1. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data
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Anstey, NM, Price, RN, Davis, TME, Karunajeewa, HA, Mueller, I, D'Alessandro, U, Massougbodji, A, Nikiema, F, Ouedraogo, J-B, Tinto, H, Zongo, I, Same-Ekobo, A, Kone, M, Menan, H, Toure, AO, Yavo, W, Kofoed, P-E, Alemayehu, BH, Jima, D, Baudin, E, Espie, E, Nabasumba, C, Pinoges, L, Schramm, B, Cot, M, Deloron, P, Faucher, J-F, Guthmann, J-P, Lell, B, Borrmann, S, Adjei, GO, Ursing, J, Tjitra, E, Marsh, K, Peshu, J, Juma, E, Ogutu, BR, Omar, SA, Sawa, P, Talisuna, AO, Khanthavong, M, Mayxay, M, Newton, PN, Piola, P, Djimde, AA, Doumbo, OK, Fofana, B, Sagara, I, Bassat, Q, Gonzalez, R, Menendez, C, Smithuis, F, Bousema, T, Kager, PA, Mens, PF, Schallig, HDFH, Van den Broek, I, Van Vugt, M, Ibrahim, ML, Falade, CO, Meremikwu, M, Gil, JP, Karema, C, Ba, MS, Faye, B, Faye, O, Gaye, O, Ndiaye, J-L, Pene, M, Sow, D, Sylla, K, Tine, RCK, Penali, LK, Barnes, KI, Workman, LJ, Lima, A, Adam, I, Gadalla, NB, Malik, EFM, Bjorkman, A, Martensson, A, Ngasala, BE, Rombo, L, Aliu, P, Duparc, S, Filler, S, Genton, B, Hodel, EM, Olliaro, P, Abdulla, S, Kamugisha, E, Premji, Z, Shekalaghe, SA, Ashley, EA, Carrara, VI, McGready, R, Nosten, F, Faiz, AM, Lee, SJ, White, NJ, Dondorp, AM, Smith, JJ, Tarning, J, Achan, J, Bukirwa, H, Yeka, A, Arinaitwe, E, Staedke, SG, Kamya, MR, Kironde, F, Drakeley, CJ, Oguike, M, Sutherland, CJ, Checchi, F, Dahal, P, Flegg, JA, Guerin, PJ, Moreira, C, Nsanzabana, C, Sibley, CH, Stepniewska, K, Gething, PW, Hay, SI, Greenwood, B, Ward, SA, Winstanley, PA, Dorsey, G, Greenhouse, B, Rosenthal, PJ, Grivoyannis, A, Hamed, K, Hwang, J, Kachur, PS, Nambozi, M, and Resistance, WA
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Male ,Artemether/lumefantrine ,Polymerase Chain Reaction ,Efficacy ,chemistry.chemical_compound ,Artemether ,Malaria, Falciparum ,Child ,Aged, 80 and over ,Clinical Trials as Topic ,Malaria, Falciparum/drug therapy ,Middle Aged ,Artemisinins ,3. Good health ,Drug Combinations ,Treatment Outcome ,Infectious Diseases ,Ethanolamines ,Child, Preschool ,Female ,DNA, Protozoan/genetics ,medicine.drug ,Adult ,medicine.medical_specialty ,Asia ,Adolescent ,Plasmodium falciparum ,Fluorenes/administration & dosage ,Lumefantrine ,Lower risk ,Article ,Antimalarials ,Young Adult ,Ethanolamines/administration & dosage ,Internal medicine ,medicine ,Humans ,Risk factor ,Aged ,Fluorenes ,Dose-Response Relationship, Drug ,business.industry ,Artemether, Lumefantrine Drug Combination ,Plasmodium falciparum/genetics ,Infant ,Odds ratio ,DNA, Protozoan ,Surgery ,Artemisinins/administration & dosage ,Regimen ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,chemistry ,Africa ,Antimalarials/administration & dosage ,business - Abstract
Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: Bill & Melinda Gates Foundation.
- Published
- 2015
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