Phenotypic and genotypic characterisation of drug-resistant Plasmodium vivax

Abstract

In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance.

Figure 1

Reports of CQR Plasmodium vivax in 2009. Red stars highlight areas of confirmed resistance as defined by greater than 10% recurrence (and greater than five clinical treatment failures) by day 28 with or without measurement of chloroquine drug concentration; orange diamonds locate area suggestive of resistance as defined by less than 10% recurrence (or less than five clinical treatment failures) by day 28, with chloroquine drug concentrations; yellow circles locate sites of possible resistance as defined by less than 10% recurrence (or less than five clinical treatment failures) by day 28, without drug concentrations. Adapted from [16].

Figure 2

Ex vivo drug susceptibility for isolates initially at majority ring stage (black bars) and majority trophozoite stage (white bars). Marked reduced susceptibility of P. vivax and P. malariae trophozoites to chloroquine (CQ) compared to ring stages. This difference is not apparent in P. falciparum or following exposure to amodiaquine (AQ) or mefloquine (MFQ). Data derived from [36,49,90].