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

A systematic review and meta-analysis of individual patient data

WWARN Gametocyte Study Group

Research output: Contribution to journalArticle

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 Results: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the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 languageEnglish (US)
Article number79
JournalBMC Medicine
Volume14
Issue number1
DOIs
StatePublished - May 24 2016
Externally publishedYes

Fingerprint

Falciparum Malaria
dihydroartemisinin
Meta-Analysis
Mefloquine
Parasites
Therapeutics
Antimalarials
Malaria
Odds Ratio
artemisinine
Culicidae
PubMed
lumefantrine
artemether
Microscopy
Hemoglobins
Fever
Regression Analysis
artesunate
piperaquine

Keywords

  • Drug resistance
  • Gametocyte
  • Malaria
  • Plasmodium falciparum

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{61e3e8eb24c445c3be7125d3f11e9d0c,
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 = "{WWARN Gametocyte Study Group} and 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 Faucher, {Jean Francois} 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.}",
year = "2016",
month = "5",
day = "24",
doi = "10.1186/s12916-016-0621-7",
language = "English (US)",
volume = "14",
journal = "BMC Medicine",
issn = "1741-7015",
publisher = "BioMed Central",
number = "1",

}

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 - WWARN Gametocyte Study Group

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.

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

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

U2 - 10.1186/s12916-016-0621-7

DO - 10.1186/s12916-016-0621-7

M3 - Article

VL - 14

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

M1 - 79

ER -