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.

Bibliometric analysis of publications pertaining to artemisinin resistance in Plasmodium falciparum based on Web of Science from 2011 to 2022 / 中国血吸虫病防治杂志

Objective To analyze the global literature output and citation of publications pertaining to artemisinin (ART) resistance in Plasmodium falciparum from 2011 to 2021, so as to provide insights into researches on resistance of P. falciparum to ART. Methods The publications pertaining to ART resistance in P. falciparum were retrieved from the Science Citation Index Expanded (SCIE) database in Web of Science during the period from January 2011 through May 2022. The subject, journal, country, affiliation and author distributions and citations of publications were descriptively analyzed. Results A total of 1 640 publications pertaining to ART resistance in P. falciparum were retrieved in the SCIE database during the period from January 2011 through May 2022, and the number of publications appeared an overall tendency towards a rise during the study period. These articles were published in 343 journals, and the three most productive journals included Malaria Journal (341 publications, 20.79%), Antimicrobial Agents and Chemotherapy (141 publications, 8.60%), American Journal of Aropical Medicine and Hygiene (68 publications, 4.15%), with infectious diseases (565 publications, 34.45%), parasitology (531 publications, 32.38%), and tropical medicine (517 publications, 31.54%) as the predominant subject. The three most productive countries included the United States of America (627 publications, 38.23%), United Kingdom (395 publications, 24.08%), and Thailand (294 publications, 17.94%), with total citations of 25 280, 18 622 and 15 474, respectively, and the most productive countries included Mahidol University (Thailand), Oxford University (England) and London University (England), with 234, 220 publications and 142 publications and 15 058, 15 421 citations and 6 191 citations, respectively. The three most productive authors were all from Mahidol University, with 85, 77 and 63 publications, respectively; and among the three most cited authors, two were from Mahidol University, Thailand, with 8 623 and 7 961 total citations, and one from National Institutes of Health, the United States of America, with 6 267 total citations. A total of 138 articles were published by Chinese scientists, with 3 434 total citations, and National Institute of Parasitic Diseases of Chinese Center for the Diseases Control and Prevention was the most productive Chinese institution, with 35 publications, 1 165 total citations and 33.29 citations per publication. Conclusions The literature output of ART resistance in P. falciparum was relatively high in the United States of America, Europe, and Southeast Asian countries during the period from 2011 to 2021, with a relatively high academic impact. Publications in Malaria Journal and Antimicrobial Agents and Chemotherapy are recommended to be paid much attention by Chinese scientists to understand the latest advances and extend the research interests.

Protecting future antimalarials from the trap of resistance:Lessons from artemisinin-based combination therapy(ACT)failures / 药物分析学报

Having faced increased clinical treatment failures with dihydroartemisinin-piperaquine(DHA-PPQ),Cambodia swapped the first line artemisinin-based combination therapy(ACT)from DHA-PPQ to artesunate-mefloquine given that parasites resistant to piperaquine are susceptible to mefloquine.However,triple mutants have now emerged,suggesting that drug rotations may not be adequate to keep resistance at bay.There is,therefore,an urgent need for alternative treatment strategies to tackle resistance and prevent its spread.A proper understanding of all contributors to artemisinin resistance may help us identify novel strategies to keep artemisinins effective until new drugs become available for their replacement.This review highlights the role of the key players in artemisinin resistance,the current strategies to deal with it and suggests ways of protecting future antimalarial drugs from bowing to resistance as their predecessors did.

The research progress on artemisinin resistance and mechanism of spleen clearing Plasmodium / 中国药理学通报

The resistance to artemisinin generated by plasmodium is defined as follows: After being treated with ACTs for three days, the time to clear plasmodium from the blood of patients with malaria becomes prolonged. The elimination rate of plasmodium in vivo is not only related to the parasiticidal efficacy of antimalarial drugs, but also affected by biological factors such as the mutation of plasmodium themselves, the regulation of human immune function(such as the recognition and processing of phagocytes) , and the efflux of foreign l>odies from immune organs. This article primarily reviews the mutation of plasmodium themselves , the physical and biochemical process of the spleen eliminating plasmodium, including K13 changes, the two blood circulation pathways of the spleen. Since the endothelial cell gap of the splenic venous sinus is elastic, plasmodium or red blood cell debris can be trapped by physical and mechanical sensing methods. The red pulp is the main venue to filter blood, where the immune cells are responsible for the removal of the residues of plasmodium. The physical process of the splenic venous sinus trapping plasmodium is called pitting, and its incidence is influenced by the growth cycle of plasmodium and therapeutic drugs. In this paper, the function of the spleen to eliminate plasmodium will be explained, in an attempt to provide a reference for the biological nature of the artemisinin resistance generated by plasmo-dium.

In vitro and in vivo antimalarial activity of the volatile oil of Cyperus articulatus (Cyperaceae)

Malaria is a disease of global tropical distribution, being endemic in more than 90 countries and responsible for about 212 million cases worldwide in 2016. To date, the strategies used to eradicate this disease have been ineffective, without specific preventive measures such as vaccines. Currently, the existing therapeutic arsenal is limited and has become ineffective against the expansion of artemisinin-resistant Plasmodium, demonstrating the need for studies that would allow the development of new compounds against this disease. In this context, we studied the volatile oil obtained from rhizomes of Cyperus articulatus (VOCA), a plant species commonly found in the Amazon region and popularly used as a therapeutic alternative for the treatment of malaria, in order to confirm its potential as an antimalarial agent by in vitro and in vivo assays. We cultured Plasmodium falciparum W2 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains in erythrocytes and exposed them to VOCA at different concentrations in 96-well microplates. In vivo antimalarial activity was tested in BALB/c mice inoculated with approximately 106 erythrocytes infected with Plasmodium berghei. VOCA showed a high antimalarial potential against the two P. falciparum strains, with IC50 = 1.21 µg mL-1 for W2 and 2.30 µg mL-1 for 3D7. VOCA also significantly reduced the parasitemia and anemia induced by P. berghei in mice. Our results confirmed the antimalarial potential of the volatile oil of Cyperus articulatus. (AU)

Molecular Surveillance of Pfkelch13 and Pfmdr1 Mutations in Plasmodium falciparum Isolates from Southern Thailand

Artemisinin-based combination therapy (ACT) resistance is widespread throughout the Greater Mekong Subregion. This raises concern over the antimalarial treatment in Thailand since it shares borders with Cambodia, Laos, and Myanmar where high ACT failure rates were reported. It is crucial to have information about the spread of ACT resistance for efficient planning and treatment. This study was to identify the molecular markers for antimalarial drug resistance: Pfkelch13 and Pfmdr1 mutations from 5 provinces of southern Thailand, from 2012 to 2017, of which 2 provinces on the Thai- Myanmar border (Chumphon and Ranong), one on Thai-Malaysia border (Yala) and 2 from non-border provinces (Phang Nga and Surat Thani). The results showed that C580Y mutation of Pfkelch13 was found mainly in the province on the Thai-Myanmar border. No mutations in the PfKelch13 gene were found in Surat Thani and Yala. The Pfmdr1 gene isolated from the Thai-Malaysia border was a different pattern from those found in other areas (100% N86Y) whereas wild type strain was present in Phang Nga. Our study indicated that the molecular markers of artemisinin resistance were spread in the provinces bordering along the Thai-Myanmar, and the pattern of Pfmdr1 mutations from the areas along the international border of Thailand differed from those of the non-border provinces. The information of the molecular markers from this study highlighted the recent spread of artemisinin resistant parasites from the endemic area, and the data will be useful for optimizing antimalarial treatment based on regional differences.

Assessment of the risk posed to Singapore by the emergence of artemisinin-resistant malaria in the Greater Mekong Subregion

Objective@#To assess the public health risk to Singapore posed by the emergence of artemisinin-resistant (ART-R) malaria in the Greater Mekong Subregion (GMS).@*Methods@#We assessed the likelihood of importation of drug-resistant malaria into Singapore and the impact on public health of its subsequent secondary spread in Singapore. Literature on the epidemiology and contextual factors associated with ART-R malaria was reviewed. The epidemiology of malaria cases in Singapore was analysed. The vulnerability and receptivity of Singapore were examined, including the connectivity with countries reporting ART-R malaria, as well as the preparedness of Singaporean health authorities. Sources of information include international journals, World Health Organization guidelines, data from the Singapore Ministry of Health and National Public Health Laboratory of the National Centre for Infectious Diseases, and the International Air Transport Association.@*Results@#The importation of ART-R malaria into Singapore is possible given the close proximity and significant travel volume between Singapore and the GMS countries reporting artemisinin resistance. Singapore’s vulnerability is further enhanced by the presence of foreign workers from neighbouring endemic countries. Nonetheless, the overall likelihood of such an event is low based on the rarity and decreasing trend of imported malaria incidence. With the presence of Anopheles vectors in Singapore, imported cases of drug-resistant malaria could cause secondary transmission. Nevertheless, the risk of sustained spread is likely to be mitigated by the comprehensive surveillance and control system in place for both infected vectors and human cases.@*Discussion@#This risk assessment highlights the need for a continued high degree of vigilance of ART-R malaria locally and globally to minimize the risk and public health impact of drug-resistant malaria in Singapore.

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.

Intestinal Parasitosis among Primary School Pupils in Coastal Areas of the Cape Coast Metropolis, Ghana.

Malaria caused 350 to 500 million clinical episodes in the year 2000 and remains the fifth most deadly infectious disease worldwide after respiratory infections, HIV/AIDS, diarrhoeal diseases, and tuberculosis. Though malaria remains a global health concern in developing nations, the approximate malaria-infected cases reduced from 227 million cases in 2000 to 198 million cases in 2013 globally. Notably in Africa over the last decades, malaria eradication programmes have received greater international attention leading to reduction of parasite-infected cases by 26%, with a decrease in cases from 173 million in 2000 to 128 million in 2013. Nevertheless malaria remains a global health concern in developing nations. The World Health Organization (WHO) South-East Asia Region (SEAR) comprises of 11 member states (Bangladesh, Bhutan, Democratic People's Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste) of which 10 countries are malaria endemic while Maldives has been declared malaria-free nation since 1984. Presently no licensed malaria vaccine is available and vaccine developers are working on several novel approaches to make a breakthrough as these vaccines would probably be crucial factor to prevent the transmission and onset of malaria. Further due to excessive dependence on artemisinin-based combination therapy (ACTs), emergence of drug resistant parasites, malaria coinfection in immunocompromised patients and newer P. knowlesi strains are fuelling this severe public health problem. Effective measures such as routine surveillance of the antimalarial drug efficacy, newer rapid diagnostic tools (RDTs) and appropriate treatment regimes will help to monitor and limit this deadly disease especially in the malaria-endemic countries. In this review, the various intertwined factors leading to malaria burden – a continuing problem for global health- specially in South-East Asia region are highlighted.

Containing artemisinin resistance of Plasmodium falciparum in Myanmar: achievements, challenges and the way forward.

Artemisinin resistance is a major threat to global malaria control and elimination efforts. Myanmar detected the first indication of the resistance in 2009 in the eastern part of the country, bordering Thailand. Since 2010, WHO has played a vital role in ensuring that a comprehensive programme on the containment of the resistance is in place. This paper documents achievement made in terms of output, outcomes and early impact on malaria from July 2011 to December 2013. It also identifies enabling factors to success and, most importantly, challenges awaiting the national programme and its partners.

Evidence of an increased incidence of day 3 parasitaemia in Suriname: an indicator of the emerging resistance of Plasmodium falciparum to artemether

The emerging resistance to artemisinin derivatives that has been reported in South-East Asia led us to assess the efficacy of artemether-lumefantrine as the first line therapy for uncomplicated Plasmodium falciparum infections in Suriname. This drug assessment was performed according to the recommendations of the World Health Organization in 2011. The decreasing number of malaria cases in Suriname, which are currently limited to migrating populations and gold miners, precludes any conclusions on artemether efficacy because adequate numbers of patients with 28-day follow-up data are difficult to obtain. Therefore, a comparison of day 3 parasitaemia in a 2011 study and in a 2005/2006 study was used to detect the emergence of resistance to artemether. The prevalence of day 3 parasitaemia was assessed in a study in 2011 and was compared to that in a study in 2005/2006. The same protocol was used in both studies and artemether-lumefantrine was the study drug. Of 48 evaluable patients in 2011, 15 (31%) still had parasitaemia on day 3 compared to one (2%) out of 45 evaluable patients in 2005/2006. Overall, 11 evaluable patients in the 2011 study who were followed up until day 28 had negative slides and similar findings were obtained in all 38 evaluable patients in the 2005/2006 study. The significantly increased incidence of parasite persistence on day 3 may be an indication of emerging resistance to artemether.