Portal de Periódicos da CAPES

The effect of dose on the antimalarial efficacy of artemether–lumefantrine: a systematic review and pooled analysis of individual patient data

2015; Elsevier BV; Volume: 15; Issue: 6 Linguagem: Inglês

10.1016/s1473-3099(15)70024-1

1474-4457

N. M. Anstey, Ric N. Price, Timothy M. E. Davis, HA Karunajeewa, Ivo Müeller, Umberto D’Alessandro, Achille Massougbodji, Frédéric Nikièma, Jean‐Bosco Ouédraogo, Halidou Tinto, Issaka Zongo, A Samé‐Ekobo, Moussa Koné, Hervé Ménan, AO Touré, William Yavo, P‐E Kofoed, BH Alemayehu, Daddi Jima, Elisabeth Baudin, Emmanuelle Espié, Carolyn Nabasumba, Loretxu Pinoges, Birgit Schramm, Michel Cot, Philippe Deloron, JF Faucher, JP Guthmann, Bertrand Lell, Steffen Borrmann, GO Adjei, Johan Ursing, Emiliana Tjitra, Kevin Marsh, J Peshu, Elizabeth Juma, BR Ogutu, SA Omar, Patrick Sawa, AO Talisuna, Maniphone Khanthavong, Mayfong Mayxay, Paul N. Newton, Patrice Piola, AA Djimde, OK Doumbo, Bakary Fofana, Issaka Sagara, Quique Bassat, Raquel González, Clara Menéndez, Frank Smithuis, Teun Bousema, PA Kager, Pètra F. Mens, Henk D. F. H. Schallig, Ingrid van den Broek, Michèle van Vugt, ML Ibrahim, CO Falade, Martin Meremikwu, José Pedro Gil, Corine Karema, Ba, Babacar Faye, Oumar Faye, Oumar Gaye, JL Ndiaye, Mor Pène, Dominique A. Caugant, Khadime Sylla, Roger Tine, LK Penali, Karen I. Barnes, LJ Workman, Aldo Â. M. Lima, Ishag Adam, Nahla B. Gadalla, Efm Malik, Anders Björkman, Andreas Mårtensson, BE Ngasala, Lars Rombo, Paul Aliu, Stephan Duparc, Scott Filler, Blaise Genton, Eva Maria Hodel, Piero Olliaro, Salim Abdulla, Erasmus Kamugisha, Zul Premji, SA Shekalaghe, Elizabeth A. Ashley, Verena I. Carrara, Rose McGready, François Nosten, A Faiz, SJ Lee, Nicholas J. White, Arjen M. Dondorp, JJ Smith, Joel Tärning, Jane Achan, Hasifa Bukirwa, Adoke Yeka, Emmanuel Arinaitwe, SG Staedke, Kamya, Fred Kironde, CJ Drakeley, Mary C. Oguike, CJ Sutherland, Francesco Checchi, Prabin Dahal, Jennifer A. Flegg, Philippe J. Guérin, Clarissa Moreira, Christian Nsanzabana, CH Sibley, Kasia Stepniewska, Peter W. Gething, Simon I Hay, Brian Greenwood, Stephen A. Ward, PA Winstanley, Grant Dorsey, Bryan Greenhouse, P Rosenthal, Anastasia Grivoyannis, Kamal Hamed, Jimee Hwang, PS Kachur, Michael Nambozi,

Drug-Induced Hepatotoxicity and Protection

Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings.We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites.We included 61 studies done between January, 1998, and December, 2012, and included 14,327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose).The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups.Bill & Melinda Gates Foundation.