Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis: 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’Alessandro; Timothy 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; Sarah Staedke

doi:10.1186/s12936-021-03980-z

Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis: 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, Sarah Staedke

Liverpool School of Tropical Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Malaria Journal
DOIs	https://doi.org/10.1186/s12936-021-03980-z
Publication status	Published - 24 Mar 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s12936-021-03980-zLicence: CC BY

s12936-021-03980-zFinal published version, 2.2 MBLicence: CC BY

Cite this

Dahal, P., Simpson, J. A., Abdulla, S., Achan, J., Adam, I., Agarwal, A., Allan, R., Anvikar, A. R., Arinaitwe, E., Ashley, E. A., Awab, G. R., Bassat, Q., Björkman, A., Borrmann, S., Bousema, T., Bukirwa, H., Carrara, V. I., Corsi, M., Cot, M., ... Staedke, S. (2022). Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis: an individual participant data meta-analysis. Malaria Journal. https://doi.org/10.1186/s12936-021-03980-z

@article{2d5d7ad2ba7a449fb612daaee8037fbd,

title = "Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis: an individual participant data meta-analysis",

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.",

author = "Prabin Dahal and Simpson, \{Julie Anne\} and Salim Abdulla and Jane Achan and Ishag Adam and Aarti Agarwal and Richard Allan and Anvikar, \{Anupkumar R.\} and Emmanuel Arinaitwe and Ashley, \{Elizabeth A.\} and Awab, \{Ghulam Rahim\} and Quique Bassat and Anders Bj{\"o}rkman and Steffen Borrmann and Teun Bousema and Hasifa Bukirwa and Carrara, \{Verena I.\} and Marco Corsi and Michel Cot and Umberto D{\textquoteright}Alessandro and Davis, \{Timothy M.E.\} and Philippe Deloron and Meghna Desai and Dimbu, \{Pedro Rafael\} and Djibrine Djalle and Abdoulaye Djimde and Grant Dorsey and Drakeley, \{Chris J.\} and Stephan Duparc and Edstein, \{Michael D.\} and Emmanuelle Espie and Abul Faiz and Catherine Falade and Caterina Fanello and Faucher, \{Jean Francois\} and Babacar Faye and \{de Jesus Fortes\}, Filomeno and Gadalla, \{Nahla B.\} and Oumar Gaye and Gil, \{J. Pedro\} and Julius Gilayeneh and Brian Greenwood and Anastasia Grivoyannis and Hien, \{Tran Tinh\} and Jimee Hwang and Bart Janssens and Elizabeth Juma and Erasmus Kamugisha and Corine Karema and Sarah Staedke",

year = "2022",

month = mar,

day = "24",

doi = "10.1186/s12936-021-03980-z",

language = "English",

journal = "Malaria Journal",

issn = "1475-2875",

publisher = "BioMed Central Ltd",

}

Dahal, P, Simpson, JA, Abdulla, S, Achan, J, Adam, I, Agarwal, A, Allan, R, Anvikar, AR, Arinaitwe, E, Ashley, EA, Awab, GR, Bassat, Q, Björkman, A, Borrmann, S, Bousema, T, Bukirwa, H, Carrara, VI, Corsi, M, Cot, M, D’Alessandro, U, Davis, TME, Deloron, P, Desai, M, Dimbu, PR, Djalle, D, Djimde, A, Dorsey, G, Drakeley, CJ, Duparc, S, Edstein, MD, Espie, E, Faiz, A, Falade, C, Fanello, C, Faucher, JF, Faye, B, de Jesus Fortes, F, Gadalla, NB, Gaye, O, Gil, JP, Gilayeneh, J, Greenwood, B, Grivoyannis, A, Hien, TT, Hwang, J, Janssens, B, Juma, E, Kamugisha, E, Karema, C & Staedke, S 2022, 'Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis: an individual participant data meta-analysis', Malaria Journal. https://doi.org/10.1186/s12936-021-03980-z

TY - JOUR

T1 - Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis: an individual participant data meta-analysis

AU - Dahal, Prabin

AU - Simpson, Julie Anne

AU - Abdulla, Salim

AU - Achan, Jane

AU - Adam, Ishag

AU - Agarwal, Aarti

AU - Allan, Richard

AU - Anvikar, Anupkumar R.

AU - Arinaitwe, Emmanuel

AU - Ashley, Elizabeth A.

AU - Awab, Ghulam Rahim

AU - Bassat, Quique

AU - Björkman, Anders

AU - Borrmann, Steffen

AU - Bousema, Teun

AU - Bukirwa, Hasifa

AU - Carrara, Verena I.

AU - Corsi, Marco

AU - Cot, Michel

AU - D’Alessandro, Umberto

AU - Davis, Timothy M.E.

AU - Deloron, Philippe

AU - Desai, Meghna

AU - Dimbu, Pedro Rafael

AU - Djalle, Djibrine

AU - Djimde, Abdoulaye

AU - Dorsey, Grant

AU - Drakeley, Chris J.

AU - Duparc, Stephan

AU - Edstein, Michael D.

AU - Espie, Emmanuelle

AU - Faiz, Abul

AU - Falade, Catherine

AU - Fanello, Caterina

AU - Faucher, Jean Francois

AU - Faye, Babacar

AU - de Jesus Fortes, Filomeno

AU - Gadalla, Nahla B.

AU - Gaye, Oumar

AU - Gil, J. Pedro

AU - Gilayeneh, Julius

AU - Greenwood, Brian

AU - Grivoyannis, Anastasia

AU - Hien, Tran Tinh

AU - Hwang, Jimee

AU - Janssens, Bart

AU - Juma, Elizabeth

AU - Kamugisha, Erasmus

AU - Karema, Corine

AU - Staedke, Sarah

PY - 2022/3/24

Y1 - 2022/3/24

N2 - 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.

AB - 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.

U2 - 10.1186/s12936-021-03980-z

DO - 10.1186/s12936-021-03980-z

M3 - Article

SN - 1475-2875

JO - Malaria Journal

JF - Malaria Journal

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this