The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial
Lorenz von Seidlein,Lorenz von Seidlein,Thomas J. Peto,Thomas J. Peto,Jordi Landier,Jordi Landier,Thuy-Nhien Nguyen,Rupam Tripura,Rupam Tripura,Rupam Tripura,Koukeo Phommasone,Koukeo Phommasone,Tiengkham Pongvongsa,Khin Maung Lwin,Lilly Keereecharoen,Ladda Kajeechiwa,May Myo Thwin,Daniel M. Parker,Daniel M. Parker,Jacher Wiladphaingern,Suphak Nosten,Stephane Proux,Vincent Corbel,Nguyen Tuong-Vy,Truong Le Phuc-Nhi,Do Hung Son,Pham Nguyen Huong-Thu,Nguyen Thi Kim Tuyen,Nguyen Thanh Tien,Le Thanh Dong,Dao Van Hue,Huynh Hong Quang,Chea Nguon,Chan Davoeung,Huy Rekol,Bipin Adhikari,Bipin Adhikari,Gisela Henriques,Gisela Henriques,Panom Phongmany,Preyanan Suangkanarat,Atthanee Jeeyapant,Benchawan Vihokhern,Rob W. van der Pluijm,Rob W. van der Pluijm,Yoel Lubell,Yoel Lubell,Lisa J. White,Lisa J. White,Ricardo Aguas,Ricardo Aguas,Cholrawee Promnarate,Pasathorn Sirithiranont,Benoit Malleret,Benoit Malleret,Laurent Rénia,Carl Onsjö,Carl Onsjö,Xin Hui S Chan,Xin Hui S Chan,Jeremy Chalk,Olivo Miotto,Olivo Miotto,Krittaya Patumrat,Kesinee Chotivanich,Borimas Hanboonkunupakarn,Podjanee Jittmala,Nils Kaehler,Phaik Yeong Cheah,Phaik Yeong Cheah,Christopher Pell,Mehul Dhorda,Mallika Imwong,Georges Snounou,Mavuto Mukaka,Mavuto Mukaka,Pimnara Peerawaranun,Sue J. Lee,Sue J. Lee,Julie A. Simpson,Sasithon Pukrittayakamee,Sasithon Pukrittayakamee,Pratap Singhasivanon,Martin P. Grobusch,Frank Cobelens,Frank Smithuis,Paul N. Newton,Paul N. Newton,Guy E. Thwaites,Nicholas P. J. Day,Nicholas P. J. Day,Mayfong Mayxay,Mayfong Mayxay,Tran Tinh Hien,Tran Tinh Hien,François Nosten,François Nosten,Arjen M. Dondorp,Arjen M. Dondorp,Nicholas J. White,Nicholas J. White +100 more
TLDR
The results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, dihydroartemisinin-piperaquine MDA can be a useful additional tool to accelerate malaria elimination.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.read more
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Journal ArticleDOI
Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria.
TL;DR: Artemisinin resistance is primarily mediated by mutations in P. falciparum Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and art Artemisinin activation.
Journal ArticleDOI
Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study
Mallika Imwong,Mehul Dhorda,Kyaw Myo Tun,Aung Myint Thu,Aung Pyae Phyo,Stephane Proux,Kanokon Suwannasin,Chanon Kunasol,Suttipat Srisutham,Jureeporn Duanguppama,Ranitha Vongpromek,Cholrawee Promnarate,Aungkana Saejeng,Nardlada Khantikul,Rungniran Sug-aram,Supinya Thanapongpichat,Nongyao Sawangjaroen,Kreepol Sutawong,Kay Thwe Han,Ye Htut,Khin Linn,Aye A. Win,Tin Maung Hlaing,Rob W. van der Pluijm,Rob W. van der Pluijm,Mayfong Mayxay,Mayfong Mayxay,Tiengkham Pongvongsa,Koukeo Phommasone,Rupam Tripura,Rupam Tripura,Thomas J. Peto,Thomas J. Peto,Lorenz von Seidlein,Lorenz von Seidlein,Chea Nguon,Dysoley Lek,Xin Hui S Chan,Xin Hui S Chan,Huy Rekol,Rithea Leang,Cheah Huch,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski,Olivo Miotto,Olivo Miotto,Olivo Miotto,Elizabeth A. Ashley,Elizabeth A. Ashley,Myat Phone Kyaw,Sasithon Pukrittayakamee,Sasithon Pukrittayakamee,Nicholas P. J. Day,Nicholas P. J. Day,Arjen M. Dondorp,Arjen M. Dondorp,Frank Smithuis,François Nosten,François Nosten,Nicholas J. White,Nicholas J. White +60 more
TL;DR: Artemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion, and in the eastern Greater Mekongs subregion a multidrug resistant P falCiparums lineage (PfPailin) dominates.
Journal ArticleDOI
Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum
Leila S. Ross,David A. Fidock +1 more
TL;DR: Four antimalarial resistance case studies are presented that differ in timeline, technical approaches, mechanisms of action, and categories of resistance: chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine.
Journal ArticleDOI
Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial.
Michelle S. Hsiang,Michelle S. Hsiang,Henry Ntuku,Kathryn W. Roberts,Mi-Suk Kang Dufour,Brooke Whittemore,Munyaradzi Tambo,Patrick McCreesh,Patrick McCreesh,Oliver F. Medzihradsky,Lisa M. Prach,Griffith Siloka,Noel Siame,Cara Smith Gueye,Leah Schrubbe,Lindsey Wu,Valerie Scott,Sofonias K. Tessema,Bryan Greenhouse,Erica Erlank,Lizette L. Koekemoer,Hugh J. W. Sturrock,Agnes Mwilima,Stark Katokele,Petrina Uusiku,Adam Bennett,Jennifer L. Smith,Immo Kleinschmidt,Immo Kleinschmidt,Immo Kleinschmidt,Davis R. Mumbengegwi,Roly Gosling,Roly Gosling +32 more
TL;DR: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria.
Journal ArticleDOI
Malaria Hotspots: Is There Epidemiological Evidence for Fine-Scale Spatial Targeting of Interventions?
TL;DR: There is no conclusive evidence that hotspot-targeted interventions accelerate malaria elimination, but there is currently limited evidence that local-scale hotspots fuel transmission.
References
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Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp,François Nosten,Poravuth Yi,Debashish Das,Aung Phae Phyo,Joel Tarning,Khin Maung Lwin,Frédéric Ariey,Warunee Hanpithakpong,Sue J. Lee,Pascal Ringwald,Kamolrat Silamut,Mallika Imwong,Kesinee Chotivanich,Pharath Lim,Trent Herdman,Sen Sam An,Shunmay Yeung,Pratap Singhasivanon,Nicholas P. J. Day,Niklas Lindegardh,Duong Socheat,Nicholas J. White +22 more
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Spread of Artemisinin Resistance in Plasmodium falciparum Malaria
Elizabeth A. Ashley,Mehul Dhorda,Rick M. Fairhurst,Chanaki Amaratunga,Pharath Lim,Seila Suon,Sokunthea Sreng,Jennifer M. Anderson,Mao S,Sam B,Chantha Sopha,Char Meng Chuor,Chea Nguon,Siv Sovannaroth,Sasithon Pukrittayakamee,Podjanee Jittamala,Kesinee Chotivanich,K Chutasmit,C Suchatsoonthorn,R Runcharoen,Tran Tinh Hien,Nguyen Thuy-Nhien,Thanh Nv,Nguyen Hoan Phu,Ye Htut,Han Kt,Kyin Hla Aye,Olugbenga A. Mokuolu,Rasaq Olaosebikan,Olaleke Oluwasegun Folaranmi,Mayfong Mayxay,Maniphone Khanthavong,Bouasy Hongvanthong,Paul N. Newton,M A Onyamboko,Caterina I. Fanello,Antoinette Tshefu,Neelima Mishra,Neena Valecha,Aung Pyae Phyo,François Nosten,Yi P,Rupam Tripura,Steffen Borrmann,Mahfudh Bashraheil,Judy Peshu,M A Faiz,Aniruddha Ghose,M A Hossain,Rasheda Samad,M. R. Rahman,Manal Hasan,Ashraful Islam,Olivo Miotto,Roberto Amato,Bronwyn MacInnis,Jim Stalker,Dominic P. Kwiatkowski,Zbynek Bozdech,Atthanee Jeeyapant,Phaik Yeong Cheah,Tharisara Sakulthaew,Jeremy Chalk,Benjamas Intharabut,Kamolrat Silamut,Lee Sj,Benchawan Vihokhern,Chanon Kunasol,Mallika Imwong,Joel Tarning,Taylor Wj,Shunmay Yeung,Charles J. Woodrow,Jennifer A. Flegg,Debashish Das,Jennifer L. Smith,Meera Venkatesan,Christopher V. Plowe,Kasia Stepniewska,Philippe J Guerin,Arjen M. Dondorp,Nicholas P. J. Day,Nicholas J. White +82 more
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.
Journal ArticleDOI
Evidence of Artemisinin-Resistant Malaria in Western Cambodia
TL;DR: Artemisinins are potent and rapidly acting antimalarial drugs, and their widespread use for treating patients with Plasmodium falciparum malaria raises the question of emerging drug resistance.
Journal ArticleDOI
A meta-analysis of the association between adherence to drug therapy and mortality
Scot H. Simpson,Dean T. Eurich,Sumit R. Majumdar,Rajdeep S Padwal,Ross T. Tsuyuki,Janice Varney,Jeffrey A. Johnson +6 more
TL;DR: The observed association between good adherence to placebo and mortality supports the existence of the “healthy adherer” effect, whereby adherence to drug therapy may be a surrogate marker for overall healthy behaviour.
Journal ArticleDOI
Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study
Chanaki Amaratunga,Pharath Lim,Seila Suon,Sokunthea Sreng,Sivanna Mao,Chantha Sopha,Baramey Sam,Dalin Dek,Vorleak Try,Roberto Amato,Roberto Amato,Daniel Blessborn,Daniel Blessborn,Lijiang Song,Lijiang Song,Gregory Tullo,Michael P. Fay,Jennifer M. Anderson,Joel Tarning,Joel Tarning,Rick M. Fairhurst +20 more
TL;DR: In Cambodia, artesunate plus mefloquine may be a viable option to treat dihydroartemisinin-piperaquine failures, and a more effective first-line ACT in areas where dihydrodynamic failures are common, and the use of single low-dose primaquine to eliminate circulating gametocytes is needed in Areas where artemisin in and ACT resistance is prevalent.
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