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; Elizabeth A. Ashley; Quique Bassat; Steffen Borrmann; Teun Bousema; Hasifa Bukirwa; Verena Carrara; Marco Corsi; 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; null 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 Martensson; Mayfong Mayxay; Herve 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 Plowe; Mateusz M. Plucinski; Oliver James Pratt; Zulfikarali Premji; Michael Ramharter; Christophe Rogier; Primum Vitare; 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 D. 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; Emmanuel Arinaitwe

doi:10.1186/s12936-021-03980-z

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, Elizabeth A. Ashley, Quique Bassat, Steffen Borrmann, Teun Bousema, Hasifa Bukirwa, Verena Carrara, Marco Corsi, Umberto D'Alessandro, Timothy M. E. Davis, Philippe Deloron, Meghna Desai, Pedro Rafael DimbuDjibrine 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 Martensson, Mayfong Mayxay, Herve 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 Plowe, Mateusz M. Plucinski, Oliver James Pratt, Zulfikarali Premji, Michael Ramharter, Christophe Rogier, Primum Vitare, 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 D. 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, Emmanuel Arinaitwe

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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.

Original language	English
Article number	106
Number of pages	13
Journal	Malaria Journal
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12936-021-03980-z
Publication status	Published - Dec 2022

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Dahal, P., Simpson, J. A., Abdulla, S., Achan, J., Adam, I., Agarwal, A., Allan, R., Anvikar, A. R., Ashley, E. A., Bassat, Q., Borrmann, S., Bousema, T., Bukirwa, H., Carrara, V., Corsi, M., D'Alessandro, U., Davis, T. M. E., Deloron, P., Desai, M., ... Arinaitwe, E. (2022). Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis. Malaria Journal, 21(1), Article 106. https://doi.org/10.1186/s12936-021-03980-z

@article{4f0f86f7182d40f7a4a549d3f837a174,

title = "Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: 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.",

keywords = "Malaria, Plasmodium falciparum, Efficacy, Follow-up, Recrudescence, Distribution, ARTEMETHER-LUMEFANTRINE, MALARIA, EFFICACY, TOLERABILITY, INFECTION, PHASE",

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 Ashley, {Elizabeth A.} and Quique Bassat and Steffen Borrmann and Teun Bousema and Hasifa Bukirwa and Verena Carrara and Marco Corsi and Umberto D'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 Jean-Francois Faucher and Babacar Faye and Fortes, {Filomeno de Jesus} 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 Karunajeewa, {Harin A.} and Kiechel, {Jean R.} and Fred Kironde and Poul-Erik Kofoed and Kremsner, {Peter G.} and Lee, {Sue J.} and Kevin Marsh and Andreas Martensson and Mayfong Mayxay and Herve Menan and Petra Mens and Mutabingwa, {Theonest K.} and Jean-Louis Ndiaye and Ngasala, {Billy E.} and Harald Noedl and Francois Nosten and Offianan, {Andre Toure} and Ogutu, {Bernhards R.} and Olliaro, {Piero L.} and Ouedraogo, {Jean Bosco} and Patrice Piola and Christopher Plowe and Plucinski, {Mateusz M.} and Pratt, {Oliver James} and Zulfikarali Premji and Michael Ramharter and Christophe Rogier and Primum Vitare and Lars Rombo and Rosenthal, {Philip J.} and Carol Sibley and Sodiomon Sirima and Frank Smithuis and Staedke, {Sarah G.} and Inge Sutanto and Talisuna, {Ambrose Otau} and Joel Tarning and Taylor, {Walter R. J.} and Emmanuel Temu and Kamala Thriemer and Nguyen Thuy-Nhien and Venkatachalam Udhayakumar and Ursing, {Johan D.} and {van Herp}, Michel and {van Lenthe}, Marit and {van Vugt}, Michele and Yavo William and Cornelis Winnips and Sophie Zaloumis and Issaka Zongo and White, {Nick J.} and Guerin, {Philippe J.} and Kasia Stepniewska and Price, {Ric N.} and Emmanuel Arinaitwe",

year = "2022",

month = dec,

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

language = "English",

volume = "21",

journal = "Malaria Journal",

issn = "1475-2875",

publisher = "BioMed Central",

number = "1",

}

Dahal, P, Simpson, JA, Abdulla, S, Achan, J, Adam, I, Agarwal, A, Allan, R, Anvikar, AR, Ashley, EA, Bassat, Q, Borrmann, S, Bousema, T, Bukirwa, H, Carrara, V, Corsi, 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, Abul Faiz, Falade, C, Fanello, C, Faucher, J-F, Faye, B, Fortes, FDJ, Gadalla, NB, Gaye, O, Gil, JP, Gilayeneh, J, Greenwood, B, Grivoyannis, A, Hien, TT, Hwang, J, Janssens, B, Juma, E, Kamugisha, E, Karema, C, Karunajeewa, HA, Kiechel, JR, Kironde, F, Kofoed, P-E, Kremsner, PG, Lee, SJ, Marsh, K, Martensson, A, Mayxay, M, Menan, H, Mens, P, Mutabingwa, TK, Ndiaye, J-L, Ngasala, BE, Noedl, H, Nosten, F, Offianan, AT, Ogutu, BR, Olliaro, PL, Ouedraogo, JB, Piola, P, Plowe, C, Plucinski, MM, Pratt, OJ, Premji, Z, Ramharter, M, Rogier, C, Vitare, P, Rombo, L, Rosenthal, PJ, Sibley, C, Sirima, S, Smithuis, F, Staedke, SG, Sutanto, I, Talisuna, AO, Tarning, J, Taylor, WRJ, Temu, E, Thriemer, K, Thuy-Nhien, N, Udhayakumar, V, Ursing, JD, van Herp, M, van Lenthe, M, van Vugt, M, William, Y, Winnips, C, Zaloumis, S, Zongo, I, White, NJ, Guerin, PJ, Stepniewska, K, Price, RN & Arinaitwe, E 2022, 'Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis', Malaria Journal, vol. 21, no. 1, 106. https://doi.org/10.1186/s12936-021-03980-z

TY - JOUR

T1 - Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy

T2 - 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 - Ashley, Elizabeth A.

AU - Bassat, Quique

AU - Borrmann, Steffen

AU - Bousema, Teun

AU - Bukirwa, Hasifa

AU - Carrara, Verena

AU - Corsi, Marco

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 - Abul Faiz, null

AU - Falade, Catherine

AU - Fanello, Caterina

AU - Faucher, Jean-Francois

AU - Faye, Babacar

AU - Fortes, Filomeno de Jesus

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 - Karunajeewa, Harin A.

AU - Kiechel, Jean R.

AU - Kironde, Fred

AU - Kofoed, Poul-Erik

AU - Kremsner, Peter G.

AU - Lee, Sue J.

AU - Marsh, Kevin

AU - Martensson, Andreas

AU - Mayxay, Mayfong

AU - Menan, Herve

AU - Mens, Petra

AU - Mutabingwa, Theonest K.

AU - Ndiaye, Jean-Louis

AU - Ngasala, Billy E.

AU - Noedl, Harald

AU - Nosten, Francois

AU - Offianan, Andre Toure

AU - Ogutu, Bernhards R.

AU - Olliaro, Piero L.

AU - Ouedraogo, Jean Bosco

AU - Piola, Patrice

AU - Plowe, Christopher

AU - Plucinski, Mateusz M.

AU - Pratt, Oliver James

AU - Premji, Zulfikarali

AU - Ramharter, Michael

AU - Rogier, Christophe

AU - Vitare, Primum

AU - Rombo, Lars

AU - Rosenthal, Philip J.

AU - Sibley, Carol

AU - Sirima, Sodiomon

AU - Smithuis, Frank

AU - Staedke, Sarah G.

AU - Sutanto, Inge

AU - Talisuna, Ambrose Otau

AU - Tarning, Joel

AU - Taylor, Walter R. J.

AU - Temu, Emmanuel

AU - Thriemer, Kamala

AU - Thuy-Nhien, Nguyen

AU - Udhayakumar, Venkatachalam

AU - Ursing, Johan D.

AU - van Herp, Michel

AU - van Lenthe, Marit

AU - van Vugt, Michele

AU - William, Yavo

AU - Winnips, Cornelis

AU - Zaloumis, Sophie

AU - Zongo, Issaka

AU - White, Nick J.

AU - Guerin, Philippe J.

AU - Stepniewska, Kasia

AU - Price, Ric N.

AU - Arinaitwe, Emmanuel

PY - 2022/12

Y1 - 2022/12

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.

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.

KW - Malaria

KW - Plasmodium falciparum

KW - Efficacy

KW - Follow-up

KW - Recrudescence

KW - Distribution

KW - ARTEMETHER-LUMEFANTRINE

KW - MALARIA

KW - EFFICACY

KW - TOLERABILITY

KW - INFECTION

KW - PHASE

UR - https://www.webofscience.com/wos/woscc/full-record/WOS:000772878900008

U2 - 10.1186/s12936-021-03980-z

DO - 10.1186/s12936-021-03980-z

M3 - Article

C2 - 35331243

SN - 1475-2875

VL - 21

JO - Malaria Journal

JF - Malaria Journal

IS - 1

M1 - 106

ER -

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

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