<i>Plasmodium falciparum</i> resistance to artemisinin-based combination therapies

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Abstract

Multidrug-resistant Plasmodium falciparum parasites are a major threat to public health in intertropical regions. Understanding the mechanistic basis, origins, and spread of resistance can inform strategies to mitigate its impact and reduce the global burden of malaria. The recent emergence in Africa of partial resistance to artemisinins, the core component of first-line combination therapies, is particularly concerning. Here, we review recent advances in elucidating the mechanistic basis of artemisinin resistance, driven primarily by point mutations in P. falciparum Kelch13, a key regulator of hemoglobin endocytosis and parasite response to artemisinin-induced stress. We also review resistance to partner drugs, including piperaquine and mefloquine, highlighting a key role for plasmepsins 2/3 and the drug and solute transporters P. falciparum chloroquine-resistance transporter and P. falciparum multidrug-resistance protein-1.

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Artemisinin resistance in Plasmodium falciparum malaria.

Arjen M. Dondorp, François Nosten, Poravuth Yi … (2009)

Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.) 2009 Massachusetts Medical Society

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Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.

Ric Price, Anne-Catrin Uhlemann, Alan Brockman … (2004)

The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine. Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days' artesunate. Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum, and potentially for predicting treatment failure in individual patients.

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Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda

Aline Uwimana, Eric Legrand, Barbara H. Stokes … (2020)

Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa 1–4 . Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance 5,6 , in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda 7 . While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9815056

Journal ID (pubmed-jr-id): 21196

Journal ID (nlm-ta): Curr Opin Microbiol

Journal ID (iso-abbrev): Curr Opin Microbiol

Title: Current opinion in microbiology

ISSN (Print): 1369-5274

ISSN (Electronic): 1879-0364

Publication date Nihms-submitted: 12 January 2023

Publication date (Print): October 2022

Publication date (Electronic): 22 August 2022

Publication date PMC-release: 18 January 2023

Volume: 69

Page: 102193

Affiliations

[1 ]Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA

[2 ]Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA

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Corresponding author: David A Fidock ( df2260@ 123456cumc.columbia.edu )

Article

Manuscript ID: NIHMS1864674

DOI: 10.1016/j.mib.2022.102193

PMC ID: 9847095

PubMed ID: 36007459

SO-VID: 7a34a3cd-ee3c-4dac-897d-4c1894ff0111

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This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

Plasmodium falciparum resistance to artemisinin-based combination therapies

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Most cited references 84

Artemisinin resistance in Plasmodium falciparum malaria.

Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.

Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda

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