Measuring windows of selection for anti-malarial drug treatments

Katherine Kay, Ian M Hastings

The 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. The 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. The 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. Previous 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.