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Published in: Malaria Journal 1/2017

Open Access 01-12-2017 | Research

Molecular surveillance of artemisinin resistance falciparum malaria among migrant goldmine workers in Myanmar

Authors: Myat Htut Nyunt, Bo Wang, Khin Myo Aye, Kyin Hla Aye, Jin-Hee Han, Seong-Kyun Lee, Kay Thwe Han, Ye Htut, Eun-Taek Han

Published in: Malaria Journal | Issue 1/2017

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Abstract

Background

Artemisinin resistance has been reported in Greater Mekong Sub-region countries, including Myanmar. After discovery of artemisinin resistance marker (K13), molecular surveillance on artemisinin resistance in endemic regions have been conducted. As the migrant population represents a high percentage of malaria cases, molecular surveillance of artemisinin resistance among migrant workers is of great concern.

Methods

A cross-sectional survey was conducted in Shwegyin Township, where migrants work in the goldmines. Blood samples were collected from uncomplicated Plasmodium falciparum-infected migrant workers by active and passive cases screening with rapid diagnostic testing (RDT) and microscopy. Amplification and sequence analysis of artemisinin resistance molecular markers, such as k13, pfarps10, pffd, pfmdr2, pfmrp1, pfrad5, and pfcnbp, were carried out and pfmdr1 copy number analysis was conducted by real-time PCR.

Results

Among the 100 falciparum-infected patients, most were male (90%), of working age (20–40 years) with median parasite density of 11,166 parasites/µL (range 270–110,472 parasites/µL). Artemisinin resistance molecular marker, k13 mutations were detected in (21/100, 21.0%) in which composed of a validated marker, C580Y (9/21, 42.9%) and candidate markers such as P574L (5/21, 23.8%), P667T (5/21, 23.8%) and M476I (2/21, 9.5%). Underlying genetic markers predisposing to become k13 mutants were found as V127M of pfarps10 (41/100, 41.0%), D153Y of pffd (64/100, 64.0%), T484I of pfmdr2 (58/100, 58.0%) and F1390I of pfmrp1 (24/100, 24.0%). The pfmdr1 copy number analysis revealed six copy numbers (1/100, 1.0%), three (2/100, 2.0%), two (8/100, 8.0%) and only one copy number (89/100, 89.0%). Only one sample showed both k13 mutation (P667T) and multiple copy number of pfmdr1.

Conclusions

High mutant rate of artemisinin resistance markers and relatively high pfmdr1 copy number among isolates collected from migrant goldmine workers alert the importance of containment measures among this target population. Clinical and molecular surveillance of artemisinin resistance among migrants should be scaled up.
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Literature
1.
go back to reference WHO. Guidelines for treatment of Malaria. Geneva: World Health Organization; 2015. WHO. Guidelines for treatment of Malaria. Geneva: World Health Organization; 2015.
2.
go back to reference WHO. Global report on antimalarial drug efficacy and drug resistance: 2000–2010. Geneva: World Health Organization; 2010. WHO. Global report on antimalarial drug efficacy and drug resistance: 2000–2010. Geneva: World Health Organization; 2010.
3.
go back to reference WHO. Status report: artemisinin and artemisinin-based combination therapy resistance. Geneva: World Health Organization; 2016. WHO. Status report: artemisinin and artemisinin-based combination therapy resistance. Geneva: World Health Organization; 2016.
4.
go back to reference Kyaw MP, Nyunt MH, Chit K, Aye MM, Aye KH, Lindegardh N, et al. Reduced susceptibility of Plasmodium falciparum to artesunate in southern Myanmar. PLoS ONE. 2013;8:e57689.CrossRefPubMedPubMedCentral Kyaw MP, Nyunt MH, Chit K, Aye MM, Aye KH, Lindegardh N, et al. Reduced susceptibility of Plasmodium falciparum to artesunate in southern Myanmar. PLoS ONE. 2013;8:e57689.CrossRefPubMedPubMedCentral
5.
go back to reference WHO. Strategic framework for artemisinin resistance containment in Myanmar (MARC) 2011–2015. Yangon: WHO country office for Myanmar; 2011. WHO. Strategic framework for artemisinin resistance containment in Myanmar (MARC) 2011–2015. Yangon: WHO country office for Myanmar; 2011.
6.
go back to reference WHO. Emergency response to artemisinin resistance in the Greater Mekong subregion. Regional framework for action 2013–2015. Geneva: World Health Organization; 2013. WHO. Emergency response to artemisinin resistance in the Greater Mekong subregion. Regional framework for action 2013–2015. Geneva: World Health Organization; 2013.
7.
go back to reference Wongsrichanalai C, Sibley CH. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance. Clin Microbiol Infect. 2013;19:908–16.CrossRefPubMed Wongsrichanalai C, Sibley CH. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance. Clin Microbiol Infect. 2013;19:908–16.CrossRefPubMed
8.
go back to reference WHO. World malaria report 2015. Geneva: World Health Organization; 2016. WHO. World malaria report 2015. Geneva: World Health Organization; 2016.
9.
go back to reference WHO. Strategy for malaria elimination in the Greater Mekong Subregion (2015–2030). Manila: World Health Organization Regional Office for the Western Pacific; 2015. WHO. Strategy for malaria elimination in the Greater Mekong Subregion (2015–2030). Manila: World Health Organization Regional Office for the Western Pacific; 2015.
10.
go back to reference Lwin KM, Imwong M, Suangkanarat P, Jeeyapant A, Vihokhern B, Wongsaen K. Elimination of Plasmodium falciparum in an area of multi-drug resistance. Malar J. 2015;14:319.CrossRefPubMedPubMedCentral Lwin KM, Imwong M, Suangkanarat P, Jeeyapant A, Vihokhern B, Wongsaen K. Elimination of Plasmodium falciparum in an area of multi-drug resistance. Malar J. 2015;14:319.CrossRefPubMedPubMedCentral
11.
go back to reference Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50–5.CrossRefPubMed Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50–5.CrossRefPubMed
12.
go back to reference MalariaGEN Plasmodium falciparum Community Project. Genomic epidemiology of artemisinin resistant malaria. eLife. 2016;5:e08714. MalariaGEN Plasmodium falciparum Community Project. Genomic epidemiology of artemisinin resistant malaria. eLife. 2016;5:e08714.
13.
go back to reference Takala-Harrison S, Clark TG, Jacob CG, Cummings MP, Miotto O, Dondorp AM, et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci USA. 2013;110:240–5.CrossRefPubMed Takala-Harrison S, Clark TG, Jacob CG, Cummings MP, Miotto O, Dondorp AM, et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci USA. 2013;110:240–5.CrossRefPubMed
14.
go back to reference Miotto O, Amato R, Ashley EA, MacInnis B, Almagro-Garcia J, Amaratunga C, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet. 2015;47:226–34.CrossRefPubMedPubMedCentral Miotto O, Amato R, Ashley EA, MacInnis B, Almagro-Garcia J, Amaratunga C, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet. 2015;47:226–34.CrossRefPubMedPubMedCentral
15.
go back to reference WHO. Global plan for artemisinin resistance containment (GPARC). Geneva: World Health Organization; 2011. WHO. Global plan for artemisinin resistance containment (GPARC). Geneva: World Health Organization; 2011.
16.
go back to reference Carrara VI, Lwin KM, Phyo AP, Ashley E, Wiladphaingern J, Sriprawat K, et al. Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai–Myanmar border, 1999–2011: an observational Study. PLoS Med. 2013;10:e1001398.CrossRefPubMedPubMedCentral Carrara VI, Lwin KM, Phyo AP, Ashley E, Wiladphaingern J, Sriprawat K, et al. Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai–Myanmar border, 1999–2011: an observational Study. PLoS Med. 2013;10:e1001398.CrossRefPubMedPubMedCentral
17.
go back to reference VBDC. Vector borne disease control center report. Naypyitaw: Ministry of Health; 2014. VBDC. Vector borne disease control center report. Naypyitaw: Ministry of Health; 2014.
19.
go back to reference Alker AP, Lim P, Sem R, Shan NK, Yi P, Bouth DM, et al. PFMDR1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian–Thai border. Am J Trop Med Hyg. 2007;76:641–7.PubMed Alker AP, Lim P, Sem R, Shan NK, Yi P, Bouth DM, et al. PFMDR1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian–Thai border. Am J Trop Med Hyg. 2007;76:641–7.PubMed
20.
go back to reference Win AA, Imwong M, Kyaw MP, Woodrow CJ, Chotivanich K, Hanboonkunupakarn B, et al. K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar. Malar J. 2016;15:110.CrossRefPubMedPubMedCentral Win AA, Imwong M, Kyaw MP, Woodrow CJ, Chotivanich K, Hanboonkunupakarn B, et al. K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar. Malar J. 2016;15:110.CrossRefPubMedPubMedCentral
21.
go back to reference Straimer J, Gnädig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347:428–31.CrossRefPubMed Straimer J, Gnädig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347:428–31.CrossRefPubMed
22.
go back to reference Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N Engl J Med. 2016;374:2453–64.CrossRefPubMedPubMedCentral Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N Engl J Med. 2016;374:2453–64.CrossRefPubMedPubMedCentral
23.
go back to reference Phyo AP, Jittamala P, Nosten FH, Pukrittayakamee S, Imwong M, White NJ, et al. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2016;16:61–9.CrossRefPubMedPubMedCentral Phyo AP, Jittamala P, Nosten FH, Pukrittayakamee S, Imwong M, White NJ, et al. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2016;16:61–9.CrossRefPubMedPubMedCentral
24.
go back to reference Nyunt MH, Hlaing T, Oo HW, Tin-Oo L-LK, Phway HP, Wang B, et al. Molecular assessment of artemisinin resistance markers, polymorphisms in the K13 propeller, and a multidrug-resistance gene in the eastern and western border areas of Myanmar. Clin Infect Dis. 2015;60:1208–15.CrossRefPubMed Nyunt MH, Hlaing T, Oo HW, Tin-Oo L-LK, Phway HP, Wang B, et al. Molecular assessment of artemisinin resistance markers, polymorphisms in the K13 propeller, and a multidrug-resistance gene in the eastern and western border areas of Myanmar. Clin Infect Dis. 2015;60:1208–15.CrossRefPubMed
25.
go back to reference Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis. 2015;15:415–21.CrossRefPubMedPubMedCentral Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis. 2015;15:415–21.CrossRefPubMedPubMedCentral
26.
go back to reference Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411–23.CrossRefPubMedPubMedCentral Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411–23.CrossRefPubMedPubMedCentral
27.
go back to reference Anderson TJC, Nair S, McDew-White M, Cheeseman IH, Nkhoma S, Bilgic F, et al. Population parameters underlying an ongoing soft sweep in southeast Asian malaria parasites. Mol Biol Evol. 2017;34:131–44.CrossRefPubMed Anderson TJC, Nair S, McDew-White M, Cheeseman IH, Nkhoma S, Bilgic F, et al. Population parameters underlying an ongoing soft sweep in southeast Asian malaria parasites. Mol Biol Evol. 2017;34:131–44.CrossRefPubMed
28.
go back to reference Nyunt MH, Shein TZ, Zaw NN, Han SS, Muh F, Lee SK, et al. Molecular evidence of drug resistance in asymptomatic malaria infections, Myanmar, 2015. Emerg Infect Dis. 2017;23:517–20.CrossRefPubMed Nyunt MH, Shein TZ, Zaw NN, Han SS, Muh F, Lee SK, et al. Molecular evidence of drug resistance in asymptomatic malaria infections, Myanmar, 2015. Emerg Infect Dis. 2017;23:517–20.CrossRefPubMed
29.
go back to reference Veiga MI, Ferreira PE, Jörnhagen L, Malmberg M, Kone A, Schmidt BA, et al. Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance. PLoS ONE. 2011;6:e20212.CrossRefPubMedPubMedCentral Veiga MI, Ferreira PE, Jörnhagen L, Malmberg M, Kone A, Schmidt BA, et al. Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance. PLoS ONE. 2011;6:e20212.CrossRefPubMedPubMedCentral
30.
go back to reference Gupta B, Xu S, Wang Z, Sun L, Miao J, Cui L, et al. Plasmodium falciparum multidrug resistance protein 1 (pfmrp1) gene and its association with in vitro drug susceptibility of parasite isolates from north-east Myanmar. J Antimicrob Chemother. 2014;69:2110–7.CrossRefPubMedPubMedCentral Gupta B, Xu S, Wang Z, Sun L, Miao J, Cui L, et al. Plasmodium falciparum multidrug resistance protein 1 (pfmrp1) gene and its association with in vitro drug susceptibility of parasite isolates from north-east Myanmar. J Antimicrob Chemother. 2014;69:2110–7.CrossRefPubMedPubMedCentral
31.
go back to reference Lim P, Alker AP, Khim N, Shah NK, Incardona S, Doung S, et al. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malar J. 2009;8:11.CrossRefPubMedPubMedCentral Lim P, Alker AP, Khim N, Shah NK, Incardona S, Doung S, et al. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malar J. 2009;8:11.CrossRefPubMedPubMedCentral
32.
go back to reference Srimuang K, Miotto O, Lim P, Fairhurst RM, Kwiatkowski DP, Woodrow CJ, et al. Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration. Malar J. 2016;15:541.CrossRefPubMedPubMedCentral Srimuang K, Miotto O, Lim P, Fairhurst RM, Kwiatkowski DP, Woodrow CJ, et al. Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration. Malar J. 2016;15:541.CrossRefPubMedPubMedCentral
Metadata
Title
Molecular surveillance of artemisinin resistance falciparum malaria among migrant goldmine workers in Myanmar
Authors
Myat Htut Nyunt
Bo Wang
Khin Myo Aye
Kyin Hla Aye
Jin-Hee Han
Seong-Kyun Lee
Kay Thwe Han
Ye Htut
Eun-Taek Han
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2017
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-017-1753-8

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