Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum

Abstract

Delaying and slowing antimalarial drug resistance evolution is a priority for the World Health Organization and for National Malaria Control Programs in malaria-endemic countries. Until novel therapies become available, the mainstay of antimalarial treatment will continue to be artemisinin combination therapy (ACT), with artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine the three primary therapies deployed worldwide. Deployment of ACTs can be optimized to minimize evolutionary pressure for drug resistance by deploying them as a set of co-equal multiple first-line therapies (MFT) rather than rotating therapies in and out of use. Here, we consider one potential detriment of MFT policies, namely, that the simultaneous deployment of multiple ACTs could drive the evolution of different resistance alleles concurrently and that these resistance alleles could then be brought together by recombination into double-resistant or triple-resistant parasites. Using an individual-based Plasmodium falciparum transmission model, we compare MFT and cycling policies over 20-year periods in malaria transmission settings ranging from 0.1% to 25% Plasmodium falciparum prevalence (PfPR2-10). We define a total risk measure for multi-drug resistance (MDR) by summing the area under the genotype-frequency curves (AUC) of double- and triple-resistant genotypes. When PfPR [≥] 1%, total MDR risk as measured by AUC is 4% to 90% lower under MFT policies than under cycling policies, irrespective of whether resistance is imported or emerges de novo. When PfPR = 0.1%, there is little statistical difference in MDR risk between MFT and cycling.