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

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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 languageEnglish
Article number79
Pages (from-to)1-18
Number of pages18
JournalBMC Medicine
Publication statusPublished - 24 May 2016


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