Abstract
Drug resistance in Plasmodium vivax may pose a challenge to malaria elimination. Previous studies have found that P. vivax has a decreased sensitivity to antimalarial drugs in some areas of the Greater Mekong Sub-region. This study aims to investigate the ex vivo drug susceptibilities of P. vivax isolates from the China–Myanmar border and genetic variations of resistance-related genes. A total of 46 P. vivax clinical isolates were assessed for ex vivo susceptibility to seven antimalarial drugs using the schizont maturation assay. The medians of IC50 (half-maximum inhibitory concentrations) for chloroquine, artesunate, and dihydroartemisinin from 46 parasite isolates were 96.48, 1.95, and 1.63 nM, respectively, while the medians of IC50 values for piperaquine, pyronaridine, mefloquine, and quinine from 39 parasite isolates were 19.60, 15.53, 16.38, and 26.04 nM, respectively. Sequence polymorphisms in pvmdr1 (P. vivax multidrug resistance-1), pvmrp1 (P. vivax multidrug resistance protein 1), pvdhfr (P. vivax dihydrofolate reductase), and pvdhps (P. vivax dihydropteroate synthase) were determined by PCR and sequencing. Pvmdr1 had 13 non-synonymous substitutions, of which, T908S and T958M were fixed, G698S (97.8%) and F1076L (93.5%) were highly prevalent, and other substitutions had relatively low prevalences. Pvmrp1 had three non-synonymous substitutions, with Y1393D being fixed, G1419A approaching fixation (97.8%), and V1478I being rare (2.2%). Several pvdhfr and pvdhps mutations were relatively frequent in the studied parasite population. The pvmdr1 G698S substitution was associated with a reduced sensitivity to chloroquine, artesunate, and dihydroartemisinin. This study suggests the possible emergence of P. vivax isolates resistant to certain antimalarial drugs at the China–Myanmar border, which demands continuous surveillance for drug resistance.
Highlights
Plasmodium vivax is the most widely distributed malaria parasite, which can cause life-threatening diseases
There is no correlation between the IC50 values of the seven antimalarial drugs of the parasite isolates in the study, except for a weak correlation between DHA and CQ (Figure 1B, r = 0.34, P < 0.05)
Comparison with other ex vivo testing conducted in other endemic areas such as central China (Lu et al, 2011a), Thailand (Tjitra et al, 2008), South Korea (Chotivanich et al, 2009), Colombia (Fernández et al, 2014), and Indonesia (Pava et al, 2016), the CQ IC50 value for the China–Myanmar border isolates was lower than Thailand and Indonesia but higher than the IC50 value for parasites from the other regions
Summary
Plasmodium vivax is the most widely distributed malaria parasite, which can cause life-threatening diseases. Countries within the Greater Mekong Sub-region (GMS) are pursuing malaria elimination by 2030 (WHO, 2015). As the GMS is progressing toward eliminating P. falciparum by 2025, the proportion of malaria cases caused by P. vivax infections has increased steadily. In most vivax-endemic areas, the combination of chloroquine (CQ) and primaquine remains the first-line treatment for uncomplicated P. vivax, but CQ resistance has been an increasing concern. Artemisinin-based combination therapies (ACTs) as a unified treatment of P. falciparum and P. vivax infection may have significant advantages in areas where both species coexist (Douglas et al, 2010), ACT treatment of vivax malaria is commonly deployed in areas such as Indonesia, where P. vivax CQ resistance was evident (Baird, 2011)
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