Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data

Salim Abdulla, Ishag Adam, George O. Adjei, Martin A. Adjuik, Bereket Alemayehu, Richard Allan, Emmanuel Arinaitwe, Elizabeth A. Ashley, Mamadou S. Ba, Hubert Barennes, Karen I. Barnes, Quique Bassat, Elisabeth Baudin, Nicole Berens-Riha, Anders Bjorkman, Francois Bompart, Maryline Bonnet, Steffen Borrmann, Teun Bousema, Philippe BrasseurHasifa Bukirwa, Francesco Checchi, Prabin Dahal, Umberto D'Alessandro, Meghna Desai, Alassane Dicko, Abdoulaye A. Djimde, Grant Dorsey, Ogobara K. Doumbo, Chris J. Drakeley, Stephan Duparc, Teferi Eshetu, Emmanuelle Espie, Jean François Etard, Abul M. Faiz, Catherine O. Falade, Caterina I. Fanello, Jean François Faucher, Babacar Faye, Oumar Faye, Scott Filler, Jennifer A. Flegg, Bakary Fofana, Carole Fogg, Nahla B. Gadalla, Oumar Gaye, Blaise Genton, Peter W. Gething, Jose P. Gil, Raquel González, Francesco Grandesso, Bryan Greenhouse, Brian Greenwood, Anastasia Grivoyannis, Philippe J. Guerin, Jean Paul Guthmann, Kamal Hamed, Sally Hamour, Simon I. Hay, Eva Maria Hode, Georgina S. Humphreys, Jimee Hwang, Maman L. Ibrahim, Daddi Jima, Joel J. Jones, Vincent Jullien, Elizabeth Juma, Patrick S. Kachur, Piet A. Kager, Erasmus Kamugisha, Moses R. Kamya, Corine Karema, Kassoum Kayentao, Jean Rene Kieche, Fred Kironde, Poul Erik Kofoed, Peter G. Kremsner, Sanjeev Krishna, Valerie Lameyre, Bertrand Lell, Angeles Lima, Michael Makanga, El Fatih M. Malik, Kevin Marsh, Andreas Martensson, Achille Massougbodji, Herve Menan, Didier Menard, Clara Menendez, Petra F. Mens, Martin Meremikwu, Clarissa Moreira, Carolyn Nabasumba, Michael Nambozi, Jean Louis Ndiaye, Billy E. Ngasala, Frederic Nikiema, Christian Nsanzabana, Francine Ntoumi, Mary Oguike, Bernhards R. Ogutu, Piero Olliaro, Sabah A. Omar, Jean Bosco Ouedraogo, Seth Owusu-Agyei, Louis K. Penali, Mbaye Pene, Judy Peshu, Patrice Piola, Christopher V. Plowe, Zul Premji, Ric N. Price, Milijaona Randrianarivelojosia, Lars Rombo, Cally Roper, Philip J. Rosenthal, Issaka Sagara, Albert Same-Ekobo, Patrick Sawa, Henk D.F.H. Schallig, Birgit Schramm, Amadou Seck, Seif A. Shekalaghe, Carol H. Sibley, Veronique Sinou, Sodiomon B. Sirima, Fabrice A. Some, Doudou Sow, Sarah G. Staedke, Kasia Stepniewska, Colin J. Sutherland, Todd D. Swarthout, Khadime Sylla, Ambrose O. Talisuna, Walter R.J. Taylor, Emmanuel A. Temu, Julie I. Thwing, Roger C.K. Tine, Halidou Tinto, Silva Tommasini, Offianan A. Toure, Johan Ursing, Michel T. Vaillant, Giovanni Valentini, Ingrid Van den Broek, Michele Van Vugt, Stephen A. Ward, Peter A. Winstanley, William Yavo, Adoke Yeka, Yah M. Zolia, Issaka Zongo, Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group

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Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).

Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data.

Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).

Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Original languageEnglish
Article number212
Pages (from-to)1-16
Number of pages16
JournalBMC Medicine
Issue number1
Publication statusPublished - 7 Sept 2015


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