The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

Tuesday 31 March 2015

Adjuik MA Allan R Anvikar AR Ashley EA Ba MS Barennes H Barnes KI Bassat Q Baudin E Björkman A Bompart F Bonnet M Borrmann S Brasseur P Bukirwa H Checchi F Cot M Dahal P D'Alessandro U Deloron P Desai M Diap G Djimde AA Dorsey G Doumbo OK Espié E Etard JF Fanello CI Faucher JF Faye B Flegg JA Gaye O Gething PW González R Grandesso F Guerin PJ Guthmann JP Hamour S Hasugian AR Hay SI Humphreys GS Jullien V Juma E Kamya MR Karema C Kiechel JR Kremsner PG Krishna S Lameyre V Ibrahim LM Lee SJ Lell B Mårtensson A Massougbodji A Menan H Ménard D Menéndez C Meremikwu M Moreira C Nabasumba C Nambozi M Ndiaye JL Nikiema F Nsanzabana C Ntoumi F Ogutu BR Olliaro P Osorio L Ouédraogo JB Penali LK Pene M Pinoges L Piola P Price RN Roper C Rosenthal PJ Rwagacondo CE Same-Ekobo A Schramm B Seck A Sharma B Sibley CH Sinou V Sirima SB Smith JJ Smithuis F Somé FA Sow D Staedke SG Stepniewska K Swarthout TD Sylla K Talisuna AO Tarning J Taylor WR Temu EA Thwing JI Tjitra E Tine RC Tinto H Vaillant MT Valecha N Van den Broek I White NJ Yeka A Zongo I

BMC medicine 2015 Mar 31; 13 66. doi: 10.1186/s12916-015-0301-z. Epub 2015 03 31

Abstract

BACKGROUND: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.

METHODS: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.

RESULTS: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P

CONCLUSIONS: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

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