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Publication Metadata only Declining Efficacy of Artemisinin Combination Therapy Against P. Falciparum Malaria on the Thai-Myanmar Border (2003-2013): The Role of Parasite Genetic Factors(2016-09-15) Aung Pyae Phyo; Elizabeth A. Ashley; Tim J.C. Anderson; Zbynek Bozdech; Verena I. Carrara; Kanlaya Sriprawat; Shalini Nair; Marina Mc Dew White; Jerzy Dziekan; Clare Ling; Stephane Proux; Kamonchanok Konghahong; Atthanee Jeeyapant; Charles J. Woodrow; Mallika Imwong; Rose McGready; Khin Maung Lwin; Nicholas P.J. Day; Nicholas J. White; Francois Nosten; Mahidol University; University of Oxford; Texas Biomedical Research Institute; Nanyang Technological University© 2016 The Author. Published by Oxford University Press for the Infectious Diseases Society of America. Background. Deployment of mefloquine-artesunate (MAS3) on the Thailand-Myanmar border has led to a sustained reduction in falciparum malaria, although antimalarial efficacy has declined substantially in recent years. The role of Plasmodium falciparum K13 mutations (a marker of artemisinin resistance) in reducing treatment efficacy remains controversial. Methods. Between 2003 and 2013, we studied the efficacy of MAS3 in 1005 patients with uncomplicated P. falciparum malaria in relation to molecular markers of resistance. Results. Polymerase chain reaction (PCR)-adjusted cure rates declined from 100% in 2003 to 81.1% in 2013 as the proportions of isolates with multiple Pfmdr1 copies doubled from 32.4% to 64.7% and those with K13 mutations increased from 6.7% to 83.4%. K13 mutations conferring moderate artemisinin resistance (notably E252Q) predominated initially but were later overtaken by propeller mutations associated with slower parasite clearance (notably C580Y). Those infected with both multiple Pfmdr1 copy number and a K13 propeller mutation were 14 times more likely to fail treatment. The PCR-adjusted cure rate was 57.8% (95% confidence interval [CI], 45.4, 68.3) compared with 97.8% (95% CI, 93.3, 99.3) in patients with K13 wild type and Pfmdr1 single copy. K13 propeller mutation alone was a strong risk factor for recrudescence (P =. 009). The combined population attributable fraction of recrudescence associated with K13 mutation and Pfmdr1 amplification was 82%. Conclusions. The increasing prevalence of K13 mutations was the decisive factor for the recent and rapid decline in efficacy of artemisinin-based combination (MAS3) on the Thailand-Myanmar border.Publication Metadata only Optimal health and disease management using spatial uncertainty: A geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia(2016-10-24) Eric P.M. Grist; Jennifer A. Flegg; Georgina Humphreys; Ignacio Suay Mas; Tim J.C. Anderson; Elizabeth A. Ashley; Nicholas P.J. Day; Mehul Dhorda; Arjen M. Dondorp; M. Abul Faiz; Peter W. Gething; Tran T. Hien; Tin M. Hlaing; Mallika Imwong; Jean Marie Kindermans; Richard J. Maude; Mayfong Mayxay; Marina McDew-White; Didier Menard; Shalini Nair; Francois Nosten; Paul N. Newton; Ric N. Price; Sasithon Pukrittayakamee; Shannon Takala-Harrison; Frank Smithuis; Nhien T. Nguyen; Kyaw M. Tun; Nicholas J. White; Benoit Witkowski; Charles J. Woodrow; Rick M. Fairhurst; Carol Hopkins Sibley; Philippe J. Guerin; WorldWide Antimalarial Resistance Network (WWARN); Nuffield Department of Clinical Medicine; Monash University; Texas Biomedical Research Institute; Mahidol University; National Institute of Allergy and Infectious Diseases; Dev Care Foundation; University of Oxford; Oxford University Clinical Research Unit; Defence Services Medical Research Centre; Medecins Sans Frontieres, Brussels; Pasteur Institute in Cambodia; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU); University of Maryland School of Medicine; Menzies School of Health Research; Myanmar Oxford Clinical Research Unit; University of Washington, Seattle; Harvard School of Public Health© 2016 The Author(s). Background: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. Methods: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. Results: The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. Conclusion: This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas.Publication Metadata only Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: A cross-sectional survey of the K13 molecular marker(2015-04-01) Kyaw M. Tun; Mallika Imwong; Khin M. Lwin; Aye A. Win; Tin M. Hlaing; Thaung Hlaing; Khin Lin; Myat P. Kyaw; Katherine Plewes; M. Abul Faiz; Mehul Dhorda; Phaik Yeong Cheah; Sasithon Pukrittayakamee; Elizabeth A. Ashley; Tim J.C. Anderson; Shalini Nair; Marina McDew-White; Jennifer A. Flegg; Eric P.M. Grist; Philippe Guerin; Richard J. Maude; Frank Smithuis; Arjen M. Dondorp; Nicholas P.J. Day; François Nosten; Nicholas J. White; Charles J. Woodrow; Myanmar Oxford Clinical Research Unit; Defence Services Medical Research Centre; Mahidol University; Shoklo Malaria Research Unit; Institute of Medicine (1); Ministry of Health; Department of Medical Research; WorldWide Antimalarial Resistance Network; Nuffield Department of Clinical Medicine; Dev Care Foundation; Texas Biomedical Research Institute; Monash University; Medical Action Myanmar© 2015 Tun et al. Background: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. Methods: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Findings: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Interpretation: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Funding: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.Publication Open Access Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.(2015-04) Tun, Kyaw M; Mallika Imwong; มัลลิกา อิ่มวงศ์; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Sasithon Pukrittayakamee; ศศิธร ผู้กฤตยาคามี; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit. Shoklo Malaria Research Unit.; Mahidol University. Faculty of Tropical Medicine.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit.BACKGROUND: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. METHODS: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. FINDINGS: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. INTERPRETATION: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. FUNDING: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.Publication Open Access Plasmodium falciparum Kelch 13 mutations and treatment response in patients in Hpa-Pun District, Northern Kayin State, Myanmar.(2017) Bonnington, Craig A.; Aung Pyae Phyo; Ashley, Elizabeth A.; Mallika Imwong; Kanlaya Sriprawat; Parker, Daniel M.; Proux, Stephane; White, Nicholas J.; Nosten, Francois; Mahidol University. Faculty of Tropical Medicine. Shoklo Malaria Research Unit; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unit; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and GeneticsBackground: Artemisinin resistance, linked to polymorphisms in the Kelch gene on chromosome 13 of Plasmodium falciparum (k13), has outpaced containment eforts in South East Asia. For national malaria control programmes in the region, it is important to establish a surveillance system which includes monitoring for k13 polymorphisms associated with the clinical phenotype. Methods: Between February and December 2013, parasite clearance was assessed in 35 patients with uncomplicated P. falciparum treated with artesunate monotherapy followed by 3-day ACT in an isolated area on the Myanmar– Thai border with relatively low artemisinin drug pressure. Molecular testing for k13 mutations was performed on dry blood spots collected on admission. Results: The proportion of k13 mutations in these patients was 41.7%, and only 5 alleles were detected: C580Y, I205T, M476I, R561H, and F446I. Of these, F446I was the most common, and was associated with a longer parasite clearance half-life (median) 4.1 (min–max 2.3–6.7) hours compared to 2.5 (min–max 1.6–8.7) in wildtype (p = 0·01). The prevalence of k13 mutant parasites was much lower than the proportion of k13 mutants detected 200 km south in a much less remote setting where the prevalence of k13 mutants was 84% with 15 distinct alleles in 2013 of which C580Y predominated. Conclusions: This study provides evidence of artemisinin resistance in a remote part of eastern Myanmar. The prevalence of k13 mutations as well as allele diversity varies considerably across short distances, presumably because of historical patterns of artemisinin use and population movements.Publication Open Access Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study(2016) Tun, Kyaw Myo; Atthanee Jeeyapant; Mallika Imwong; Min Thein; Sai Soe Moe Aung; Hlaing, Tin Maung; Prayoon Yuentrakul; Cholrawee Promnarate; Mehul Dhorda; Woodrow, Charles J.; Dondorp, Arjen M.; Ashley, Elizabeth A.; Smithuis, Frank M.; White, Nicholas J.; Day, Nicholas P. J.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research UnitBackground: Artemisinin resistance in Plasmodium falciparum extends across Southeast Asia where it is associated with worsening partner drug resistance and a decline in the efficacy of frontline artemisinin-based combination therapy. Dihydroartemisinin-piperaquine (DP) is an essential component of preventive and curative treatment in the region, but its therapeutic efficacy has fallen in Cambodia. Methods: A prospective clinical and parasitological evaluation of DP was conducted at two sites in Upper Myanmar between August 2013 and December 2014, enrolling 116 patients with acute uncomplicated falciparum malaria. Patients received DP orally for 3 days together with primaquine 0.25 mg/kg on admission. Parasite clearance half-lives based on 6 hourly blood smears, and day 42 therapeutic responses were assessed as well as parasite K13 genotypes. Results: Median parasite clearance half-life was prolonged, and clearance half-life was greater than 5 h in 21 % of patients. Delayed parasite clearance was significantly associated with mutations in the propeller region of the parasite k13 gene. The k13 F446I mutation was found in 25.4 % of infections and was associated with a median clearance halflife of 4.7 h compared with 2.7 h for infections without k13 mutations (p < 0.001). There were no failures after 42 days of follow-up, although 18 % of patients had persistent parasitaemia on day 3. Conclusion: The dominant k13 mutation observed in Upper Myanmar, F446I, appears to be associated with an intermediate rate of parasite clearance compared to other common mutations described elsewhere in the Greater Mekong Subregion. Discerning this phenotype requires relatively detailed clearance measurements, highlighting the importance of methodology in assessing artemisinin resistance.Publication Open Access Investigations on anopheline mosquitoes close to the nest sites of chimpanzees subject to malaria infection in Ugandan highlands(2012-04-17) Krief, Sabrina; Levrero, Florence; Krief, Jean-Michel; Supinya Thanapongpichat; สุภิญญา ธนาพงษ์ภิชาติ; Mallika Imwong; มัลลิกา อิ่มวงศ์; Snounou, Georges; Kasenene, John M.; Cibot, Marie; Gantier, Jean-Charles; Krief, Sabrina; Mahidol University. Faculty of Tropical MedicineBACKGROUND: Malaria parasites (Plasmodium sp.), including new species, have recently been discovered as low grade mixed infections in three wild chimpanzees (Pan troglodytes schweinfurthii) sampled randomly in Kibale National Park, Uganda. This suggested a high prevalence of malaria infection in this community. The clinical course of malaria in chimpanzees and the species of the vectors that transmit their parasites are not known. The fact that these apes display a specific behaviour in which they consume plant parts of low nutritional value but that contain compounds with anti-malarial properties suggests that the apes health might be affected by the parasite. The avoidance of the night-biting anopheline mosquitoes is another potential behavioural adaptation that would lead to a decrease in the number of infectious bites and consequently malaria. METHODS: Mosquitoes were collected over two years using suction-light traps and yeast-generated CO(2) traps at the nesting and the feeding sites of two chimpanzee communities in Kibale National Park. The species of the female Anopheles caught were then determined and the presence of Plasmodium was sought in these insects by PCR amplification. RESULTS: The mosquito catches yielded a total of 309 female Anopheles specimens, the only known vectors of malaria parasites of mammalians. These specimens belonged to 10 species, of which Anopheles implexus, Anopheles vinckei and Anopheles demeilloni dominated. Sensitive DNA amplification techniques failed to detect any Plasmodium-positive Anopheles specimens. Humidity and trap height influenced the Anopheles capture success, and there was a negative correlation between nest numbers and mosquito abundance. The anopheline mosquitoes were also less diverse and numerous in sites where chimpanzees were nesting as compared to those where they were feeding. CONCLUSIONS: These observations suggest that the sites where chimpanzees build their nests every night might be selected, at least in part, in order to minimize contact with anopheline mosquitoes, which might lead to a reduced risk in acquiring malaria infections.