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

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 < 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.

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.

Figure 1

Patient flowchart.

Figure 2

Total mg/kg dose for artesunate (A) and amodiaquine (B). The dotted line represents the WHO therapeutic dose range for artesunate (6 to 30 mg/kg) and amodiaquine (22.5 to 45 mg/kg).

Figure 3

Day 28 survival estimates. PCR adjusted recrudescence estimates on day 28 were generated using Kaplan-Meier method stratified by study sites for loose NFDC-25 [red], loose NFDC-30 [orange], co-blistered NFDC [green] and FDC [blue]. The associated error bars are 95% confidence interval (CI) for survival estimates. 95% CIs were generated using Wilson’s method in case of no failures using the number of patients at risk on day 28. Unpublished studies are represented by *. ** The risk of recrudescence by day 28 was significantly higher in three study sites (Kailahun (Sierra Leone), Kisumu (Kenya) and Rukara (Rwanda)), where patients were treated with loose NFDC-30 compared to the other study sites in the loose NFDC-30 category (hazards ratio (HR) = 6.27 [95% CI:2.40-16.32], P < 0.001). Patients treated with loose NFDC-30 in these three sites were at higher risk of recrudescence (HR = 8.40 [95% CI: 3.23-21.83], P < 0.001) compared to patients treated with FDC and those treated with co-blistered NFDC (HR = 8.22 [95% CI: 2.66-25.40], P < 0.001). The risk of recrudescence was similar between patients treated with loose NFDC-30 in the other sites compared to those treated with FDC (HR = 1.34 [95% CI: 0.77-2.34]; P = 0.300) or co-blistered NFDC (HR = 1.31 [95% CI: 0.59-2.87], P = 0.500). All the HR was derived from univariable Cox model with study sites fitted as random effect.