A Head-to-Head Comparison of Four Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children: A Randomized Trial

James G Beeson

doi:10.1371/journal.pmed.1001119

Abstract

Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce. Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28. This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria. ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750

Highlights

The burden of malaria has declined substantially in several areas of sub-Saharan Africa, in the past 3–5 y [1]
The World Health Organization (WHO), which recently produced revised guidelines for the treatment of malaria, states that the choice of artemisinin-based combination therapy (ACT) in a country or region should be based on the level of resistance to the medicine partnered to the artemisinin derivative in the combination [12]
For the PCR-adjusted adequate clinical and parasitological response (ACPR) at day 28, non-inferiority could be established for the following pair-wise comparisons: AL versus DHAPQ (95.5% [1,094/1,146] versus 97.3% [1,019/1,047]; odds ratio (OR): 0.59, 95% confidence interval (CI): 0.37–0.94), ASAQ versus DHAPQ (96.8% [880/ 909] versus 97.6% [785/804]; OR: 0.74, 95% CI: 0.41–1.34), and AL versus ASAQ (94.4% [559/592] versus 97.1% [568/585]; OR: 0.50, 95% CI: 0.28–0.92)

Summary

Introduction

The burden of malaria has declined substantially in several areas of sub-Saharan Africa, in the past 3–5 y [1]. The World Health Organization (WHO), which recently produced revised guidelines for the treatment of malaria, states that the choice of ACT in a country or region should be based on the level of resistance to the medicine partnered to the artemisinin derivative in the combination [12]. The malaria parasite quickly developed resistance to many of these monotherapies, and in the 1990 s, there was a widespread upsurge in P. falciparum malaria To combat this increase, the World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for first-line treatment of P. falciparum malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (new, fast-acting antimalarial drugs) are used in combination with another antimalarial drug (a partner drug) to reduce the chances of P. falciparum becoming resistant to either drug

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