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Lancet Infect Dis. 2015 Jun;15(6):692-702. doi: 10.1016/S1473-3099(15)70024-1. Epub 2015 Mar 16.

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

Collaborators (196)

Anstey NM, Price RN, Davis TM, Karunajeewa HA, Mueller I, Karunajeewa HA, D'Alessandro U, Massougbodji A, Nikiema F, Ouédraogo JB, Tinto H, Zongo I, Ouédraogo JB, Tinto H, Same-Ekobo A, Koné M, Menan H, Yavo W, Touré AO, Yavo W, Kofoed PE, Alemayehu BH, Jima D, Baudin E, Espié E, Nabasumba C, Pinoges L, Schramm B, Cot M, Deloron P, Faucher JF, Cot M, Deloron P, Faucher JF, Faucher JF, Faucher JF, Guthmann JP, Lell B, Borrmann S, Lell B, Adjei GO, Kofoed PE, Ursing J, Tjitra E, Borrmann S, Marsh K, Peshu J, Juma E, Ogutu BR, Omar SA, Sawa P, Talisuna AO, Talisuna AO, Khanthavong M, Mayxay M, Newton PN, Mayxay M, Piola P, Djimdé AA, Doumbo OK, Fofana B, Sagara I, Bassat Q, González R, Menéndez C, Smithuis F, Smithuis F, Bousema T, Kager PA, Mens PF, Mens PF, Schallig HD, Van den Broek I, Van Vugt M, Ibrahim ML, Falade CO, Meremikwu M, Meremikwu M, Gil JP, Karema C, Ba MS, Faye B, Faye B, Gaye O, Ndiaye JL, Pene M, Sow D, Sylla K, Tine RC, Penali LK, Barnes KI, Workman LJ, Barnes KI, Workman LJ, Bassat Q, González R, Menéndez C, Mueller I, Lima A, Adam I, Gadalla NB, Malik EF, Björkman A, Gil JP, Mårtensson A, Ngasala BE, Ursing J, Mårtensson A, Rombo L, Rombo L, Rombo L, Aliu P, Duparc S, Filler S, Genton B, Genton B, Hodel EM, Olliaro P, Abdulla S, Kamugisha E, Ngasala BE, Premji Z, Shekalaghe SA, Shekalaghe SA, Ashley EA, Carrara VI, McGready R, Nosten F, Ashley EA, Faiz AM, Lee SJ, White NJ, Carrara VI, Dondorp AM, Smith JJ, D'lessandro U, Tarning J, Achan J, Bukirwa H, Yeka A, Arinaitwe E, Staedke SG, Kamya MR, Kironde F, Nabasumba C, Bousema T, Drakeley CJ, Gadalla NB, Oguike M, Sutherland CJ, Checchi F, Dahal P, Flegg JA, Guerin PJ, Moreira C, Newton PN, Nsanzabana C, Price RN, Sibley CH, Stepniewska K, Tarning J, Dahal P, Dondorp AM, Flegg JA, Guerin PJ, Lee SJ, Marsh K, McGready R, Moreira C, Newton PN, Nosten F, Nsanzabana C, Olliaro P, Price RN, Tarning J, White NJ, Gething PW, Hay SI, Greenwood B, Hodel EM, Ward SA, Staedke SG, Van den Broek I, Winstanley PA, Dorsey G, Greenhouse B, Rosenthal PJ, Gadalla NB, Gil JP, Grivoyannis A, Hamed K, Hwang J, Kachur PS, Hwang J, Sibley CH, Nambozi M.

Erratum in

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.

Comment in

PMID:
25788162
PMCID:
PMC4632191
DOI:
10.1016/S1473-3099(15)70024-1
[Indexed for MEDLINE]
Free PMC Article

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