Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013)
Myat Htut Nyunt, Myat Thu Soe, Hla Win Myint, Htet Wai Oo, Moe Moe Aye, Soe Soe Han, Ni Ni Zaw, Cho Cho, Phyo Zaw Aung, Khin Thiri Kyaw, Thin Thin Aye, Naychi Aung San, Leonard Ortega, Krongthong Thimasarn, Maria Dorina G Bustos, Sherwin Galit, Mohammad Rafiul Hoque, Pascal Ringwald, Eun-Taek Han, Myat Phone Kyaw, Myat Htut Nyunt, Myat Thu Soe, Hla Win Myint, Htet Wai Oo, Moe Moe Aye, Soe Soe Han, Ni Ni Zaw, Cho Cho, Phyo Zaw Aung, Khin Thiri Kyaw, Thin Thin Aye, Naychi Aung San, Leonard Ortega, Krongthong Thimasarn, Maria Dorina G Bustos, Sherwin Galit, Mohammad Rafiul Hoque, Pascal Ringwald, Eun-Taek Han, Myat Phone Kyaw
Abstract
Background: Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2.
Methods: A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples.
Results: True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively).
Conclusions: Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.
Keywords: Artemisinin; Drug resistance; Falciparum; Kelch 13; Malaria; Myanmar.
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References
- WHO . Guidelines for treatment of Malaria. 3. Geneva: World Health Organization; 2015.
- Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–467. doi: 10.1056/NEJMoa0808859.
- Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379:1960–1966. doi: 10.1016/S0140-6736(12)60484-X.
- 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. doi: 10.1371/journal.pone.0057689.
- WHO . Status report: artemisinin and artemisinin-based combination therapy resistance. Geneva: World Health Organization; 2016.
- WHO . Methods for surveillance of antimalarial drug efficacy. Geneva: World Health Organization; 2009.
- WHO . Global report on antimalarial drug efficacy and drug resistance: 2000–2010. Geneva: World Health Organization; 2010.
- Ministry of Health. Health in Myanmar. Nay Pyi Taw; 2014.
- 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;60:1208–1215. doi: 10.1093/cid/ciu1160.
- Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, Lin K, Kyaw MP, Plewes K, Faiz MA, et al. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis. 2016;15:415–421. doi: 10.1016/S1473-3099(15)70032-0.
- Win AA, Imwong M, Kyaw MP, Woodrow CJ, Chotivanich K, Hanboonkunupakarn B, Pukrittayakamee S. K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar. Malar J. 2016;15:110. doi: 10.1186/s12936-016-1147-3.
- Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC, Dondorp AM, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis. 2015;211:69. doi: 10.1093/infdis/jiu491.
- Mita T, Tachibana S-I, Hashimoto M, Hirai M. Plasmodium falciparum kelch 13: a potential molecular marker for tackling artemisinin-resistant malaria parasites. Expert Rev Anti Infect Ther. 2016;14:125–135. doi: 10.1586/14787210.2016.1106938.
- WHO. Strategy for Malaria Elimination in the Greater Mekong Subregion (2015–2030). World Health Organization Regional Office for the Western Pacific; 2015.
- Mohon AN, Alam MS, Bayih AG, Folefoc A, Shahinas D, Haque R, Pillai DR. Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009–2013) Malar J. 2014;13:431. doi: 10.1186/1475-2875-13-431.
- Chatterjee M, Ganguly S, Saha P, Bankura B, Basu N, Das M, et al. No polymorphism in Plasmodium falciparum K13 propeller gene in clinical isolates from Kolkata, India. J Pathog. 2015;2015:374354. doi: 10.1155/2015/374354.
- 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;47:226–234. doi: 10.1038/ng.3189.
- Cattamanchi A, Kyabayinze D, Hubbard A, Rosenthal PJ, Dorsey G. Distinguishing recrudescence from reinfection in a longitudinal antimalarial drug efficacy study: comparison of results based on genotyping of msp-1, msp-2, and glurp. Am J Trop Med Hyg. 2003;68:133–139.
- 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;23:517–520. doi: 10.3201/eid2303.161363.
- Nyunt MH, Wang B, Aye KM, Aye KH, Han J-H, Lee S-K, et al. Molecular surveillance of artemisinin resistance falciparum malaria among migrant goldmine workers in Myanmar. Malar J. 2017;16:97. doi: 10.1186/s12936-017-1753-8.
- WHO . Global plan for artemisinin resistance containment (GPARC) Geneva: World Health Organization; 2011.
- WHO . Emergency response to artemisinin resistance in the Greater Mekong subregion. Regional framework for action 2013–2015. Geneva: World Health Organization; 2013.
- Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, Sam B, Dek D, Try V, Amato R, et al. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016;16:357–365. doi: 10.1016/S1473-3099(15)00487-9.
- Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411–423. doi: 10.1056/NEJMoa1314981.
- 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;505:50–55. doi: 10.1038/nature12876.
- MalariaGEN Plasmodium falciparum Community Project Genomic epidemiology of artemisinin resistant malaria. eLife. 2016;5:e08714. doi: 10.7554/eLife.08714.
- Ménard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, et al. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. New Engl J Med. 2016;374:2453–2464. doi: 10.1056/NEJMoa1513137.
- Leang R, Taylor WRJ, Bouth DM, Song L, Tarning J, Char MC, et al. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western cambodia: dihydroartemisinin–piperaquine open-label multicenter clinical assessment. Antimicrob Agents Chemother. 2015;59:4719–4726. doi: 10.1128/AAC.00835-15.
- Talundzic E, Okoth SA, Congpuong K, Plucinski MM, Morton L, Goldman IF, et al. Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign. PLoS Pathog. 2015;11:e1004789. doi: 10.1371/journal.ppat.1004789.
- Putaporntip C, Kuamsab N, Kosuwin R, Tantiwattanasub W, Vejakama P, Sueblinvong T, et al. Natural selection of K13 mutants of Plasmodium falciparum in response to artemisinin combination therapies in Thailand. Clin Microbiol Infect. 2016;22:285. doi: 10.1016/j.cmi.2015.10.027.
- Phyo AP, Ashley EA, Anderson TJC, Bozdech Z, Carrara VI, Sriprawat K, et al. Declining efficacy of artemisinin combination therapy against P. falciparum malaria on the Thai–Myanmar border (2003–2013): the role of parasite genetic factors. Clin Infect Dis. 2016;63:784–791. doi: 10.1093/cid/ciw388.
- Thriemer K, Hong NV, Rosanas-Urgell A, Phuc BQ, Ha DM, Pockele E, et al. Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam. Antimicrob Agents Chemother. 2014;58:7049–7055. doi: 10.1128/AAC.02746-14.
- Imwong M, Jindakhad T, Kunasol C, Sutawong K, Vejakama P, Dondorp AM. An outbreak of artemisinin resistant falciparum malaria in eastern Thailand. Sci Rep. 2015;5:17412. doi: 10.1038/srep17412.
- Ye R, Hu D, Zhang Y, Huang Y, Sun X, Wang J, et al. Distinctive origin of artemisinin-resistant Plasmodium falciparum on the China–Myanmar border. Sci Rep. 2016;6:20100. doi: 10.1038/srep20100.
- Wang Z, Wang Y, Cabrera M, Zhang Y, Gupta B, Wu Y, et al. Artemisinin resistance at the China–Myanmar border and association with mutations in the K13 propeller gene. Antimicrob Agents Chemother. 2015;59:6952–6959. doi: 10.1128/AAC.01255-15.
- Huang F, Takala-Harrison S, Jacob CG, Liu H, Sun X, Yang H, et al. A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment. J Infect Dis. 2015;212:1629–1635. doi: 10.1093/infdis/jiv249.
Source: PubMed