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Chanaki Amaratunga - One of the best experts on this subject based on the ideXlab platform.
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association of mutations in the plasmodium falciparum kelch13 gene pf3d7_1343700 with Parasite Clearance rates after artemisinin based treatments a wwarn individual patient data meta analysis
BMC Medicine, 2019Co-Authors: Chanaki Amaratunga, Anders Bjorkman, Elizabeth A Ashley, Delia Bethell, Mehul Dhorda, Arjen M Dondorp, Voahangy Hanitriniaina Andrianaranjaka, Craig A Bonnington, Roland A Cooper, Annette ErhartAbstract:Background: Plasmodium falciparum infections with slow Parasite Clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow cleara ...
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spread of artemisinin resistance in plasmodium falciparum malaria
The New England Journal of Medicine, 2014Co-Authors: Elizabeth A Ashley, Rick M Fairhurst, Mehul Dhorda, Chanaki Amaratunga, Sokunthea Sreng, Seila Suon, Jennifer M Anderson, Pharath Lim, S Mao, B SamAbstract:Background 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. Methods 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. Results 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 clear...
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novel phenotypic assays for the detection of artemisinin resistant plasmodium falciparum malaria in cambodia in vitro and ex vivo drug response studies
Lancet Infectious Diseases, 2013Co-Authors: Benoit Witkowski, Chanaki Amaratunga, Sivanna Mao, Sokunthea Sreng, Pharath Lim, Nimol Khim, Pheaktra Chim, Saorin Kim, Chantha SophaAbstract:Summary Background Artemisinin resistance in Plasmodium falciparum lengthens Parasite Clearance half-life during artemisinin monotherapy or artemisinin-based combination therapy. Absence of in-vitro and ex-vivo correlates of artemisinin resistance hinders study of this phenotype. We aimed to assess whether an in-vitro ring-stage survival assay (RSA) can identify culture-adapted P falciparum isolates from patients with slow-clearing or fast-clearing infections, to investigate the stage-dependent susceptibility of Parasites to dihydroartemisinin in the in-vitro RSA, and to assess whether an ex-vivo RSA can identify artemisinin-resistant P falciparum infections. Methods We culture-adapted Parasites from patients with long and short Parasite Clearance half-lives from a study done in Pursat, Cambodia, in 2010 (registered with ClinicalTrials.gov, number NCT00341003) and used novel in-vitro survival assays to explore the stage-dependent susceptibility of slow-clearing and fast-clearing Parasites to dihydroartemisinin. In 2012, we implemented the RSA in prospective Parasite Clearance studies in Pursat, Preah Vihear, and Ratanakiri, Cambodia (NCT01736319), to measure the ex-vivo responses of Parasites from patients with malaria. Continuous variables were compared with the Mann-Whitney U test. Correlations were analysed with the Spearman correlation test. Findings In-vitro survival rates of culture-adapted Parasites from 13 slow-clearing and 13 fast-clearing infections differed significantly when assays were done on 0–3 h ring-stage Parasites (10·88% vs 0·23%; p=0·007). Ex-vivo survival rates significantly correlated with in-vivo Parasite Clearance half-lives (n=30, r =0·74, 95% CI 0·50–0·87; p Interpretation The in-vitro RSA of 0–3 h ring-stage Parasites provides a platform for the molecular characterisation of artemisinin resistance. The ex-vivo RSA can be easily implemented where surveillance for artemisinin resistance is needed. Funding Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH.
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slow Parasite Clearance rates in response to artemether in patients with severe malaria
Lancet Infectious Diseases, 2013Co-Authors: Chanaki Amaratunga, Sivanna Mao, Sokunthea Sreng, Seila Suon, Rick M FairhurstAbstract:We recently reported artemisinin-resistant, uncomplicated Plasmodium falciparum malaria in Pursat, western Cambodia.1 Artemisinin resistance manifests as a slow Parasite Clearance rate (ie, a long Parasite Clearance half-life). A concern is that Parasite Clearance rates might be slower in patients with severe malaria2 who receive artemisinin monotherapy parenterally3 until they can take an artemisinin-based drug combination orally. To investigate this possibility, in 2010 we assessed Parasite Clearance in 30 patients with severe malaria in Pursat, with use of a protocol (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00341003","term_id":"NCT00341003"}}NCT00341003) approved by Cambodia’s National Ethics Committee for Health Research and the National Institute for Allergy and Infectious Diseases Institutional Review Board. Adults or parents of child participants gave written informed consent.
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artemisinin resistant plasmodium falciparum in pursat province western cambodia a Parasite Clearance rate study
Lancet Infectious Diseases, 2012Co-Authors: Chanaki Amaratunga, Kasia Stepniewska, Sokunthea Sreng, Seila Suon, Erika S Phelps, Chongjun Zhou, Jennifer M Anderson, Niklas Lindegardh, Hongying Jiang, Jianping SongAbstract:Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow Parasite Clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with Parasite Clearance rate but does not account for all variation. We investigated contributions of both Parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual Parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed Parasite density on thick blood films every 6 h until undetectable. The Parasite Clearance half-life was calculated from the Parasite Clearance curve. We genotyped Parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different Parasite clone groups: Parasite group 1 (PG1) and Parasite group 2 (PG2). Non-significant increases in Parasite Clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean Parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify Parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Arjen M Dondorp - One of the best experts on this subject based on the ideXlab platform.
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association of mutations in the plasmodium falciparum kelch13 gene pf3d7_1343700 with Parasite Clearance rates after artemisinin based treatments a wwarn individual patient data meta analysis
BMC Medicine, 2019Co-Authors: Chanaki Amaratunga, Anders Bjorkman, Elizabeth A Ashley, Delia Bethell, Mehul Dhorda, Arjen M Dondorp, Voahangy Hanitriniaina Andrianaranjaka, Craig A Bonnington, Roland A Cooper, Annette ErhartAbstract:Background: Plasmodium falciparum infections with slow Parasite Clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow cleara ...
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identifying artemisinin resistance from Parasite Clearance half life data with a simple shiny web application
PLOS ONE, 2017Co-Authors: Sai Thein Than Tun, Kyaw Myo Tun, Arjen M Dondorp, Yoel Lubell, Tom Fieldman, Olivier Celhay, Xin Hui S ChanAbstract:The emergence of artemisinin-resistant Plasmodium falciparum malaria is a major threat to malaria elimination. New tools for supporting the surveillance of artemisinin resistance are critical for current and future malaria control and elimination strategies. We have developed an open-access, user-friendly, web-based tool to analyse Parasite Clearance half-life data of P. falciparum infected patients after treatment with artemisinin derivatives, so that resistance to artemisinin can be identified. The tool can be accessed at bit.ly/id_artemisinin_resistance.
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severe falciparum malaria complicated by prolonged haemolysis and rhinomaxillary mucormycosis after Parasite Clearance a case report
BMC Infectious Diseases, 2015Co-Authors: Katherine Plewes, Richard J Maude, Aniruddha Ghose, Arjen M DondorpAbstract:Severe falciparum malaria may be complicated by prolonged haemolysis and recurrent fever after Parasite Clearance. However, their respective etiologies are unclear and challenging to diagnose. We report the first case of severe falciparum malaria followed by prolonged haemolytic anaemia and rhinomaxillary mucormycosis in a previously healthy adult male. A 30-year old Bangladeshi man was admitted with severe falciparum malaria complicated by hyperlactataemia and haemoglobinuria. Prior to admission he was treated with intravenous quinine and upon admission received intravenous artesunate and empiric ceftriaxone. Thirty hours later the peripheral parasitaemia cleared with resolution of fever and haemoglobinuria. Despite Parasite Clearance, on day 3 the patient developed recurrent fever and acute haemolytic anaemia requiring seven blood transfusions over six days with no improvement of his haemoglobin or haemoglobinuria. On day 10, he was treated with high-dose dexamethasone and meropenem with discontinuation of the ceftriaxone. Two days later the haemoglobinuria resolved. Ceftriaxone-induced haemolysis was the suspected final diagnosis. On day 16, the patient had progressively worsening right-sided facial pain and swelling; a necrotic ulceration of the hard palate was observed. Rhinomaxillary mucormycosis was diagnosed supported by microscopy findings. The patient initially responded to treatment with urgent surgical debridement, itraconazole, followed by two weeks of amphotericin B deoxycholate, however was subsequently lost to follow up. This case highlights the range of potential alternative aetiologies of acute, prolonged haemolysis and recurrent fever following Parasite Clearance in severe falciparum malaria. It emphasizes the importance of a high degree of suspicion for alternative causes of haemolysis in order to avoid unnecessary treatments, including blood transfusion and steroids. It is critical to consider and identify common invasive bacterial and rare opportunistic co-infections as a cause of fever in severe malaria patients remaining febrile after Parasite Clearance to promote antimicrobial stewardship and prompt emergency care.
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independent emergence of artemisinin resistance mutations among plasmodium falciparum in southeast asia
The Journal of Infectious Diseases, 2015Co-Authors: Shannon Takalaharrison, Mark M Fukuda, Arjen M Dondorp, Christopher G Jacob, Tran Tinh Hien, Cesar Arze, Michael P Cummings, Joana C Silva, Mayfong MayxayAbstract:The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia.P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between Parasite genotypes and Parasite Clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently.The presence of nonreference K13 alleles was associated with prolonged Parasite Clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer Parasite Clearance half-lives than Parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas.K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.
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independent emergence of plasmodium falciparum artemisinin resistance mutations in southeast asia
The Journal of Infectious Diseases, 2014Co-Authors: Shannon Takalaharrison, Mark M Fukuda, Arjen M Dondorp, Christopher G Jacob, Tran Tinh Hien, Cesar Arze, Michael P Cummings, Joana C Silva, Mayfong MayxayAbstract:BACKGROUND The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. METHODS P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33,716 genome-wide single nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between Parasite genotypes and Parasite Clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread, or emerged independently. RESULTS The presence of non-reference K13 alleles was associated with prolonged Parasite Clearance half-life (p=1.97E-12). Parasites with a mutation in any of the K13 kelch domains displayed longer Parasite Clearance half-lives than Parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. CONCLUSIONS K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.
Kasia Stepniewska - One of the best experts on this subject based on the ideXlab platform.
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Global Malaria Programme, World Health Organization
2020Co-Authors: Debashish Das, Kasia Stepniewska, Joel Tarning, Aung Pyae Phyo, Sue J Lee, Rupam Tripura, Khin Maung Lwin, Warunee Hanpithakpong, Didier Menard, Pascal RingwaldAbstract:Background. The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves Parasite Clearance in falciparum malaria in the 2 regions. Methods. In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009Thailand ( -2010, patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a oncedaily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite Clearance and recrudescence for up to 63 days of follow-up were assessed. Results. A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) Parasitemia half-life (half-life) was 6.03 (4.89-7.28) hours in Pailin versus 3.42 (2.20-4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68). Conclusions. Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve Parasite Clearance in either artemisinin resistant or more sensitive infections with P. falciparum. Clinical Trials Registration. ISRCTN15351875
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malaria Parasite Clearance rate regression an r software package for a bayesian hierarchical regression model
BioMed Central, 2019Co-Authors: Saeed Sharifimalvajerdi, Jennifer A. Flegg, Kasia Stepniewska, Feiyu Zhu, Colin B Fogarty, Michael P Fay, Rick M Fairhurst, Dylan S SmallAbstract:Emerging resistance to anti-malarial drugs has led malaria researchers to investigate what covariates (Parasite and host factors) are associated with resistance. In this regard, investigation of how covariates impact malaria Parasites Clearance is often performed using a two-stage approach in which the WWARN Parasite Clearance Estimator or PCE is used to estimate Parasite Clearance rates and then the estimated Parasite Clearance is regressed on the covariates. However, the recently developed Bayesian Clearance Estimator instead leads to more accurate results for hierarchial regression modelling which motivated the authors to implement the method as an R package, called “bhrcr”. Given malaria Parasite Clearance profiles of a set of patients, the “bhrcr” package performs Bayesian hierarchical regression to estimate malaria Parasite Clearance rates along with the effect of covariates on them in the presence of “lag” and “tail” phases. In particular, the model performs a linear regression of the log Clearance rates on covariates to estimate the effects within a Bayesian hierarchical framework. All posterior inferences are obtained by a “Markov Chain Monte Carlo” based sampling scheme which forms the core of the package. The “bhrcr” package can be utilized to study malaria Parasite Clearance data, and specifically, how covariates affect Parasite Clearance rates. In addition to estimating the Clearance rates and the impact of covariates on them, the “bhrcr” package provides tools to calculate the WWARN PCE estimates of the Parasite Clearance rates as well. The fitted Bayesian model to the Clearance profile of each individual, as well as the WWARN PCE estimates, can also be plotted by this package. This paper explains the Bayesian Clearance Estimator for malaria researchers including describing the freely available software, thus making these methods accessible and practical for modelling covariates’ effects on Parasite Clearance rates.
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genetic evaluation of the performance of malaria Parasite Clearance rate metrics
The Journal of Infectious Diseases, 2013Co-Authors: Standwell Nkhoma, Kasia Stepniewska, Shalini Nair, Aung Pyae Phyo, Rose Mcgready, Francois Nosten, Tim J AndersonAbstract:Accurate measurement of malaria Parasite Clearance rates (CRs) following artemisinin (ART) treatment is critical for resistance surveillance and research, and various CR metrics are currently used. We measured 13 CR metrics in 1472 ART-treated hyperParasitemia infections for which 6-hour Parasite counts and Parasite genotypes (93 single nucleotide polymorphisms [SNPs]) were available. We used heritability to evaluate the performance of each metric. Heritability ranged from 0.06 ± 0.06 (SD) for 50% Parasite Clearance times to 0.67 ± 0.04 (SD) for Clearance half-lives estimated from 6-hour Parasite counts. These results identify the measures that should be avoided and show that reliable Clearance measures can be obtained with abbreviated monitoring protocols.
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plasmodium falciparum Clearance rates in response to artesunate in malian children with malaria effect of acquired immunity
The Journal of Infectious Diseases, 2013Co-Authors: Tatiana M Loperamesa, Saibou Doumbia, Serena Chiang, Amir E Zeituni, Drissa Konate, Mory Doumbouya, Abdoul S Keita, Karim Traore, Kasia Stepniewska, Seidina A S DiakiteAbstract:Artemisinins rapidly kill all asexual blood stages of Plasmodium falciparum [1], including young ring forms before they sequester in the microvessels of vital organs, and are thus more effective than quinolines in reducing malaria morbidity and mortality [2, 3]. For this reason, artemisinin-based combination therapies (ACTs) are first-line treatments for P. falciparum malaria worldwide [4]. ACTs are the use of artemisinin or one of its derivatives—artesunate, artemether, dihydroartemisinin (DHA)—in combination with a partner drug. DHA, the active metabolite of all artemisinins, has a short half-life (approximately 1–3 hours) in plasma; therefore, partner drugs with longer half-lives (ie, approximately 7–21 days) are needed to eliminate residual Parasites [5, 6]. Parasite resistance to nearly every commonly used partner drug is entrenched or emerging in western Cambodia [7]. Reports of artemisinin resistance in western Cambodia [8, 9] and western Thailand [10]—where antimalarial-resistant Parasites have previously emerged and spread to Africa [11–13]—are thus extremely worrisome. This phenotype manifests as a slow Parasite Clearance rate in response to an artemisinin taken orally to treat uncomplicated malaria [14]. Unlike quinoline resistance, artemisinin resistance does not associate with known molecular markers of drug resistance or reduced Parasite drug susceptibility in vitro [8, 9, 15]. Slow Parasite Clearance may be partly defined as a Parasite-heritable trait [9, 10, 16] and was recently associated with a major region of the Parasite genome [17]. Microsatellite-defined Parasite genetics, however, has not been able to account for all the variation in Parasite Clearance rates in Cambodia and Thailand [9, 10, 16]. Few studies have explored how host factors, such as naturally acquired immunity and red blood cell (RBC) polymorphisms, influence Parasite Clearance rates in response to artemisinins. A retrospective analysis of 18 699 patients with P. falciparum malaria treated with artemisinins found that Parasite Clearance was slowest in low-transmission settings and relatively fast in high-transmission settings, suggesting that acquired immunity accelerates Parasite Clearance [18]. A recent prospective study suggested that hemoglobin (Hb) E is associated with slow Parasite Clearance rate in Pursat, western Cambodia [9], but the effect of acquired immunity on this parameter is not well defined. This is because, in southeast Asia, age is an inadequate surrogate of immunity to malaria and no in vitro correlate of Parasite-clearing immunity has been identified. Few Parasite Clearance rates have been reported from Africa [19], where ACTs were recently introduced and artemisinin monotherapies have been used for 15 years in some areas [20]. The proposed mechanism of action of artemisinins involves endoperoxide-derived, free radicals that alkylate and oxidize the proteins and lipids of intraerythrocytic Parasites [21]. Artemisinin-treated Parasites undergo pyknosis rapidly in vivo and are cleared from the bloodstream by “pitting” in the spleen, which returns previously infected, intact RBCs back into circulation (Figure (Figure11A) [22–25]. Although largely determined by the rates of pyknosis and pitting, the Parasite Clearance rate is nonetheless a complex phenotype produced by a combination of Parasite and host factors. Parasite expression of cytoadherence ligands, for example, can determine when late ring-stage Parasites sequester in microvessels and disappear from peripheral blood (Figure (Figure11C) [26]. If Parasites sequester en masse [26] while Parasite Clearance is being monitored, Parasite densities may decrease markedly by an artemisinin-independent mechanism. Host antibody responses that prevent sequestration and opsonize parasitized RBCs may also accelerate Parasite Clearance (Figure (Figure11B). Figure 1. Clearance of ring-stage Plasmodium falciparum Parasites from peripheral blood during a Parasite Clearance rate study. Dihydroartemisinin, the active metabolite of all artemisinins, causes ring-stage Parasites to undergo pyknosis (A). These circulating ... To obtain baseline surveillance data for the emergence or spread of artemisinin resistance in Africa and to investigate the role of acquired immunity in Parasite Clearance, we measured Parasite Clearance rates in response to artesunate in a high transmission area of Mali, where ACTs were introduced only 2 years previously and where children rapidly acquire antimalarial immunity with age.
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artemisinin resistant plasmodium falciparum in pursat province western cambodia a Parasite Clearance rate study
Lancet Infectious Diseases, 2012Co-Authors: Chanaki Amaratunga, Kasia Stepniewska, Sokunthea Sreng, Seila Suon, Erika S Phelps, Chongjun Zhou, Jennifer M Anderson, Niklas Lindegardh, Hongying Jiang, Jianping SongAbstract:Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow Parasite Clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with Parasite Clearance rate but does not account for all variation. We investigated contributions of both Parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual Parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed Parasite density on thick blood films every 6 h until undetectable. The Parasite Clearance half-life was calculated from the Parasite Clearance curve. We genotyped Parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different Parasite clone groups: Parasite group 1 (PG1) and Parasite group 2 (PG2). Non-significant increases in Parasite Clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean Parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify Parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Sokunthea Sreng - One of the best experts on this subject based on the ideXlab platform.
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spread of artemisinin resistance in plasmodium falciparum malaria
The New England Journal of Medicine, 2014Co-Authors: Elizabeth A Ashley, Rick M Fairhurst, Mehul Dhorda, Chanaki Amaratunga, Sokunthea Sreng, Seila Suon, Jennifer M Anderson, Pharath Lim, S Mao, B SamAbstract:Background 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. Methods 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. Results 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 clear...
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novel phenotypic assays for the detection of artemisinin resistant plasmodium falciparum malaria in cambodia in vitro and ex vivo drug response studies
Lancet Infectious Diseases, 2013Co-Authors: Benoit Witkowski, Chanaki Amaratunga, Sivanna Mao, Sokunthea Sreng, Pharath Lim, Nimol Khim, Pheaktra Chim, Saorin Kim, Chantha SophaAbstract:Summary Background Artemisinin resistance in Plasmodium falciparum lengthens Parasite Clearance half-life during artemisinin monotherapy or artemisinin-based combination therapy. Absence of in-vitro and ex-vivo correlates of artemisinin resistance hinders study of this phenotype. We aimed to assess whether an in-vitro ring-stage survival assay (RSA) can identify culture-adapted P falciparum isolates from patients with slow-clearing or fast-clearing infections, to investigate the stage-dependent susceptibility of Parasites to dihydroartemisinin in the in-vitro RSA, and to assess whether an ex-vivo RSA can identify artemisinin-resistant P falciparum infections. Methods We culture-adapted Parasites from patients with long and short Parasite Clearance half-lives from a study done in Pursat, Cambodia, in 2010 (registered with ClinicalTrials.gov, number NCT00341003) and used novel in-vitro survival assays to explore the stage-dependent susceptibility of slow-clearing and fast-clearing Parasites to dihydroartemisinin. In 2012, we implemented the RSA in prospective Parasite Clearance studies in Pursat, Preah Vihear, and Ratanakiri, Cambodia (NCT01736319), to measure the ex-vivo responses of Parasites from patients with malaria. Continuous variables were compared with the Mann-Whitney U test. Correlations were analysed with the Spearman correlation test. Findings In-vitro survival rates of culture-adapted Parasites from 13 slow-clearing and 13 fast-clearing infections differed significantly when assays were done on 0–3 h ring-stage Parasites (10·88% vs 0·23%; p=0·007). Ex-vivo survival rates significantly correlated with in-vivo Parasite Clearance half-lives (n=30, r =0·74, 95% CI 0·50–0·87; p Interpretation The in-vitro RSA of 0–3 h ring-stage Parasites provides a platform for the molecular characterisation of artemisinin resistance. The ex-vivo RSA can be easily implemented where surveillance for artemisinin resistance is needed. Funding Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH.
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slow Parasite Clearance rates in response to artemether in patients with severe malaria
Lancet Infectious Diseases, 2013Co-Authors: Chanaki Amaratunga, Sivanna Mao, Sokunthea Sreng, Seila Suon, Rick M FairhurstAbstract:We recently reported artemisinin-resistant, uncomplicated Plasmodium falciparum malaria in Pursat, western Cambodia.1 Artemisinin resistance manifests as a slow Parasite Clearance rate (ie, a long Parasite Clearance half-life). A concern is that Parasite Clearance rates might be slower in patients with severe malaria2 who receive artemisinin monotherapy parenterally3 until they can take an artemisinin-based drug combination orally. To investigate this possibility, in 2010 we assessed Parasite Clearance in 30 patients with severe malaria in Pursat, with use of a protocol (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00341003","term_id":"NCT00341003"}}NCT00341003) approved by Cambodia’s National Ethics Committee for Health Research and the National Institute for Allergy and Infectious Diseases Institutional Review Board. Adults or parents of child participants gave written informed consent.
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artemisinin resistant plasmodium falciparum in pursat province western cambodia a Parasite Clearance rate study
Lancet Infectious Diseases, 2012Co-Authors: Chanaki Amaratunga, Kasia Stepniewska, Sokunthea Sreng, Seila Suon, Erika S Phelps, Chongjun Zhou, Jennifer M Anderson, Niklas Lindegardh, Hongying Jiang, Jianping SongAbstract:Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow Parasite Clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with Parasite Clearance rate but does not account for all variation. We investigated contributions of both Parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual Parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed Parasite density on thick blood films every 6 h until undetectable. The Parasite Clearance half-life was calculated from the Parasite Clearance curve. We genotyped Parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different Parasite clone groups: Parasite group 1 (PG1) and Parasite group 2 (PG2). Non-significant increases in Parasite Clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean Parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify Parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
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artemisinin resistant plasmodium falciparum in pursat province western cambodia a Parasite Clearance rate study
Lancet Infectious Diseases, 2012Co-Authors: Chanaki Amaratunga, Kasia Stepniewska, Sivanna Mao, Sokunthea Sreng, Seila Suon, Erika S Phelps, Chongjun Zhou, Jennifer M Anderson, Pharath Lim, Niklas LindegardhAbstract:Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow Parasite Clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with Parasite Clearance rate but does not account for all variation. We investigated contributions of both Parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual Parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed Parasite density on thick blood films every 6 h until undetectable. The Parasite Clearance half-life was calculated from the Parasite Clearance curve. We genotyped Parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different Parasite clone groups: Parasite group 1 (PG1) and Parasite group 2 (PG2). Non-significant increases in Parasite Clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean Parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify Parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
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Parasite host dynamics throughout antimalarial drug development stages complicate the translation of Parasite Clearance
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Lydia Burgert, Sophie Zaloumis, Saber Dini, Louise Marquart, Pengxing Cao, Mohammed Cherkaoui, Nathalie Gobeau, James S Mccarthy, Julie A Simpson, Jorg J MohrleAbstract:Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite Clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture Parasite growth and drug Clearance along the drug development pathway and estimated Parasite Clearance rates. When comparing the three infection experiments, we identified different relationships of Parasite Clearance with dose and different maximum Parasite Clearance rates. In Plasmodium berghei-NMRI mouse infections, we estimated a maximum Parasite Clearance rate of 0.2 (1/h); in Plasmodium falciparum-SCID mouse infections, 0.05 (1/h); and in human volunteer infection studies with P. falciparum, we found a maximum Parasite Clearance rate of 0.12 (1/h) and 0.18 (1/h) after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-Parasite driven processes account for up to 25% of variance in Parasite Clearance for medium-high doses of antimalarials. Although there are limitations in translating Parasite Clearance rates across these experiments, they provide insight into characterizing key parameters of drug action and dose response and assist in decision-making regarding dosage for further drug development.
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Parasite strain host immunity and circulating blood cells with dead Parasites why predicting malaria Parasite Clearance is not a simple task
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Julie A Simpson, James M Mccaw, Freya J I FowkesAbstract:Hastings et al. ([1][1]) bring to our attention the potential limitation of malaria Parasite Clearance rates as indicators of the effectiveness of the artemisinin-based combination therapies. While their conclusions concur with earlier findings by Dogovski et al. ([2][2]), who made use of in vitro
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a robust design for identification of the Parasite Clearance estimator
Malaria Journal, 2013Co-Authors: Kris Jamsen, Stephen B Duffull, Joel Tarning, Ric N Price, Julie A SimpsonAbstract:Background Anti-malarial efficacy needs to be monitored continually to ensure optimal dosing in the face of emerging anti-malarial drug resistance. The efficacy of artemisinin based combination therapies (ACT) is assessed by repeated measurements of Parasite density in the blood of patients following treatment. Parasite density is measured from a capillary or venous blood sample, but this can be logistically and ethically challenging if multiple samples are required within a short time period. The aim of this work was to apply optimal design theory to derive clinically feasible blood sampling schedules from which Parasite Clearance could be defined using the Parasite Clearance Estimator (PCE), a recently developed tool to identify and quantify artemisinin resistance.
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a robust design for identification of the Parasite Clearance estimator
Malaria Journal, 2013Co-Authors: Kris Jamsen, Stephen B Duffull, Joel Tarning, Ric N Price, Julie A SimpsonAbstract:Anti-malarial efficacy needs to be monitored continually to ensure optimal dosing in the face of emerging anti-malarial drug resistance. The efficacy of artemisinin based combination therapies (ACT) is assessed by repeated measurements of Parasite density in the blood of patients following treatment. Parasite density is measured from a capillary or venous blood sample, but this can be logistically and ethically challenging if multiple samples are required within a short time period. The aim of this work was to apply optimal design theory to derive clinically feasible blood sampling schedules from which Parasite Clearance could be defined using the Parasite Clearance Estimator (PCE), a recently developed tool to identify and quantify artemisinin resistance. Robust T-optimal design methodology was applied to offer a sampling schedule that allows for discrimination across models that best describe an individual patient’s Parasite-time profile. The design was based on typical Parasite-time profiles derived from the literature combined with key sampling constraints of no more than six samples per patient within 48 hours of initial treatment. The design was evaluated with a simulation-estimation procedure that implemented the PCE. The optimal sampling times (sampling windows) were: 0 (0 to 1.1), 5.8 (4.0 to 6.0), 9.9 (8.4 to 11.5), 24.8 (24.0 to 24.9), 36.3 (34.8 to 37.2) and 48 (47.3, 48.0) hours post initial treatment. The simulation-estimation procedure showed that the design supported identification of the appropriate method by the PCE to determine an individual’s Parasite Clearance rate constant (the main output calculation from the PCE). The proposed sampling design requires six samples per patient within the first 48 hours. The derived design requires validation in a real world setting, but should be considered for future studies that intend to employ the PCE.
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the mechanisms of Parasite Clearance after antimalarial treatment of plasmodium falciparum malaria
The Journal of Infectious Diseases, 2000Co-Authors: Kesinee Chotivanich, Julie A Simpson, Arjen M Dondorp, Rachanee Udomsangpetch, Sasithon Pukrittayakamee, Sornchai Looareesuwan, Trevor Williams, Brian Angus, C I NewboldAbstract:Studies were conducted to determine how malaria Parasites are cleared from the blood after antimalarial treatment. Neither artesunate nor quinine decreased parasitized red cell deformability or increased antibody binding. In acute falciparum malaria, ring-infected erythrocyte surface antigen (RESA) was observed in erythrocytes without malaria Parasites (RESA‐red blood cell [RBC]), indicating prior parasitization. In uncomplicated malaria, RESA-RBC numbers increased significantly ( ) within 24 h of starting artesunate but rose much P p .002 more slowly (7 days) after quinine treatment. In severe malaria, RESA-RBC increased significantly ( ) within hours of starting artesunate but not with quinine treatment P p .001 ( ). RESA-RBCs were not produced after drug treatment of malaria Parasite cultures P p .43 in vitro. Rapid malaria Parasite Clearance after treatment with artemisinin derivatives results mainly from the extraction of drug-affected Parasites from host erythrocytes—presumably by the spleen. This explains why the fall in hematocrit after treatment of hyperParasitemia is often less than that predicted from loss of parasitized cells. Antimalarial treatment with artemisinin or one of its derivatives, is associated with a more rapid decline in Parasitemia than with other antimalarials [1]. The rate of fall exceeds that associated with inhibition of schizogony alone. This suggests that these drugs induce rapid changes in the circulating ring stage‐infected erythrocytes that allow recognition by the hostdefense system. Using the 2 most widely used treatments of severe malaria, quinine and artesunate, we have investigated 3 potential mechanisms that might explain this phenomenon: drug-induced changes in infected erythrocyte deformability, antibody binding, or “pitting”—that is, removal of intraerythrocytic Parasites without host red cell destruction.
