Artemisinin Resistance and Malaria Elimination: Where Are We Now?

Overview

Journal Front Pharmacol

Date 2022 Oct 10

PMID 36210819

Authors

Borimas Hanboonkunupakarn

Joel Tarning

Sasithon Pukrittayakamee

Kesinee Chotivanich

Affiliations

Soon will be listed here.

Abstract

The emergence of artemisinin resistance is a major obstacle to the global malaria eradication/elimination programs. Artemisinin is a very fast-acting antimalarial drug and is the most important drug in the treatment of severe and uncomplicated malaria. For the treatment of acute uncomplicated falciparum malaria, artemisinin derivatives are combined with long half-life partner drugs and widely used as artemisinin-based combination therapies (ACTs). Some ACTs have shown decreased efficacy in the Southeast Asian region. Fortunately, artemisinin has an excellent safety profile and resistant infections can still be treated successfully by modifying the ACT. This review describes the pharmacological properties of ACTs, mechanisms of artemisinin resistance and the potential changes needed in the treatment regimens to overcome resistance. The suggested ACT modifications are extension of the duration of the ACT course, alternating use of different ACT regimens, and addition of another antimalarial drug to the standard ACTs (Triple-ACT). Furthermore, a malaria vaccine (e.g., RTS,S vaccine) could be added to mass drug administration (MDA) campaigns to enhance the treatment efficacy and to prevent further artemisinin resistance development. This review concludes that artemisinin remains the most important antimalarial drug, despite the development of drug-resistant falciparum malaria.

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References

Miotto O, Sekihara M, Tachibana S, Yamauchi M, Pearson R, Amato R . Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea. PLoS Pathog. 2020; 16(12):e1009133. PMC: 7771869. DOI: 10.1371/journal.ppat.1009133. View

Leang R, Taylor W, Mey Bouth D, Song L, Tarning J, Char M . 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(8):4719-26. PMC: 4505193. DOI: 10.1128/AAC.00835-15. View

Thuy-Nhien N, Tuyen N, Tong N, Vy N, Thanh N, Van H . K13 Propeller Mutations in Plasmodium falciparum Populations in Regions of Malaria Endemicity in Vietnam from 2009 to 2016. Antimicrob Agents Chemother. 2017; 61(4). PMC: 5365681. DOI: 10.1128/AAC.01578-16. View

Intharabut B, Kingston H, Srinamon K, Ashley E, Imwong M, Dhorda M . Artemisinin Resistance and Stage Dependency of Parasite Clearance in Falciparum Malaria. J Infect Dis. 2019; 219(9):1483-1489. PMC: 6467186. DOI: 10.1093/infdis/jiy673. View

White N . Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997; 41(7):1413-22. PMC: 163932. DOI: 10.1128/AAC.41.7.1413. View

Peto T, Tripura R, Callery J, Lek D, Nghia H, Nguon C . 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. 2022; 22(6):867-878. PMC: 9132777. DOI: 10.1016/S1473-3099(21)00692-7. View

Rogers W, Sem R, Tero T, Chim P, Lim P, Muth S . Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malar J. 2009; 8:10. PMC: 2628668. DOI: 10.1186/1475-2875-8-10. View

Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C . Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016; 16(3):357-65. PMC: 4792715. DOI: 10.1016/S1473-3099(15)00487-9. View

Uwimana A, Umulisa N, Venkatesan M, Svigel S, Zhou Z, Munyaneza T . 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. 2021; 21(8):1120-1128. PMC: 10202849. DOI: 10.1016/S1473-3099(21)00142-0. View

10.

Sa J, Kaslow S, Krause M, Melendez-Muniz V, Salzman R, Kite W . Artemisinin resistance phenotypes and K13 inheritance in a cross and model. Proc Natl Acad Sci U S A. 2018; 115(49):12513-12518. PMC: 6298093. DOI: 10.1073/pnas.1813386115. View

11.

Zhang J, Li N, Siddiqui F, Xu S, Geng J, Zhang J . In vitro susceptibility of Plasmodium falciparum isolates from the China-Myanmar border area to artemisinins and correlation with K13 mutations. Int J Parasitol Drugs Drug Resist. 2019; 10:20-27. PMC: 6479106. DOI: 10.1016/j.ijpddr.2019.04.002. View

12.

Agnandji S, Lell B, Fernandes J, Abossolo B, Methogo B, Lumeka Kabwende A . A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med. 2012; 367(24):2284-95. PMC: 10915853. DOI: 10.1056/NEJMoa1208394. View

13.

Rocamora F, Zhu L, Liong K, Dondorp A, Miotto O, Mok S . Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLoS Pathog. 2018; 14(3):e1006930. PMC: 5868857. DOI: 10.1371/journal.ppat.1006930. View

14.

Suresh N, Haldar K . Mechanisms of artemisinin resistance in Plasmodium falciparum malaria. Curr Opin Pharmacol. 2018; 42:46-54. PMC: 6314025. DOI: 10.1016/j.coph.2018.06.003. View

15.

Leang R, Ros S, Duong S, Navaratnam V, Lim P, Ariey F . Therapeutic efficacy of fixed dose artesunate-mefloquine for the treatment of acute, uncomplicated Plasmodium falciparum malaria in Kampong Speu, Cambodia. Malar J. 2013; 12:343. PMC: 3852322. DOI: 10.1186/1475-2875-12-343. View

16.

Whitlock A, Juliano J, Mideo N . Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread. PLoS Comput Biol. 2021; 17(7):e1008577. PMC: 8321109. DOI: 10.1371/journal.pcbi.1008577. View

17.

Mok S, Ashley E, Ferreira P, Zhu L, Lin Z, Yeo T . Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2014; 347(6220):431-5. PMC: 5642863. DOI: 10.1126/science.1260403. View

18.

Witkowski B, Duru V, Khim N, Ross L, Saintpierre B, Beghain J . A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect Dis. 2016; 17(2):174-183. PMC: 5266792. DOI: 10.1016/S1473-3099(16)30415-7. View

19.

Tun K, Jeeyapant A, Hpone Myint A, Kyaw Z, Dhorda M, Mukaka M . Effectiveness and safety of 3 and 5 day courses of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar. Malar J. 2018; 17(1):258. PMC: 6042398. DOI: 10.1186/s12936-018-2404-4. View

20.

Saralamba S, Pan-Ngum W, Maude R, Lee S, Tarning J, Lindegardh N . Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2010; 108(1):397-402. PMC: 3017155. DOI: 10.1073/pnas.1006113108. View