scholarly journals Resistance to Artemisinin Combination Therapies (ACTs): Do Not Forget the Partner Drug!

2019 ◽  
Vol 4 (1) ◽  
pp. 26 ◽  
Author(s):  
Christian Nsanzabana
Keyword(s):  
Molecular Markers ◽  
Half Life ◽  
Artemisinin Resistance ◽  
Surveillance Systems ◽  
Combination Therapies ◽  
Artemisinin Derivatives ◽  
Steep Decrease ◽  
Almost All ◽  
Greater Mekong Subregion ◽  
Fast Acting

Artemisinin-based combination therapies (ACTs) have become the mainstay for malaria treatment in almost all malaria endemic settings. Artemisinin derivatives are highly potent and fast acting antimalarials; but they have a short half-life and need to be combined with partner drugs with a longer half-life to clear the remaining parasites after a standard 3-day ACT regimen. When introduced, ACTs were highly efficacious and contributed to the steep decrease of malaria over the last decades. However, parasites with decreased susceptibility to artemisinins have emerged in the Greater Mekong Subregion (GMS), followed by ACTs’ failure, due to both decreased susceptibility to artemisinin and partner drug resistance. Therefore, there is an urgent need to strengthen and expand current resistance surveillance systems beyond the GMS to track the emergence or spread of artemisinin resistance. Great attention has been paid to the spread of artemisinin resistance over the last five years, since molecular markers of decreased susceptibility to artemisinin in the GMS have been discovered. However, resistance to partner drugs is critical, as ACTs can still be effective against parasites with decreased susceptibility to artemisinins, when the latter are combined with a highly efficacious partner drug. This review outlines the different mechanisms of resistance and molecular markers associated with resistance to partner drugs for the currently used ACTs. Strategies to improve surveillance and potential solutions to extend the useful therapeutic lifespan of the currently available malaria medicines are proposed.

scholarly journals Emergence and Spread of kelch13 Mutations Associated with Artemisinin Resistance in Plasmodium falciparum Parasites in 12 Thai Provinces from 2007 to 2016

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Theerayot Kobasa ◽  
Eldin Talundzic ◽  
Rungniran Sug-aram ◽  
Patcharida Boondat ◽  
Ira F. Goldman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Resistance Mutations ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Reduced Ring ◽  
Control And Prevention ◽  
Greater Mekong Subregion

ABSTRACT Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS) and manifests as slow parasite clearance in patients and reduced ring stage susceptibility to artemisinins in survival assays. The P. falciparum kelch13 gene mutations associated with artemisinin-resistant parasites are now widespread in the GMS. We genotyped 277 samples collected during an observational study from 2012 to 2016 from eight provinces in Thailand to identify P. falciparum kelch13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of P. falciparum kelch13 mutations from 2007 to 2016 in that country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistance-conferring Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was found only in western Thailand and R561H only in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall, the prevalence of artemisinin resistance mutations increased over the last 10 years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.

scholarly journals In Silico Investigation of the Decline in Clinical Efficacy of Artemisinin Combination Therapies Due to Increasing Artemisinin and Partner Drug Resistance

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Sophie G. Zaloumis ◽  
Pengxing Cao ◽  
Saber Dini ◽  
Miles P. Davenport ◽  
Deborah Cromer ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
In Silico ◽  
Artemisinin Resistance ◽  
Exact Nature ◽  
Artemisinin Derivative ◽  
Combination Therapies ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
The Impact

ABSTRACT Antimalarial treatment currently relies on an artemisinin derivative and a longer-acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An in silico exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two artemisinin-based combination therapies that are commonly used in Southeast Asia, was performed. The percentage of treatment failures was simulated from a within-host pharmacokinetic-pharmacodynamic (PKPD) model, assuming that parasites developed increasing levels of (i) artemisinin derivative resistance or (ii) concomitant resistance to both the artemisinin derivative and the partner drug. Because the exact nature of how resistant Plasmodium falciparum parasites respond to treatment is unknown, we examined the impact on treatment failure rates of artemisinin resistance that (i) reduced the maximal killing rate, (ii) increased the concentration of drug required for 50% killing, or (iii) shortened the window of parasite stages that were susceptible to artemisinin derivatives until the drugs had no effect on the ring stages. The loss of the ring-stage activity of the artemisinin derivative caused the greatest increase in the treatment failure rate, and this result held irrespective of whether partner drug resistance was assumed to be present or not. To capture the uncertainty regarding how artemisinin derivative and partner drug resistance affects the assumed concentration-killing effect relationship, a variety of changes to this relationship should be considered when using within-host PKPD models to simulate clinical outcomes to guide treatment strategies for resistant infections.

scholarly journals Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces, Angola

2014 ◽  
Vol 59 (1) ◽  
pp. 437-443 ◽  
Author(s):  
Mateusz M. Plucinski ◽  
Eldin Talundzic ◽  
Lindsay Morton ◽  
Pedro Rafael Dimbu ◽  
Aleixo Panzo Macaia ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Artemisinin Resistance ◽  
Molecular Evidence ◽  
Combination Therapies ◽  
Open Label ◽  
Content Type ◽  
Development Of Resistance ◽  
Late Treatment ◽  
Clinical Responses ◽  
Parasitological Response

ABSTRACTThe development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February through May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uíge Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicatedPlasmodium falciparummonoinfection were measured over 28 days, and the main outcome was a PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13 propeller gene. In the 320 children finishing the study, 25 treatment failures were observed: 24 in the AL arms and 1 in the DP arm. The PCR-corrected ACPR proportions on day 28 for AL were 88% (95% confidence interval [CI], 78 to 95%) in Zaire and 97% (91 to 100%) in Uíge. For DP, the proportions were 100% (95 to 100%) in Zaire, and 100% (96 to 100%) in Uíge. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL late-treatment failures had markers associated with lumefantrine resistance on the day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored.

scholarly journals Time to scale up molecular surveillance for anti-malarial drug resistance in sub-saharan Africa

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Christian Nsanzabana
Keyword(s):  
Drug Resistance ◽  
Molecular Markers ◽  
Ex Vivo ◽  
Scale Up ◽  
Artemisinin Resistance ◽  
Drug Efficacy ◽  
Sub Saharan Africa ◽  
Surveillance Systems ◽  
Early Emergence ◽  
Emergence Of Resistance

AbstractArtemisinin resistance has emerged and spread in the Greater Mekong Sub-region (GMS), followed by artemisinin-based combination therapy failure, due to both artemisinin and partner drug resistance. More worrying, artemisinin resistance has been recently reported and confirmed in Rwanda. Therefore, there is an urgent need to strengthen surveillance systems beyond the GMS to track the emergence or spread of artemisinin and partner drug resistance in other endemic settings. Currently, anti-malarial drug efficacy is monitored primarily through therapeutic efficacy studies (TES). Even though essential for anti-malarial drug policy change, these studies are difficult to conduct, expensive, and may not detect the early emergence of resistance. Additionally, results from TES may take years to be available to the stakeholders, jeopardizing their usefulness. Molecular markers are additional and useful tools to monitor anti-malarial drug resistance, as samples collected on dried blood spots are sufficient to monitor known and validated molecular markers of resistance, and could help detecting and monitoring the early emergence of resistance. However, molecular markers are not monitored systematically by national malaria control programmes, and are often assessed in research studies, but not in routine surveillance. The implementation of molecular markers as a routine tool for anti-malarial drug resistance surveillance could greatly improve surveillance of anti-malarial drug efficacy, making it possible to detect resistance before it translates to treatment failures. When possible, ex vivo assays should be included as their data could be useful complementary, especially when no molecular markers are validated.

scholarly journals Characterization of pfmdr1, pfcrt, pfK13, pfubp1, and pfap2mu in travelers returning from Africa with Plasmodium falciparum infections reported in China from 2014–2018

2021 ◽  
Author(s):  
Jun Feng ◽  
Dongmei Xu ◽  
Xiangli Kong ◽  
Kangming Lin ◽  
He Yan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Artemisinin Resistance ◽  
Nucleotide Polymorphisms ◽  
Combination Therapies ◽  
Single Nucleotide ◽  
Synonymous Mutations ◽  
Different Types ◽  
Kelch 13

The artemisinin-based combination therapies (ACTs) used to treat Plasmodium falciparum in Africa are threatened by the emergence of parasites in Asia carrying variants of the Kelch 13 (K13) locus with delayed clearance in response to ACTs. Single nucleotide polymorphisms (SNPs) in other molecular markers, such as ap2mu and ubp1, were associated with artemisinin resistance in rodent malaria and clinical failure in African malaria patients. Here, we characterized the polymorphisms in pfmdr1, pfcrt, pfK13, pfubp1 and pfap2mu among African isolates reported in Shandong and Guangxi provinces in China. Among 144 patients with P. falciparum returning from Africa in 2014–2018, pfmdr1 N86Y (8.3%) and pfcrt K76T (2.1%) were the major mutant alleles. The most common genotype for pfcrt was I74E75T76 (8.3%), followed by E75T76 (2.1%). For K13 polymorphisms, a limited number of mutated alleles were observed, and A578S was the most frequently detected allele in 3 isolates (2.1%). A total of 27.1% (20/144) of the isolates were found to contain pfubp1 mutations, including 6 nonsynonymous and 2 synonymous mutations. The pfubp1 genotypes associated with ART resistance were D1525E (10.4%) and E1528D (8.3%). Furthermore, 11 SNPs were identified in pfap2mu, and S160N was the major polymorphism (4.2%). Additionally, 4 different types of insertions were found in pfap2mu, and the codon AAT, encoding aspartic acid, was more frequently observed at codons 226 (18.8%) and 326 (10.7%). Moreover, 4 different types of insertions were observed in pfubp1 at codon 1520, which was the most common (6.3%). These findings indicate a certain degree of variation in other potential molecular markers, such as pfubp1 and pfap2mu, and their roles either in the parasite’s mechanism of resistance or the mode of action should be evaluated or elucidated further.

Mechanism of anteroposterior axis specification in vertebrates. Lessons from the amphibians

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 285-302 ◽  
Author(s):  
J.M. Slack ◽  
D. Tannahill
Keyword(s):  
Molecular Markers ◽  
Expression Patterns ◽  
Signal Transduction Pathway ◽  
Homeobox Gene ◽  
Neural Induction ◽  
High Sensitivity ◽  
Neural Plate ◽  
Mesoderm Induction ◽  
Inducing Factors ◽  
Almost All

Interest in the problem of anteroposterior specification has quickened because of our near understanding of the mechanism in Drosophila and because of the homology of Antennapedia-like homeobox gene expression patterns in Drosophila and vertebrates. But vertebrates differ from Drosophila because of morphogenetic movements and interactions between tissue layers, both intimately associated with anteroposterior specification. The purpose of this article is to review classical findings and to enquire how far these have been confirmed, refuted or extended by modern work. The “pre-molecular” work suggests that there are several steps to the process: (i) Formation of anteroposterior pattern in mesoderm during gastrulation with posterior dominance. (ii) Regional specific induction of ectoderm to form neural plate. (iii) Reciprocal interactions from neural plate to mesoderm. (iv) Interactions within neural plate with posterior dominance. Unfortunately, almost all the observable markers are in the CNS rather than in the mesoderm where the initial specification is thought to occur. This has meant that the specification of the mesoderm has been assayed indirectly by transplantation methods such as the Einsteckung. New molecular markers now supplement morphological ones but they are still mainly in the CNS and not the mesoderm. A particular interest attaches to the genes of the Antp-like HOX clusters since these may not only be markers but actual coding factors for anteroposterior levels. We have a new understanding of mesoderm induction based on the discovery of activins and fibroblast growth factors (FGFs) as candidate inducing factors. These factors have later consequences for anteroposterior pattern with activin tending to induce anterior, and FGF posterior structures. Recent work on neural induction has implicated cAMP and protein kinase C (PKC) as elements of the signal transduction pathway and has provided new evidence for the importance of tangential neural induction. The regional specificity of neural induction has been reinvestigated using molecular markers and provides conclusions rather similar to the classical work. Defects in the axial pattern may be produced by retinoic acid but it remains unclear whether its effects are truly coordinate ones or are concentrated in certain regions of high sensitivity. In general the molecular studies have supported and reinforced the “pre-molecular ones”. Important questions still remain: (i) How much pattern is there in the mesoderm (how many states?) (ii) How is this pattern generated by the invaginating organizer? (iii) Is there one-to-one transmission of codings to the neural plate? (iv) What is the nature of the interactions within the neural plate? (v) Are the HOX cluster genes really the anteroposterior codings?

scholarly journals Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine and prevalence of molecular markers associated with resistance, Guinea: an open-label two-arm randomized controlled trial

2020 ◽  
Author(s):  
Abdoul Habib Beavogui ◽  
Alioune Camara ◽  
Alexandre Delamou ◽  
Abdoulaye Doumbouya ◽  
Karifa Kourouma ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Molecular Markers ◽  
Treatment Failure ◽  
Uncomplicated Malaria ◽  
Controlled Trial ◽  
Artemisinin Resistance ◽  
Efficacy And Safety ◽  
Open Label ◽  
Randomized Controlled ◽  
Kaplan Meier

Abstract ​ Background: Antimalarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labé Health Districts in Guinea in 2016. Methods: This was a two-arm randomized controlled trial of the efficacy of AL and ASAQ among children aged 6-59 months with uncomplicated P. falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan-Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes. Results: A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labé. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan-Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2-100%) for ASAQ and 99% (97.1-100%) for AL in Labé. The majority of successfully analyzed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13 . All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analyzed for pfmdr1 . Vomiting was the most common observed side effect (14%) across all arms. Conclusions: This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular makers of resistance in Guinea is important to detect emergence of parasite resistance and to inform evidence-based malaria treatment policies.

scholarly journals Effect of Drug Pressure on Promoting the Emergence of Antimalarial-Resistant Parasites among Pregnant Women in Ghana

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Bernard Tornyigah ◽  
Romain Coppée ◽  
Pascal Houze ◽  
Kwadwo A. Kusi ◽  
Bright Adu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pregnant Women ◽  
Marker Gene ◽  
Intermittent Preventive Treatment ◽  
Artemisinin Resistance ◽  
Preventive Treatment ◽  
Drug Pressure ◽  
Gene Markers ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACT The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes, including the pfdhps A581G and A613S/T mutations, was high at delivery among post-SP treatment isolates (18.2%) compared to those of first antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine [IPTp-SP]; 6.1%; P = 0.03). Regarding the pfk13 marker gene, two nonsynonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance of additional mutations associated with increased SP resistance as well as emergence of resistance against artemisinin derivatives.

scholarly journals Spontaneous Mutations in thePlasmodium falciparumSarcoplasmic/ Endoplasmic Reticulum Ca2+-ATPase (PfATP6) Gene among Geographically Widespread Parasite Populations Unexposed to Artemisinin-Based Combination Therapies

2010 ◽  
Vol 55 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Kazuyuki Tanabe ◽  
Sedigheh Zakeri ◽  
Nirianne Marie Q. Palacpac ◽  
Manada Afsharpad ◽  
Milijaona Randrianarivelojosia ◽  
...  
Keyword(s):  
Amino Acid ◽  
South America ◽  
Artemisinin Resistance ◽  
Common Snps ◽  
Nucleotide Polymorphisms ◽  
Combination Therapies ◽  
Single Nucleotide ◽  
Baseline Information ◽  
A Minor ◽  
Parasite Populations

ABSTRACTRecent reports on the decline of the efficacy of artemisinin-based combination therapies (ACTs) indicate a serious threat to malaria control. The endoplasmic/sarcoplasmic reticulum Ca2+-ATPase ortholog ofPlasmodium falciparum(PfSERCA) has been suggested to be the target of artemisinin and its derivatives. It is assumed that continuous artemisinin pressure will affect polymorphism of the PfSERCA gene (serca) if the protein is the target. Here, we investigated the polymorphism ofsercain parasite populations unexposed to ACTs to obtain baseline information for the study of potential artemisinin-driven selection of resistant parasites. Analysis of 656 full-length sequences from 13 parasite populations in Africa, Asia, Oceania, and South America revealed 64 single nucleotide polymorphisms (SNPs), of which 43 were newly identified and 38 resulted in amino acid substitutions. No isolates showed L263E and S769N substitutions, which were reportedly associated with artemisinin resistance. Among the four continents, the number of SNPs was highest in Africa. In Africa, Asia, and Oceania, common SNPs, or those with a minor allele frequency of ≥0.05, were less prevalent, with most SNPs noted to be continent specific, whereas in South America, common SNPs were highly prevalent and often shared with those in Africa. Of 50 amino acid haplotypes observed, only one haplotype (3D7 sequence) was seen in all four continents (64%). Forty-eight haplotypes had frequencies of less than 5%, and 40 haplotypes were continent specific. The geographical difference in the diversity and distribution ofsercaSNPs and haplotypes lays the groundwork for assessing whether some artemisinin resistance-associated mutations and haplotypes are selected by ACTs.

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