Abstract
Artemisinin (ART) combination therapy is the main treatment for malaria. Pfk13 mutations (or K13 mutations, Kelch 13) are associated with ART resistance. This study aims to conduct a systematic review and meta-analysis of the prevalence of K13 mutations with ART resistance in malaria-endemic countries. An electronic search of studies in 2018 and a manual search in 2020 were performed to identify relevant studies. The risk of bias was assessed using the National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies. Data analysis was performed using R 4.1.0. Heterogeneity was estimated using the statistic I2 and Cochran Q test. A total of 170 studies were included in our review. Of these, 55 studies investigated the prevalence of K13 mutations in Southeast Asia. The meta-analysis showed that Southeast Asia had the highest prevalence of K13 mutations, whereas Africa, South America, Oceania, and other Asian countries outside Southeast Asia had a low prevalence of K13 mutations. The C580Y mutation was the most common in Southeast Asia with 35.5% (95%CI: 25.4–46.4%), whereas the dominant mutation in Africa was K189T (22.8%, 95%CI: 7.6–43.2%). This study revealed the emergence of ART resistance associated with K13 mutations in Southeast Asia. The diversity of each type of K13 mutation in other regions was also reported.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Ahouidi A, Oliveira R, Lobo L, Diedhiou C, Mboup S, Nogueira F (2021) Prevalence of pfk13 and pfmdr1 polymorphisms in Bounkiling. Southern Senegal Plos One 16(3):e0249357. https://doi.org/10.1371/journal.pone.0249357
Ariey F et al (2014) A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505(7481):50–55. https://doi.org/10.1038/nature12876
Arya A, Kojom Foko LP, Chaudhry S, Sharma A, Singh V (2021) Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: a systematic review of clinical studies from two malaria endemic regions - India and sub-Saharan Africa. Int J Parasitol Drugs Drug Resist 15:43–56. https://doi.org/10.1016/j.ijpddr.2020.11.006
Arzika II et al (2023) Plasmodium falciparum kelch13 polymorphisms identified after treatment failure with artemisinin-based combination therapy in Niger. Malar J 22(1):142. https://doi.org/10.1186/s12936-023-04571-w
Aung Pyae P, François N (2018) The artemisinin resistance in southeast asia: an imminent global threat to malaria elimination. In: Sylvie M, Vas D (eds) Towards Malaria Elimination. IntechOpen, Rijeka, p Ch. 2. https://doi.org/10.5772/intechopen.76519
Balduzzi S, Rücker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 22:153–160
Balikagala B et al (2021) Evidence of artemisinin-resistant malaria in Africa. N Engl J Med 385(13):1163–1171. https://doi.org/10.1056/NEJMoa2101746
Boualam MA, Pradines B, Drancourt M, Barbieri R (2021) Malaria in Europe: a historical perspective. Front Med (lausanne) 8:691095. https://doi.org/10.3389/fmed.2021.691095
Daily JP, Minuti A, Khan N (2022) Diagnosis, Treatment, and Prevention of Malaria in the US: a review. JAMA 328(5):460–471. https://doi.org/10.1001/jama.2022.12366
Doolan DL (2021) Malaria research in Australia: looking through the lens of the past towards the future. Int J Parasitol 51(13–14):1255–1263. https://doi.org/10.1016/j.ijpara.2021.11.005
Fola AA et al (2023) Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia. Nat Microbiol 8(10):1911–1919. https://doi.org/10.1038/s41564-023-01461-4
Ghanchi NK, Qurashi B, Raees H, Beg MA (2021) Molecular surveillance of drug resistance: Plasmodium falciparum artemisinin resistance single nucleotide polymorphisms in Kelch protein propeller (K13) domain from Southern Pakistan. Malar J 20(1):176. https://doi.org/10.1186/s12936-021-03715-0
Hanboonkunupakarn B, White NJ (2016) The threat of artemisinin resistant malaria in Southeast Asia. Travel Med Infect Dis 14(6):548–550. https://doi.org/10.1016/j.tmaid.2016.11.016
Liberati A et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6(7):e1000100. https://doi.org/10.1371/journal.pmed.1000100
Mathenge PG et al (2020) Efficacy and resistance of different artemisinin-based combination therapies: a systematic review and network meta-analysis. Parasitol Int 74:101919. https://doi.org/10.1016/j.parint.2019.04.016
Mok S et al (2021) Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival. Nat Commun 12(1):530. https://doi.org/10.1038/s41467-020-20805-w
NIH Tool (2020) National heart lung and blood institute study quality assessment tools. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
Ndwiga L et al (2021) A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa. Int J Parasitol Drugs Drug Resist 16:155–161. https://doi.org/10.1016/j.ijpddr.2021.06.001
Niba PTN et al (2023) Evolution of Plasmodium falciparum antimalarial drug resistance markers post-adoption of artemisinin-based combination therapies in Yaounde, Cameroon. Int J Infect Dis 132:108–117. https://doi.org/10.1016/j.ijid.2023.03.050
Ocan M et al (2019) K13-propeller gene polymorphisms in Plasmodium falciparum parasite population in malaria affected countries: a systematic review of prevalence and risk factors. Malar J 18(1):60. https://doi.org/10.1186/s12936-019-2701-6
Owoloye A, Olufemi M, Idowu ET, Oyebola KM (2021) Prevalence of potential mediators of artemisinin resistance in African isolates of Plasmodium falciparum. Malar J 20(1):451. https://doi.org/10.1186/s12936-021-03987-6
Pai MP, Cottrell ML, Kashuba ADM, Bertino JSJ (2014) Pharmacokinetics and pharmacodynamics of anti-infective agents. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases pp 252–262. https://doi.org/10.1016/B978-1-4557-4801-3.00019-9
Peto TJ et al (2022) Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial. Lancet Infect Dis 22(6):867–878. https://doi.org/10.1016/s1473-3099(21)00692-7
Plucinski MM et al (2017) Evaluating malaria case management at public health facilities in two provinces in Angola. Malar J 16(1):186. https://doi.org/10.1186/s12936-017-1843-7
Rasmussen C, Alonso P, Ringwald P (2022) Current and emerging strategies to combat antimalarial resistance. Expert Rev Anti Infect Ther 20(3):353–372. https://doi.org/10.1080/14787210.2021.1962291
Schmedes SE PD, Dhal S, Kelley J, Svigel SS, Dimbu PR, et al. (2021) Plasmodium falciparum kelch 13 Mutations, 9 Countries in Africa, 2014-2018. Emerging Infect Dis Plasmodium falciparum kelch 13 mutations, 9 countries in Africa, 2014–2018. Emerging Infectious Diseases 27(7):1902-08. https://doi.org/10.3201/eid2707.203230
R Core Team (2018) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/
Tran L et al (2022) A systematic review of antimalarial activities of Morinda species. S Afr J Bot 148:396–406. https://doi.org/10.1016/j.sajb.2022.05.007
Uwimana A et al (2021) Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. Lancet Infect Dis 21(8):1120–1128. https://doi.org/10.1016/s1473-3099(21)00142-0
Vassar M, Atakpo P, Kash MJ (2016) Manual search approaches used by systematic reviewers in dermatology. J Med Libr Assoc 104(4):302–304. https://doi.org/10.3163/1536-5050.104.4.009
Witmer K et al (2020) Transmission of artemisinin-resistant malaria parasites to mosquitoes under antimalarial drug pressure. Antimicrob Agents Chemother 65(1):e00898–20. https://doi.org/10.1128/aac.00898-20
World Health Organization (2020) World malaria report 2020: 20 years of global progress and challenges. https://iris.who.int/handle/10665/337660. Accessed 14 Oct 2023
World Health Organization (2022) WHO guidelines for malaria. https://iris.who.int/. Accessed 14 Oct 2023
Yang C et al (2017) Polymorphisms of Plasmodium falciparum k13-propeller gene among migrant workers returning to Henan Province. China from Africa BMC Infect Dis 17(1):560. https://doi.org/10.1186/s12879-017-2634-z
Acknowledgements
We would like to thank Kirellos Said Abbas (Faculty of Medicine, Alexandria University, Alexandria, Egypt) and Gehad Mohamed Tawfik (Department of Otorhinolaryngology, Faculty of Medicine, Ain Shams University, Cairo, Egypt) for their contributions during the initial stages of the study. We also thank Peterson Gtionga Mathenge (Harvard Medical School, USA) for proofreading the manuscript.
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KH and NTH developed the idea, conceived, and designed the study. DTH, LT, and DNHT performed literature search and data collection. DTH analyzed and synthesized the data. DTH assessed the quality of the included studies. DTH, LT, and AA interpreted the results and wrote the manuscript. All authors critically checked the data, reviewed and edited the manuscript. KH, NTH provided supervision and project administration. All authors have read and approved the final manuscript.
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Hung, D.T., Tran, L., Tam, D.N.H. et al. The prevalence of Pfk13 polymorphism in malaria patients treated with artemisinin-based therapy: a systematic review and meta-analysis. Parasitol Res 123, 209 (2024). https://doi.org/10.1007/s00436-024-08203-3
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DOI: https://doi.org/10.1007/s00436-024-08203-3