Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis

Prabin Dahal (1) , Julie Anne Simpson , Salim Abdullah , Jane Achan , Ishag Adam , Aarti Agarwal , Richard Allan , Anupkumar R Anvikar , Emmanuel Arinaitwe , Elizabeth Ashley , Ghulam Rahim-Awab , Quique Bassat , Anders Björkman , François Bompart , Steffen Borrmann , Teun Bousema , Ingrid Broek , Hasifa Bukirwa , Verena Carrara , Marco Corsi , Michel Cot , Umberto d'Allessandro , Timothy Me Davis , Marit de Wit , Philippe Deloron , Meghna Desai , Pedro Rafael Dimbu , Djibrine Djalle , Abdoulaye Djimde , Grant Dorsey , Ogobara K Doumbo , Chris J Drakeley , Stephan Duparc , Michael D Edstein , Emmanuelle Espié , Abul Faiz , Catherine Falade , Caterina Fanello , Jean-François Faucher (2, 3) , Babacar Faye , Filomeno de Jesus Fortes , Nahla B. Gadalla , Oumar Gaye , José Pedro Gil , Brian Greenwood , Anastasia Grivoyannis , Kamal Hamed , Tinh Hien Tran , David Hughes , Georgina Humphreys , Jimee Hwang , Maman Laminou Ibrahim , Bart Janssens , Vincent Jullien , Elizabeth Juma , Erasmus Kamugisha , Corine K Karema , Harin Karunajeewa , Jean-René Kiechel , Fred Kironde , Poul Erik Kofoed , Peter G Kremsner , Valerie Lameyre , Sue J. Lee , Kevin Marsh , Andreas Martensson , Mayfong Mayxay , Hervé Menan , Petra Mens , Theonest K Mutabingwa , Jean Louis Ndiaye , Billy E Ngasala , Harald Noedl , Francois Nosten , André Toure Offianan , Maryse Oguike , Bernhards Ogutu , Piero Olliaro , Jean Bosco Ouedraogo , Patrice Piola , Christopher V. Plowe , Mateusz M Plucinski , Oliver James Pratt , Zulfikarali Premji , Michael Ramharter , Christophe Rogier , Lars Rombo , Philip Jon Rosenthal , Patrick Sawa , Birgit Schramm , Carol H Sibley , Veronique Sinou (4) , Sodiomon B. Sirima , Frank Smithuis , Sarah G Staedke , Inge Sutanto , Ambrose Otau Talisuna , Joel Tarning , Walter Rj Taylor , Emmanuel Temu , Kamala L. Thriemer , Thuy Nhien Nguyen , Venkatachalam Udhayakumar , Johan Ursing , Michel van Herp , Christopher Whitty , Yavo William , Cornelis Winnips , Issaka Zongo , Philippe Guérin , Ric N. Price , Kasia Stepniewka

1 WWARN - WorldWide Antimalarial Resistance Network
2 NET - Neuroépidémiologie Tropicale
3 Service des Maladies infectieuses et tropicales [CHU Limoges]
4 MCT - Membranes et cibles thérapeutiques

BACKGROUND: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections. METHODS: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model. RESULTS: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (ρ): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [ρ: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold. CONCLUSIONS: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.

Mots clés: Competing risk even; Plasmodium falciparum; Treatment efficacy study

Domaines: Santé publique et épidémiologie; Sciences du Vivant [q-bio]

Prabin Dahal, Julie Anne Simpson, Salim Abdullah, Jane Achan, Ishag Adam, et al.. Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis. Malaria Journal, 2019, 18 (1), pp.225. ⟨10.1186/s12936-019-2837-4⟩. ⟨hal-02310530⟩