Date Published: February 15, 2019
Publisher: Public Library of Science
Author(s): Lorenz von Seidlein, Thomas J. Peto, Jordi Landier, Thuy-Nhien Nguyen, Rupam Tripura, Koukeo Phommasone, Tiengkham Pongvongsa, Khin Maung Lwin, Lilly Keereecharoen, Ladda Kajeechiwa, May Myo Thwin, 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, Gisela Henriques, Panom Phongmany, Preyanan Suangkanarat, Atthanee Jeeyapant, Benchawan Vihokhern, Rob W. van der Pluijm, Yoel Lubell, Lisa J. White, Ricardo Aguas, Cholrawee Promnarate, Pasathorn Sirithiranont, Benoit Malleret, Laurent Rénia, Carl Onsjö, Xin Hui Chan, Jeremy Chalk, Olivo Miotto, Krittaya Patumrat, Kesinee Chotivanich, Borimas Hanboonkunupakarn, Podjanee Jittmala, Nils Kaehler, Phaik Yeong Cheah, Christopher Pell, Mehul Dhorda, Mallika Imwong, Georges Snounou, Mavuto Mukaka, Pimnara Peerawaranun, Sue J. Lee, Julie A. Simpson, Sasithon Pukrittayakamee, Pratap Singhasivanon, Martin P. Grobusch, Frank Cobelens, Frank Smithuis, Paul N. Newton, Guy E. Thwaites, Nicholas P. J. Day, Mayfong Mayxay, Tran Tinh Hien, Francois H. Nosten, Arjen M. Dondorp, Nicholas J. White, James G. Beeson
Abstract: BackgroundThe 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 findingsAfter 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.ConclusionsAdded 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 registrationClinicalTrials.gov NCT01872702
Partial Text: Considerable advances in malaria control and elimination have been achieved globally over the last decade. Since 2010 several former malaria endemic countries have been certified malaria-free. These include Sri Lanka, which had a high malaria burden (>100,000 cases/annually) at the beginning of the century while suffering from the consequences of a 25-year civil war . Such success stories show that a determined malaria control programme with widespread use of long-lasting insecticide-treated bednets, insecticide spraying where appropriate, early diagnosis, and effective treatment can control and eliminate malaria. However, these conventional control tools are failing in some areas. Susceptibility of malaria vectors to most insecticides has decreased, often markedly, over the last decade , while the first-line treatments for P. falciparum malaria, artemisinin combination therapies (ACTs), are losing their efficacy in the Greater Mekong Subregion (GMS), home to more than 300 million people [3–6]. This is particularly worrying as resistance against earlier first-line antimalarial treatments (chloroquine, sulphadoxine-pyrimethamine) started in the GMS, spread to India and then to Africa, and killed millions of children . More recently, parasites with resistance to both artemisinin and piperaquine emerged in western Cambodia and then spread to neighbouring countries [8,9]. Mefloquine resistance has re-emerged on the Thailand–Myanmar border. The decline in the effectiveness of the current first-line malaria drugs leaves few treatment options for falciparum malaria in the GMS. The spread of ACT-resistant P. falciparum strains into sub-Saharan Africa could become a public health emergency. Stopping the spread of antimalarial resistance requires the interruption of P. falciparum transmission.
The MDAs started on 27 May 2013 in the sites in Myanmar, followed by Vietnam on 11 November 2013, Cambodia on 21 July 2015, and Lao PDR on 21 April 2016, and the study ended with the completion of follow-up of the Lao PDR villages on 12 June 2017 (S2 Table). There was a 12-day delay between the start of the study on 27 May 2013 and the public registration of the trial on 7 June 2013 due to an administrative delay.
The de jure population in the 16 villages was 9,897 (4,738 in early MDA and 5,159 in deferred MDA villages). The de facto population at M0 was 8,445 (4,135 in early MDA and 4,310 in deferred MDA villages), with a median of 495 residents per village (Fig 2). The median age of participants was 20 years (interquartile range 9 to 36). The large majority reported using insecticide-treated bednets regularly (4,579/5,620; 82%; Table 1). At baseline (M0), uPCR detected an overall mean P. falciparum prevalence of 6.2% (95% CI 5.6% to 6.8%). The baseline P. falciparum prevalence was lower in early MDA villages (5.1%, 95% CI 4.4% to 5.9%) compared to villages with deferred MDA (7.2%, 95% CI 6.4% to 8.1%), as was the P. falciparum density: geometric mean 3,363 parasites/ml (95% CI 2,472 to 4,575) in early MDA villages compared with 10,607 parasites/ml (8,146 to 13,812) in villages assigned to deferred MDA.
This cluster randomised trial demonstrated that in a setting where early diagnosis, effective treatment, and insecticide-treated bednets have already been made available, mass antimalarial drug administration with DP can substantially reduce the transmission of P. falciparum infections over a 1-year period. This period of protection afforded by the MDA was much longer than the post-treatment prophylactic effect provided by piperaquine (the slowly eliminated and therefore longer acting component of the antimalarial regimen), suggesting that the reduction of the asymptomatic parasite reservoir made a lasting impact on transmission of P. falciparum infections. An analysis starting 1 month after the last drug dose (i.e., from M3 to M12), after the complete implementation of the intervention and after the prophylactic period, showed a substantial benefit. Twelve months after early DP MDA, the P. falciparum prevalence had become very low or reached 0 in 4 of 8 intervention villages. However, malaria was also reduced substantially in control villages that did not receive early DP MDA, which was probably related to uninterrupted access to basic malaria control measures in all villages. The intensive community engagement conducted alongside the study activities played a critical role in promoting uptake. Overall, 86% of the target population participated in at least 1 round of the early MDAs, and 81% participated in at least 1 round of the deferred MDAs. In Myanmar and Vietnam, where DP MDA was less effective than in Cambodia and Lao PDR, the proportions of residents participating in all 3 rounds of the MDA was only 57% during the early MDAs and 38% in the deferred MDAs. Completion of the 3-round regimen was significantly associated with a reduction in the risk of becoming infected with P. falciparum in a multivariable regression model, while completion of a single round was not. Despite widespread artemisinin resistance, we found an overall clearance of 94% of subclinical P. falciparum infections after 1 or more rounds of MDA. The DP MDA drug regimen with a single low dose of primaquine was safe and remarkably well tolerated. There were no drug-attributable SAEs.