authors.identifier: http://orcid.org/0000-0001-5821-1685
authors.initials: EM
authors.lastname: Hodel
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D037621:Artemisinins / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077332:Artesunate; D002648:Child; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D004351:Drug Resistance; D006801:Humans; D007113:Immunity, Innate; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D015767:Mefloquine / Q000493:pharmacokinetics / Q000494:pharmacology; D015233:Models, Statistical; D018512:Parasitemia / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D004338:Drug Combinations; D015767:Mefloquine; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines