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.T he timely provision of effective antimalarial drugs is a public health priority in most of the developing world (1). The current generation of antimalarial drugs centers on artemisininbased combination therapies (ACTs), and recent reports that tolerance of and/or resistance to artemisinins is evolving (2-7) have caused considerable concern (8-12). ACTs remain largely effective in clearing malaria infections, but reduced parasite clearance rates (i.e., the rate at which parasitemia declines after treatment [13]) have been widely interpreted as indicating the presence of reduced parasite sensitivity to the artemisinin component and hence indicative of the early stages of resistance (2-12). Parasite clearance rates have also been used to evaluate the likely clinical impact of alterations in artemisinin or ACT dosing regimens (14) that may be able to increase ACT effectiveness and hence reduce the threat of resistance. It therefore seems reasonable to expect that parasite clearance rates are a well-validated, demonstrably robust measure of drug effectiveness and resistance. Unfortunately, this appears not to be the case, as reflected in concerns raised in recent commentaries (15-17). Herein, the pharmacology of drug action, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following...

Artemisinin Resistance and the Blame Game

“…They then make an unsupported assertion that the definition of "artemisinin resistance" by ourselves [2] may have contributed to a failure to contain artemisinin-based treatment failures in the greater Mekong area. This has put us firmly in the distinguished company of 2 other independent groups who also critically assessed the term 'artemisinin resistance' and with whom we shared similar conclusions [2][3][4].…”

Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

“…Immunity may therefore confound the interpretation of parasite clearance measures in drugefficacy studies. The operational implications of an effect of host immunity on parasite clearance measures are that in populations with high levels of immunity and faster parasite clearance, early signs of low-grade drug resistance could go undetected, and conversely, that in populations with lower immunity and slower parasite clearance, a false impression of reduced drug efficacy could arise (16)(17)(18). The available immunological evidence for this comes from previous single-study-site investigations, predominantly in hightransmission settings in Africa, which have reported conflicting associations between immunity and treatment failure to historical first-line treatments (e.g., chloroquine, sulfadoxine-pyrimethamine) and ACTs (19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

“…These do not satisfactorily explain why increasing dosing frequency does not increase parasite killing substantially and therefore accelerate parasite clearance and augment cure rates (13). Saturation of splenic clearance with accumulation of dead parasites in the circulation has been proposed to explain these apparent contradictions (58,59) but there is no evidence for this (51). The constructs used in the current and previous studies may be oversimplifications.…”