Fitness cost of resistance for lumefantrine and piperaquine-resistant plasmodium berghei in a murine model

Abstract

The evolution of drug resistant malaria parasites poses a large threat for the effective control of malaria. The behavior of drug-resistant mutants in the absence of drug pressure is of clinical relevance. Reports on how development of resistance in field populations of malaria parasites impacts on parasite fitness are very few. Moreover, information regarding fitness cost of resistance in malaria parasites is ambivalent, although available data is largely skewed towards loss of fitness of the resistant mutants relative to the wil~-type forms. The aim of this study was to investigate how resistance against two quinoline-based antimalarial drugs; lumefantrine (LM) and piperaquine (PQ) impacts parasite fitness. The stability of P. berghei ANKA lines that had been previously selected for LM and PQ resistance was evaluated using 4-day and established infection tests in mice. Drug sensitivity studies confirmed that PQ resistance was stable. During serial passaging in the absence of the drug, resistant parasite maintained low growth rates (parasiternia=5.6o/o±2.3)relative to the wild-type (28.4o/o±6.6)translating into a fitness cost of resistance of 80.3% for the resistant line. The resistant parasite was less fit than the wild-type, therefore would more likely to be outcompeted by the sensitive parasite even in the field, in the absence of drug pressure. Considering the recent reports of high failure rates associated with Artemisinin-based combination therapies/ACTs; the currently most potent antimalarial drugs; this finding is relevant as piperaquine is one of the long-acting partner drugs used. Understanding of fitness costs associated with resistance may aid in the development of effective malaria control strategies, since in malariaendemic counties such as Kenya, even partial resumption of drug sensitivity may positively impact public health