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Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis

Julien Zwang1*, Piero Olliaro2, Hubert Barennes3, Maryline Bonnet4, Philippe Brasseur5, Hasifa Bukirwa6, Sandra Cohuet4, Umberto D'Alessandro7, Abdulaye Djimdé8, Corine Karema9, Jean-Paul Guthmann4, Sally Hamour4, Jean-Louis Ndiaye10, Andreas Mårtensson11, Claude Rwagacondo9, Issaka Sagara8, Albert Same-Ekobo12, Sodiomon B Sirima13, Ingrid van den Broek14, Adoke Yeka6, Walter RJ Taylor2, Grant Dorsey15 and Milijaona Randrianarivelojosia16

Author Affiliations

1 Shoklo Malaria Research Unit (SMRU), Mae Sot, Thailand

2 UNICEF/UNDP/WB/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland

3 Institut de la Francophonie pour la Médecine Tropicale, BP 9519, Vientiane, Lao PDR

4 Epicentre, Paris, France

5 Institut de Recherche pour le Développement (IRD), Dakar, Sénégal

6 Uganda Malaria Surveillance Project, Kampala, Uganda

7 Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium

8 Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine and Pharmacy, University of Bamako, Bamako, Mali

9 National Malaria Control Programme, Kigali, Rwanda

10 Department of Parasitology, Faculty of Medicine, Cheikh Anta Diop University, Dakar, Senegal

11 Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden

12 Laboratoire de Parasitologie, Centre Hospitalier Universitaire, Yaoundé, Cameroun

13 Centre National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, Ouagadougou, Burkina Faso

14 Médecins sans Frontières, London, UK

15 Department of Medicine, University of California San Francisco, San Francisco, California, USA

16 Unité de Recherche sur le Paludisme, Institut Pasteur, Antananarivo, Madagascar

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Malaria Journal 2009, 8:203  doi:10.1186/1475-2875-8-203

Published: 23 August 2009

Abstract

Background

Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy.

Methods

An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints.

Results

A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT).

AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6–77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2–94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery.

Conclusion

AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.