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      Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study

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          Abstract

          Francois Nosten and colleagues evaluate malaria prevalence and incidence in the mobile population on the Myanmar side of the border with Thailand between 1999 and 2011, and also assess resistance to artemisinin.

          Abstract

          Background

          The Shoklo Malaria Research Unit has been working on the Thai–Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period.

          Methods and Findings

          Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76–80) (1,048/1,344 consultations) to 7% (95% CI 6.2–7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3–1.4) to 0.7 (95% CI 0.7–0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04–0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0–28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8–4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20–62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13–45) (8/29 patients) in 2011.

          Conclusions

          Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai–Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          According to latest figures, the World Health Organization estimates that there are over 200 million cases of malaria each year, with over three-quarters of a million deaths. Several Plasmodium parasites cause malaria (the most serious being Plasmodium falciparum) and are transmitted to people through the bites of infected night-flying mosquitoes. Malaria transmission can be prevented by using insecticides to control the mosquitoes and by sleeping under insecticide-treated bed nets. However, in Southeast Asia the effectiveness of these measures is limited. Treating infected people with antimalarial drugs, particularly with artemisinin-based combination treatments (ACTs), is a key strategy in reducing the deaths and disability caused by malaria. However, progress is now threatened by the emergence in Southeast Asia of P. falciparum isolates that are resistant to artesunate (a common component of ACT). This development is concerning, as resistance to the artemisinin family of drugs, of which artesunate is a member, could trigger a resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria.

          Why Was This Study Done?

          P. falciparum resistance to artemisinin has been confirmed in the area around the border between Thailand and Myanmar. Malaria control in this border area is particularly challenging, as there is a reservoir of malaria in Myanmar (where the disease burden is higher than in Thailand), frequent population movement, and differences in adequate control measures on the two sides of the border. In this study the authors evaluated malaria prevalence and incidence in the mobile population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to early diagnosis and treatment with ACT was associated with a decline in the malaria burden.

          What Did the Researchers Do and Find?

          The Shoklo Malaria Research Unit (SMRU) has been working on the Thai–Myanmar border for 25 years providing early diagnosis and treatment of malaria and has extended its services from two to 11 health care facilities (health posts) on the Myanmar side of the border over the past few years. In order to evaluate any changes in the malaria burden since the expansion of services, the researchers recorded the number of consultations in all SMRU clinics and health posts with confirmed malaria diagnosis and tracked changes in the prevalence of malaria in the population on the Myanmar side of the border (via cross-sectional surveys in villages). The researchers also assessed the incidence of malaria in a cohort of pregnant women living on both sides of the border and monitored antimalarial drug efficacy over this time period.

          The researchers found that although the mobile population on the Thai side of the border remained constant, the population in villages covered by the clinics and health posts in the border area increased four-fold. Over the time period, the researchers found that the number of confirmed malaria cases ( P. falciparum) increased initially, rising from just over 5,000 in 2000 to a peak of 13,764 in 2006, and then declined to just over 3,500 in 2011. A striking finding was the predominance of infections in young adult males (50,316/90,321; 55.7%). Encouragingly, the percentage of consultations due to malaria in children under five years fell from 78% to 7%, and the incidence of malaria declined from 1.1 to 0.1 episodes per pregnant woman-year. In addition, the proportion of patients admitted to hospital with severe disease was stable, and the number of deaths from malaria remained extremely low, with an overall case fatality rate of 0.05%. The researchers also found that the ratio of P. falciparum to P. vivax infections declined from 1.4 to 0.7, and the prevalence of P. falciparum decreased from 24.3% to 3.4%. However, worryingly, in the small number of patients undertaking drug efficacy tests, the drug efficacy of artesunate declined steadily, with the proportion of patients still infected with malaria at day 3 of treatment increasing from 0% in 2000 to 28% in 2011.

          What Do These Findings Mean?

          These findings indicate that despite the emergence of resistance to artesunate in P. falciparum, and the decline in the efficacy of ACT, the strategy of early diagnosis and treatment with ACTs has been associated with a reduction in malaria in the population living on the Thai–Myanmar border. Furthermore, these findings suggest that an aggressive strategy based on early detection and treatment of cases, combined with vector control and information, could be the way forward to eliminate malaria. Although there were only a small number of patients involved in drug efficacy tests in 2011, this study shows that alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.

          Additional Information

          Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001398.

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          Author and article information

          Contributors
          Role: Academic Editor
          Journal
          PLoS Med
          PLoS Med
          PLoS
          plosmed
          PLoS Medicine
          Public Library of Science (San Francisco, USA )
          1549-1277
          1549-1676
          March 2013
          March 2013
          5 March 2013
          : 10
          : 3
          Affiliations
          [1 ]Shoklo Malaria Research Unit, Mae Sot, Thailand
          [2 ]Mahidol Oxford University Research Unit, Bangkok, Thailand
          [3 ]Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom
          [4 ]Department of Obstetrics, University Medical Center Utrecht, Utrecht, The Netherlands
          [5 ]Academic Medical Center, Amsterdam, The Netherlands
          [6 ]Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
          Médecins Sans Frontières, South Africa
          Author notes

          The authors have declared that no competing interests exist.

          Contributed to the clinical work and the data collection: VIC KML APP EA MR MB RMG CC FN. Responsible for the laboratory work and the QC: SP KS. Managed the data: JW. Performed the analysis: VIC FN. Supervised the program and revised the manuscript: PS NW. Wrote the first draft of the manuscript: VIC EA FN. Contributed to the writing of the manuscript: VIC KM AP EA JW KS MR MB RM SP CC PS NW FN. ICMJE criteria for authorship read and met: VIC KM AP EA JW KS MR MB RM SP CC PS NW FN. Agree with manuscript results and conclusions: VIC KM AP EA JW KS MR MB RM SP CC PS NW FN.

          Article
          PMEDICINE-D-12-01768
          10.1371/journal.pmed.1001398
          3589269
          23472056

          This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

          Page count
          Pages: 16
          Funding
          This research was a part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme, supported by the Wellcome Trust of Great Britain (Major Overseas Programme—Thailand Unit Core Grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Categories
          Research Article
          Medicine
          Infectious Diseases
          Infectious Disease Control

          Medicine

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