Methodology

Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children

Elizabeth A Ashley¹ , Loretxu Pinoges¹ , Eleanor Turyakira¹ , Grant Dorsey² , Francesco Checchi³ , Hasifa Bukirwa⁴ , Ingrid van den Broek^5,6 , Issaka Zongo⁷ , Pedro Pablo Palma Urruta⁸ , Michel van Herp⁹ , Suna Balkan¹⁰ , Walter R Taylor^11,12 , Piero Olliaro^13,14 and Jean-Paul Guthmann^1,15

¹  Epicentre, 8 rue Saint Sabin, 75011, Paris, France

²  Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA

³  London School of Hygiene and Tropical Medicine, Keppel St, London, UK

⁴  Uganda Malaria Surveillance Project, Kampala, Uganda

⁵  Médecins sans Frontières, Amsterdam, The Netherlands

⁶  Center for Infectious Disease Control, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands

⁷  Institut de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso

⁸  Médecins sans Frontières, Barcelona, Spain

⁹  Médecins sans Frontières, Brussels, Belgium

¹⁰  Médecins sans Frontières, Paris, France

¹¹  Oxford University Clinical Research Unit, National Institute for Infectious and Tropical Diseases, Hanoi, Vietnam

¹²  Travel and Migration Medicine Unit, Geneva University Hospital, Rue Micheli-du-Crest 24, 1211 Geneva, 14, Switzerland

¹³  UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases, WHO, Geneva, Switzerland

¹⁴  Centre for Tropical Medicine and Vaccinology, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK

¹⁵  Unité Maladies à Prévention Vaccinale, Département des Maladies Infectieuses, Institut de Veille Sanitaire, 12, rue du Val d'Osne, 94415, Saint-Maurice, cedex, France

author email corresponding author email

Malaria Journal 2008, 7:154doi:10.1186/1475-2875-7-154

Published:	9 August 2008

Abstract

Background

Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy.

Methods

Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only.

Results

Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).

Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to24.8], (ii) method 2a = 1.1% [0 to21.5], and (iii) method 2b = 0% [-38 to19.3].

The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used.

Conclusion

The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.