Advantages of Injectable Artesunate for severe

WHO recommended treatment

Severe malaria is a medical emergency and is fatal60 if000 untreated. Every year an estimated 655,000 people die of malaria, 86% of whom are children under50 000 the49 age 950 of 5. As death from severe malaria 40 000 often occurs within hours of admission to a hospital or clinic, it is essential34 800 that patients receive effective treatment as soon as possible. The WHO strongly recommends30 000 injectable artesunateNumber of death over estimated for 20 000 per type of treatment for 1 300 000 patients treated the treatment of severe P. falciparum malaria in both 10children 000 and adults . 0 Quinine Artesunate

Ø Injectable artesunate can save more lives Artesunate substantially reduces mortality than quinine fromArtesunate severe substantially malaria compared reduces mortality to quinine with severe malaria compared to quinine Clinical evidence from two large-scale, multi-centre trials in South 2 3 East Asia (SEAQUAMAT) and Africa (AQUAMAT) showed a 25 34.7% Quinine Artesunate reduction in the risk of death using injectable artesunate compared relative reduction 20 22.4 in mortality. 22.5% to quinine. If used throughout Africa, injectable artesunate could p=0.0002 relative reduction 15 in mortality save up to an additional 195,000 lives each year 4. p=0.0022

Mortality rates (%) 14.7 10 This equates to saving one extra life for every 41 children 10.9 treated. This life-saving benefit of artesunate for severe malaria 5 8.5

derives from its rapid ability to kill the parasite across all its life 0 stages unlike quinine which is slower and stage-specific, mainly SeaquamatSEAQUAMA 2005 T Aquamat 2010AQUAMAT 5 1431 patients. 5425 patients (children under 15 years old). affecting the mature blood stage . Bangladesh, India, Indonesia, Nigeria, Uganda,Tanzania, DRC, Rwanda, Myanmar. Kenya, Ghana, Gambia, Mozambique.

Ø Treatment with artesunate is cost-effective For over a century, quinine administered by injection Although the average cost of injectable artesunate is currently has been the best treatment available for treating higher than quinine ($3.3 vs. $1.3), overall costs are found to “ severe malaria, but thanks to the development of be equivalent. Cost analysis from the trials in Asia and Africa show that if total costs are considered (in particular the cost the compounds, we now have a safer and of administering the drugs and management of side-effects) much more effective treatment.7 artesunate is found to be cost-effective.6 Prof Nick White ” Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Case study Number of deaths estimated The comparative benefits of injectable under 5 years of age. The anticipated total 60 000 per type of treatment for 435,600 patients treated artesunate relative to quinine in the treatment cost of treatment would be $2,909,460.6 The 50 000 47,480 of severe malaria are significant. A case clinical studies showed that the expected 40 000 37,026 study was prepared based on a hypothetical mortality rate would be 28,2% higher with 30 000 country with an average of 435,600 cases quinine compared to artesunate.3 Therefore 20 000 of severe malaria treated each year in health artesunate can save 10,454 additional lives 10 000 facilities, among which half are children (5,05% of the treated population). 0 Quinine Artesunate Number of death estimated per type of treatment for 300,000 patients treated Defeating Malaria Together Ø Artesunate is better tolerated than quinine Supporting governments in the use Combi-pack and has fewer severe side effects of injectable artesunate Clinical trials show that artesunate produces fewer life-threatening Combi-pack side-effects than quinine, with fewer recorded incidences of low User-friendly pack blood sugar (hypoglycaemia), and anaemia. Furthemore, quinine At present, only injectable artesunate 60mg has can induce potentially serious hyperinsulinaemic hypoglycaemia, been prequalified by the WHO. To simplify its use, especially during and cardiotoxicity. Quinine IM is also a new combi-pack including a saline vial should painful and locally toxic.8 be soon on the shelves.

Job-Aid Ø Injectable artesunate is easier MMV, with key partners, has developed a poster for health workers to administer than quinine to facilitate the preparation and administration of the treatment. Injectable artesunate is simpler to administer, with the treatment This material is available at www.mmv.org/access-delivery. delivered in five minutes. Due to risk of cardiotoxicity, intravenous quinine administration needs rate-controlled infusion 9 over four hours, three times a day, accompanied by cardiac monitoring if possible. A study examining malaria deaths showed that one in four patients had received incorrect dosing.10

Ø Current production levels of injectable artesunate ensure continuity of supply There is currently more than sufficient supply of injectable artesunate to meet demand. The present WHO pre-qualified supplier has reported excess capacity.

The many advantages of injectable artesunate justify its Funding calculator adoption in line with WHO recommendations. This will MMV and MORU (Mahidol-Oxford Tropical Medicine Research Unit) need sustained support from national health ministries, have developed a calculator to estimate funding requirements and WHO, malaria partnerships, manufacturers and donors. health impact in terms of estimated number of lives saved from injectable artesunate. This Excel-based calculator is available at www.mmv.org/access-delivery. The calculator is easy to use and allows country stakeholders to update the model with individual country data. 1 World Health Organization. Guidelines for the treatment of malaria, Second edition(2010): www.who.int/malaria/publications/atoz/mal_treatchild_revised.pdf 2 Dondorp A et al. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group: Injectable artesunate funding and impact calculator Notes and guidance Start here Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. The Lancet. 366(9487): 715-725 (2005). 3 Dondorp A et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. The Lancet. 376( 9753):1647-57 (2010). 50,000 $ 238,198 4 Médecins Sans Frontières. Malaria: Making the Switch (2011):www.msf.org/shadomx/apps/fms/fms- 45,000 40,000 download.cfm?file_uuid=27E406A3-2B31-4C64-8D47-6EB733128EDF&siteName=msf 35,000 Under 5s Artesunate 5 White NJ., The parasite clearance curve, Malaria Journal 10:278 (2011). 30,000 5 to 15 y/o Quinine $ 707,995 6 Lubell et al. Cost-effectiveness of parenteral artesunate for treating children with severe malaria 25,000 Adults 20,000 in sub-Saharan Africa. Bulletin, World Health Organization (2011). 15,000 7 «Major prompts call for change to treatment guidelines for severe malaria worldwide», 10,000 $ 1,857,011 Media release from Welcome Trust, 6 Nov. 2010. 5,000 - 8 White NJ et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med Under 5s 5 to 15 y/o Adults 309:61–66 (1983). 9 World Health Organization. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (suppl 2): Total number of severe malaria admissions 658,600 1–65 (1990). Total number of artesunate 60ml vials required 2,107,520 10 Mehta Z et al. Malaria deaths as sentinel events to monitor healthcare delivery andantimalarial drug safety. The total funding requirement for artesunate is $2,848,204 Trop Med Int Health 12:617-28 (2007). Estimated number of lives saved 22,357 Cost per death averted $127

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Injectable artesunate saves more lives