1. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: a cluster randomised trial
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Von Seidlein, L, Peto, TJ, Landier, J, Nguyen, T-N, Tripura, R, Phommasone, K, Pongvongsa, T, Lwin, KM, Keereecharoen, L, Kajeechiwa, L, Thwin, MM, Parker, DM, Wiladphaingern, J, Nosten, S, Proux, S, Corbel, V, Tuong-Vy, N, Phuc-Nhi, TL, Son, DH, Huong-Thu, PN, Tuyen, NTK, Tien, NT, Dong, LT, Hue, DV, Quang, HH, Nguon, C, Davoeung, C, Rekol, H, Adhikari, B, Henriques, G, Phongmany, P, Suangkanarat, P, Jeeyapant, A, Vihokhern, B, Van Der Pluijm, RW, Lubell, Y, White, LJ, Aguas, R, Promnarate, C, Sirithiranont, P, Malleret, B, Rénia, L, Onsjö, C, Chan, XH, Chalk, J, Miotto, O, Patumrat, K, Chotivanich, K, Hanboonkunupakarn, B, Jittmala, P, Kaehler, N, Cheah, PY, Pell, C, Dhorda, M, Imwong, M, Snounou, G, Mukaka, M, Peerawaranun, P, Lee, SJ, Simpson, JA, Pukrittayakamee, S, Singhasivanon, P, Grobusch, MP, Cobelens, F, Smithuis, F, Newton, PN, Thwaites, GE, Day, NPJ, Mayxay, M, Hien, TT, Nosten, FH, Dondorp, AM, White, NJ, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Department of Infectious Diseases [Amsterdam, Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA)-Center for Tropical and Travel Medicine [Amsterdam, Netherlands], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], Savannakhet Provincial Health Department [Lao People’s Democratic Republic], Savannakhet Province [Lao People’s Democratic Republic], Department of Clinical Tropical Medicine [Bangkok, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok], Department of Population Health and Disease Prevention [Irvine, CA, USA], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institute of Malariology, Parasitology, and Entomology [Ho Chi Minh City, Vietnam] (IMPE), Center for Malariology, Parasitology and Entomology [Ninh Thuan Province, Vietnam] (CMPE), Institute of Malariology, Parasitology, and Entomology [Quy Nhon, Vietnam] (IMPE), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Provincial Health Department [Battambang, Cambodia] (PHD), Department of Pathogen Molecular Biology [London, UK], London School of Hygiene and Tropical Medicine (LSHTM), WWARN Asia Regional Centre [Bangkok, Thailand], Department of Microbiology & Immunology [Singapore] (Yong Loo Lin School of Medicine), National University of Singapore (NUS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Department of Oncology, Clinical and Experimental Medicine, Faculty of Health Sciences [Linköping University ], Linköping University (LIU), Wellcome Trust Sanger Institute [Hinxton, UK], Department of Molecular Tropical Medicine and Genetics [Bangkok, Thailand] (Faculty of Tropical Medicine), Department of Tropical Hygiene [Bangkok, Thailand] (Faculty of Tropical Medicine), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Epidemiology and Biostatistics [Victoria, Australia], University of Melbourne-Melbourne School of Population and Global Health [Victoria, Australia], Royal Society of Thailand [Bangkok, Thailand], Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), NJW is the recipient of the Wellcome Trust Award Number: 101148/Z/13/Z. AMD is the recipient of the Bill and Melinda Gates Foundation Award Number: OPP1081420. JAS is the recipient of the National Health and Medical Research Council Award Number: 1104975., Dupuis, Christine, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Laboratoire de Lutte contre les Insectes Nuisibles, National Institute of Malariology, Parasitology and Entomology, National Center for Parasitology, Entomology, and Malaria Control, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Faculty of Tropical Medicine [Bangkok, Thailand], University of Oxford [Oxford], Faculty of Tropical Medicine, University of Oxford-Mahidol University [Bangkok], National Institute of Malariology, Parasitology and Entomology [Hanoi] (NIMPE), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford]-University of Oxford [Oxford], University of California [Irvine] (UCI), University of California-University of California, Graduate School, AII - Infectious diseases, APH - Aging & Later Life, APH - Global Health, APH - Methodology, Global Health, Infectious diseases, APH - Health Behaviors & Chronic Diseases, and APH - Quality of Care
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Male ,Plasmodium ,Myanmar ,Medical and Health Sciences ,Geographical Locations ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Medicine and Health Sciences ,Cluster Analysis ,Malaria, Falciparum ,Child ,Asia, Southeastern ,ComputingMilieux_MISCELLANEOUS ,Cross-Over Studies ,Pharmaceutics ,Drugs ,Drug Resistance, Multiple ,Vietnam ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Medicine ,Mass Drug Administration ,Female ,Cambodia ,Research Article ,Adult ,Drug Administration ,Asia ,Adolescent ,Elimination ,Plasmodium falciparum ,Microbiology ,Antimalarials ,Young Adult ,Drug Therapy ,Microbial Control ,General & Internal Medicine ,Parasite Groups ,parasitic diseases ,Parasitic Diseases ,Humans ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,Disease Eradication ,Pharmacology ,Biology and Life Sciences ,Tropical Diseases ,Malaria ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,People and Places ,Parasitology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Antimicrobial Resistance ,Apicomplexa - Abstract
Background The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People’s Democratic Republic, where artemisinin resistance is prevalent. Methods and findings After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Conclusions Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. Trial registration ClinicalTrials.gov NCT01872702, In a cluster-randomized trial, Lorenz von Seidlin & colleagues investigate whether mass drug administration can accelerate malaria elimination in the Greater Mekong Subregion., Author summary Why was this study done? The emergence and spread of multidrug resistance in the Greater Mekong Subregion (GMS) threaten regional and global malaria control. Mass drug administrations (MDAs) are controversial but could be useful in the control and elimination of malaria. We wanted to know whether well-resourced MDAs can accelerate malaria elimination in the GMS. What did the researchers do and find? We randomised 16 villages (clusters) to receive MDAs with antimalarial drugs (dihydroartemisinin-piperaquine [DP] plus low-dose primaquine) either in year 1 or year 2 of the study. The entire village population (except pregnant women and children under the age of 6 months) was invited to take 3 consecutive daily doses of antimalarial drugs 3 times at monthly intervals. Everyone was followed up for 1 year; all malaria cases were recorded, and quarterly malaria surveys were conducted using highly sensitive high-volume PCR detection. Most (87%) of the villagers completed at least 1 round of the antimalarial drugs, which were well tolerated. The intervention had a substantial impact on the prevalence of P. falciparum infections by month 3 after the start of the MDAs. Over the subsequent 9 months, P. falciparum infections returned but stayed below baseline levels. What do these findings mean? MDAs might be a useful tool to accelerate falciparum malaria elimination in low-endemicity settings. The effectiveness of MDAs depends on continued support for village health workers, adequate drug efficacy, high levels of community participation, and carefully planned roll out to minimise the risk of malaria reintroduction.
- Published
- 2019
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