Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis
Authors:   The WorldWide Antimalarial Resistance Network Methodology Study Group, Dahal Prabin , Simpson Julie Anne , Abdulla Salim , Achan Jane , Adam Ishag , Agarwal Aarti , Allan Richard , Anvikar Anupkumar R. , Arinaitwe Emmanuel , Ashley Elizabeth A. , Awab Ghulam Rahim , Bassat Quique , Björkman Anders , Borrmann Steffen , Bousema Teun , Bukirwa Hasifa , Carrara Verena I. , Corsi Marco , Cot Michel , D’Alessandro Umberto , Davis Timothy M. E. , Deloron Philippe , Desai Meghna , Dimbu Pedro Rafael , Djalle Djibrine , Djimde Abdoulaye , Dorsey Grant , Drakeley Chris J. , Duparc Stephan , Edstein Michael D. , Espie Emmanuelle , Faiz Abul , Falade Catherine , Fanello Caterina , Faucher Jean-Francois , Faye Babacar , de Jesus Fortes Filomeno , Gadalla Nahla B. , Gaye Oumar , Gil J. Pedro , Gilayeneh Julius , Greenwood Brian , Grivoyannis Anastasia , Hien Tran Tinh , Hwang Jimee , Janssens Bart , Juma Elizabeth , Kamugisha Erasmus , Karema Corine , Karunajeewa Harin A. , Kiechel Jean R. , Kironde Fred , Kofoed Poul-Erik , Kremsner Peter G. , Lee Sue J. , Marsh Kevin , Mårtensson Andreas , Mayxay Mayfong , Menan Hervé , Mens Petra , Mutabingwa Theonest K. , Ndiaye Jean-Louis , Ngasala Billy E. , Noedl Harald , Nosten Francois , Offianan Andre Toure , Ogutu Bernhards R. , Olliaro Piero L. , Ouedraogo Jean Bosco , Piola Patrice , Plowe Christopher V. , Plucinski Mateusz M. , Pratt Oliver James , Premji Zulfikarali , Ramharter Michael , Rogier Christophe , Rombo Lars , Rosenthal Philip J. , Sibley Carol , Sirima Sodiomon , Smithuis Frank , Staedke Sarah G. , Sutanto Inge , Talisuna Ambrose Otau , Tarning Joel , Taylor Walter R. J. , Temu Emmanuel , Thriemer Kamala , Thuy-Nhien Nguyen , Udhayakumar Venkatachalam , Ursing Johan , van Herp Michel , van Lenthe Marit , van Vugt Michele , William Yavo , Winnips Cornelis , Zaloumis Sophie , Zongo Issaka , White Nick J. , Guerin Philippe J. , Stepniewska Kasia , Price Ric N. 
Published: March 2022

Abstract
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.