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      Artemisinin resistance – modelling the potential human and economic costs

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          Abstract

          Background

          Artemisinin combination therapy is recommended as first-line treatment for falciparum malaria across the endemic world and is increasingly relied upon for treating vivax malaria where chloroquine is failing. Artemisinin resistance was first detected in western Cambodia in 2007, and is now confirmed in the Greater Mekong region, raising the spectre of a malaria resurgence that could undo a decade of progress in control, and threaten the feasibility of elimination. The magnitude of this threat has not been quantified.

          Methods

          This analysis compares the health and economic consequences of two future scenarios occurring once artemisinin-based treatments are available with high coverage. In the first scenario, artemisinin combination therapy (ACT) is largely effective in the management of uncomplicated malaria and severe malaria is treated with artesunate, while in the second scenario ACT are failing at a rate of 30%, and treatment of severe malaria reverts to quinine. The model is applied to all malaria-endemic countries using their specific estimates for malaria incidence, transmission intensity and GDP. The model describes the direct medical costs for repeated diagnosis and retreatment of clinical failures as well as admission costs for severe malaria. For productivity losses, the conservative friction costing method is used, which assumes a limited economic impact for individuals that are no longer economically active until they are replaced from the unemployment pool.

          Results

          Using conservative assumptions and parameter estimates, the model projects an excess of 116,000 deaths annually in the scenario of widespread artemisinin resistance. The predicted medical costs for retreatment of clinical failures and for management of severe malaria exceed US$32 million per year. Productivity losses resulting from excess morbidity and mortality were estimated at US$385 million for each year during which failing ACT remained in use as first-line treatment.

          Conclusions

          These ‘ballpark’ figures for the magnitude of the health and economic threat posed by artemisinin resistance add weight to the call for urgent action to detect the emergence of resistance as early as possible and contain its spread from known locations in the Mekong region to elsewhere in the endemic world.

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          Most cited references 29

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          Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

          Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.
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            Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.

            In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). Artesunate should become the treatment of choice for severe falciparum malaria in adults.
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              Changes in the burden of malaria in sub-Saharan Africa.

              The burden of malaria in countries in sub-Saharan Africa has declined with scaling up of prevention, diagnosis, and treatment. To assess the contribution of specific malaria interventions and other general factors in bringing about these changes, we reviewed studies that have reported recent changes in the incidence or prevalence of malaria in sub-Saharan Africa. Malaria control in southern Africa (South Africa, Mozambique, and Swaziland) began in the 1980s and has shown substantial, lasting declines linked to scale-up of specific interventions. In The Horn of Africa, Ethiopia and Eritrea have also experienced substantial decreases in the burden of malaria linked to the introduction of malaria control measures. Substantial increases in funding for malaria control and the procurement and distribution of effective means for prevention and treatment are associated with falls in malaria burden. In central Africa, little progress has been documented, possibly because of publication bias. In some countries a decline in malaria incidence began several years before scale-up of malaria control. In other countries, the change from a failing drug (chloroquine) to a more effective drug (sulphadoxine plus pyrimethamine or an artemisinin combination) led to immediate improvements; in others malaria reduction seemed to be associated with the scale-up of insecticide-treated bednets and indoor residual spraying. 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                yoel@tropmedres.ac
                arjen@tropmedres.ac
                philippe.guerin@wwarn.org
                tom.d@tropmedres.ac
                s.meek@malariaconsortium.org
                e.ashley@doctors.org.uk
                nickd@tropmedres.ac
                nickwdt@tropmedres.ac
                lisa@tropmedres.ac
                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                23 November 2014
                23 November 2014
                2014
                : 13
                : 1
                Affiliations
                [ ]Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [ ]Centre for Tropical Medicine, Nuffield Department of Medicine, Oxford, UK
                [ ]Worldwide Antimalarial Resistance Network (WWARN), Churchill Hospital, University of Oxford, Oxford, UK
                [ ]The Malaria Consortium, London, UK
                Article
                3610
                10.1186/1475-2875-13-452
                4254187
                25418416
                © Lubell et al.; licensee BioMed Central Ltd. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Infectious disease & Microbiology

                malaria, artemisinins, anti-malarial resistance, economics

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