The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data
Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group, N M Anstey, R N Price, T M E Davis, H A Karunajeewa, I Mueller, H A Karunajeewa, U D'Alessandro, A Massougbodji, F Nikiema, J-B Ouédraogo, H Tinto, I Zongo, J-B Ouédraogo, H Tinto, A Same-Ekobo, M Koné, H Menan, W Yavo, A O Touré, W Yavo, P-E Kofoed, B H Alemayehu, D Jima, E Baudin, E Espié, C Nabasumba, L Pinoges, B Schramm, M Cot, P Deloron, J-F Faucher, M Cot, P Deloron, J-F Faucher, J-F Faucher, J-F Faucher, J-P Guthmann, B Lell, S Borrmann, B Lell, G O Adjei, P-E Kofoed, J Ursing, E Tjitra, S Borrmann, K Marsh, J Peshu, E Juma, B R Ogutu, S A Omar, P Sawa, A O Talisuna, A O Talisuna, M Khanthavong, M Mayxay, P N Newton, M Mayxay, P Piola, A A Djimdé, O K Doumbo, B Fofana, I Sagara, Q Bassat, R González, C Menéndez, F Smithuis, F Smithuis, T Bousema, P A Kager, P F Mens, P F Mens, H D F H Schallig, I Van den Broek, M Van Vugt, M L Ibrahim, C O Falade, M Meremikwu, M Meremikwu, J P Gil, C Karema, M S Ba, B Faye, B Faye, O Gaye, J-L Ndiaye, M Pene, D Sow, K Sylla, R C K Tine, L K Penali, K I Barnes, L J Workman, K I Barnes, L J Workman, Q Bassat, R González, C Menéndez, I Mueller, A Lima, I Adam, N B Gadalla, E F M Malik, A Björkman, J P Gil, A Mårtensson, B E Ngasala, J Ursing, A Mårtensson, L Rombo, L Rombo, L Rombo, P Aliu, S Duparc, S Filler, B Genton, B Genton, E M Hodel, P Olliaro, S Abdulla, E Kamugisha, B E Ngasala, Z Premji, S A Shekalaghe, S A Shekalaghe, E A Ashley, V I Carrara, R McGready, F Nosten, E A Ashley, A M Faiz, S J Lee, N J White, V I Carrara, A M Dondorp, J J Smith, U D'lessandro, J Tarning, J Achan, H Bukirwa, A Yeka, E Arinaitwe, S G Staedke, M R Kamya, F Kironde, C Nabasumba, T Bousema, C J Drakeley, N B Gadalla, M Oguike, C J Sutherland, F Checchi, P Dahal, J A Flegg, P J Guerin, C Moreira, P N Newton, C Nsanzabana, R N Price, C H Sibley, K Stepniewska, J Tarning, P Dahal, A M Dondorp, J A Flegg, P J Guerin, S J Lee, K Marsh, R McGready, C Moreira, P N Newton, F Nosten, C Nsanzabana, P Olliaro, R N Price, J Tarning, N J White, P W Gething, S I Hay, B Greenwood, E M Hodel, S A Ward, S G Staedke, I Van den Broek, P A Winstanley, G Dorsey, B Greenhouse, P J Rosenthal, N B Gadalla, J P Gil, A Grivoyannis, K Hamed, J Hwang, P S Kachur, J Hwang, C H Sibley, M Nambozi, Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group, N M Anstey, R N Price, T M E Davis, H A Karunajeewa, I Mueller, H A Karunajeewa, U D'Alessandro, A Massougbodji, F Nikiema, J-B Ouédraogo, H Tinto, I Zongo, J-B Ouédraogo, H Tinto, A Same-Ekobo, M Koné, H Menan, W Yavo, A O Touré, W Yavo, P-E Kofoed, B H Alemayehu, D Jima, E Baudin, E Espié, C Nabasumba, L Pinoges, B Schramm, M Cot, P Deloron, J-F Faucher, M Cot, P Deloron, J-F Faucher, J-F Faucher, J-F Faucher, J-P Guthmann, B Lell, S Borrmann, B Lell, G O Adjei, P-E Kofoed, J Ursing, E Tjitra, S Borrmann, K Marsh, J Peshu, E Juma, B R Ogutu, S A Omar, P Sawa, A O Talisuna, A O Talisuna, M Khanthavong, M Mayxay, P N Newton, M Mayxay, P Piola, A A Djimdé, O K Doumbo, B Fofana, I Sagara, Q Bassat, R González, C Menéndez, F Smithuis, F Smithuis, T Bousema, P A Kager, P F Mens, P F Mens, H D F H Schallig, I Van den Broek, M Van Vugt, M L Ibrahim, C O Falade, M Meremikwu, M Meremikwu, J P Gil, C Karema, M S Ba, B Faye, B Faye, O Gaye, J-L Ndiaye, M Pene, D Sow, K Sylla, R C K Tine, L K Penali, K I Barnes, L J Workman, K I Barnes, L J Workman, Q Bassat, R González, C Menéndez, I Mueller, A Lima, I Adam, N B Gadalla, E F M Malik, A Björkman, J P Gil, A Mårtensson, B E Ngasala, J Ursing, A Mårtensson, L Rombo, L Rombo, L Rombo, P Aliu, S Duparc, S Filler, B Genton, B Genton, E M Hodel, P Olliaro, S Abdulla, E Kamugisha, B E Ngasala, Z Premji, S A Shekalaghe, S A Shekalaghe, E A Ashley, V I Carrara, R McGready, F Nosten, E A Ashley, A M Faiz, S J Lee, N J White, V I Carrara, A M Dondorp, J J Smith, U D'lessandro, J Tarning, J Achan, H Bukirwa, A Yeka, E Arinaitwe, S G Staedke, M R Kamya, F Kironde, C Nabasumba, T Bousema, C J Drakeley, N B Gadalla, M Oguike, C J Sutherland, F Checchi, P Dahal, J A Flegg, P J Guerin, C Moreira, P N Newton, C Nsanzabana, R N Price, C H Sibley, K Stepniewska, J Tarning, P Dahal, A M Dondorp, J A Flegg, P J Guerin, S J Lee, K Marsh, R McGready, C Moreira, P N Newton, F Nosten, C Nsanzabana, P Olliaro, R N Price, J Tarning, N J White, P W Gething, S I Hay, B Greenwood, E M Hodel, S A Ward, S G Staedke, I Van den Broek, P A Winstanley, G Dorsey, B Greenhouse, P J Rosenthal, N B Gadalla, J P Gil, A Grivoyannis, K Hamed, J Hwang, P S Kachur, J Hwang, C H Sibley, M Nambozi
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.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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Source: PubMed