Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Abstract

Purpose of review: Artemisinin-based combination therapies (ACTs) have been deployed globally with remarkable success for more than 10 years without having lost their malaria treatment efficacy. However, recent reports from the Thai-Cambodian border reveal evidence of emerging resistance to artemisinins. The latest published clinical and molecular findings are summarized herein.

Recent findings: Clinical studies have identified delayed parasite clearance time as the most robust marker of artemisinin resistance. Resistance has only been documented from South-east Asia and has been observed in isolates that show no significant decrease in drug susceptibility in vitro. Genetic investigations have yet to uncover robust molecular markers. In-vitro studies have identified parasite quiescence or dormancy mechanisms that protect early 'ring-stage' intra-erythrocytic parasites against short-term artemisinin exposure. This might be achieved by reducing the rate of hemoglobin degradation, important for artemisinin bioactivation.

Summary: Should ACTs fail, no suitable alternatives exist as first-line treatments of P. falciparum malaria. Intensified efforts are essential to monitor the spread of resistance, define therapeutic and operational strategies to counter its impact, and understand its molecular basis. Success in these areas is critical to ensuring that recent gains in reducing the burden of malaria are not lost.

Figure 1. Current global distribution of artemisinin-based combination therapies as the first-line treatment of uncomplicated falciparum malaria

This distribution was collated from maps of country-wide artemisinin-based combination therapy use, as published in [1]. , Artemether–lumefantrine; , dihydroartemisinin–piperaquine; , artesunate–amodiaquine; , artesunate–mefloquine; , artesunate–sulphadoxine/pyrimethamine.

Figure 2. Schematic representation of recent events relating to the emergence of and response to artemisinin resistance

AFRIMS, Armed Forces Research Institute of Medical Sciences; ARC3, artemisinin resistance project: pilot studies to confirm, characterize and plan for containment; the Gates Foundation, Bill & Melinda Gates Foundation; GPARC, Global Plan for Artemisinin Resistance Containment; WHA, World Health Assembly; WHO, World Health Organization. Reproduced with permission from [1].

Figure 3. Depiction of an intra-erythrocytic Plasmodium falciparum parasite showing proteins and biological processes implicated in artemisinin action

Several parasite proteins have been implicated in decreased susceptibility to artemisinins (ARTs), including PfATP6 (proposed to be in the endoplasmic reticulum [41]), PfMDR1 on the digestive vacuole [42], PfMRP1 on the parasite plasma membrane [43], and UBP-1 whose ortholog in Plasmodium chabaudi is associated with ART resistance [44]. The digestive vacuole protein PfCRT is also indicated as mutations that confer chloroquine resistance have been shown to significantly increase susceptibility to ARTs [45]. Host hemoglobin is delivered via cytostomes to the digestive vacuole, wherein it is proteolytically degraded. This liberates iron-heme (Fe-protoporphyrin IX) moieties, with subsequent oxidation of iron. Iron-heme is detoxified via its incorporation into hemozoin crystals. Iron-heme is thought to activate ARTs via interaction with the endoperoxide bridge, with the resulting ART radicals causing cellular damage [46^••]. Investigations of field isolates and drug-pressured laboratory lines have implicated quiescence or dormancy of early ring-stage parasites in resistance to ART action [–49^•]. ART, artemisinin; AP, apicoplast; Cs, cytostome; DV, digestive vacuole; ER, endoplasmic reticulum; Hb, hemoglobin; Hz, hemozoin; MT, mitochondria; NUC, nucleus.