Amplification ofpvmdr1Associated with Multidrug‐ResistantPlasmodium vivax

Abstract

Amplification of pvmdr1 and single-nucleotide polymorphisms are correlated with susceptibility of P. vivax to multiple antimalarial drugs. Chloroquine and mefloquine appear to exert competitive evolutionary pressure on pvmdr1, similar to that observed with pfmdr1 in Plasmodium falciparum.

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

“…Data shown in Figure 3 indicate that pvmdr-1 amplification remains relatively rare worldwide, with the exception of Tak Province, Thailand (Supplemental Table 2). 16,25 The pvmdr-1 duplication has not reached prevalence rates more than 3% in any location outside Tak, and the only two isolates with three copies of pvmdr-1 so far characterized also came from Tak. 16 Interestingly, P. vivax isolates have been exposed to antimalarial drugs such as mefloquine (either alone or in combination with artesunate) in many other malaria-endemic sites, such as Brazil 6 and most of Southeast Asia, and to artesunate plus amodiaquine in Mauritania, 28 but pvmdr-1 gene amplification does not seem to have been positively selected by these antimalarial drug regimens in most of these malaria-endemic areas.…”

“…However, the lack of a robust, wellstandardized and widely applicable protocol for long-term continuous in vitro culture remains a major gap in P. vivax malaria research. 29 As an alternative, short-term ex vivo assays have been successfully used to monitor P. vivax resistance to CQ across Southeast Asia, 8,16,25,27 but so far there is no published report of in vitro antimalarial resistance patterns of Latin American strains of P. vivax. Moreover, comparing 50% inhibitory concentration (IC 50 ) values across different malaria-endemic sites and establishing cut-off IC 50 values for defining resistance to CQ and other antimalarial drugs is complicated by factors such as the varying proportion of early trophozoites in the initial blood sample (late trophozoites of P. vivax are usually CQ tolerant), 30 differences in the time delay between sample collection and in vitro analysis, and variation in the duration of the ex vivo assay.…”

“…31 Molecular markers can represent a more practical tool for monitoring introduction and spread of drug resistance in P. vivax populations. The ATP binding cassette transporters such as P-glycoprotein, which is encoded by the pvmdr-1 gene, have recently been shown to modulate P. vivax responses to CQ and other antimalarial drugs, 8,10,13,16,25 but further work is needed to assess the predictive value of assays focused on pvmdr-1 SNPs and copy number variation as resistance monitoring tools.…”

“…Amplification of the pvmdr-1 gene correlates with increased susceptibility to CQ and decreased susceptibility to amodiaquine, artesunate and mefloquine in vitro. 16 Because parasites are exposed to different drug treatment regimens in each country, local adaptation may theoretically favor parasites with increased pvmdr-1 copy number or select for Y976F alleles in different malaria-endemic sites.…”

Diagnosis and Treatment of Plasmodium vivax Malaria

“…[79][80][81][82] The inability to sustain in vitro growth restricts analysis of field isolates to a single time point making an assessment of reproducibility difficult. Despite its limitations, the current schizont maturation assay has demonstrated utility in discriminating parasite populations with different degrees of CQR, [83][84][85] characterizing drug susceptibility profiles of P. vivax to commonly used antimalarial drugs, 86,87 and screening susceptibility to novel therapeutic agents. [88][89][90][91][92][93] Development of methods capable of sustaining P. vivax in continuous in vitro culture will transform the current ex vivo assay, accommodating cryopreservation of field isolates to reduce the reliance on the analysis of fresh isolates.…”