Artemisinin drug resistance and monitoring: a narrative review

Artemisinin drug resistance is one of the major reasons for malaria treatment failures in the sub-Saharan African countries where artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria. The occurrence of single nucleotide polymorphisms (SNPs) is found to correlate with antimalarial drug resistance. With artemisinin, the SNPs occurs at the Kelch 13-propeller gene locus on chromosome 13. The artemisinin drug resistance surveillance strategy involves continuous monitoring of Kelch 13-propeller biomarker to detect emergence of mutations which could herald drug resistance in the region. In this narrative review paper, we examined existing literature to bridge the knowledge gap and accentuate the importance of routine surveillance for artemisinin resistance in sub-Saharan Africa. We conducted our search on PubMed database and Google Scholar to identify peer-reviewed articles, reports, and abstracts on artemisinin drug resistance using the following keywords; 'artemisinin drug resistance', 'antimalarial drug resistance', 'artemisinin-based combination therapy', 'Kelch 13-propeller', 'K13- propeller gene', and 'K13 molecular marker'. The review provided pertinent information on artemisinin derivatives, artemisinin-based combination therapy, molecular action of artemisinin, definition of artemisinin resistance, genetic basis of artemisinin drug resistance and discovery of Kelch 13, and the importance of artemisinin resistance surveillance. Molecular surveillance can provide healthcare policy makers a forecast of impending threats to malaria treatment. This is more so when drugs are in combination therapy, for instance, molecular surveillance can give a hint that one drug is failing despite the fact that in combination, it is still apparently clinically effective.

Artemisinin drug resistance and monitoring: a narrative review

Artemisinin drug resistance is one of the major reasons for malaria treatment failures in the sub-Saharan African countries where artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria. The occurrence of single nucleotide polymorphisms (SNPs) is found to correlate with antimalarial drug resistance. With artemisinin, the SNPs occurs at the Kelch 13-propeller gene locus on chromosome 13. The artemisinin drug resistance surveillance strategy involves continuous monitoring of Kelch 13-propeller biomarker to detect emergence of mutations which could herald drug resistance in the region. In this narrative review paper, we examined existing literature to bridge the knowledge gap and accentuate the importance of routine surveillance for artemisinin resistance in sub-Saharan Africa. We conducted our search on PubMed database and Google Scholar to identify peer-reviewed articles, reports, and abstracts on artemisinin drug resistance using the following keywords; 'artemisinin drug resistance', 'antimalarial drug resistance', 'artemisinin-based combination therapy', 'Kelch 13-propeller', 'K13- propeller gene', and 'K13 molecular marker'. The review provided pertinent information on artemisinin derivatives, artemisinin-based combination therapy, molecular action of artemisinin, definition of artemisinin resistance, genetic basis of artemisinin drug resistance and discovery of Kelch 13, and the importance of artemisinin resistance surveillance. Molecular surveillance can provide healthcare policy makers a forecast of impending threats to malaria treatment. This is more so when drugs are in combination therapy, for instance, molecular surveillance can give a hint that one drug is failing despite the fact that in combination, it is still apparently clinically effective.

La résistance aux médicaments à base d'artémisinine est l'une des principales raisons des échecs du traitement du paludisme dans les pays d'Afrique subsaharienne où la polythérapie à base d'artémisinine (ACT) est le traitement de première intention du paludisme simple. L'apparition de polymorphismes mononucléotidiques (SNP) est corrélée à la résistance aux médicaments antipaludiques. Avec l'artémisinine, les SNP se produisent au locus du gène Kelch 13- propeller sur le chromosome 13. La stratégie de surveillance de la résistance aux médicaments à base d'artémisinine implique une surveillance continue du biomarqueur Kelch 13-propeller pour détecter l'émergence de mutations qui pourraient annoncer une résistance aux médicaments dans la région. Dans cet article de revue narrative, nous avons examiné la littérature existante pour combler le manque de connaissances et accentuer l'importance de la surveillance de routine de la résistance à l'artémisinine en Afrique subsaharienne. Nous avons effectué notre recherche sur la base de données PubMed et Google Scholar pour identifier des articles, des rapports et des résumés évalués par des pairs sur la résistance aux médicaments à base d'artémisinine en utilisant les mots-clés suivants; «résistance aux médicaments à base d'artémisinine¼, «résistance aux médicaments antipaludiques¼, «thérapie combinée à base d'artémisinine¼, «Kelch 13-propeller¼, «gène K13-propeller¼ et «marqueur moléculaire K13¼. L'examen a fourni des informations pertinentes sur les dérivés de l'artémisinine, la polythérapie à base d'artémisinine, l'action moléculaire de l'artémisinine, la définition de la résistance à l'artémisinine, la base génétique de la résistance aux médicaments à base d'artémisinine et la découverte de Kelch 13, ainsi que l'importance de la surveillance de la résistance à l'artémisinine. La surveillance moléculaire peut fournir aux responsables des politiques de santé une prévision des menaces imminentes pour le traitement du paludisme. C'est d'autant plus vrai lorsque les médicaments sont en thérapie combinée, par exemple, la surveillance moléculaire peut donner un indice qu'un médicament échoue malgré le fait qu'en combinaison, il est toujours apparemment cliniquement efficace.

Molecular characterization of Plasmodium Falciparum Kelch-13 among febrile patients in selected Government Hospitals in Nigeria

@#Malaria is a life-threatening disease caused by protozoan Plasmodium species. Plasmodium falciparum is the deadliest species. Reducing and eliminating malaria burden are linked to most of the Sustainable Development Goals (SDG), central to SDG3 targeting the end of malaria by 2030. This study was aimed at assessing the Management of malaria and prevalence of P. falciparum kelch-13 among febrile patients in selected Government Hospitals in Nigeria. Malaria patients (399) attending outpatient clinics of the Hospitals between August, 2019 and January, 2021, were enlisted in the study, following ethical approval and informed consents. Blood (5mL) was collected from patients for microscopic and molecular investigation of malaria parasite. DNA extraction, PCR amplification, BLAST, and alignment were performed. Plasmodium resistance to Artemether/lumefantrine was determined by PCR amplification of extracted DNA using Kelch-13 gene primer. Data obtained were subjected to One-way Analysis of Variance and Linear Regression. The VapA gene primer amplified 55 (68.75%) out of the 80 DNA extracts tested. Twenty-five strains of P. falciparum belonging to 3 clades phylogenetically were identified and they showed evolutionary relationships with others. Plasmodium falciparum resistant Kelch-13 gene was detected in 70% of the isolates. This study observed a high prevalence of resistant gene to ACT drugs in the study area. Monitoring the effectiveness of ACTs must be done routinely to ensure timely changes in National treatment policies.

Monitoring and analysis of kelch13 C580Y mutation in imported Plasmodium falciparum in Wuhan, China / 中国热带医学

@#Abstract: Objective To investigate the prevalence of C580Y mutation of kelch13 gene in the imported P. falciparum cases in Wuhan City, China, and to provide a reference basis for the prevention and treatment of imported falciparum malaria. Methods From 2009 to 2015, blood samples were collected from returnees who infected with P. falciparum in endemic areas of Africa and Southeast Asia in Wuhan City. The P. falciparum DNA was extracted from the blood samples, and kelch13 gene was amplified by loop-mediated isothermal amplification (LAMP), and the distribution of C580Y mutation was analyzed. Results C580Y mutation was detected in 16 of the 208 cases tested by LAMP. No mutations were detected in 69 cases of imported falciparum malaria from Africa during 2009-2012, while 13 cases of the C580Y mutation were detected in 114 cases from 2013 to 2015, with a mutation rate of 11.4%. The mutation rate in South Africa, West Africa, and Central Africa was 12.5%, 9.6%, and 19.0%, respectively, with no mutations detected in cases from North Africa and East Africa. Among the 25 cases of falciparum malaria from Southeast Asia between 2009 and 2013, three cases were positive for the C580Y mutation, all from Myanmar, with a mutation rate of 14.3% (3/21) in Myanmar and 12.0% (3/25) in Southeast Asia. There was no significant difference in the mutation rate between Africa and Southeast Asia after 2013 (P>0.05). Conclusions Our findings highlight the varying degrees of C580Y mutations of kelch13 gene in imported P. falciparum cases in Wuhan and suggest the need for enhanced monitoring and evaluation of related resistance genes.

Plasmodium falciparum malarial parasites from Brazil lack artemisinin resistance-associated mutations in the kelch13 gene

Abstract INTRODUCTION Mutations in the propeller domain of the Plasmodium falciparum kelch13 (k13) gene are associated with artemisinin resistance. METHODS: We developed a PCR protocol to sequence the pfk13 gene and determined its sequence in a batch of 50 samples collected from 2003 to 2016 in Brazil. RESULTS: We identified 1 K189T substitution located outside the propeller domain of the PfK13 protein in 36% of samples. CONCLUSIONS: Although the sample size is relatively small, these results suggest that P. falciparum artemisinin-resistant mutants do not exist in Brazil, thereby supporting the continuation of current treatment programs based on artemisinin-based combination therapy.