The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial

Lorenz von Seidlein (1, 2) , Thomas J Peto (1, 2) , Jordi Landier (3, 4) , Thuy-Nhien Nguyen (5) , Rupam Tripura (1, 2, 6) , Koukeo Phommasone (7, 8) , Tiengkham Pongvongsa (9, 10) , Khin Maung Lwin (4) , Lilly Keereecharoen (4) , Ladda Kajeechiwa (4) , May Myo Thwin (4) , Daniel M Parker (4, 11) , Jacher Wiladphaingern (4) , Suphak Nosten (4) , Stephane Proux (4) , Vincent Corbel (12) , Nguyen Tuong-Vy (5) , Truong Le Phuc-Nhi (5) , Do Hung Son (5) , Pham Nguyen Huong-Thu (5) , Nguyen Thi Kim Tuyen (5) , Nguyen Thanh Tien (5) , Le Thanh Dong (13) , Dao van Hue (14) , Huynh Hong Quang (15) , Chea Nguon (16) , Chan Davoeung (17) , Huy Rekol (16) , Bipin Adhikariid (1, 2) , Gisela Henriques (1, 18) , Panom Phongmany (9) , Preyanan Suangkanarat (7) , Atthanee Jeeyapant (1) , Benchawan Vihokhern (1) , Rob W van Der Pluijm (1, 2) , Yoel Lubell (1, 2) , Lisa J White (1, 2) , Ricardo Aguas (1, 2) , Cholrawee Promnarate (1, 19) , Pasathorn Sirithiranont (1) , Benoit Malleret (20, 21) , Laurent Rénia (21) , Carl Onsjö (1, 22) , Xin Hui Chan (1, 2) , Jeremy Chalk (1) , Olivo Miotto (1, 23) , Krittaya Patumrat (24) , Kesinee Chotivanich (1, 25) , Borimas Hanboonkunupakarn (1, 10) , Podjanee Jittmala (1, 10) , Nils Kaehler (1) , Phaik Yeong Cheah (1, 2) , Christopher Pell (8) , Mehul Dhorda (1) , Mallika Imwong (1, 24) , Georges Snounou (26) , Mavuto Mukaka (1, 2) , Pimnara Peerawaranun (1) , Sue J Lee (1, 2) , Julie A Simpson (27) , Sasithon Pukrittayakamee (1, 10, 28) , Pratap Singhasivanon (25) , Martin P Grobusch (6) , Frank Cobelens (8) , Frank Smithuis (29) , Paul N Newton (2, 7) , Guy E Thwaites (2, 5) , Nicholas P J Day (1, 2) , Mayfong Mayxay (30, 7) , Tran Tinh Hien (2, 3) , Francois H Nosten (2, 4) , Arjen M Dondorp (1, 2) , Nicholas J White (1, 2)

1 MORU - Mahidol Oxford Tropical Medicine Research Unit
2 Centre for Tropical Medicine and Global Health [Oxford, UK]
3 SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale
4 SMRU - Shoklo Malaria Research Unit [Mae Sot, Thailand]
5 OUCRU - Oxford University Clinical Research Unit [Ho Chi Minh City]
6 Academic Medical Center - Department of Infectious Diseases [Amsterdam, Netherlands]
7 LOMWRU - Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit
8 Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands]
9 Savannakhet Provincial Health Department [Lao People’s Democratic Republic]
10 Faculty of Tropical Medicine - Department of Clinical Tropical Medicine [Bangkok, Thailand]
11 Department of Population Health and Disease Prevention [Irvine, CA, USA]
12 MIVEGEC - Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle
13 IMPE - Institute of Malariology, Parasitology, and Entomology [Ho Chi Minh City, Vietnam]
14 CMPE - Center for Malariology, Parasitology and Entomology [Ninh Thuan Province, Vietnam]
15 IMPE - Institute of Malariology, Parasitology, and Entomology [Quy Nhon, Vietnam]
16 CNM - National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia]
17 PHD - Provincial Health Department [Battambang, Cambodia]
18 Department of Pathogen Molecular Biology [London, UK]
19 WWARN Asia Regional Centre [Bangkok, Thailand]
20 Yong Loo Lin School of Medicine - Department of Microbiology & Immunology [Singapore]
21 SIgN - Singapore Immunology Network
22 Department of Oncology, Clinical and Experimental Medicine, Faculty of Health Sciences [Linköping University ]
23 Wellcome Trust Sanger Institute [Hinxton, UK]
24 Faculty of Tropical Medicine - Department of Molecular Tropical Medicine and Genetics [Bangkok, Thailand]
25 Faculty of Tropical Medicine - Department of Tropical Hygiene [Bangkok, Thailand]
26 IMVA - U1184 - Immunologie des Maladies Virales et Autoimmunes
27 Centre for Epidemiology and Biostatistics [Victoria, Australia]
28 Royal Society of Thailand [Bangkok, Thailand]
29 Myanmar Oxford Clinical Research Unit [Yangon, Myanmar]
30 Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic]

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.

Domaines: Santé publique et épidémiologie; Maladies infectieuses

Lorenz von Seidlein, Thomas J Peto, Jordi Landier, Thuy-Nhien Nguyen, Rupam Tripura, et al.. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial. PLoS Medicine, 2019, 16 (2), pp.e1002745. ⟨10.1371/journal.pmed.1002745⟩. ⟨inserm-02143366⟩