Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: A systematic review and meta-analysis of individual patient data

Salim Abdulla; Jane Achan; Adoke Yeka; Umberto D'Alessandro; Ishag Adam; Bereket Hailegiorgis Alemayehu; Richard Allan; Emmanuel A. Temu; Elizabeth N. Allen; Karen I Barnes; Anupkumar R. Anvikar; Neena Valecha; Emmanuel Arinaitwe; Elizabeth A. Ashley; Verena I. Carrara; Rose McGready; Francois Nosten; Sue J Lee; Nicholas J White; Puji Budi Setia Asih; Ghulam Rahim Awab; Arjen Dondorp; Caterina Fanello; Charles J. Woodrow; Prabin Dahal; Philippe J. Guerin; Georgina S. Humphreys; Clarissa Moreira; Christian Nsanzabana; Ric N. Price; Carol Hopkins Sibley; Kasia Stepniewska; Quique Bassat; Raquel Gonzalez; Elisabeth Baudin; Francesco Checchi; Emmanuelle Espie; Francesco Grandesso; Carolyn Nabasumba; Birgit Schramm; Anders Björkman; Francois Bompart; Valerie Lameyre; Maryline Bonnet; Steffen Borrmann; Teun Bousema; Fabio Cenci; Michel Cot; Jean François Faucher; Melissa Kapulu; Kevin Marsh; Mayfong Mayxay; Paul N Newton; Cally Roper; Philippe Deloron; Abdoulaye Djimde; Bakary Fofana; Ogobara K. Doumbo; Issaka Sagara; Grant Dorsey; Philip J. Rosenthal; Chris J. Drakeley; Stephan Duparc; Abul Faiz; Catherine O. Falade; Babacar Faye; Oumar Gaye; Mbaye Pene; Scott Filler; Carole Fogg; Adama Gansane; Sodiomon B. Sirima; Blaise Genton; Peter W. Gething; Brian Greenwood; Anastasia Grivoyannis; Kamal Hamed,; Christoph Hatz; Simon I. Hay; Eva Maria Hodel; Jimee Hwang; S. Patrick Kachur; Bart Janssens; Michel van Herp; Judy Peshu; Daddi Jima; Elizabeth Juma; Piet Kager; Moses R. Kamya; Corine Karema; Kassoum Kayentao; Jean R. Kiechel; Julien Zwang; Poul Erik Kofoed; Bertrand Lell; Nines Lima; Andreas Mårtensson; Johan Ursing; Achille Massougbodji; Hervé Menan; Clara Menendez; Petra Mens; Henk D.F.H. Schallig; Michele van Vugt; Martin Meremikwu; Frank P. Mockenhaupt; Michael Nambozi; Jean Louis Ndiaye; Billy E. Ngasala; Toure Offianan Andre Toure Offianan; Mary Oguike; Colin J. Sutherland; Bernhards R. Ogutu; Piero Olliaro; Sabah A. Omar; Lyda Osorio; Seth Owusu-Agyei; Louis K. Penali; Patrice Piola; Zul Premji; Michael Ramharter; Lars Rombo; Patrick Sawa; Seif A. Shekalaghe; Frank Smithuis; Doudou Sow; Sarah G. Staedke; Inge Sutanto; Todd D. Swarthout; Ingrid Van den Broek; Din Syafruddin; Khadime Sylla; Ambrose O. Talisuna; Walter R J Taylor; Feiko O. Ter Kuile; Halidou Tinto; Emiliana Tjitra; Stephen A. Ward; Peter A. Winstanley; WWARN Gametocyte Study Group

doi:10.1186/s12916-016-0621-7

Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: A systematic review and meta-analysis of individual patient data

Salim Abdulla, Jane Achan, Adoke Yeka, Umberto D'Alessandro, Ishag Adam, Bereket Hailegiorgis Alemayehu, Richard Allan, Emmanuel A. Temu, Elizabeth N. Allen, Karen I Barnes, Anupkumar R. Anvikar, Neena Valecha, Emmanuel Arinaitwe, Elizabeth A. Ashley, Verena I. Carrara, Rose McGready, Francois Nosten, Sue J Lee, Nicholas J White, Puji Budi Setia AsihGhulam Rahim Awab, Arjen Dondorp, Caterina Fanello, Charles J. Woodrow, Prabin Dahal, Philippe J. Guerin, Georgina S. Humphreys, Clarissa Moreira, Christian Nsanzabana, Ric N. Price, Carol Hopkins Sibley, Kasia Stepniewska, Quique Bassat, Raquel Gonzalez, Elisabeth Baudin, Francesco Checchi, Emmanuelle Espie, Francesco Grandesso, Carolyn Nabasumba, Birgit Schramm, Anders Björkman, Francois Bompart, Valerie Lameyre, Maryline Bonnet, Steffen Borrmann, Teun Bousema, Fabio Cenci, Michel Cot, Jean François Faucher, Melissa Kapulu, Kevin Marsh, Mayfong Mayxay, Paul N Newton, Cally Roper, Philippe Deloron, Abdoulaye Djimde, Bakary Fofana, Ogobara K. Doumbo, Issaka Sagara, Grant Dorsey, Philip J. Rosenthal, Chris J. Drakeley, Stephan Duparc, Abul Faiz, Catherine O. Falade, Babacar Faye, Oumar Gaye, Mbaye Pene, Scott Filler, Carole Fogg, Adama Gansane, Sodiomon B. Sirima, Blaise Genton, Peter W. Gething, Brian Greenwood, Anastasia Grivoyannis, Kamal Hamed,, Christoph Hatz, Simon I. Hay, Eva Maria Hodel, Jimee Hwang, S. Patrick Kachur, Bart Janssens, Michel van Herp, Judy Peshu, Daddi Jima, Elizabeth Juma, Piet Kager, Moses R. Kamya, Corine Karema, Kassoum Kayentao, Jean R. Kiechel, Julien Zwang, Poul Erik Kofoed, Bertrand Lell, Nines Lima, Andreas Mårtensson, Johan Ursing, Achille Massougbodji, Hervé Menan, Clara Menendez, Petra Mens, Henk D.F.H. Schallig, Michele van Vugt, Martin Meremikwu, Frank P. Mockenhaupt, Michael Nambozi, Jean Louis Ndiaye, Billy E. Ngasala, Toure Offianan Andre Toure Offianan, Mary Oguike, Colin J. Sutherland, Bernhards R. Ogutu, Piero Olliaro, Sabah A. Omar, Lyda Osorio, Seth Owusu-Agyei, Louis K. Penali, Patrice Piola, Zul Premji, Michael Ramharter, Lars Rombo, Patrick Sawa, Seif A. Shekalaghe, Frank Smithuis, Doudou Sow, Sarah G. Staedke, Inge Sutanto, Todd D. Swarthout, Ingrid Van den Broek, Din Syafruddin, Khadime Sylla, Ambrose O. Talisuna, Walter R J Taylor, Feiko O. Ter Kuile, Halidou Tinto, Emiliana Tjitra, Stephen A. Ward, Peter A. Winstanley, WWARN Gametocyte Study Group

Research output: Contribution to journal › Review article › peer-review

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Abstract

Background: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP).

Methods: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data.

Results: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7.

Conclusions: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

Original language	English
Article number	79
Pages (from-to)	1-18
Number of pages	18
Journal	BMC Medicine
Volume	14
DOIs	https://doi.org/10.1186/s12916-016-0621-7
Publication status	Published - 24 May 2016

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Abdulla, S., Achan, J., Yeka, A., D'Alessandro, U., Adam, I., Alemayehu, B. H., Allan, R., Temu, E. A., Allen, E. N., Barnes, K. I., Anvikar, A. R., Valecha, N., Arinaitwe, E., Ashley, E. A., Carrara, V. I., McGready, R., Nosten, F., Lee, S. J., White, N. J., ... WWARN Gametocyte Study Group (2016). Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: A systematic review and meta-analysis of individual patient data. BMC Medicine, 14, 1-18. [79]. https://doi.org/10.1186/s12916-016-0621-7

@article{020ef3fac7e9446da728f18a6dbeefe4,

title = "Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: A systematic review and meta-analysis of individual patient data",

abstract = "Background: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). Methods: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. Results: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. Conclusions: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.",

keywords = "Drug resistance, Gametocyte, Malaria, Plasmodium falciparum",

author = "Salim Abdulla and Jane Achan and Adoke Yeka and Umberto D'Alessandro and Ishag Adam and Alemayehu, {Bereket Hailegiorgis} and Richard Allan and Temu, {Emmanuel A.} and Allen, {Elizabeth N.} and Barnes, {Karen I} and Anvikar, {Anupkumar R.} and Neena Valecha and Emmanuel Arinaitwe and Ashley, {Elizabeth A.} and Carrara, {Verena I.} and Rose McGready and Francois Nosten and Lee, {Sue J} and White, {Nicholas J} and Asih, {Puji Budi Setia} and Awab, {Ghulam Rahim} and Arjen Dondorp and Caterina Fanello and Woodrow, {Charles J.} and Prabin Dahal and Guerin, {Philippe J.} and Humphreys, {Georgina S.} and Clarissa Moreira and Christian Nsanzabana and Price, {Ric N.} and Sibley, {Carol Hopkins} and Kasia Stepniewska and Quique Bassat and Raquel Gonzalez and Elisabeth Baudin and Francesco Checchi and Emmanuelle Espie and Francesco Grandesso and Carolyn Nabasumba and Birgit Schramm and Anders Bj{\"o}rkman and Francois Bompart and Valerie Lameyre and Maryline Bonnet and Steffen Borrmann and Teun Bousema and Fabio Cenci and Michel Cot and Faucher, {Jean Fran{\c c}ois} and Melissa Kapulu and Kevin Marsh and Mayfong Mayxay and Newton, {Paul N} and Cally Roper and Philippe Deloron and Abdoulaye Djimde and Bakary Fofana and Doumbo, {Ogobara K.} and Issaka Sagara and Grant Dorsey and Rosenthal, {Philip J.} and Drakeley, {Chris J.} and Stephan Duparc and Abul Faiz and Falade, {Catherine O.} and Babacar Faye and Oumar Gaye and Mbaye Pene and Scott Filler and Carole Fogg and Adama Gansane and Sirima, {Sodiomon B.} and Blaise Genton and Gething, {Peter W.} and Brian Greenwood and Anastasia Grivoyannis and Kamal Hamed, and Christoph Hatz and Hay, {Simon I.} and Hodel, {Eva Maria} and Jimee Hwang and {Patrick Kachur}, S. and Bart Janssens and {van Herp}, Michel and Judy Peshu and Daddi Jima and Elizabeth Juma and Piet Kager and Kamya, {Moses R.} and Corine Karema and Kassoum Kayentao and Kiechel, {Jean R.} and Julien Zwang and Kofoed, {Poul Erik} and Bertrand Lell and Nines Lima and Andreas M{\aa}rtensson and Johan Ursing and Achille Massougbodji and Herv{\'e} Menan and Clara Menendez and Petra Mens and Schallig, {Henk D.F.H.} and {van Vugt}, Michele and Martin Meremikwu and Mockenhaupt, {Frank P.} and Michael Nambozi and Ndiaye, {Jean Louis} and Ngasala, {Billy E.} and {Andre Toure Offianan}, {Toure Offianan} and Mary Oguike and Sutherland, {Colin J.} and Ogutu, {Bernhards R.} and Piero Olliaro and Omar, {Sabah A.} and Lyda Osorio and Seth Owusu-Agyei and Penali, {Louis K.} and Patrice Piola and Zul Premji and Michael Ramharter and Lars Rombo and Patrick Sawa and Shekalaghe, {Seif A.} and Frank Smithuis and Doudou Sow and Staedke, {Sarah G.} and Inge Sutanto and Swarthout, {Todd D.} and {Van den Broek}, Ingrid and Din Syafruddin and Khadime Sylla and Talisuna, {Ambrose O.} and Taylor, {Walter R J} and {Ter Kuile}, {Feiko O.} and Halidou Tinto and Emiliana Tjitra and Ward, {Stephen A.} and Winstanley, {Peter A.} and {WWARN Gametocyte Study Group}",

year = "2016",

month = may,

day = "24",

doi = "10.1186/s12916-016-0621-7",

language = "English",

volume = "14",

pages = "1--18",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

}

Abdulla, S, Achan, J, Yeka, A, D'Alessandro, U, Adam, I, Alemayehu, BH, Allan, R, Temu, EA, Allen, EN, Barnes, KI, Anvikar, AR, Valecha, N, Arinaitwe, E, Ashley, EA, Carrara, VI, McGready, R, Nosten, F, Lee, SJ, White, NJ, Asih, PBS, Awab, GR, Dondorp, A, Fanello, C, Woodrow, CJ, Dahal, P, Guerin, PJ, Humphreys, GS, Moreira, C, Nsanzabana, C, Price, RN, Sibley, CH, Stepniewska, K, Bassat, Q, Gonzalez, R, Baudin, E, Checchi, F, Espie, E, Grandesso, F, Nabasumba, C, Schramm, B, Björkman, A, Bompart, F, Lameyre, V, Bonnet, M, Borrmann, S, Bousema, T, Cenci, F, Cot, M, Faucher, JF, Kapulu, M, Marsh, K, Mayxay, M, Newton, PN, Roper, C, Deloron, P, Djimde, A, Fofana, B, Doumbo, OK, Sagara, I, Dorsey, G, Rosenthal, PJ, Drakeley, CJ, Duparc, S, Faiz, A, Falade, CO, Faye, B, Gaye, O, Pene, M, Filler, S, Fogg, C, Gansane, A, Sirima, SB, Genton, B, Gething, PW, Greenwood, B, Grivoyannis, A, Hamed, K, Hatz, C, Hay, SI, Hodel, EM, Hwang, J, Patrick Kachur, S, Janssens, B, van Herp, M, Peshu, J, Jima, D, Juma, E, Kager, P, Kamya, MR, Karema, C, Kayentao, K, Kiechel, JR, Zwang, J, Kofoed, PE, Lell, B, Lima, N, Mårtensson, A, Ursing, J, Massougbodji, A, Menan, H, Menendez, C, Mens, P, Schallig, HDFH, van Vugt, M, Meremikwu, M, Mockenhaupt, FP, Nambozi, M, Ndiaye, JL, Ngasala, BE, Andre Toure Offianan, TO, Oguike, M, Sutherland, CJ, Ogutu, BR, Olliaro, P, Omar, SA, Osorio, L, Owusu-Agyei, S, Penali, LK, Piola, P, Premji, Z, Ramharter, M, Rombo, L, Sawa, P, Shekalaghe, SA, Smithuis, F, Sow, D, Staedke, SG, Sutanto, I, Swarthout, TD, Van den Broek, I, Syafruddin, D, Sylla, K, Talisuna, AO, Taylor, WRJ, Ter Kuile, FO, Tinto, H, Tjitra, E, Ward, SA, Winstanley, PA & WWARN Gametocyte Study Group 2016, 'Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: A systematic review and meta-analysis of individual patient data', BMC Medicine, vol. 14, 79, pp. 1-18. https://doi.org/10.1186/s12916-016-0621-7

TY - JOUR

T1 - Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy

T2 - A systematic review and meta-analysis of individual patient data

AU - Abdulla, Salim

AU - Achan, Jane

AU - Yeka, Adoke

AU - D'Alessandro, Umberto

AU - Adam, Ishag

AU - Alemayehu, Bereket Hailegiorgis

AU - Allan, Richard

AU - Temu, Emmanuel A.

AU - Allen, Elizabeth N.

AU - Barnes, Karen I

AU - Anvikar, Anupkumar R.

AU - Valecha, Neena

AU - Arinaitwe, Emmanuel

AU - Ashley, Elizabeth A.

AU - Carrara, Verena I.

AU - McGready, Rose

AU - Nosten, Francois

AU - Lee, Sue J

AU - White, Nicholas J

AU - Asih, Puji Budi Setia

AU - Awab, Ghulam Rahim

AU - Dondorp, Arjen

AU - Fanello, Caterina

AU - Woodrow, Charles J.

AU - Dahal, Prabin

AU - Guerin, Philippe J.

AU - Humphreys, Georgina S.

AU - Moreira, Clarissa

AU - Nsanzabana, Christian

AU - Price, Ric N.

AU - Sibley, Carol Hopkins

AU - Stepniewska, Kasia

AU - Bassat, Quique

AU - Gonzalez, Raquel

AU - Baudin, Elisabeth

AU - Checchi, Francesco

AU - Espie, Emmanuelle

AU - Grandesso, Francesco

AU - Nabasumba, Carolyn

AU - Schramm, Birgit

AU - Björkman, Anders

AU - Bompart, Francois

AU - Lameyre, Valerie

AU - Bonnet, Maryline

AU - Borrmann, Steffen

AU - Bousema, Teun

AU - Cenci, Fabio

AU - Cot, Michel

AU - Faucher, Jean François

AU - Kapulu, Melissa

AU - Marsh, Kevin

AU - Mayxay, Mayfong

AU - Newton, Paul N

AU - Roper, Cally

AU - Deloron, Philippe

AU - Djimde, Abdoulaye

AU - Fofana, Bakary

AU - Doumbo, Ogobara K.

AU - Sagara, Issaka

AU - Dorsey, Grant

AU - Rosenthal, Philip J.

AU - Drakeley, Chris J.

AU - Duparc, Stephan

AU - Faiz, Abul

AU - Falade, Catherine O.

AU - Faye, Babacar

AU - Gaye, Oumar

AU - Pene, Mbaye

AU - Filler, Scott

AU - Fogg, Carole

AU - Gansane, Adama

AU - Sirima, Sodiomon B.

AU - Genton, Blaise

AU - Gething, Peter W.

AU - Greenwood, Brian

AU - Grivoyannis, Anastasia

AU - Hamed,, Kamal

AU - Hatz, Christoph

AU - Hay, Simon I.

AU - Hodel, Eva Maria

AU - Hwang, Jimee

AU - Patrick Kachur, S.

AU - Janssens, Bart

AU - van Herp, Michel

AU - Peshu, Judy

AU - Jima, Daddi

AU - Juma, Elizabeth

AU - Kager, Piet

AU - Kamya, Moses R.

AU - Karema, Corine

AU - Kayentao, Kassoum

AU - Kiechel, Jean R.

AU - Zwang, Julien

AU - Kofoed, Poul Erik

AU - Lell, Bertrand

AU - Lima, Nines

AU - Mårtensson, Andreas

AU - Ursing, Johan

AU - Massougbodji, Achille

AU - Menan, Hervé

AU - Menendez, Clara

AU - Mens, Petra

AU - Schallig, Henk D.F.H.

AU - van Vugt, Michele

AU - Meremikwu, Martin

AU - Mockenhaupt, Frank P.

AU - Nambozi, Michael

AU - Ndiaye, Jean Louis

AU - Ngasala, Billy E.

AU - Andre Toure Offianan, Toure Offianan

AU - Oguike, Mary

AU - Sutherland, Colin J.

AU - Ogutu, Bernhards R.

AU - Olliaro, Piero

AU - Omar, Sabah A.

AU - Osorio, Lyda

AU - Owusu-Agyei, Seth

AU - Penali, Louis K.

AU - Piola, Patrice

AU - Premji, Zul

AU - Ramharter, Michael

AU - Rombo, Lars

AU - Sawa, Patrick

AU - Shekalaghe, Seif A.

AU - Smithuis, Frank

AU - Sow, Doudou

AU - Staedke, Sarah G.

AU - Sutanto, Inge

AU - Swarthout, Todd D.

AU - Van den Broek, Ingrid

AU - Syafruddin, Din

AU - Sylla, Khadime

AU - Talisuna, Ambrose O.

AU - Taylor, Walter R J

AU - Ter Kuile, Feiko O.

AU - Tinto, Halidou

AU - Tjitra, Emiliana

AU - Ward, Stephen A.

AU - Winstanley, Peter A.

AU - WWARN Gametocyte Study Group

PY - 2016/5/24

Y1 - 2016/5/24

N2 - Background: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). Methods: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. Results: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. Conclusions: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

AB - Background: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). Methods: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. Results: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. Conclusions: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

KW - Drug resistance

KW - Gametocyte

KW - Malaria

KW - Plasmodium falciparum

UR - http://www.scopus.com/inward/record.url?scp=84969921822&partnerID=8YFLogxK

U2 - 10.1186/s12916-016-0621-7

DO - 10.1186/s12916-016-0621-7

M3 - Review article

C2 - 27221542

SN - 1741-7015

VL - 14

SP - 1

EP - 18

JO - BMC Medicine

JF - BMC Medicine

M1 - 79

ER -

Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: A systematic review and meta-analysis of individual patient data

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