Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: An individual participant data meta-analysis

Prabin Dahal, Julie Anne Simpson, Salim Abdulla, Jane Achan, Ishag Adam, Aarti Agarwal, Richard Allan, Anupkumar R. Anvikar, Emmanuel Arinaitwe, Elizabeth A. Ashley, Ghulam Rahim Awab, Quique Bassat, Anders Björkman, Steffen Borrmann, Teun Bousema, Hasifa Bukirwa, Verena I. Carrara, Marco Corsi, Michel Cot, Umberto D’AlessandroTimothy M. E. Davis, Philippe Deloron, Meghna Desai, Pedro Rafael Dimbu, Djibrine Djalle, Abdoulaye Djimde, Grant Dorsey, Chris J. Drakeley, Stephan Duparc, Michael D. Edstein, Emmanuelle Espie, Abul Faiz, Catherine Falade, Caterina Fanello, Jean-Francois Faucher, Babacar Faye, Filomeno de Jesus Fortes, Nahla B. Gadalla, Oumar Gaye, J. Pedro Gil, Julius Gilayeneh, Brian Greenwood, Anastasia Grivoyannis, Tran Tinh Hien, Jimee Hwang, Bart Janssens, Elizabeth Juma, Erasmus Kamugisha, Corine Karema, Harin A. Karunajeewa, Jean R. Kiechel, Fred Kironde, Poul-Erik Kofoed, Peter G. Kremsner, Sue J. Lee, Kevin Marsh, Andreas Mårtensson, Mayfong Mayxay, Hervé Menan, Petra Mens, Theonest K. Mutabingwa, Jean-Louis Ndiaye, Billy E. Ngasala, Harald Noedl, Francois Nosten, Andre Toure Offianan, Bernhards R. Ogutu, Piero L. Olliaro, Jean Bosco Ouedraogo, Patrice Piola, Christopher V. Plowe, Mateusz M. Plucinski, Oliver James Pratt, Zulfikarali Premji, Michael Ramharter, Christophe Rogier, Lars Rombo, Philip J. Rosenthal, Carol Sibley, Sodiomon Sirima, Frank Smithuis, Sarah G. Staedke, Inge Sutanto, Ambrose Otau Talisuna, Joel Tarning, Walter R. J. Taylor, Emmanuel Temu, Kamala Thriemer, Nguyen Thuy-Nhien, Venkatachalam Udhayakumar, Johan Ursing, Michel van Herp, Marit van Lenthe, Michele van Vugt, Yavo William, Cornelis Winnips, Sophie Zaloumis, Issaka Zongo, Nick J. White, Philippe J. Guerin, Kasia Stepniewska, Ric N. Price, The WorldWide Antimalarial Resistance Network Methodology Study Group

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Background: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. 

Methods: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. 

Results: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47–74%] of recrudescences in African children and 32% [95% CI 15–45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19–90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0–22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution. 

Conclusions: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.

Original languageEnglish
Article number106
Pages (from-to)1-13
Number of pages13
JournalMalaria Journal
Issue number106
Publication statusPublished - Dec 2022


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