Browsing by Author "Char Meng Chuor"

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    Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in Northern Cambodia: An open-label randomized trial
    (2014-03-25) Chanthap Lon; Jessica E. Manning; Pattaraporn Vanachayangkul; Mary So; Darapiseth Sea; Youry Se; Panita Gosi; Charlotte Lanteri; Suwanna Chaorattanakawee; Sabaithip Sriwichai; Soklyda Chann; Worachet Kuntawunginn; Nillawan Buathong; Samon Nou; Douglas S. Walsh; Stuart D. Tyner; Jonathan J. Juliano; Jessica Lin; Michele Spring; Delia Bethell; Jaranit Kaewkungwal; Douglas Tang; Char Meng Chuor; Prom Satharath; David Saunders; Armed Forces Research Institute of Medical Sciences, Thailand; Brigham and Women's Hospital; Armed Forces Research Institute of Medical Sciences; Royal Cambodian Armed Forces; National Center for Parasitology, Entomology and Malaria Control; The University of North Carolina at Chapel Hill; Mahidol University; Fast Track Biologics
    Introduction: Emerging antimalarial drug resistance in mobile populations remains a significant public health concern. We compared two regimens of dihydroartemisinin-piperaquine in military and civilians on the Thai-Cambodian border to evaluate national treatment policy. Methods: Efficacy and safety of two and three-day regimens of dihydroartemisinin-piperaquine were compared as a nested open-label evaluation within a malaria cohort study in 222 otherwise healthy volunteers (18% malaria-infected at baseline). The first 80 volunteers with slide-confirmed Plasmodium falciparum or vivax malaria were randomized 1:1 to receive either regimen (total dose 360mg dihydroartemisinin and 2880mg piperaquine) and followed weekly for up to 6 months. The primary endpoint was malaria recurrence by day 42. Volunteers with vivax infection received primaquine at study discharge with six months follow-up. Results: Eighty patients (60 vivax, 15 falciparum, and 5 mixed) were randomized to dihydroartemisinin-piperaquine. Intention-to-treat all-species efficacy at Day 42 was 85% for the two-day regimen (95% CI 69-94) and 90% for the three-day regimen (95% CI 75-97). PCR-adjusted falciparum efficacy was 75% in both groups with nearly half (45%) still parasitemic at Day 3. Plasma piperaquine levels were comparable to prior published reports, but on the day of recrudescence were below measurable in vitro piperaquine IC50 levels in all falciparum treatment failures. Conclusions: In the brief period since introduction of dihydroartemisinin-piperaquine, there is early evidence suggesting declining efficacy relative to previous reports. Parasite IC50 levels in excess of plasma piperaquine levels seen only in treatment failures raises concern for clinically significant piperaquine resistance in Cambodia. These findings warrant improved monitoring of clinical outcomes and follow-up, given few available alternative drugs. Trial Registration: ClinicalTrials.gov NCT01280162.
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    Field survey focused on Opisthorchis viverrini infection in five provinces of Cambodia
    (2014-04-01) Kazuko Miyamoto; Masashi Kirinoki; Hajime Matsuda; Naoko Hayashi; Yuichi Chigusa; Muth Sinuon; Char Meng Chuor; Viroj Kitikoon; Dokkyo Medical University; Ministry of Health (MOH; Mahidol University
    Background: Opisthorchiasis is endemic in Thailand and Lao People's Democratic Republic and constitutes a major public health problem throughout the Mekong Basin. Although Cambodia is located in the Mekong Basin, the status of O. viverrini infection in that country was not previously clarified. This research was conducted to document the extent and distribution of O. viverrini infection in Cambodia. Methods: Surveillance was conducted in 55 villages in five Cambodian provinces. Research tools included stool examination using the Kato-Katz thick-smear technique, identification of intermediate hosts, and interviews covering factors related to O. viverrini infection. Some larvae and egg-positive stool samples were examined using PCR to detect O. viverrini DNA. Results: A total of 16,082 stool samples from the 55 villages were examined, of which 1232 were egg positive. In 15 villages with egg-positive rates of greater than 10%, eggs were found in 998 of 3585 stool samples, for an egg-positive rate of 27.8%. PCR analysis showed that 30 of 33 samples were positive for O. viverrini DNA from five villages in Kampong Cham and Kampong Thom provinces. The first intermediate host Bithynia siamensis siamensis was identified in the target areas of Takaev, Kandal, and Kampong Cham provinces. Cercariae were identified morphologically as O. viverrini and some were confirmed using PCR. Metacercariae of O. viverrini were identified by morphologic observations, animal experiments, or PCR in six species of fish in the target areas. Discussion and conclusions: Four Cambodian provinces were identified as endemic areas of O. viverrini infection. Careful planning is necessary for effective field surveys, because complex environmental factors might be involved in the distribution of O. viverrini infection-endemic areas in Cambodia. Many problems remain to be resolved regarding the status of O. viverrini infection in Cambodia, and a nationwide baseline survey is necessary. © 2013 Elsevier B.V.
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    Genetic architecture of artemisinin-resistant Plasmodium falciparum
    (2015-02-25) Olivo Miotto; Roberto Amato; Elizabeth A. Ashley; Bronwyn Macinnis; Jacob Almagro-Garcia; Chanaki Amaratunga; Pharath Lim; Daniel Mead; Samuel O. Oyola; Mehul Dhorda; Mallika Imwong; Charles Woodrow; Magnus Manske; Jim Stalker; Eleanor Drury; Susana Campino; Lucas Amenga-Etego; Thuy Nhien Nguyen Thanh; Hien Tinh Tran; Pascal Ringwald; Delia Bethell; Francois Nosten; Aung Pyae Phyo; Sasithon Pukrittayakamee; Kesinee Chotivanich; Char Meng Chuor; Chea Nguon; Seila Suon; Sokunthea Sreng; Paul N. Newton; Mayfong Mayxay; Maniphone Khanthavong; Bouasy Hongvanthong; Ye Htut; Kay Thwe Han; Myat Phone Kyaw; Md Abul Faiz; Caterina I. Fanello; Marie Onyamboko; Olugbenga A. Mokuolu; Christopher G. Jacob; Shannon Takala-Harrison; Christopher V. Plowe; Nicholas P. Day; Arjen M. Dondorp; Chris C.A. Spencer; Gilean Mcvean; Rick M. Fairhurst; Nicholas J. White; Dominic P. Kwiatkowski; Wellcome Trust Sanger Institute; University of Oxford; Mahidol University; Wellcome Trust Centre for Human Genetics; Nuffield Department of Clinical Medicine; National Institute of Allergy and Infectious Diseases; National Center for Parasitology, Entomology and Malaria Control; University of Maryland School of Medicine; Navrongo Health Research Center; Oxford University Clinical Research Unit; Organisation Mondiale de la Sante; Armed Forces Research Institute of Medical Sciences, Thailand; Mahosot Hospital; University of Health Sciences; Ministry of Health; Department of Medical Research; Dev Care Foundation; Kinshasa School of Public Health; University of Ilorin
    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.
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    Laboratory detection of artemisinin-resistant plasmodium falciparum
    (2014-01-01) Kesinee Chotivanich; Rupam Tripura; Debashish Das; Poravuth Yi; Nicholas P J Day; Sasithon Pukrittayakamee; Char Meng Chuor; Duong Socheat; Arjen M. Dondorp; Nicholas J. White; Mahidol University; National Center for Parasitology, Entomology and Malaria Control; Churchill Hospital
    Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-resistant Plasmodium falciparum, defined phenotypically by low in vivo parasite clearance rates. We hypothesized originally that this discrepancy was explained by a loss of ring-stage susceptibility and so developed a simple field-Adapted 24-h trophozoite maturation inhibition (TMI) assay focusing on the ring stage and compared it to the standard 48-h schizont maturation inhibition (WHO) test. In Pailin, western Cambodia, where artemisinin-resistant P. falciparum is prevalent, the TMI test mean (95% confidence interval) 50% inhibitory concentration (IC50) for artesunate was 6.8 (5.2 to 8.3) ng/ml compared with 1.5 (1.2 to 1.8) ng/ml for the standard 48-hWHO test (P=0.001). TMI IC50s correlated significantly with the in vivo responses to artesunate (parasite clearance time [r=0.44, P=0.001] and parasite clearance half-life [r=0.46, P=0.001]), whereas the standard 48-h test values did not. On continuous culture of two resistant isolates, the artemisinin-resistant phenotype was lost after 6 weeks (IC50s fell from 10 and 12 ng/ml to 2.7 and 3 ng/ml, respectively). Slow parasite clearance in falciparum malaria in western Cambodia results from reduced ring-stage susceptibility. © 2014, American Society for Microbiology.
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    A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
    (2014-01-01) Frédéric Ariey; Benoit Witkowski; Chanaki Amaratunga; Johann Beghain; Anne Claire Langlois; Nimol Khim; Saorin Kim; Valentine Duru; Christiane Bouchier; Laurence Ma; Pharath Lim; Rithea Leang; Socheat Duong; Sokunthea Sreng; Seila Suon; Char Meng Chuor; Denis Mey Bout; Sandie Ménard; William O. Rogers; Blaise Genton; Thierry Fandeur; Olivo Miotto; Pascal Ringwald; Jacques Le Bras; Antoine Berry; Jean Christophe Barale; Rick M. Fairhurst; Françoise Benoit-Vical; Odile Mercereau-Puijalon; Didier Ménard; Institut Pasteur, Paris; CNRS Centre National de la Recherche Scientifique; Institut Pasteur du Cambodge; National Institute of Allergy and Infectious Diseases; National Center for Parasitology, Entomology and Malaria Control; CHU de Toulouse; Naval Medical Research Unit-2; Swiss Tropical and Public Health Institute (Swiss TPH); University of Oxford; Mahidol University; Wellcome Trust Sanger Institute; Organisation Mondiale de la Sante; Hopital Bichat-Claude-Bernard AP-HP; Universite de Toulouse
    Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7-1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread. © 2014 Macmillan Publishers Limited.
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    Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia
    (2013-06-01) Olivo Miotto; Jacob Almagro-Garcia; Magnus Manske; Bronwyn MacInnis; Susana Campino; Kirk A. Rockett; Chanaki Amaratunga; Pharath Lim; Seila Suon; Sokunthea Sreng; Jennifer M. Anderson; Socheat Duong; Chea Nguon; Char Meng Chuor; David Saunders; Youry Se; Chantap Lon; Mark M. Fukuda; Lucas Amenga-Etego; Abraham V.O. Hodgson; Victor Asoala; Mallika Imwong; Shannon Takala-Harrison; François Nosten; Xin Zhuan Su; Pascal Ringwald; Frédéric Ariey; Christiane Dolecek; Tran Tinh Hien; Maciej F. Boni; Cao Quang Thai; Alfred Amambua-Ngwa; David J. Conway; Abdoulaye A. Djimdé; Ogobara K. Doumbo; Issaka Zongo; Jean Bosco Ouedraogo; Daniel Alcock; Eleanor Drury; Sarah Auburn; Oliver Koch; Mandy Sanders; Christina Hubbart; Gareth Maslen; Valentin Ruano-Rubio; Dushyanth Jyothi; Alistair Miles; John O'Brien; Chris Gamble; Samuel O. Oyola; Julian C. Rayner; Chris I. Newbold; Matthew Berriman; Chris C.A. Spencer; Gilean McVean; Nicholas P. Day; Nicholas J. White; Delia Bethell; Arjen M. Dondorp; Christopher V. Plowe; Rick M. Fairhurst; Dominic P. Kwiatkowski; University of Oxford; Mahidol University; Wellcome Trust Sanger Institute; Wellcome Trust Centre for Human Genetics; National Institute of Allergy and Infectious Diseases; National Center for Parasitology, Entomology and Malaria Control; Armed Forces Research Institute of Medical Sciences, Thailand; USAMC-AFRIMS; Armed Forces Health Surveillance Center; Navrongo Health Research Center; University of Maryland School of Medicine; Shoklo Malaria Research Unit; Organisation Mondiale de la Sante; Institut Pasteur, Paris; Oxford University Clinical Research Unit; Medical Research Council Laboratories Gambia; London School of Hygiene & Tropical Medicine; University of Sciences; Institut de Recherche en Sciences de la Santé; Menzies School of Health Research; Weatherall Institute of Molecular Medicine
    We describe an analysis of genome variation in 825 P. falciparum samples from Asia and Africa that identifies an unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western Cambodia. Within this relatively small geographic area, we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalog of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in transporter proteins and DNA mismatch repair proteins. These data provide a population-level genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist in its elimination. © 2013 Nature America, Inc. All rights reserved.
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    Spatial and temporal epidemiology of clinical malaria in Cambodia 2004-2013
    (2014-09-30) Richard J. Maude; Chea Nguon; Po Ly; Tol Bunkea; Pengby Ngor; Sara E. Canavati De La Torre; Nicholas J. White; Arjen M. Dondorp; Nicholas P.J. Day; Lisa J. White; Char Meng Chuor; Mahidol University; Nuffield Department of Clinical Medicine; National Centre for Parasitology, Entomology and Malaria Control
    © 2014 Maude et al.; licensee BioMed Central Ltd. Background: Artemisinin-resistant Plasmodium falciparum malaria has recently been identified on the Thailand-Cambodia border and more recently in parts of Thailand, Myanmar and Vietnam. There is concern that if this resistance were to spread, it would severely hamper malaria control and elimination efforts worldwide. Efforts are currently underway to intensify malaria control activities and ultimately eliminate malaria from Cambodia. To support these efforts, it is crucial to have a detailed picture of disease burden and its major determinants over time. Methods: An analysis of spatial and temporal data on clinical malaria in Cambodia collected by the National Centre for Parasitology, Entomology and Malaria Control (CNM) and the Department of Planning and Health Information, Ministry of Health Cambodia from 2004 to 2013 is presented. Results: There has been a marked decrease of 81% in annual cases due to P. falciparum since 2009 coinciding with a rapid scale-up in village malaria workers (VMWs) and insecticide-treated bed nets (ITNs). Concurrently, the number of cases with Plasmodium vivax has greatly increased. It is estimated that there were around 112,000 total cases in 2012, 2.8 times greater than the WHO estimate for that year, and 68,000 in 2013 (an annual parasite incidence (API) of 4.6/1000). With the scale-up of VMWs, numbers of patients presenting to government facilities did not fall and it appears likely that those who saw VMWs had previously accessed healthcare in the private sector. Malaria mortality has decreased, particularly in areas with VMWs. There has been a marked decrease in cases in parts of western Cambodia, especially in Pailin and Battambang Provinces. In the northeast, the fall in malaria burden has been more modest, this area having the highest API in 2013. Conclusion: The clinical burden of falciparum malaria in most areas of Cambodia has greatly decreased from 2009 to 2013, associated with roll-out of ITNs and VMWs. Numbers of cases with P. vivax have increased. Possible reasons for these trends are discussed and areas requiring further study are highlighted. Although malaria surveillance data are prone to collection bias and tend to underestimate disease burden, the finding of similar trends in two independent datasets in this study greatly increased the robustness of the findings.