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Maniphone Khanthavong

Bio: Maniphone Khanthavong is an academic researcher. The author has contributed to research in topics: Plasmodium falciparum & Malaria. The author has an hindex of 15, co-authored 18 publications receiving 3116 citations.

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Journal ArticleDOI
TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Abstract: 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 clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

1,777 citations

Journal ArticleDOI
TL;DR: Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance.
Abstract: We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.

507 citations

Journal ArticleDOI
Didier Menard1, Nimol Khim1, Johann Beghain, Ayola A. Adegnika2, Ayola A. Adegnika3, Mohammad Shafiul-Alam4, Olukemi K. Amodu5, Ghulam Rahim-Awab6, Ghulam Rahim-Awab7, Céline Barnadas8, Céline Barnadas9, Céline Barnadas10, Antoine Berry, Yap Boum11, Yap Boum12, Maria Dorina Bustos13, Jun Cao14, Jun Hu Chen15, Louis Collet, Liwang Cui16, Garib Das Thakur, Alioune Dieye1, Alioune Dieye17, Djibrine Djalle1, Monique A. Dorkenoo18, Carole E. Eboumbou-Moukoko19, Fe Espino20, Thierry Fandeur, Maria de Fátima Ferreira-da-Cruz21, Abebe A. Fola9, Abebe A. Fola22, Hans-Peter Fuehrer, Abdillahi Mohamed Hassan13, Sócrates Herrera, Bouasy Hongvanthong, Sandrine Houzé, Maman Laminou Ibrahim, Mohammad Jahirul-Karim, Lubin Jiang23, Shigeyuki Kano1, Wasif Ali-Khan4, Maniphone Khanthavong, Peter G. Kremsner2, Marcus V. G. Lacerda21, Rithea Leang, Mindy Leelawong24, Mei Li15, Khin Lin, Jean Baptiste Mazarati, Sandie Menard, Isabelle Morlais25, Hypolite Muhindo-Mavoko26, Hypolite Muhindo-Mavoko27, Lise Musset1, Kesara Na-Bangchang28, Michael Nambozi, Karamoko Niaré29, Harald Noedl30, Jean-Bosco Ouédraogo, Dylan R. Pillai31, Bruno Pradines, Bui Quang-Phuc, Michael Ramharter30, Michael Ramharter3, Milijaona Randrianarivelojosia1, Jetsumon Sattabongkot7, Abdiqani Sheikh-Omar, Kigbafori D. Silué32, Sodiomon B. Sirima, Colin J. Sutherland33, Din Syafruddin34, Rachida Tahar, Lin Hua Tang15, Offianan Andre Toure1, Patrick Tshibangu-Wa-Tshibangu27, Inès Vigan-Womas1, Marian Warsame, Lyndes Wini35, Sedigheh Zakeri1, Saorin Kim1, Rotha Eam1, Laura Berne1, Chanra Khean1, Sophy Chy1, Malen Ken1, Kaknika Loch1, Lydie Canier1, Valentine Duru1, Eric Legrand1, Jean Christophe Barale, Barbara H. Stokes36, Judith Straimer36, Benoit Witkowski1, David A. Fidock36, Christophe Rogier1, Pascal Ringwald, Frédéric Ariey37, Odile Mercereau-Puijalon 
TL;DR: In this article, the authors analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic and identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution.
Abstract: BACKGROUND: Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale. METHODS: We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci. RESULTS: We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas--one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China--with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay. CONCLUSIONS: No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.).

398 citations

Journal ArticleDOI
TL;DR: While there was some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar, and K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia.
Abstract: 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.

390 citations

Journal ArticleDOI
30 Jul 2010-PLOS ONE
TL;DR: DHA/PQP was a highly efficacious drug for P. falciparum malaria in areas where multidrug parasites are prevalent and can play an important role in the first-line treatment of uncomplicated falcIParUM malaria.
Abstract: BACKGROUND: The artemisinin-based combination treatment (ACT) of dihydroartemisinin (DHA) and piperaquine (PQP) is a promising novel anti-malarial drug effective against multi-drug resistant falciparum malaria. The aim of this study was to show non-inferiority of DHA/PQP vs. artesunate-mefloquine (AS+MQ) in Asia. METHODS AND FINDINGS: This was an open-label, randomised, non-inferiority, 63-day follow-up study conducted in Thailand, Laos and India. Patients aged 3 months to 65 years with Plasmodium falciparum mono-infection or mixed infection were randomised with an allocation ratio of 2:1 to a fixed-dose DHA/PQP combination tablet (adults: 40 mg/320 mg; children: 20 mg/160 [DOSAGE ERROR CORRECTED] mg; n = 769) or loose combination of AS+MQ (AS: 50 mg, MQ: 250 mg; n = 381). The cumulative doses of study treatment over the 3 days were of about 6.75 mg/kg of DHA and 54 mg/kg of PQP and about 12 mg/kg of AS and 25 mg/kg of MQ. Doses were rounded up to the nearest half tablet. The primary endpoint was day-63 polymerase chain reaction (PCR) genotype-corrected cure rate. Results were 87.9% for DHA/PQP and 86.6% for AS+MQ in the intention-to-treat (ITT; 97.5% one-sided confidence interval, CI: >-2.87%), and 98.7% and 97.0%, respectively, in the per protocol population (97.5% CI: >-0.39%). No country effect was observed. Kaplan-Meier estimates of proportions of patients with new infections on day 63 (secondary endpoint) were significantly lower for DHA/PQP than AS+MQ: 22.7% versus 30.3% (p = 0.0042; ITT). Overall gametocyte prevalence (days 7 to 63; secondary endpoint), measured as person-gametocyte-weeks, was significantly higher for DHA/PQP than AS+MQ (10.15% versus 4.88%; p = 0.003; ITT). Fifteen serious adverse events were reported, 12 (1.6%) in DHA/PQP and three (0.8%) in AS+MQ, among which six (0.8%) were considered related to DHA/PQP and three (0.8%) to AS+MQ. CONCLUSIONS: DHA/PQP was a highly efficacious drug for P. falciparum malaria in areas where multidrug parasites are prevalent. The DHA/PQP combination can play an important role in the first-line treatment of uncomplicated falciparum malaria. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN81306618.

81 citations


Cited by
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TL;DR: In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
Abstract: The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

1,199 citations

Journal ArticleDOI
TL;DR: How control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed are drawn together to show how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir.
Abstract: Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.

651 citations

Journal ArticleDOI
04 May 2018-Science
TL;DR: Saturation-scale mutagenesis allows prioritization of intervention targets in the genome of the most important cause of malaria, and confirms the proteasome-degradation pathway is a high-value druggable target.
Abstract: INTRODUCTION Malaria remains a devastating global parasitic disease, with the majority of malaria deaths caused by the highly virulent Plasmodium falciparum . The extreme AT-bias of the P. falciparum genome has hampered genetic studies through targeted approaches such as homologous recombination or CRISPR-Cas9, and only a few hundred P. falciparum mutants have been experimentally generated in the past decades. In this study, we have used high-throughput piggyBac transposon insertional mutagenesis and quantitative insertion site sequencing (QIseq) to reach saturation-level mutagenesis of this parasite. RATIONALE Our study exploits the AT-richness of the P. falciparum genome, which provides numerous piggyBac transposon insertion targets within both gene coding and noncoding flanking sequences, to generate more than 38,000 P. falciparum mutants. At this level of mutagenesis, we could distinguish essential genes as nonmutable and dispensable genes as mutable. Subsequently, we identified 2680 genes essential for in vitro asexual blood-stage growth. RESULTS We calculated mutagenesis index scores (MISs) and mutagenesis fitness scores (MFSs) in order to functionally define the relative fitness cost of disruption for 5399 genes. A competitive growth phenotype screen confirmed that MIS and MFS were predictive of the fitness cost for in vitro asexual growth. Genes predicted to be essential included genes implicated in drug resistance—such as the “ K13 ” Kelch propeller, mdr , and dhfr-ts —as well as targets considered to be high value for drugs development, such as pkg and cdpk5 . The screen revealed essential genes that are specific to human Plasmodium parasites but absent from rodent-infective species, such as lipid metabolic genes that may be crucial to transmission commitment in human infections. MIS and MFS profiling provides a clear ranking of the relative essentiality of gene ontology (GO) functions in P. falciparum . GO pathways associated with translation, RNA metabolism, and cell cycle control are more essential, whereas genes associated with protein phosphorylation, virulence factors, and transcription are more likely to be dispensable. Last, we confirm that the proteasome-degradation pathway is a high-value druggable target on the basis of its high ratio of essential to dispensable genes, and by functionally confirming its link to the mode of action of artemisinin, the current front-line antimalarial. CONCLUSION Saturation-scale mutagenesis allows prioritization of intervention targets in the genome of the most important cause of malaria. The identification of more than 2680 essential genes, including ~1000 Plasmodium -conserved essential genes, will be valuable for antimalarial therapeutic research.

622 citations

Journal ArticleDOI
TL;DR: Most malaria endemic countries have now adopted artemisinin-based combination treatments as first-line treatment of falciparum malaria, but in most of these only a minority of the patients that need artesunate-mefloquine, artemether-lumefantrine, and dihydroartemisin in-piperaquine actually receive them.
Abstract: Artemisinin-based combination treatments (ACTs) are now generally accepted as the best treatments for uncomplicated falciparum malaria. They are rapidly and reliably effective. Efficacy is determined by the drug partnering the artemisinin derivative and, for artesunate-mefloquine, artemether-lumefantrine, and dihydroartemisinin-piperaquine, this usually exceeds 95%. Artesunate-sulfadoxine-pyrimethamine and artesunate-amodiaquine are effective in some areas, but in other areas resistance to the partner precludes their use. There is still uncertainty over the safety of artemisinin derivatives in the first trimester of pregnancy, when they should not be used unless there are no effective alternatives. Otherwise, except for occasional hypersensitivity reactions, the artemisinin derivatives are safe and remarkably well tolerated. The adverse effect profiles of the artemisinin-based combination treatments are determined by the partner drug. Most malaria endemic countries have now adopted artemisinin-based combination treatments as first-line treatment of falciparum malaria, but in most of these only a minority of the patients that need artemisinin-based combination treatments actually receive them.

605 citations

Journal ArticleDOI
23 Jan 2015-Science
TL;DR: The data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites and imperils efforts to reduce the global malaria burden.
Abstract: The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.

570 citations