Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2019

Open Access 01-12-2019 | Plasmodium Falciparum | Research article

Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis

Author: WWARN K13 Genotype-Phenotype Study Group

Published in: BMC Medicine | Issue 1/2019

Login to get access

Abstract

Background

Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa.

Methods

A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site.

Results

Both the pfk13 genotypes and the PC1/2 were available from 3250 (95%) patients (n = 3012 from Asia (93%), n = 238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC1/2 compared to the PC1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4–1.6) longer PC1/2. None of the isolates from four countries in Africa showed a significant difference between the PC1/2 of parasites with or without pfk13 propeller region mutations.
Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.

Conclusion

Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.
Appendix
Available only for authorised users
Literature
1.
Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant malaria in western Cambodia. New Eng J Med. 2008;359(24):2619–20.PubMedCrossRef
2.
Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, et al. Artemisinin resistance in Plasmodium falciparum malaria. New Eng J Med. 2009;361(5):455–67.PubMedCrossRef
3.
Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois A-C, Khim N, Kim S, Duru V, Bouchier C, Ma L, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505(7481):50–5.PubMedCrossRef
4.
5.
Cheeseman IH, Miller BA, Nair S, Nkhoma S, Tan A, Tan JC, Al Saai S, Phyo AP, Moo CL, Lwin KM, et al. A major genome region underlying artemisinin resistance in malaria. Science. 2012;336(6077):79–82.PubMedPubMedCentralCrossRef
6.
Takala-Harrison S, Clark TG, Jacob CG, Cummings MP, Miotto O, Dondorp AM, Fukuda MM, Nosten F, Noedl H, Imwong M, et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Nat Acad Sci U S A. 2013;110(1):240–5.CrossRef
7.
Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, Lim P, Mao S, Sopha C, Sam B, et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis. 2013;13(12):1043–9.PubMedPubMedCentralCrossRef
8.
Chotivanich K, Tripura R, Das D, Yi P, Day NPJ, Pukrittayakamee S, Chuor CM, Socheat D, Dondorp AM, White NJ. Laboratory detection of artemisinin-resistant Plasmodium falciparum. Antimicrob Agents Chemother. 2014;58(6):3157–61.PubMedPubMedCentralCrossRef
9.
10.
Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, Dacheux M, Khim N, Zhang L, Lam S, et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347(6220):428–31.PubMedCrossRef
11.
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. New Eng J Med. 2014;371(5):411–23.PubMedCrossRef
12.
Nyunt MH, Hlaing T, Oo HW, Tin-Oo LL, Phway HP, Wang B, Zaw NN, Han SS, Tun T, San KK, 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(8):1208–15.PubMedCrossRef
13.
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. 2015;15(4):415–21.PubMedPubMedCentralCrossRef
14.
Wang Z, Wang Y, Cabrera M, Zhang Y, Gupta B, Wu Y, Kemirembe K, Hu Y, Liang X, Brashear A, et al. Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene. Antimicrob Agents Chemother. 2015;59(11):6952–9.PubMedPubMedCentralCrossRef
15.
Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC, Dondorp AM, Fukuda MM, Hien TT, Mayxay M, Noedl H, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis. 2015;211(5):670–9.PubMedCrossRef
16.
Huang F, Takala-Harrison S, Jacob CG, Liu H, Sun X, Yang H, Nyunt MM, Adams M, Zhou S, Xia Z, 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(10):1629–35.PubMedPubMedCentralCrossRef
17.
Ye R, Hu D, Zhang Y, Huang Y, Sun X, Wang J, Chen X, Zhou H, Zhang D, Mungthin M, et al. Distinctive origin of artemisinin-resistant Plasmodium falciparum on the China-Myanmar border. SciRep. 2016;6:20100.
18.
Phyo AP, Ashley EA, Anderson TJC, Bozdech Z, Carrara VI, Sriprawat K, Nair S, White MM, Dziekan J, Ling C, 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(6):784–91.PubMedPubMedCentralCrossRef
19.
Bonnington CA, Phyo AP, Ashley EA, Imwong M, Sriprawat K, Parker DM, Proux S, White NJ, Nosten F. Plasmodium falciparum Kelch 13 mutations and treatment response in patients in Hpa-Pun District, Northern Kayin State, Myanmar. Malar J. 2017;16(1):480.PubMedPubMedCentralCrossRef
20.
Myint MK, Rasmussen C, Thi A, Bustos D, Ringwald P, Lin K. Therapeutic efficacy and artemisinin resistance in northern Myanmar: evidence from in vivo and molecular marker studies. Malar J. 2017;16(1):143.PubMedPubMedCentralCrossRef
21.
Nyunt MH, Soe MT, Myint HW, Oo HW, Aye MM, Han SS, Zaw NN, Cho C, Aung PZ, Kyaw KT, et al. Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013). Malar J. 2017;16(1):333.PubMedPubMedCentralCrossRef
22.
Thuy-Nhien N, Tuyen NK, Tong NT, Vy NT, Thanh NV, Van HT, Huong-Thu P, Quang HH, Boni MF, Dolecek C, et al. K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016. Antimicrob Agents Chemother. 2017;61(4):e01578-01516.
23.
Taylor SM, Parobek CM, DeConti DK, Kayentao K, Coulibaly SO, Greenwood BM, Tagbor H, Williams J, Bojang K, Njie F, et al. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis. 2015;211(5):680–8.PubMedCrossRef
24.
Kamau E, Campino S, Amenga-Etego L, Drury E, Ishengoma D, Johnson K, Mumba D, Kekre M, Yavo W, Mead D, et al. K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. J Infect Dis. 2015;211(8):1352–5.PubMed
25.
Talundzic E, Ndiaye YD, Deme AB, Olsen C, Patel DS, Biliya S, Daniels R, Vannberg FO, Volkman SK, Udhayakumar V, et al. Molecular epidemiology of Plasmodium falciparum kelch13 mutations in senegal determined by using targeted amplicon deep sequencing. Antimicrob Agents Chemother. 2017;61(3):e02116.
26.
Mvumbi DM, Bobanga TL, Kayembe J-MN, Mvumbi GL, Situakibanza HN-T, Benoit-Vical F, Melin P, De Mol P, Hayette M-P. Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo. PLoS One. 2017;12(6):e0179142.PubMedPubMedCentralCrossRef
27.
Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, Rahim-Awab G, Barnadas C, Berry A, Boum Y, et al. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. New Eng J Med. 2016;374(25):2453–64.PubMedCrossRef
28.
MalariaGEN. Genomic epidemiology of artemisinin resistant malaria. eLife. 2016;5:e08714.CrossRef
29.
Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, D'Alessandro U, Day NP, de Vries PJ, Dorsey G, et al. In vivo parasitological measures of artemisinin susceptibility. J Infect Dis. 2010;201(4):570–9.PubMedPubMedCentralCrossRef
30.
Flegg JA, Guerin PJ, White NJ, Stepniewska K. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 2011;10:339.PubMedPubMedCentralCrossRef
31.
Nkhoma SC, Stepniewska K, Nair S, Phyo AP, McGready R, Nosten F, Anderson TJ. Genetic evaluation of the performance of malaria parasite clearance rate metrics. J Infect Dis. 2013;208(2):346–50.PubMedPubMedCentralCrossRef
32.
Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, Smithuis FM, Hlaing TM, Tun KM, van der Pluijm RW, et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis. 2017;17(5):491–7.PubMedPubMedCentralCrossRef
33.
Amato R, Lim P, Miotto O, Amaratunga C, Dek D, Pearson RD, Almagro-Garcia J, Neal AT, Sreng S, Suon S, et al. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect Dis. 2017;17(2):164–73.PubMedCrossRef
34.
Imwong M, Hien TT, Thuy-Nhien NT, Dondorp AM, White NJ. Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam. Lancet Infect Dis. 2017;17(10):1022–3.PubMedCrossRef
35.
Amato R, Pearson RD, Almagro-Garcia J, Amaratunga C, Lim P, Suon S, Sreng S, Drury E, Stalker J, Miotto O, et al. Origins of the current outbreak of multidrug-resistant malaria in Southeast Asia: a retrospective genetic study. Lancet Infect Dis. 2018;18(3):337–45.PubMedPubMedCentralCrossRef
36.
Conrad MD, Bigira V, Kapisi J, Muhindo M, Kamya MR, Havlir DV, Dorsey G, Rosenthal PJ. Polymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children. PLoS One. 2014;9(8):e105690.PubMedPubMedCentralCrossRef
37.
Maiga AW, Fofana B, Sagara I, Dembele D, Dara A, Traore OB, Toure S, Sanogo K, Dama S, Sidibe B, et al. No evidence of delayed parasite clearance after oral artesunate treatment of uncomplicated falciparum malaria in Mali. Am J Trop Med Hyg. 2012;87(1):23–8.PubMedPubMedCentralCrossRef
38.
Ouattara A, Kone A, Adams M, Fofana B, Maiga AW, Hampton S, Coulibaly D, Thera MA, Diallo N, Dara A, et al. Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali. Am J Trop Med Hye. 2015;92(6):1202–6.CrossRef
39.
Chenet SM, Akinyi Okoth S, Huber CS, Chandrabose J, Lucchi NW, Talundzic E, Krishnalall K, Ceron N, Musset L, Macedo de Oliveira A, et al. Independent emergence of the Plasmodium falciparum Kelch propeller domain mutant allele C580Y in Guyana. J Infect Dis. 2016;213(9):1472–5.PubMedCrossRef
40.
Tacoli C, Gai PP, Bayingana C, Sifft K, Geus D, Ndoli J, Sendegeya A, Gahutu JB, Mockenhaupt FP. Artemisinin resistance-associated K13 polymorphisms of Plasmodium falciparum in southern Rwanda, 2010-2015. Am J Trop Med Hyg. 2016;95(5):1090–3.PubMedPubMedCentralCrossRef
41.
Flegg JA, Guerin PJ, Nosten F, Ashley EA, Phyo AP, Dondorp AM, Fairhurst RM, Socheat D, Borrmann S, Bjorkman A, et al. Optimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivatives. Malar J. 2013;12:411.PubMedPubMedCentralCrossRef
42.
43.
Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, Tierney JF, Group P-ID. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD statement. JAMA. 2015;313(16):1657–65.PubMedCrossRef
44.
Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, et al. Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial. PLoS One. 2011;6(5):e19283.PubMedPubMedCentralCrossRef
45.
Das D, Tripura R, Phyo AP, Lwin KM, Tarning J, Lee SJ, Hanpithakpong W, Stepniewska K, Menard D, Ringwald P, et al. Effect of high-dose or split-dose artesunate on parasite clearance in artemisinin-resistant falciparum malaria. Clin Infect Dis. 2013;56(5):e48–58.PubMedCrossRef
46.
Hien T, Thuy-Nhien N, Phu N, Boni M, Thanh N, Nha-Ca N, Thai L, Thai C, Toi P, Thuan P, et al. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J. 2012;11(1):355.PubMedPubMedCentralCrossRef
47.
Mayxay M, Khanthavong M, Chanthongthip O, Imwong M, Lee S, Stepniewska K, Soonthornsata B, Pongvongsa T, Phompida S, Hongvanthong B, et al. No evidence for spread of Plasmodium falciparum artemisinin resistance to Savannakhet Province, southern Laos. Am J Trop Med Hyg. 2012;86(3):403–8.PubMedPubMedCentralCrossRef
48.
Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, ler Moo C, Al-Saai S, Dondorp AM, Lwin KM, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379(9830):1960–6.PubMedPubMedCentralCrossRef
49.
Starzengruber P, Swoboda P, Fuehrer HP, Khan WA, Hofecker V, Siedl A, Fally M, Graf O, Teja-Isavadharm P, Haque R, et al. Current status of artemisinin-resistant falciparum malaria in South Asia: a randomized controlled artesunate monotherapy trial in Bangladesh. PLoS One. 2012;7(12):e52236.PubMedPubMedCentralCrossRef
50.
Thriemer K, Hong NV, Rosanas-Urgell A, Phuc BQ, Ha do M, Pockele E, Guetens P, Van NV, Duong TT, Amambua-Ngwa A et al: Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam. Antimicrob Agents Chemother 2014, 58(12):7049–7055.
51.
Tun KM, Jeeyapant A, Imwong M, Thein M, Aung SSM, Hlaing TM, Yuentrakul P, Promnarate C, Dhorda M, Woodrow CJ, et al. Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study. Malar J. 2016;15(1):185.PubMedPubMedCentralCrossRef
52.
53.
54.
Talundzic E, Okoth SA, Congpuong K, Plucinski MM, Morton L, Goldman IF, Kachur PS, Wongsrichanalai C, Satimai W, Barnwell JW, et al. Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign. PLoS Path. 2015;11(4):e1004789.CrossRef
55.
Kobasa T, Talundzic E, Sug-aram R, Boondat P, Goldman IF, Lucchi NW, Dharmarak P, Sintasath D, Fukuda M, Whistler T, et al. Emergence and spread of kelch13 mutations associated with artemisinin resistance in Plasmodium falciparum parasites in 12 Thai provinces from 2007 to 2016. Antimicrob Agents Chemother. 2018;62(4):e02141-02117.
56.
WHO, editor. Methods and techniques for assessing exposure to antimalarial drugs in clinical field studies. Geneva: World Health Organization; 2011.
57.
58.
Ataide R, Ashley EA, Powell R, Chan J-A, Malloy MJ, O’Flaherty K, Takashima E, Langer C, Tsuboi T, Dondorp AM, et al. Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort. Proc Natl Acad Sci U S A. 2017;114(13):3515-20.
59.
60.
Alin MH, Ashton M, Kihamia CM, Mtey GJ, Bjorkman A. Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria. Br J Clin Pharmacol. 1996;41(6):587–92.PubMedCrossRef
61.
Lopera-Mesa TM, Doumbia S, Chiang S, Zeituni AE, Konate DS, Doumbouya M, Keita AS, Stepniewska K, Traore K, Diakite SA, et al. Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity. J Infect Dis. 2013;207(11):1655–63.PubMedPubMedCentralCrossRef
62.
Cooper RA, Conrad MD, Watson QD, Huezo SJ, Ninsiima H, Tumwebaze P, Nsobya SL, Rosenthal PJ. Lack of artemisinin resistance in Plasmodium falciparum in Uganda based on parasitological and molecular assays. Antimicrob Agents Chemother. 2015;59(8):5061–4.PubMedPubMedCentralCrossRef
63.
Sissoko S, Kone A, Fofana B, Sangaré C, Dembele D, Toure S, Sanogo K, Diakite H, Toure S, Doumbia D, et al. PF3D7_1343700 Kelch propeller (K13-propeller) polymorphisms and artesunate monotherapy efficacy in uncomplicated malaria treatment in Mali. BMJ Global Health. 2017;2(Suppl 2):A18.CrossRef
64.
Straimer J, Gnädig NF, Stokes BH, Ehrenberger M, Crane AA, Fidock DA. Plasmodium falciparum K13 mutations differentially impact ozonide susceptibility and parasite fitness in vitro. mBio. 2017;8(2):e00303-17.
65.
Menegon M, Nurahmed AM, Talha AA, Nour BYM, Severini C. Molecular surveillance of antimalarial drug resistance related genes in Plasmodium falciparum isolates from Eritrea. Acta Trop. 2016;157:158–61.PubMedCrossRef
66.
Muwanguzi J, Henriques G, Sawa P, Bousema T, Sutherland CJ, Beshir KB. Lack of K13 mutations in Plasmodium falciparum persisting after artemisinin combination therapy treatment of Kenyan children. Malar J. 2016;15(1):36.PubMedPubMedCentralCrossRef
67.
Guerra M, Neres R, Salgueiro P, Mendes C, Ndong-Mabale N, Berzosa P, de Sousa B, Arez AP. Plasmodium falciparum genetic diversity in continental Equatorial Guinea before and after introduction of artemisinin-based combination therapy. Antimicrob Agents Chemother. 2017;61(1):e00303-17.
68.
Ljolje D, Dimbu PR, Kelley J, Goldman I, Nace D, Macaia A, Halsey ES, Ringwald P, Fortes F, Udhayakumar V, et al. Prevalence of molecular markers of artemisinin and lumefantrine resistance among patients with uncomplicated Plasmodium falciparum malaria in three provinces in Angola, 2015. Malar J. 2018;17(1):84.PubMedPubMedCentralCrossRef
69.
Ocan M, Bwanga F, Okeng A, Katabazi F, Kigozi E, Kyobe S, Ogwal-Okeng J, Obua C. Prevalence of K13-propeller gene polymorphisms among Plasmodium falciparum parasites isolated from adult symptomatic patients in northern Uganda. BMC Infect Dis. 2016;16(1):428.PubMedPubMedCentralCrossRef
70.
Huang B, Deng C, Yang T, Xue L, Wang Q, Huang S, Su XZ, Liu Y, Zheng S, Guan Y, et al. Polymorphisms of the artemisinin resistant marker (K13) in Plasmodium falciparum parasite populations of Grande Comore Island 10 years after artemisinin combination therapy. Parasit Vectors. 2015;8:634.PubMedPubMedCentralCrossRef
71.
Torrentino-Madamet M, Collet L, Lepère JF, Benoit N, Amalvict R, Ménard D, Pradines B. K13-propeller polymorphisms in Plasmodium falciparum isolates from patients in Mayotte in 2013 and 2014. Antimicrob Agents Chemother. 2015;59(12):7878–81.PubMedPubMedCentralCrossRef
72.
Zhang M, Wang C, Otto TD, Oberstaller J, Liao X, Adapa SR, Udenze K, Bronner IF, Casandra D, Mayho M, et al. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science. 2018;360(6388): eaap7847.
73.
Jiang H, Patel JJ, Yi M, Mu J, Ding J, Stephens R, Cooper RA, Ferdig MT, Su X-Z. Genome-wide compensatory changes accompany drug-selected mutations in the Plasmodium falciparum crt gene. PLoS One. 2008;3(6):e2484.PubMedPubMedCentralCrossRef
74.
Kümpornsin K, Modchang C, Heinberg A, Ekland EH, Jirawatcharadech P, Chobson P, Suwanakitti N, Chaotheing S, Wilairat P, Deitsch KW, et al. Origin of robustness in generating drug-resistant malaria parasites. Mol Biol Evol. 2014;31(7):1649–60.PubMedPubMedCentralCrossRef
75.
Cheeseman IH, McDew-White M, Phyo AP, Sriprawat K, Nosten F, Anderson TJC. Pooled sequencing and rare variant association tests for identifying the determinants of emerging drug resistance in malaria parasites. Mol Biol Evol. 2015;32(4):1080–90.PubMedCrossRef
76.
Miotto O, Amato R, Ashley EA, MacInnis B, Almagro-Garcia J, Amaratunga C, Lim P, Mead D, Oyola SO, Dhorda M, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet. 2015;47(3):226–34.PubMedPubMedCentralCrossRef
77.
Dwivedi A, Reynes C, Kuehn A, Roche DB, Khim N, Hebrard M, Milanesi S, Rivals E, Frutos R, Menard D, et al. Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia. Malar J. 2017;16(1):493.PubMedPubMedCentralCrossRef
78.
Anderson TJ, Nair S, McDew-White M, Cheeseman IH, Nkhoma S, Bilgic F, McGready R, Ashley E, Pyae Phyo A, White NJ, et al. Population parameters underlying an ongoing soft sweep in southeast Asian malaria parasites. Mol Biol Evol. 2017;34(1):131–44.PubMedCrossRef
79.
Cerqueira GC, Cheeseman IH, Schaffner SF, Nair S, McDew-White M, Phyo AP, Ashley EA, Melnikov A, Rogov P, Birren BW, et al. Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance. Genome Biol. 2017;18(1):78.PubMedPubMedCentralCrossRef
80.
Tilley L, Straimer J, Gnadig NF, Ralph SA, Fidock DA. Artemisinin action and resistance in Plasmodium falciparum. Trends Parasitol. 2016;32(9):682–96.PubMedPubMedCentralCrossRef
81.
Mok S, Ashley EA, Ferreira PE, Zhu L, Lin Z, Yeo T, Chotivanich K, Imwong M, Pukrittayakamee S, Dhorda M, et al. Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2015;347(6220):431–5.PubMedCrossRef
82.
Mbengue A, Bhattacharjee S, Pandharkar T, Liu H, Estiu G, Stahelin RV, Rizk SS, Njimoh DL, Ryan Y, Chotivanich K, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature. 2015;520(7549):683–7.PubMedPubMedCentralCrossRef
83.
Mukherjee A, Bopp S, Magistrado P, Wong W, Daniels R, Demas A, Schaffner S, Amaratunga C, Lim P, Dhorda M, et al. Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia. Malar J. 2017;16(1):195.PubMedPubMedCentralCrossRef
84.
Rocamora F, Zhu L, Liong KY, Dondorp A, Miotto O, Mok S, Bozdech Z. Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLoS Path. 2018;14(3):e1006930.CrossRef
85.
Siddiqui FA, Cabrera M, Wang M, Brashear A, Kemirembe K, Wang Z, Miao J, Chookajorn T, Yang Z, Cao Y, et al. Plasmodium falciparum Falcipain-2a polymorphisms in Southeast Asia and their association with artemisinin resistance. J Infect Dis. 2018;218(3):434–42.PubMedCrossRef
86.
Straimer J, Gnadig NF, Stokes BH, Ehrenberger M, Crane AA, Fidock DA. Plasmodium falciparum K13 mutations differentially impact ozonide susceptibility and parasite fitness in vitro. mBio. 2017;8(2):e00303-17.
87.
Ikeda M, Kaneko M, Tachibana SI, Balikagala B, Sakurai-Yatsushiro M, Yatsushiro S, Takahashi N, Yamauchi M, Sekihara M, Hashimoto M, et al. Artemisinin-resistant Plasmodium falciparum with high survival rates, Uganda, 2014-2016. Emerg Infect Dis. 2018;24(4):718–26.PubMedPubMedCentralCrossRef
Metadata
Title
Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis
Author
WWARN K13 Genotype-Phenotype Study Group
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2019
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-018-1207-3

Other articles of this Issue 1/2019

BMC Medicine 1/2019 Go to the issue

Research article

HBV vaccination and PMTCT as elimination tools in the presence of HIV: insights from a clinical cohort and dynamic model

Research article

Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis

Research article

Building a learning community of Australian clinical genomics: a social network study of the Australian Genomic Health Alliance

Research article

The introduction of ‘No jab, No school’ policy and the refinement of measles immunisation strategies in high-income countries

Research article

Predicting COPD 1-year mortality using prognostic predictors routinely measured in primary care

Research article

Population-level mathematical modeling of antimicrobial resistance: a systematic review