Abstract
BackgroundThe long half-lives of malaria ‘partner’ drugs are a potent force selecting for drug resistance. Clinical trials can quantify this effect by estimating a window of selection (WoS), defined as the amount of time post-treatment when drug levels are sufficiently high that resistant parasites can re-establish an infection while preventing drug-sensitive parasites from establishing viable infections.MethodsThe ability of clinical data to accurately estimate the true WoS was investigated using standard pharmacokinetic–pharmacodynamic models for three widely used malaria drugs: artemether–lumefantrine (AR-LF), artesunate–mefloquine (AS-MQ) and dihydroartemisinin–piperaquine (DHA-PPQ). Estimates of the clinical WoS either (1) ignored all new infections occurring after the 63-day follow-up period, as is currently done in clinical trials, or, (2) recognized that all individuals would eventually be re-infected and arbitrarily assigned them a new infection day.ResultsThe results suggest current methods of estimating the clinical WoS underestimate the true WoS by as much as 9 days for AR-LF, 33 days for AS-MQ and 7 days for DHA-PPQ. The new method of estimating clinical WoS (i.e., retaining all individuals in the analysis) was significantly better at estimating the true WoS for AR-LF and AS-MQ.ConclusionsPrevious studies, based on clinically observed WoS, have probably underestimated the ‘true’ WoS and hence the role of drugs with long half-lives in driving resistance. This has important policy implications: high levels of drug use are inevitable in mass drug administration programmes and intermittent preventative treatment programmes and the analysis herein suggests these policies will be far more potent drivers of resistance than previously thought.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0810-4) contains supplementary material, which is available to authorized users.
Highlights
The long half-lives of malaria ‘partner’ drugs are a potent force selecting for drug resistance
Previous studies, based on clinically observed window of selection (WoS), have probably underestimated the ‘true’ WoS and the role of drugs with long half-lives in driving resistance. This has important policy implications: high levels of drug use are inevitable in mass drug administration programmes and intermittent preventative treatment programmes and the analysis suggests these policies will be far more potent drivers of resistance than previously thought
The rapid elimination of artemisinin means the partner drugs are present as a monotherapy during this prophylactic period, which may be a potent force selecting for resistant parasites
Summary
The long half-lives of malaria ‘partner’ drugs are a potent force selecting for drug resistance. The rapid elimination of artemisinin means the partner drugs are present as a monotherapy during this prophylactic period, which may be a potent force selecting for resistant parasites. This process can drive increasing drug tolerance to the partner drug and the eventual loss of therapeutic effectiveness, resulting in failure of the ACT [4,5,6]. Mass drug deployment (MDA) policies were widely used in the 1950s and 1960s (reviewed by Von Seidlein and Greenwood [7]), but fell from favour as, used in isolation, they had only a transitory effect on malaria transmission and drove drug
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