Ex vivo Sensitivity Profile of  Plasmodium falciparum  Clinical Isolates to a Panel of Antimalarial Drugs in Ghana 13 Years After National Policy Change

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Abstract

Purpose

Malaria continues to be a major health issue globally with almost 85% of the global burden and deaths borne by sub-Saharan Africa and India. Although the current artemisinin derived combination therapies in Ghana are still efficacious against the Plasmodium falciparum ( Pf) parasite, compounding evidence of artemisinin and amodiaquine resistance establish the need for a full, up-to-date understanding and monitoring of antimalarial resistance to provide evidence for planning control strategies.

Materials and Methods

The study was cross-sectional and was conducted during the peak malaria transmission seasons of 2015, 2016, and 2017 in two ecological zones of Ghana. Study participants included children aged 6 months to 14 years. Using ex vivo 4,6-diamidino-2-phenylindole (DAPI) drug sensitivity assay, 330 Pf isolates were used to investigate susceptibility to five antimalarial drugs: chloroquine (CQ), amodiaquine (AMD) dihydroartemisinin (DHA), artesunate (ART) and mefloquine (MFQ).

Results

The pooled geometric mean IC ₅₀S (GMIC ₅₀) of the five drugs against the parasites from Cape Coast and Begoro were 15.5, 42.4, 18.9, 4.6 and 27.3nM for CQ, AMD, DHA, ART, and MFQ, respectively. The GMIC ₅₀ values for CQ (p<0.001), ART (p<0.011) and DHA (p<0.018) were significantly higher for Cape Coast isolates as compared to Begoro isolates. However, GMIC ₅₀ estimates for MFQ (p<0.022) were significantly higher for Begoro isolates. Positive correlations were found between each pair of drugs with the weakest found between MFQ and DHA ( r = 0.34;p<0.001), and the strongest between ART and DHA ( r =0.66; p<0.001).

Conclusion

The parasites showed reduced sensitivities to three (AMD, DHA and MFQ) out of the five drugs assessed. The study also demonstrated the continual return of chloroquine-sensitive parasites after 13 years of its withdrawal as the first-line drug for the treatment of uncomplicated malaria in Ghana. The ex vivo DAPI assay is a reliable method for assessing antimalarial drug sensitivities of Pf field isolates under field settings.

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Most cited references 47

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Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

Aung Pyae Phyo, Aung Phyo, Standwell Nkhoma … (2012)

Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.

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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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Spread of artemisinin resistance in Plasmodium falciparum malaria.

Elizabeth A Ashley, Mehul Dhorda, Rick Fairhurst … (2014)

Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

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Author and article information

Journal

Journal ID (nlm-ta): Infect Drug Resist

Journal ID (iso-abbrev): Infect Drug Resist

Journal ID (publisher-id): idr

Journal ID (pmc): idr

Title: Infection and Drug Resistance

Publisher: Dove

ISSN (Electronic): 1178-6973

Publication date (Electronic): 28 January 2021

Publication date Collection: 2021

Volume: 14

Pages: 267-276

Affiliations

[1 ]Immunology Department, Noguchi Memorial Institute for Medical Research, University of Ghana , Legon, Accra, Ghana

[2 ]Epidemiology Department, Noguchi Memorial Institute for Medical Research,University of Ghana , Legon, Accra, Ghana

[3 ]Ewim Polyclinic, Ghana Health Service , Cape Coast, Ghana

[4 ]Begoro District Hospital, Ghana Health Service , Begoro, Ghana

[5 ]Parasitology Department, Noguchi Memorial Institute for Medical Research, University of Ghana , Legon, Accra, Ghana

Author notes

Correspondence: Michael Fokuo Ofori Immunology Department, Noguchi Memorial Institute for Medical Research, University of Ghana , Post Office Box LG581, Legon, GhanaTel +233 244 715975Fax +233 302 502182 Email mofori@noguchi.ug.edu.gh

[*]

These authors contributed equally to this work

Author information

Michael Fokuo Ofori http://orcid.org/0000-0003-2341-7514

Emma E Kploanyi http://orcid.org/0000-0003-2829-7945

Kwadwo A Koram http://orcid.org/0000-0003-4274-6516

Article

Publisher ID: 295277

DOI: 10.2147/IDR.S295277

PMC ID: 7850388

PubMed ID: 33536768

SO-VID: 5d7226a8-a095-4ebd-8fec-f3cb9353f586

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This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 03 December 2020

Date accepted : 09 January 2021

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Figures: 3, Tables: 3, References: 52, Pages: 10

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Ex vivo Sensitivity Profile of Plasmodium falciparum Clinical Isolates to a Panel of Antimalarial Drugs in Ghana 13 Years After National Policy Change

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Abstract

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Materials and Methods

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Malaria vaccine development

Most cited references 47

Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

Artemisinin resistance in Plasmodium falciparum malaria.

Spread of artemisinin resistance in Plasmodium falciparum malaria.

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