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

Chanaki Amaratunga, Voahangy Hanitriniaina Andrianaranjaka, Elizabeth Ashley, Delia Bethell, Anders Björkman, Craig A. Bonnington, Roland A. Cooper, Mehul Dhorda, Arjen Dondorp, Annette Erhart, Rick M. Fairhurst, Abul Faiz, Caterina Fanello, Mark M. Fukuda, Philippe Guérin, Rob Hooft Van Huijsduijnen, Tran Tinh Hien, N. V. Hong, Ye Htut, Fang HuangGeorgina Humphreys, Mallika Imwong, Kalynn Kennon, Pharath Lim, Khin Lin, Chanthap Lon, Andreas Mårtensson, Mayfong Mayxay, Olugbenga Mokuolu, Ulrika Morris, Billy E. Ngasala, Alfred Amambua-Ngwa, Harald Noedl, François Nosten, Marie Onyamboko, Aung Pyae Phyo, Christopher V. Plowe, Sasithon Pukrittayakamee, Milijaona Randrianarivelojosia, Philip J. Rosenthal, David L. Saunders, Carol Hopkins Sibley, Frank Smithuis, Michele D. Spring, Paul Sondo, Sokunthea Sreng, Peter Starzengruber, Kasia Stepniewska, Seila Suon, Shannon Takala-Harrison, Kamala Thriemer, Nguyen Thuy-Nhien, Kyaw Myo Tun, Nicholas J. White, Charles Woodrow

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    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 (PC 1/2 ) 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 PC 1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. 

    Results: Both the pfk13 genotypes and the PC 1/2 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 PC 1/2 compared to the PC 1/2 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 PC 1/2 . None of the isolates from four countries in Africa showed a significant difference between the PC 1/2 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.

    Original languageEnglish
    Article number1
    Pages (from-to)1-20
    Number of pages20
    JournalBMC Medicine
    Volume17
    DOIs
    Publication statusPublished - 17 Jan 2019

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    Amaratunga, C., Andrianaranjaka, V. H., Ashley, E., Bethell, D., Björkman, A., Bonnington, C. A., Cooper, R. A., Dhorda, M., Dondorp, A., Erhart, A., Fairhurst, R. M., Faiz, A., Fanello, C., Fukuda, M. M., Guérin, P., Van Huijsduijnen, R. H., Hien, T. T., Hong, N. V., Htut, Y., ... Woodrow, C. (2019). 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. BMC Medicine, 17, 1-20. [1]. https://doi.org/10.1186/s12916-018-1207-3