Plasmodium falciparum and Plasmodium vivax Demonstrate Contrasting Chloroquine Resistance Reversal Phenotypes

Abstract

High-grade chloroquine (CQ) resistance has emerged in both <i>Plasmodium falciparum</i> and <i>P. vivax</i> The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 <i>P. falciparum</i> and 34 <i>P. vivax</i> clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In <i>P. falciparum</i>, CQ 50% inhibitory concentrations (IC₅₀s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in <i>P. falciparum</i> was highly correlated with CQ susceptibility for all CQRRAs (<i>R</i>² = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in <i>P. falciparum</i> laboratory strains. In contrast, no reduction in the CQ IC₅₀s was observed with any of the CQRRAs in <i>P. vivax</i>, even in those isolates with high chloroquine IC₅₀s. The differential effect of CQRRAs in <i>P. falciparum</i> and <i>P. vivax</i> suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.