#Antimalarial #drug #resistance in #Africa: the calm before the storm? (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Antimalarial drug resistance in Africa: the calm before the storm?

Melissa D Conrad, PhD, Prof Philip J Rosenthal, MD

Published: July 30, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30261-0

 

Summary

Antimalarial drug resistance, in particular resistance to Plasmodium falciparum, challenges the treatment and control of malaria. In this Review, we summarise evolving patterns of antimalarial drug resistance in Africa. Resistance to aminoquinolines and antifolates is long-standing, yet with greatly decreased use of chloroquine to treat malaria, the prevalence of resistance to chloroquine has decreased. Resistance to antifolates, which are used to prevent malaria in some settings, remains widespread. Resistance to artemisinin-based combination therapies, the standard treatments for malaria in Africa, has emerged in southeast Asia. At present, resistance to artemisinins or key partner drugs included in combination therapies does not appear to be a substantial problem in Africa. However, emergence of resistance to artemisinin-based combination therapies in Africa would probably have devastating consequences, and continued surveillance for the emergence of resistance on this continent is a high priority.

Keywords: Malaria; Plasmodium falciparum; Drugs Resistance; Artemisin; Chloroquine; Aminoquinolines; Antifolates; Africa region.

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Molecular #surveillance of #drug #resistance of #Plasmodium falciparum isolates imported from #Angola in #Henan Province, #China (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Molecular surveillance of drug resistance of Plasmodium falciparum isolates imported from Angola in Henan Province, China

Ruimin Zhou, Chengyun Yang, Suhua Li, Yuling Zhao, Ying Liu, Dan Qian, Hao Wang, Deling Lu, Hongwei Zhang, Fang Huang

DOI: 10.1128/AAC.00552-19

 

ABSTRACT

Angola was the main origin country for the imported malaria in Henan Province, China. The antimalarial drug resistance has posed a threat to the control and elimination of malaria. Several molecular markers were confirmed to be associated with the antimalarial drug resistance such as pfcrt, pfmdr1, pfdhfr, pfdhps and K13. This study will evaluate the drug resistance of the 180 imported Plasmodium falciparum isolates from Angola via nested PCR by Sanger sequencing. The prevalence of pfcrt C72V73M74N75K76, pfmdr1 N86Y184S1034N1042D1246, pfdhfr A16N51C59S108D139I164 and pfdhps S436A437A476K540A581 was 69.4%, 59.9%, 1.3% and 6.3%, respectively. Three nonsynonymous (A578S, M579I and Q613E) and one synonymous (R471R) mutation of K13 were found, the prevalence of which was 2.5% and 1.3%, respectively. The single nucleotide polymorphisms (SNPs) in pfcrt, pfmdr1, pfdhfr and pfdhps were generally shown as multiple mutations. The mutant prevalence of pfcrt reduced gradually, but pfdhfr and pfdhps still showed high mutant prevalence, while pfmdr1 was relatively low. The mutation of K13 gene was rare. Molecular surveillance of artemisinin-resistance (ART-resistance) will be as a tool to evaluate the real time efficacy of the artemisinin-based combination therapies (ACTs) and the ART-resistance situation as well.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Plasmodium falciparum; Malaria; Drugs Resistance; Artemisin; Angola; Henan; China.

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Determinants of dihydro- #artemisinin-piperaquine #treatment #failure in #Plasmodium falciparum #malaria in #Cambodia, #Thailand, and #Vietnam: a prospective clinical, pharmacological, and genetic study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

Rob W van der Pluijm, MD, Prof Mallika Imwong, PhD, Nguyen Hoang Chau, MD, Nhu Thi Hoa, MD, Nguyen Thanh Thuy-Nhien, PhD, Ngo Viet Thanh, MD, et al.

Open Access / Published: July 22, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30391-3

 

Summary

Background

The emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015–18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year.

Methods

Patients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial. The primary outcome was the PCR-corrected efficacy at day 42. Next-generation sequencing was used to assess the prevalence of molecular markers associated with artemisinin resistance (kelch13 mutations, in particular Cys580Tyr) and piperaquine resistance (plasmepsin-2 and plasmepsin-3amplifications and crt mutations). This study is registered with ClinicalTrials.gov, number NCT02453308.

Findings

Between Sept 28, 2015, and Jan 18, 2018, 539 patients with acute P falciparum malaria were screened for eligibility, 292 were enrolled, and 140 received dihydroartemisinin-piperaquine. The overall Kaplan-Meier estimate of PCR-corrected efficacy of dihydroartemisinin-piperaquine at day 42 was 50·0% (95% CI 41·1–58·3). PCR-corrected efficacies for individual sites were 12·7% (2·2–33·0) in northeastern Thailand, 38·2% (15·9–60·5) in western Cambodia, 73·4% (57·0–84·3) in Ratanakiri (northeastern Cambodia), and 47·1% (33·5–59·6) in Binh Phuoc (southwestern Vietnam). Treatment failure was associated independently with plasmepsin2/3amplification status and four mutations in the crt gene (Thr93Ser, His97Tyr, Phe145Ile, and Ile218Phe). Compared with the results of our previous TRACI trial in 2011–13, the prevalence of molecular markers of artemisinin resistance (kelch13 Cys580Tyr mutations) and piperaquine resistance (plasmepsin2/3 amplifications and crtmutations) has increased substantially in the Greater Mekong subregion in the past decade.

Interpretation

Dihydroartemisinin-piperaquine is not treating malaria effectively across the eastern Greater Mekong subregion. A highly drug-resistant P falciparum co-lineage is evolving, acquiring new resistance mechanisms, and spreading. Accelerated elimination of P falciparum malaria in this region is needed urgently, to prevent further spread and avoid a potential global health emergency.

Funding

UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and National Institutes of Health.

Keywords: Malaria; Plasmodium falciparum; Artemisin; Drugs resistance; Thailand; Cambodia; Laos; Vietnam.

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#Evolution and #expansion of #MDR #malaria in southeast #Asia: a #genomic #epidemiology study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study

William L Hamilton, PhD †, Roberto Amato, PhD †, Rob W van der Pluijm, MD, Christopher G Jacob, PhD, Huynh Hong Quang, PhD, Nguyen Thanh Thuy-Nhien, PhD, et al.

Open Access / Published: July 22, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30392-5

 

Summary

Background

A multidrug-resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia in 2008–13, causing high rates of treatment failure with the frontline combination therapy dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.

Methods

For this genomic epidemiology study, we analysed whole genome sequencing data from P falciparum clinical samples collected from patients with malaria between 2007 and 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam, through the MalariaGEN P falciparum Community Project. Previously unpublished samples were provided by two large-scale multisite projects: the Tracking Artemisinin Resistance Collaboration II (TRAC2) and the Genetic Reconnaissance in the Greater Mekong Subregion (GenRe-Mekong) project. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.

Findings

We analysed 1673 whole genome sequences that passed quality filters, and determined KEL1/PLA1 status in 1615. Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016–17 its prevalence had risen to higher than 50% in all of the surveyed countries except for Laos. In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80% of the most recent P falciparum parasites. KEL1/PLA1 parasites maintained high genetic relatedness and low diversity, reflecting a recent common origin. Several subgroups of highly related parasites have recently emerged within this co-lineage, with diverse geographical distributions. The three largest of these subgroups (n=84, n=79, and n=47) mostly emerged since 2016 and were all present in Cambodia, Laos, and Vietnam. These expanding subgroups carried new mutations in the crt gene, which arose on a specific genetic background comprising multiple genomic regions. Four newly emerging crt mutations were rare in the early period and became more prevalent by 2016–17 (Thr93Ser, rising to 19·8%; His97Tyr to 11·2%; Phe145Ile to 5·5%; and Ile218Phe to 11·1%).

Interpretation

After emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts.

Funding

Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.

Keywords: Malaria; Plasmodium falciparum; Drugs resistance; Artemisin; Cambodia; Laos; Thailand; Vietnam.

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Decreased in vitro #artemisinin sensitivity of #Plasmodium falciparum across #India (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Decreased in vitro artemisinin sensitivity of Plasmodium falciparum across India

Rimi Chakrabarti, John White, Prasad H. Babar, Shiva Kumar, Devaraja Gouda Mudeppa, Anjali Mascarenhas, Ligia Pereira, Rashmi Dash, Jennifer N. Maki, Ambika Sharma, Kabita Gogoi,Devojit K. Sarma, Ipsita Pal Bhowmick, Suresh Kumar Manoharan, Edwin Gomes, Jagadish Mahanta, Pradyumna Kishore Mohapatra, Laura Chery, Pradipsinh K. Rathod

DOI: 10.1128/AAC.00101-19

 

ABSTRACT

Artemisinin Combination Therapy (ACT) has been used to treat uncomplicated Plasmodium falciparum infections in India since 2004. Since 2008 decreasing artemisinin effectiveness has been seen throughout the Greater Mekong Subregion. The geographic proximity and ecological similarities of northeastern India to southeast Asia may differentially affect the long-term management and sustainability of ACT in India. In order to collect baseline data on variations in ACT sensitivity in Indian parasites, 12 P. falciparum isolates from northeast India and 10 isolated from southwest India were studied in vitro. Ring Stage Survival Assay (RSA) showed reduced sensitivity to dihydroartemisinin in 50% of the 2014-2015 northeast Indian samples. Two of the 10 assayed samples from the southwest region of India, from as far back as 2012, also showed decreased sensitivity to artemisinin. In both these regions, kelch gene sequences were not predictive of reduced artemisinin sensitivity as measured by RSA. The present data justifies future investments in integrated approaches involving clinical follow-up studies, in vitrosurvival assays, and molecular markers, for tracking potential changes in artemisinin effectiveness against P. falciparum throughout India.

Copyright © 2019 Chakrabarti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Malaria; Plasmodium falciparum; Drugs resistance; Artemisin; India.

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#Origins of the current #outbreak of #MDR #malaria in southeast #Asia: a retrospective genetic study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study

Roberto Amato, PhD, Richard D Pearson, PhD, Jacob Almagro-Garcia, PhD, Chanaki Amaratunga, PhD, Pharath Lim, MD, Seila Suon, MD, Sokunthea Sreng, Eleanor Drury, Sc, Jim Stalker, MA, Olivo Miotto, PhD, Rick M Fairhurst, MD, Prof Dominic P Kwiatkowski, FRCP

Published: 01 February 2018 / Open Access / DOI: https://doi.org/10.1016/S1473-3099(18)30068-9

© 2018 The Author(s). Published by Elsevier Ltd.

 

Summary

Background

Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin–piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports.

Methods

We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13artemisinin resistance locus and the plasmepsin 2–3 piperaquine resistance locus.

Findings

We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin–piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia.

Interpretation

The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin–piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia.

Funding

Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Keywords: Malaria; Asia Region; Antibiotics; Drugs Resistance; Artemisin; Piperaquine.

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Synthesis of #Thymoquinone – #Artemisinin Hybrids: New Potent #Antileukemia, #Antiviral, and #Antimalarial Agents (ACS Med Chem Lett., abstract)

[Source: ACS Medicinal Chemistry Letters, full page: (LINK). Abstract, edited.]

Synthesis of Thymoquinone–Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents

Tony Fröhlich†, Christoph Reiter†, Mohamed E. M. Saeed‡, Corina Hutterer§, Friedrich Hahn§, Maria Leidenberger∥, Oliver Friedrich∥, Barbara Kappes∥, Manfred Marschall§, Thomas Efferth‡, and Svetlana B. Tsogoeva*†

† Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany; ‡ Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany; § Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany; ∥ Institute of Medical Biotechnology, Friedrich-Alexander University of Erlangen-Nürnberg, Paul-Gordon-Straße 3, 91052 Erlangen, Germany

ACS Med. Chem. Lett., Article ASAP / DOI: 10.1021/acsmedchemlett.7b00412

Publication Date (Web): December 21, 2017

Copyright © 2017 American Chemical Society

*Tel: (+) 49 9131 85 65573. E-mail: svetlana.tsogoeva@fau.de.

 

Abstract

A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate 14 starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone–artemisinin hybrids 6a/b stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy human foreskin fibroblasts and thus being selective. They exhibited EC50values of 0.2 μM against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Moreover, they showed to be five times more active than the standard drug ganciclovir and nearly eight times more active than artesunic acid against HCMV. In addition, hybrids 6a/b possessed excellent antimalarial activity (EC50 = 5.9/3.7 nM), which was better than that of artesunic acid (EC50 = 8.2 nM) and chloroquine (EC50 = 9.8 nM). Overall, most of the presented thymoquinone–artemisinin-based hybrids exhibit an excellent and broad variety of biological activities (anticancer, antimalarial, and antiviral) combined with a low toxicity/high selectivity profile.

Keywords: anticancer activity; antimalarial activity; antiviral activity; Artemisinin; natural product hybrid; thymoquinone

Keywords: Antivirals; Thymoquinone; Artemisin; Cancer; CMV; Malaria.

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