Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data

Salim Abdulla; Ishag Adam; George O. Adjei; Martin A. Adjuik; Bereket Alemayehu; Richard Allan; Emmanuel Arinaitwe; Elizabeth A. Ashley; Mamadou S. Ba; Hubert Barennes; Karen I. Barnes; Quique Bassat; Elisabeth Baudin; Nicole Berens-Riha; Anders Bjorkman; Francois Bompart; Maryline Bonnet; Steffen Borrmann; Teun Bousema; Philippe Brasseur; Hasifa Bukirwa; Francesco Checchi; Prabin Dahal; Umberto D'Alessandro; Meghna Desai; Alassane Dicko; Abdoulaye A. Djimde; Grant Dorsey; Ogobara K. Doumbo; Chris J. Drakeley; Stephan Duparc; Teferi Eshetu; Emmanuelle Espie; Jean François Etard; Abul M. Faiz; Catherine O. Falade; Caterina I. Fanello; Jean François Faucher; Babacar Faye; Oumar Faye; Scott Filler; Jennifer A. Flegg; Bakary Fofana; Carole Fogg; Nahla B. Gadalla; Oumar Gaye; Blaise Genton; Peter W. Gething; Jose P. Gil; Raquel González; Francesco Grandesso; Bryan Greenhouse; Brian Greenwood; Anastasia Grivoyannis; Philippe J. Guerin; Jean Paul Guthmann; Kamal Hamed; Sally Hamour; Simon I. Hay; Eva Maria Hode; Georgina S. Humphreys; Jimee Hwang; Maman L. Ibrahim; Daddi Jima; Joel J. Jones; Vincent Jullien; Elizabeth Juma; Patrick S. Kachur; Piet A. Kager; Erasmus Kamugisha; Moses R. Kamya; Corine Karema; Kassoum Kayentao; Jean Rene Kieche; Fred Kironde; Poul Erik Kofoed; Peter G. Kremsner; Sanjeev Krishna; Valerie Lameyre; Bertrand Lell; Angeles Lima; Michael Makanga; El Fatih M. Malik; Kevin Marsh; Andreas Martensson; Achille Massougbodji; Herve Menan; Didier Menard; Clara Menendez; Petra F. Mens; Martin Meremikwu; Clarissa Moreira; Carolyn Nabasumba; Michael Nambozi; Jean Louis Ndiaye; Billy E. Ngasala; Frederic Nikiema; Christian Nsanzabana; Francine Ntoumi; Mary Oguike; Bernhards R. Ogutu; Piero Olliaro; Sabah A. Omar; Jean Bosco Ouedraogo; Seth Owusu-Agyei; Louis K. Penali; Mbaye Pene; Judy Peshu; Patrice Piola; Christopher V. Plowe; Zul Premji; Ric N. Price; Milijaona Randrianarivelojosia; Lars Rombo; Cally Roper; Philip J. Rosenthal; Issaka Sagara; Albert Same-Ekobo; Patrick Sawa; Henk D.F.H. Schallig; Birgit Schramm; Amadou Seck; Seif A. Shekalaghe; Carol H. Sibley; Veronique Sinou; Sodiomon B. Sirima; Fabrice A. Some; Doudou Sow; Sarah G. Staedke; Kasia Stepniewska; Colin J. Sutherland; Todd D. Swarthout; Khadime Sylla; Ambrose O. Talisuna; Walter R.J. Taylor; Emmanuel A. Temu; Julie I. Thwing; Roger C.K. Tine; Halidou Tinto; Silva Tommasini; Offianan A. Toure; Johan Ursing; Michel T. Vaillant; Giovanni Valentini; Ingrid Van den Broek; Michele Van Vugt; Stephen A. Ward; Peter A. Winstanley; William Yavo; Adoke Yeka; Yah M. Zolia; Issaka Zongo; Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group

doi:10.1186/s12916-015-0445-x

Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data

Salim Abdulla, Ishag Adam, George O. Adjei, Martin A. Adjuik, Bereket Alemayehu, Richard Allan, Emmanuel Arinaitwe, Elizabeth A. Ashley, Mamadou S. Ba, Hubert Barennes, Karen I. Barnes, Quique Bassat, Elisabeth Baudin, Nicole Berens-Riha, Anders Bjorkman, Francois Bompart, Maryline Bonnet, Steffen Borrmann, Teun Bousema, Philippe BrasseurHasifa Bukirwa, Francesco Checchi, Prabin Dahal, Umberto D'Alessandro, Meghna Desai, Alassane Dicko, Abdoulaye A. Djimde, Grant Dorsey, Ogobara K. Doumbo, Chris J. Drakeley, Stephan Duparc, Teferi Eshetu, Emmanuelle Espie, Jean François Etard, Abul M. Faiz, Catherine O. Falade, Caterina I. Fanello, Jean François Faucher, Babacar Faye, Oumar Faye, Scott Filler, Jennifer A. Flegg, Bakary Fofana, Carole Fogg, Nahla B. Gadalla, Oumar Gaye, Blaise Genton, Peter W. Gething, Jose P. Gil, Raquel González, Francesco Grandesso, Bryan Greenhouse, Brian Greenwood, Anastasia Grivoyannis, Philippe J. Guerin, Jean Paul Guthmann, Kamal Hamed, Sally Hamour, Simon I. Hay, Eva Maria Hode, Georgina S. Humphreys, Jimee Hwang, Maman L. Ibrahim, Daddi Jima, Joel J. Jones, Vincent Jullien, Elizabeth Juma, Patrick S. Kachur, Piet A. Kager, Erasmus Kamugisha, Moses R. Kamya, Corine Karema, Kassoum Kayentao, Jean Rene Kieche, Fred Kironde, Poul Erik Kofoed, Peter G. Kremsner, Sanjeev Krishna, Valerie Lameyre, Bertrand Lell, Angeles Lima, Michael Makanga, El Fatih M. Malik, Kevin Marsh, Andreas Martensson, Achille Massougbodji, Herve Menan, Didier Menard, Clara Menendez, Petra F. Mens, Martin Meremikwu, Clarissa Moreira, Carolyn Nabasumba, Michael Nambozi, Jean Louis Ndiaye, Billy E. Ngasala, Frederic Nikiema, Christian Nsanzabana, Francine Ntoumi, Mary Oguike, Bernhards R. Ogutu, Piero Olliaro, Sabah A. Omar, Jean Bosco Ouedraogo, Seth Owusu-Agyei, Louis K. Penali, Mbaye Pene, Judy Peshu, Patrice Piola, Christopher V. Plowe, Zul Premji, Ric N. Price, Milijaona Randrianarivelojosia, Lars Rombo, Cally Roper, Philip J. Rosenthal, Issaka Sagara, Albert Same-Ekobo, Patrick Sawa, Henk D.F.H. Schallig, Birgit Schramm, Amadou Seck, Seif A. Shekalaghe, Carol H. Sibley, Veronique Sinou, Sodiomon B. Sirima, Fabrice A. Some, Doudou Sow, Sarah G. Staedke, Kasia Stepniewska, Colin J. Sutherland, Todd D. Swarthout, Khadime Sylla, Ambrose O. Talisuna, Walter R.J. Taylor, Emmanuel A. Temu, Julie I. Thwing, Roger C.K. Tine, Halidou Tinto, Silva Tommasini, Offianan A. Toure, Johan Ursing, Michel T. Vaillant, Giovanni Valentini, Ingrid Van den Broek, Michele Van Vugt, Stephen A. Ward, Peter A. Winstanley, William Yavo, Adoke Yeka, Yah M. Zolia, Issaka Zongo, Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group

Global and Tropical Health

Research output: Contribution to journal › Article › peer-review

59 Citations (Scopus)

61 Downloads (Pure)

Abstract

Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).

Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data.

Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).

Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Original language	English
Article number	212
Pages (from-to)	1-16
Number of pages	16
Journal	BMC Medicine
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s12916-015-0445-x
Publication status	Published - 7 Sept 2015

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Abdulla, S., Adam, I., Adjei, G. O., Adjuik, M. A., Alemayehu, B., Allan, R., Arinaitwe, E., Ashley, E. A., Ba, M. S., Barennes, H., Barnes, K. I., Bassat, Q., Baudin, E., Berens-Riha, N., Bjorkman, A., Bompart, F., Bonnet, M., Borrmann, S., Bousema, T., ... WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, A. B. C. T. A. B. S. G. (2015). Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data. BMC Medicine, 13(1), 1-16. Article 212. https://doi.org/10.1186/s12916-015-0445-x

@article{38aa86b873384d74999d82b4c3bac962,

title = "Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data",

abstract = "Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.",

keywords = "amodiaquine, amodiaquine plus artesunate, arteether, artemether, artemether plus benflumetol, artemisinin, artesunate, atovaquone, atovaquone plus proguanil, azithromycin, benflumetol, chloroquine, chlorproguanil, clindamycin, cycloguanil, dapsone, dihydroartemisinin, dihydroartemisinin plus piperaquine, doxycycline, halofantrine, mefloquine, naphthoquinone, piperaquine, primaquine, proguanil, pyrimethamine, pyronaridine, quinidine, quinine, unindexed drug, Africa south of the Sahara, African, anemia, Article, disease severity, drug response, factorial analysis, fever, human, malaria falciparum, meta analysis, nonhuman, outcome assessment, parasite clearance, parasitemia, patient information, prospective study, randomized controlled trial (topic), risk assessment, risk factor, statistical analysis, systematic review",

author = "Salim Abdulla and Ishag Adam and Adjei, {George O.} and Adjuik, {Martin A.} and Bereket Alemayehu and Richard Allan and Emmanuel Arinaitwe and Ashley, {Elizabeth A.} and Ba, {Mamadou S.} and Hubert Barennes and Barnes, {Karen I.} and Quique Bassat and Elisabeth Baudin and Nicole Berens-Riha and Anders Bjorkman and Francois Bompart and Maryline Bonnet and Steffen Borrmann and Teun Bousema and Philippe Brasseur and Hasifa Bukirwa and Francesco Checchi and Prabin Dahal and Umberto D'Alessandro and Meghna Desai and Alassane Dicko and Djimde, {Abdoulaye A.} and Grant Dorsey and Doumbo, {Ogobara K.} and Drakeley, {Chris J.} and Stephan Duparc and Teferi Eshetu and Emmanuelle Espie and Etard, {Jean Fran{\c c}ois} and Faiz, {Abul M.} and Falade, {Catherine O.} and Fanello, {Caterina I.} and Faucher, {Jean Fran{\c c}ois} and Babacar Faye and Oumar Faye and Scott Filler and Flegg, {Jennifer A.} and Bakary Fofana and Carole Fogg and Gadalla, {Nahla B.} and Oumar Gaye and Blaise Genton and Gething, {Peter W.} and Gil, {Jose P.} and Raquel Gonz{\'a}lez and Francesco Grandesso and Bryan Greenhouse and Brian Greenwood and Anastasia Grivoyannis and Guerin, {Philippe J.} and Guthmann, {Jean Paul} and Kamal Hamed and Sally Hamour and Hay, {Simon I.} and Hode, {Eva Maria} and Humphreys, {Georgina S.} and Jimee Hwang and Ibrahim, {Maman L.} and Daddi Jima and Jones, {Joel J.} and Vincent Jullien and Elizabeth Juma and Kachur, {Patrick S.} and Kager, {Piet A.} and Erasmus Kamugisha and Kamya, {Moses R.} and Corine Karema and Kassoum Kayentao and Kieche, {Jean Rene} and Fred Kironde and Kofoed, {Poul Erik} and Kremsner, {Peter G.} and Sanjeev Krishna and Valerie Lameyre and Bertrand Lell and Angeles Lima and Michael Makanga and Malik, {El Fatih M.} and Kevin Marsh and Andreas Martensson and Achille Massougbodji and Herve Menan and Didier Menard and Clara Menendez and Mens, {Petra F.} and Martin Meremikwu and Clarissa Moreira and Carolyn Nabasumba and Michael Nambozi and Ndiaye, {Jean Louis} and Ngasala, {Billy E.} and Frederic Nikiema and Christian Nsanzabana and Francine Ntoumi and Mary Oguike and Ogutu, {Bernhards R.} and Piero Olliaro and Omar, {Sabah A.} and Ouedraogo, {Jean Bosco} and Seth Owusu-Agyei and Penali, {Louis K.} and Mbaye Pene and Judy Peshu and Patrice Piola and Plowe, {Christopher V.} and Zul Premji and Price, {Ric N.} and Milijaona Randrianarivelojosia and Lars Rombo and Cally Roper and Rosenthal, {Philip J.} and Issaka Sagara and Albert Same-Ekobo and Patrick Sawa and Schallig, {Henk D.F.H.} and Birgit Schramm and Amadou Seck and Shekalaghe, {Seif A.} and Sibley, {Carol H.} and Veronique Sinou and Sirima, {Sodiomon B.} and Some, {Fabrice A.} and Doudou Sow and Staedke, {Sarah G.} and Kasia Stepniewska and Sutherland, {Colin J.} and Swarthout, {Todd D.} and Khadime Sylla and Talisuna, {Ambrose O.} and Taylor, {Walter R.J.} and Temu, {Emmanuel A.} and Thwing, {Julie I.} and Tine, {Roger C.K.} and Halidou Tinto and Silva Tommasini and Toure, {Offianan A.} and Johan Ursing and Vaillant, {Michel T.} and Giovanni Valentini and {Van den Broek}, Ingrid and Vugt, {Michele Van} and Ward, {Stephen A.} and Winstanley, {Peter A.} and William Yavo and Adoke Yeka and Zolia, {Yah M.} and Issaka Zongo and {WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group}, {Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group}",

year = "2015",

month = sep,

day = "7",

doi = "10.1186/s12916-015-0445-x",

language = "English",

volume = "13",

pages = "1--16",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

number = "1",

}

Abdulla, S, Adam, I, Adjei, GO, Adjuik, MA, Alemayehu, B, Allan, R, Arinaitwe, E, Ashley, EA, Ba, MS, Barennes, H, Barnes, KI, Bassat, Q, Baudin, E, Berens-Riha, N, Bjorkman, A, Bompart, F, Bonnet, M, Borrmann, S, Bousema, T, Brasseur, P, Bukirwa, H, Checchi, F, Dahal, P, D'Alessandro, U, Desai, M, Dicko, A, Djimde, AA, Dorsey, G, Doumbo, OK, Drakeley, CJ, Duparc, S, Eshetu, T, Espie, E, Etard, JF, Faiz, AM, Falade, CO, Fanello, CI, Faucher, JF, Faye, B, Faye, O, Filler, S, Flegg, JA, Fofana, B, Fogg, C, Gadalla, NB, Gaye, O, Genton, B, Gething, PW, Gil, JP, González, R, Grandesso, F, Greenhouse, B, Greenwood, B, Grivoyannis, A, Guerin, PJ, Guthmann, JP, Hamed, K, Hamour, S, Hay, SI, Hode, EM, Humphreys, GS, Hwang, J, Ibrahim, ML, Jima, D, Jones, JJ, Jullien, V, Juma, E, Kachur, PS, Kager, PA, Kamugisha, E, Kamya, MR, Karema, C, Kayentao, K, Kieche, JR, Kironde, F, Kofoed, PE, Kremsner, PG, Krishna, S, Lameyre, V, Lell, B, Lima, A, Makanga, M, Malik, EFM, Marsh, K, Martensson, A, Massougbodji, A, Menan, H, Menard, D, Menendez, C, Mens, PF, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, JL, Ngasala, BE, Nikiema, F, Nsanzabana, C, Ntoumi, F, Oguike, M, Ogutu, BR, Olliaro, P, Omar, SA, Ouedraogo, JB, Owusu-Agyei, S, Penali, LK, Pene, M, Peshu, J, Piola, P, Plowe, CV, Premji, Z, Price, RN, Randrianarivelojosia, M, Rombo, L, Roper, C, Rosenthal, PJ, Sagara, I, Same-Ekobo, A, Sawa, P, Schallig, HDFH, Schramm, B, Seck, A, Shekalaghe, SA, Sibley, CH, Sinou, V, Sirima, SB, Some, FA, Sow, D, Staedke, SG, Stepniewska, K, Sutherland, CJ, Swarthout, TD, Sylla, K, Talisuna, AO, Taylor, WRJ, Temu, EA, Thwing, JI, Tine, RCK, Tinto, H, Tommasini, S, Toure, OA, Ursing, J, Vaillant, MT, Valentini, G, Van den Broek, I, Vugt, MV, Ward, SA, Winstanley, PA, Yavo, W, Yeka, A, Zolia, YM, Zongo, I & WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, ABCTABSG 2015, 'Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data', BMC Medicine, vol. 13, no. 1, 212, pp. 1-16. https://doi.org/10.1186/s12916-015-0445-x

Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data. / Abdulla, Salim; Adam, Ishag; Adjei, George O. et al.
In: BMC Medicine, Vol. 13, No. 1, 212, 07.09.2015, p. 1-16.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria

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

AU - Abdulla, Salim

AU - Adam, Ishag

AU - Adjei, George O.

AU - Adjuik, Martin A.

AU - Alemayehu, Bereket

AU - Allan, Richard

AU - Arinaitwe, Emmanuel

AU - Ashley, Elizabeth A.

AU - Ba, Mamadou S.

AU - Barennes, Hubert

AU - Barnes, Karen I.

AU - Bassat, Quique

AU - Baudin, Elisabeth

AU - Berens-Riha, Nicole

AU - Bjorkman, Anders

AU - Bompart, Francois

AU - Bonnet, Maryline

AU - Borrmann, Steffen

AU - Bousema, Teun

AU - Brasseur, Philippe

AU - Bukirwa, Hasifa

AU - Checchi, Francesco

AU - Dahal, Prabin

AU - D'Alessandro, Umberto

AU - Desai, Meghna

AU - Dicko, Alassane

AU - Djimde, Abdoulaye A.

AU - Dorsey, Grant

AU - Doumbo, Ogobara K.

AU - Drakeley, Chris J.

AU - Duparc, Stephan

AU - Eshetu, Teferi

AU - Espie, Emmanuelle

AU - Etard, Jean François

AU - Faiz, Abul M.

AU - Falade, Catherine O.

AU - Fanello, Caterina I.

AU - Faucher, Jean François

AU - Faye, Babacar

AU - Faye, Oumar

AU - Filler, Scott

AU - Flegg, Jennifer A.

AU - Fofana, Bakary

AU - Fogg, Carole

AU - Gadalla, Nahla B.

AU - Gaye, Oumar

AU - Genton, Blaise

AU - Gething, Peter W.

AU - Gil, Jose P.

AU - González, Raquel

AU - Grandesso, Francesco

AU - Greenhouse, Bryan

AU - Greenwood, Brian

AU - Grivoyannis, Anastasia

AU - Guerin, Philippe J.

AU - Guthmann, Jean Paul

AU - Hamed, Kamal

AU - Hamour, Sally

AU - Hay, Simon I.

AU - Hode, Eva Maria

AU - Humphreys, Georgina S.

AU - Hwang, Jimee

AU - Ibrahim, Maman L.

AU - Jima, Daddi

AU - Jones, Joel J.

AU - Jullien, Vincent

AU - Juma, Elizabeth

AU - Kachur, Patrick S.

AU - Kager, Piet A.

AU - Kamugisha, Erasmus

AU - Kamya, Moses R.

AU - Karema, Corine

AU - Kayentao, Kassoum

AU - Kieche, Jean Rene

AU - Kironde, Fred

AU - Kofoed, Poul Erik

AU - Kremsner, Peter G.

AU - Krishna, Sanjeev

AU - Lameyre, Valerie

AU - Lell, Bertrand

AU - Lima, Angeles

AU - Makanga, Michael

AU - Malik, El Fatih M.

AU - Marsh, Kevin

AU - Martensson, Andreas

AU - Massougbodji, Achille

AU - Menan, Herve

AU - Menard, Didier

AU - Menendez, Clara

AU - Mens, Petra F.

AU - Meremikwu, Martin

AU - Moreira, Clarissa

AU - Nabasumba, Carolyn

AU - Nambozi, Michael

AU - Ndiaye, Jean Louis

AU - Ngasala, Billy E.

AU - Nikiema, Frederic

AU - Nsanzabana, Christian

AU - Ntoumi, Francine

AU - Oguike, Mary

AU - Ogutu, Bernhards R.

AU - Olliaro, Piero

AU - Omar, Sabah A.

AU - Ouedraogo, Jean Bosco

AU - Owusu-Agyei, Seth

AU - Penali, Louis K.

AU - Pene, Mbaye

AU - Peshu, Judy

AU - Piola, Patrice

AU - Plowe, Christopher V.

AU - Premji, Zul

AU - Price, Ric N.

AU - Randrianarivelojosia, Milijaona

AU - Rombo, Lars

AU - Roper, Cally

AU - Rosenthal, Philip J.

AU - Sagara, Issaka

AU - Same-Ekobo, Albert

AU - Sawa, Patrick

AU - Schallig, Henk D.F.H.

AU - Schramm, Birgit

AU - Seck, Amadou

AU - Shekalaghe, Seif A.

AU - Sibley, Carol H.

AU - Sinou, Veronique

AU - Sirima, Sodiomon B.

AU - Some, Fabrice A.

AU - Sow, Doudou

AU - Staedke, Sarah G.

AU - Stepniewska, Kasia

AU - Sutherland, Colin J.

AU - Swarthout, Todd D.

AU - Sylla, Khadime

AU - Talisuna, Ambrose O.

AU - Taylor, Walter R.J.

AU - Temu, Emmanuel A.

AU - Thwing, Julie I.

AU - Tine, Roger C.K.

AU - Tinto, Halidou

AU - Tommasini, Silva

AU - Toure, Offianan A.

AU - Ursing, Johan

AU - Vaillant, Michel T.

AU - Valentini, Giovanni

AU - Van den Broek, Ingrid

AU - Vugt, Michele Van

AU - Ward, Stephen A.

AU - Winstanley, Peter A.

AU - Yavo, William

AU - Yeka, Adoke

AU - Zolia, Yah M.

AU - Zongo, Issaka

AU - WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group

PY - 2015/9/7

Y1 - 2015/9/7

N2 - Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

AB - Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

KW - amodiaquine

KW - amodiaquine plus artesunate

KW - arteether

KW - artemether

KW - artemether plus benflumetol

KW - artemisinin

KW - artesunate

KW - atovaquone

KW - atovaquone plus proguanil

KW - azithromycin

KW - benflumetol

KW - chloroquine

KW - chlorproguanil

KW - clindamycin

KW - cycloguanil

KW - dapsone

KW - dihydroartemisinin

KW - dihydroartemisinin plus piperaquine

KW - doxycycline

KW - halofantrine

KW - mefloquine

KW - naphthoquinone

KW - piperaquine

KW - primaquine

KW - proguanil

KW - pyrimethamine

KW - pyronaridine

KW - quinidine

KW - quinine

KW - unindexed drug

KW - Africa south of the Sahara

KW - African

KW - anemia

KW - Article

KW - disease severity

KW - drug response

KW - factorial analysis

KW - fever

KW - human

KW - malaria falciparum

KW - meta analysis

KW - nonhuman

KW - outcome assessment

KW - parasite clearance

KW - parasitemia

KW - patient information

KW - prospective study

KW - randomized controlled trial (topic)

KW - risk assessment

KW - risk factor

KW - statistical analysis

KW - systematic review

UR - http://www.scopus.com/inward/record.url?scp=84941618712&partnerID=8YFLogxK

U2 - 10.1186/s12916-015-0445-x

DO - 10.1186/s12916-015-0445-x

M3 - Article

C2 - 605898075

SN - 1741-7015

VL - 13

SP - 1

EP - 16

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 212

ER -

Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: A literature review and meta-analysis of individual patient data

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