Plasmodium falciparum and P. vivax demonstrate contrasting chloroquine resistance reversal phenotypes [PublishAheadOfPrint]

High-grade chloroquine (CQ) resistance has emerged in both P. falciparum and P. vivax. The aim of the present study was to investigate 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 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay.

In P. falciparum, CQ 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 P. falciparum was highly correlated with CQ susceptibility for all CQRRAs: VP (R²=0.951), (R²=0.852), L7 (R²=0.962), and PQ (R²=0.901), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in CQ IC₅₀s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC₅₀s.

The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and potentially the likely mechanism of CQ resistance between these two species.

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