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

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

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

92 Citations (Scopus)

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 then on-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics

Original language	English
Pages (from-to)	79
Journal	BMC medicine
Volume	14
DOIs	https://doi.org/10.1186/s12916-016-0621-7
Publication status	Published - 2016

Access to Document

https://doi.org/10.1186/s12916-016-0621-7

Cite this

Abdulla, S., Achan, J., Adam, I., Alemayehu, B. H., Allan, R., Allen, E. N., Anvikar, A. R., Arinaitwe, E., Ashley, E. A., Asih, P. B. S., Awab, G. R., Barnes, K. I., Bassat, Q., Baudin, E., Bjorkman, A., Bompart, F., Bonnet, M., Borrmann, S., Bousema, T., ... Zwang, J. (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, 79. https://doi.org/10.1186/s12916-016-0621-7

@article{673b25b80b0c442195f5302842c8b465,

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 then on-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics",

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

year = "2016",

doi = "https://doi.org/10.1186/s12916-016-0621-7",

language = "English",

volume = "14",

pages = "79",

journal = "BMC medicine",

issn = "1464-2662",

publisher = "BioMed Central",

}

Abdulla, S, Achan, J, Adam, I, Alemayehu, BH, Allan, R, Allen, EN, Anvikar, AR, Arinaitwe, E, Ashley, EA, Asih, PBS, Awab, GR, Barnes, KI, Bassat, Q, Baudin, E, Bjorkman, A, Bompart, F, Bonnet, M, Borrmann, S, Bousema, T, Carrara, VI, Cenci, F, Checchi, F, Cot, M, Dahal, P, d'Alessandro, U, Deloron, P, Djimde, A, Dondorp, A, Dorsey, G, Doumbo, OK, Drakeley, CJ, Duparc, S, Espie, E, Faiz, A, Falade, CO, Fanello, C, Faucher, J-F, Faye, B, Filler, S, Fofana, B, Fogg, C, Gansane, A, Gaye, O, Genton, B, Gething, PW, Gonzalez, R, Grandesso, F, Greenwood, B, Grivoyannis, A, Guerin, PJ, Hamed, K, Hatz, C, Hay, SI, Hodel, EM, Humphreys, GS, Hwang, J, Janssens, B, Jima, D, Juma, E, Kachur, SP, Kager, P, Kamya, MR, Kapulu, M, Karema, C, Kayentao, K, Kiechel, JR, Kofoed, P-E, Lameyre, V, Lee, SJ, Lell, B, Lima, N, Marsh, K, Martensson, A, Massougbodji, A, Mayxay, M, McGready, R, Menan, H, Menendez, C, Mens, P, Meremikwu, M, Mockenhaupt, FP, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, J-L, Newton, PN, Ngasala, BE, Nosten, F, Nsanzabana, C, Offianan, AT, Oguike, M, Ogutu, BR, Olliaro, P, Omar, SA, Osorio, L, Owusu-Agyei, S, Penali, LK, Pene, M, Peshu, J, Piola, P, Premji, Z, Price, RN, Ramharter, M, Rombo, L, Roper, C, Rosenthal, PJ, Sagara, I, Sawa, P, Schallig, HDFH, Schramm, B, Shekalaghe, SA, Sibley, CH, Sirima, S, Smithuis, F, Sow, D, Staedke, SG, Stepniewska, K, Sutanto, I, Sutherland, CJ, Swarthout, TD, Syafruddin, D, Sylla, K, Talisuna, AO, Taylor, WR, Temu, EA, ter Kuile, F, Tinto, H, Tjitra, E, Ursing, J, Valecha, N, van den Broek, I, van Herp, M, van Vugt, M, Ward, SA, White, NJ, Winstanley, PA, Woodrow, CJ, Yeka, A & Zwang, J 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, pp. 79. 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: a systematic review and meta-analysis of individual patient data

AU - Abdulla, Salim

AU - Achan, Jane

AU - Adam, Ishag

AU - Alemayehu, Bereket H.

AU - Allan, Richard

AU - Allen, Elizabeth N.

AU - Anvikar, Anupkumar R.

AU - Arinaitwe, Emmanuel

AU - Ashley, Elizabeth A.

AU - Asih, Puji Budi Setia

AU - Awab, Ghulam Rahim

AU - Barnes, Karen I.

AU - Bassat, Quique

AU - Baudin, Elisabeth

AU - Bjorkman, Anders

AU - Bompart, Francois

AU - Bonnet, Maryline

AU - Borrmann, Steffen

AU - Bousema, Teun

AU - Carrara, Verena I.

AU - Cenci, Fabio

AU - Checchi, Francesco

AU - Cot, Michel

AU - Dahal, Prabin

AU - d'Alessandro, Umberto

AU - Deloron, Philippe

AU - Djimde, Abdoulaye

AU - Dondorp, Arjen

AU - Dorsey, Grant

AU - Doumbo, Ogobara K.

AU - Drakeley, Chris J.

AU - Duparc, Stephan

AU - Espie, Emmanuelle

AU - Faiz, Abul

AU - Falade, Catherine O.

AU - Fanello, Caterina

AU - Faucher, Jean-Francois

AU - Faye, Babacar

AU - Filler, Scott

AU - Fofana, Bakary

AU - Fogg, Carole

AU - Gansane, Adama

AU - Gaye, Oumar

AU - Genton, Blaise

AU - Gething, Peter W.

AU - Gonzalez, Raquel

AU - Grandesso, Francesco

AU - Greenwood, Brian

AU - Grivoyannis, Anastasia

AU - Guerin, Philippe J.

AU - Hamed, Kamal

AU - Hatz, Christoph

AU - Hay, Simon I.

AU - Hodel, Eva Maria

AU - Humphreys, Georgina S.

AU - Hwang, Jimee

AU - Janssens, Bart

AU - Jima, Daddi

AU - Juma, Elizabeth

AU - Kachur, S. Patrick

AU - Kager, Piet

AU - Kamya, Moses R.

AU - Kapulu, Melissa

AU - Karema, Corine

AU - Kayentao, Kassoum

AU - Kiechel, Jean R.

AU - Kofoed, Poul-Erik

AU - Lameyre, Valerie

AU - Lee, Sue J.

AU - Lell, Bertrand

AU - Lima, Nines

AU - Marsh, Kevin

AU - Martensson, Andreas

AU - Massougbodji, Achille

AU - Mayxay, Mayfong

AU - McGready, Rose

AU - Menan, Herve

AU - Menendez, Clara

AU - Mens, Petra

AU - Meremikwu, Martin

AU - Mockenhaupt, Frank P.

AU - Moreira, Clarissa

AU - Nabasumba, Carolyn

AU - Nambozi, Michael

AU - Ndiaye, Jean-Louis

AU - Newton, Paul N.

AU - Ngasala, Billy E.

AU - Nosten, Francois

AU - Nsanzabana, Christian

AU - Offianan, Andre Toure

AU - Oguike, Mary

AU - Ogutu, Bernhards R.

AU - Olliaro, Piero

AU - Omar, Sabah A.

AU - Osorio, Lyda

AU - Owusu-Agyei, Seth

AU - Penali, Louis K.

AU - Pene, Mbaye

AU - Peshu, Judy

AU - Piola, Patrice

AU - Premji, Zul

AU - Price, Ric N.

AU - Ramharter, Michael

AU - Rombo, Lars

AU - Roper, Cally

AU - Rosenthal, Philip J.

AU - Sagara, Issaka

AU - Sawa, Patrick

AU - Schallig, Henk D. F. H.

AU - Schramm, Birgit

AU - Shekalaghe, Seif A.

AU - Sibley, Carol H.

AU - Sirima, Sodiomon

AU - Smithuis, Frank

AU - Sow, Doudou

AU - Staedke, Sarah G.

AU - Stepniewska, Kasia

AU - Sutanto, Inge

AU - Sutherland, Colin J.

AU - Swarthout, Todd D.

AU - Syafruddin, Din

AU - Sylla, Khadime

AU - Talisuna, Ambrose O.

AU - Taylor, Walter R.

AU - Temu, Emmanuel A.

AU - ter Kuile, Feiko

AU - Tinto, Halidou

AU - Tjitra, Emiliana

AU - Ursing, Johan

AU - Valecha, Neena

AU - van den Broek, Ingrid

AU - van Herp, Michel

AU - van Vugt, Michele

AU - Ward, Stephen A.

AU - White, Nicholas J.

AU - Winstanley, Peter A.

AU - Woodrow, Charles J.

AU - Yeka, Adoke

AU - Zwang, Julien

PY - 2016

Y1 - 2016

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 then on-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 then on-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics

U2 - https://doi.org/10.1186/s12916-016-0621-7

DO - https://doi.org/10.1186/s12916-016-0621-7

M3 - Review article

C2 - 27221542

SN - 1464-2662

VL - 14

SP - 79

JO - BMC medicine

JF - BMC medicine

ER -