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

Abstract

BackgroundArtesunate-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.MethodsIndividual 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.ResultsForty-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 < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites.ConclusionsThere 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0301-z) contains supplementary material, which is available to authorized users.

Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger

“…Age acts as a strong confounder in investigating this association. It has been negatively associated with lumefantrine concentration in this study and others [31, 33], and children < 3 years have usually lower exposure to lumefantrine [15]. Additionally, unmeasured factors linked to age modulate the exposition and susceptibility to malaria: different exposure to mosquito bites in relation to behavioral changes in older children possibly mediated by different utilization of insecticide-treated nets [34], and different immune premunition switching from transmitted maternal immunity via breastfeeding to acquired host immunity.…”

“…We confirmed here that the relation between the dose-weight received and the lumefantrine concentration measured in blood is not straightforward, the higher dose-weight received in younger SAM children resulted in a lower day 7 concentration [31]. Though not correlated with a higher risk of treatment failure or reinfection in our study, the low concentration achieved in SAM and young children is still a concern, as sub-optimal exposure to antimalarials is the first step to the emergence of parasite resistance [35].…”

“…Of note, older SAM children were also those who experienced more reinfections. A day-7 concentration over 200 ng/mL (previously pointed by WWARN as an efficacy threshold) [31], was achieved in 57.1 % of younger SAM, 66.7 % of younger non-SAM, 75.0 % of older SAM, and 82.8 % of older non-SAM ( P  = 0.002 overall) patients. We did not find a statistically significant association between lumefantrine concentration on day 7 and protection from reinfection by day 28 (in Cox modelling, HR = 1.05, 95 % CI, 0.68–1.64, P  = 0.818 for the measure of association between reinfection and log-transformed lumefantrine concentration in continuous variables, after adjusting for age).

Fig.

…”

“…A recent meta-analysis conducted by WWARN also pointed out that day 7 lumefantrine concentration was lower in younger and underweight children, though it did not investigate the effect of SAM specifically [31]. …”

Fixed-Dose Artesunate–Amodiaquine Combination vs Chloroquine for Treatment of Uncomplicated Blood Stage P. vivax Infection in the Brazilian Amazon: An Open-Label Randomized, Controlled Trial

“…Neutropenia and elevation of ALT were considered AEs of special interest [42–44]. An independent data monitoring committee comprised of 3 renowned experts reviewed the study protocol and evaluated the results of efficacy and safety analyses.…”