Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Htun, Myo Win; Mon, Nan Cho Nwe; Aye, Khin Myo; Hlaing, Chan Myae; Kyaw, Myat Phone; Handayuni, Irene; Trimarsanto, Hidayat; Bustos, Dorina; Ringwald, Pascal; Price, Ric N.; Auburn, Sarah

doi:10.1186/s12936-017-1912-y

Cited by 25 publications

(23 citation statements)

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“…The present study showed that all samples were fixed at K76T and A220S mutations in pfcrt , but remained wild type at the pfmdr1 N86 and D1246. The high prevalence of mutations in pfcrt gene may be the result of continued drug pressure of CQ for treating P. vivax infections in Myanmar [ 64 ]. In pfmdr1 gene, Y184F had a frequency of 23.3% and there was no statistically significant association between Y184F and the day-3 parasite-positive and -negative phenotypes ( P = 1.000, Fisher’s exact test).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of artemether-lumefantrine for treating uncomplicated Plasmodium falciparum cases and molecular surveillance of drug resistance genes in Western Myanmar

Soe

Aung

et al. 2020

Malar J

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Background Currently, artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment in malaria-endemic areas. However, resistance in Plasmodium falciparum to artemisinin-based combinations emerging in the Greater Mekong Sub-region is a major problem hindering malaria elimination. To continuously monitor the potential spread of ACT-resistant parasites, this study assessed the efficacy of artemether-lumefantrine (AL) for falciparum malaria in western Myanmar. Methods Ninety-five patients with malaria symptoms from Paletwa Township, Chin State, Myanmar were screened for P. falciparum infections in 2015. After excluding six patients with a parasite density below 100 or over 150,000/µL, 41 P. falciparum patients were treated with AL and followed for 28 days. Molecular markers associated with resistance to 4-amino-quinoline drugs ( pfcrt and pfmdr1 ), antifolate drugs ( pfdhps and pfdhfr ) and artemisinin ( pfk13 ) were genotyped to determine the prevalence of mutations associated with anti-malarial drug resistance. Results For the 41 P. falciparum patients (27 children and 14 adults), the 28-day AL therapeutic efficacy was 100%, but five cases (12.2%) were parasite positive on day 3 by microscopy. For the pfk13 gene, the frequency of NN insert after the position 136 was 100% in the day-3 parasite-positive group as compared to 50.0% in the day-3 parasite-negative group, albeit the difference was not statistically significant ( P = 0.113). The pfk13 K189T mutation (10.0%) was found in Myanmar for the first time. The pfcrt K76T and A220S mutations were all fixed in the parasite population. In pfmdr1 , the Y184F mutation was present in 23.3% of the parasite population, and found in both day-3 parasite-positive and -negative parasites. The G968A mutation of pfmdr1 gene was first reported in Myanmar. Prevalence of all the mutations in pfdhfr and pfdhps genes assessed was over 70%, with the exception of the pfdhps A581G mutation, which was 3.3%. Conclusions AL remained highly efficacious in western Myanmar. Pfk13 mutations associated with artemisinin resistance were not found. The high prevalence of mutations in pfcrt , pfdhfr and pfdhps suggests high-degree resistance to chloroquine and antifolate drugs. The pfmdr1 N86/184F/D1246 haplotype associated with selection by AL in Africa reached...

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Section: Discussionmentioning

confidence: 99%

Efficacy of artemether-lumefantrine for treating uncomplicated Plasmodium falciparum cases and molecular surveillance of drug resistance genes in Western Myanmar

Soe

Aung

et al. 2020

Malar J

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“…Chloroquine and PQ are still the drugs of choice for the treatment of P. vivax in some countries, especially in Latin America [ 28 – 31 ]. However, CQRPv has emerged in several parts of the world [ 32 , 33 ], including Malaysia [ 30 ], Myanmar [ 34 ], India [ 33 ] and Brazil [ 7 , 35 ]. The molecular mechanism of CQRPv is still not well defined.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine resistance is associated to multi-copy pvcrt-o gene in Plasmodium vivax malaria in the Brazilian Amazon

Silva

Almeida

Silva

et al. 2018

Malar J

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BackgroundThe resistance of Plasmodium vivax to chloroquine has become an obstacle to control strategies based on the use of anti-malarials. The current study investigated the association between P. vivax CQ-resistance in vivo with copy number variation and mutations in the promoter region in pvcrt-o and pvmdr1 genes.MethodsThe study included patients with P. vivax that received supervised treatment with chloroquine and primaquine. Recurrences were actively recorded during this period.ResultsAmong the 60 patients with P. vivax, 25 were CQ-resistant and 35 CQ-susceptible. A frequency of 7.1% of multi-copy pvcrt-o was observed in CQ-susceptible samples and 7.7% in CQ-resistant at D0 (P > 0.05) and 33.3% in CQ-resistant at DR (P < 0.05). For pvmdr1, 10.7% of the CQ-susceptible samples presented multiple copies compared to 11.1% in CQ-resistant at D0 and 0.0% in CQ-resistant at DR (P > 0.05). A deletion of 19 bp was found in 11/23 (47.6%) of the patients with CQ-susceptible P. vivax and 3/10 (23.1%) of the samples with in CQRPv at D0. At day DR, 55.5% of the samples with CQRPv had the 19 bp deletion. For the pvmdr-1 gene, was no variation in the analysed gene compared to the P. vivax reference Sal-1.ConclusionsThis was the first study with 42-day clinical follow-up to evaluate the variation of the number of copies and polymorphisms in the promoter region of the pvcrt-o and pvmdr1 genes in relation to treatment outcomes. Significantly higher frequency of multi-copy pvcrt-o was found in CQRPv samples at DR compared to CQ-susceptible, indicating parasite selection of this genotype after CQ treatment and its association with CQ-resistance in vivo.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2411-5) contains supplementary material, which is available to authorized users.

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“…In the GMS, although CQ remains generally effective for the treatment of P. vivax cases [13][14], there have been sporadic reports of CQR P. vivax in most GMS countries. CQR P. vivax malaria has been documented in Myanmar as early as in 1993 [15][16][17], and in recent years clinical failures after CQ treatment have been reported in multiple regions of Myanmar [18,19]. Although the recurrent rates of P. vivax infections within 28 days of CQ treatment remained low in Vietnam (3.5%) and western Thailand (8%) [14,21], CQR P. vivax isolates have been confirmed in these areas [20,21].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Ex vivo susceptibilities of Plasmodium vivax isolates from the China-Myanmar border to antimalarial drugs and association with polymorphisms in Pvmdr1 and Pvcrt-o genes

Zhang

et al. 2020

PLoS Negl Trop Dis

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Background Vivax malaria is an important public health problem in the Greater Mekong Subregion (GMS), including the China-Myanmar border. Previous studies have found that Plasmodium vivax has decreased sensitivity to antimalarial drugs in some areas of the GMS, but the sensitivity of P. vivax to antimalarial drugs is unclear in the China-Myanmar border. Here, we investigate the drug sensitivity profile and genetic variations for two drug resistance related genes in P. vivax isolates to provide baseline information for future drug studies in the China-Myanmar border. Methodology/Principal findings A total of 64 P. vivax clinical isolates collected from the China-Myanmar border area were assessed for ex vivo susceptibility to eight antimalarial drugs by the schizont maturation assay. The medians of IC 50 (half-maximum inhibitory concentrations) for chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate, artemether, dihydroartemisinin were 84.2 nM, 34.9 nM, 4.0 nM, 22.3 nM, 41.4 nM, 2.8 nM, 2.1 nM and 2.0 nM, respectively. Twelve P. vivax clinical isolates were found over the cutoff IC 50 value (220 nM) for chloroquine resistance. In addition, sequence polymorphisms in pvmdr1 (P. vivax multidrug resistance-1), pvcrt-o (P. vivax chloroquine resistance transporter-o), and difference in pvmdr1 copy number were studied. Sequencing of the pvmdr1 gene in 52 samples identified 12 amino acid substitutions, among which two (G698S and T958M) were fixed, M908L were present in 98.1% of the isolates, while Y976F and F1076L were present in 3.8% and 78.8% of the isolates, respectively. Amplification of the pvmdr1 gene was only detected in 4.8% of PLOS NEGLECTED TROPICAL DISEASES

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Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Cited by 25 publications

References 50 publications

Efficacy of artemether-lumefantrine for treating uncomplicated Plasmodium falciparum cases and molecular surveillance of drug resistance genes in Western Myanmar

Efficacy of artemether-lumefantrine for treating uncomplicated Plasmodium falciparum cases and molecular surveillance of drug resistance genes in Western Myanmar

Chloroquine resistance is associated to multi-copy pvcrt-o gene in Plasmodium vivax malaria in the Brazilian Amazon

Ex vivo susceptibilities of Plasmodium vivax isolates from the China-Myanmar border to antimalarial drugs and association with polymorphisms in Pvmdr1 and Pvcrt-o genes

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