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1. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

Author

Adjuik MA, Allan R, Anvikar AR, Ashley EA, Ba MS, Barennes H, Barnes KI, Bassat Q, Baudin E, Björkman A, Bompart F, Bonnet M, Borrmann S, Brasseur P, Bukirwa H, Checchi F, Cot M, Dahal P, D'Alessandro U, Deloron P, Desai M, Diap G, Djimde AA, Dorsey G, Doumbo OK, Espié E, Etard JF, Fanello CI, Faucher JF, Faye B, Flegg JA, Gaye O, Gething PW, González R, Grandesso F, Guerin PJ, Guthmann JP, Hamour S, Hasugian AR, Hay SI, Humphreys GS, Jullien V, Juma E, Kamya MR, Karema C, Kiechel JR, Kremsner PG, Krishna S, Lameyre V, Ibrahim LM, Lee SJ, Lell B, Mårtensson A, Massougbodji A, Menan H, Ménard D, Menéndez C, Meremikwu M, Moreira C, Nabasumba C, Nambozi M, Ndiaye JL, Nikiema F, Nsanzabana C, Ntoumi F, Ogutu BR, Olliaro P, Osorio L, Ouédraogo JB, Penali LK, Pene M, Pinoges L, Piola P, Price RN, Roper C, Rosenthal PJ, Rwagacondo CE, Same-Ekobo A, Schramm B, Seck A, Sharma B, Sibley CH, Sinou V, Sirima SB, Smith JJ, Smithuis F, Somé FA, Sow D, Staedke SG, Stepniewska K, Swarthout TD, Sylla K, Talisuna AO, Tarning J, Taylor WR, Temu EA, Thwing JI, Tjitra E, Tine RC, Tinto H, Vaillant MT, Valecha N, Van den Broek I, White NJ, Yeka A, and Zongo I

Subjects
Africa, Dose-Response Relationship, Drug, Drug Combinations, Female, Humans, Male, Middle Aged, Recurrence, Risk Factors, Treatment Outcome, Amodiaquine administration & dosage, Antimalarials administration & dosage, Artemisinins administration & dosage, Malaria, Falciparum drug therapy
Abstract

Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria., Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites., Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites., Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Published
2015
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2. Comparison of azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Africa: a randomized, open-label study.

Author

Chandra R, Ansah P, Sagara I, Sie A, Tiono AB, Djimde AA, Zhao Q, Robbins J, Penali LK, and Ogutu B

Subjects
Africa South of the Sahara epidemiology, Antimalarials adverse effects, Antimalarials blood, Antimalarials pharmacokinetics, Artemether, Lumefantrine Drug Combination, Artemisinins adverse effects, Artemisinins blood, Artemisinins pharmacokinetics, Azithromycin adverse effects, Azithromycin blood, Azithromycin pharmacokinetics, Child, Child, Preschool, Chloroquine adverse effects, Chloroquine blood, Chloroquine pharmacokinetics, Drug Combinations, Ethanolamines adverse effects, Ethanolamines blood, Ethanolamines pharmacokinetics, Female, Fluorenes adverse effects, Fluorenes blood, Fluorenes pharmacokinetics, Humans, Infant, Male, Antimalarials therapeutic use, Artemisinins therapeutic use, Azithromycin therapeutic use, Chloroquine therapeutic use, Ethanolamines therapeutic use, Fluorenes therapeutic use, Malaria, Falciparum drug therapy, Malaria, Falciparum epidemiology
Abstract

Background: This randomized, open-label study was conducted to establish the non-inferiority of a combination of azithromycin (AZ) and chloroquine (CQ) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in children from six sites in sub-Saharan Africa., Methods: Children with uncomplicated Plasmodium falciparum malaria between six and 59 months of age were randomized 1:1 to either AZCQ (30 mg/kg AZ + 10 mg/kg CQ base) or AL per prescribing information for three days (Days 0, 1, 2). Each site could enrol in the study population once the treatment of uncomplicated malaria in five children five to 12 years of age was deemed to be effective and well tolerated. The primary efficacy evaluation was the proportion of subjects in both the modified intent-to-treat (MITT) and per-protocol (PP) populations with an adequate clinical and parasitological response (PCR corrected) at Day 28. Non-inferiority was concluded if the lower bound of the 95% confidence interval comparing the two groups was 10 percentage points or greater., Results: A total of 255 children were enrolled in the efficacy analysis (AZCQ, n = 124; AL, n = 131). The PCR corrected clearance rates were 89% (AZCQ) versus 98% (AL) for MITT, a difference of -9.10 (95% confidence interval; -16.02, -2.18) and 93% (AZCQ) versus 99% (AL) for PP, a difference of -6.08 (-12.10, -0.05). Early and late treatment failures were more common in subjects receiving AZCQ. Adverse events were more common in subjects treated with AZCQ. Drug concentrations obtained at specified time points following AZCQ administration had a large coefficient of variation partially due to sparse sampling with sample collection time window., Conclusions: In this study, non-inferiority of AZCQ to AL was not demonstrated., Trial Registration: ClinicalTrials.gov NCT00677833 .

Published
2015
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3. Artesunate/mefloquine paediatric formulation vs. artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Anonkoua kouté, Côte d'Ivoire.

Author

Toure OA, Kouame MG, Didier YJ, Berenger AA, Djerea K, Genevieve GO, and Penali LK

Subjects
Antimalarials adverse effects, Artemether, Lumefantrine Drug Combination, Artemisinins adverse effects, Artemisinins therapeutic use, Artesunate, Child, Preschool, Drug Combinations, Epidemiologic Methods, Ethanolamines adverse effects, Ethanolamines therapeutic use, Female, Fever drug therapy, Fever parasitology, Fluorenes adverse effects, Fluorenes therapeutic use, Humans, Infant, Malaria, Falciparum complications, Malaria, Falciparum parasitology, Male, Mefloquine adverse effects, Mefloquine therapeutic use, Plasmodium falciparum isolation & purification, Treatment Outcome, Antimalarials therapeutic use, Malaria, Falciparum drug therapy
Abstract

Objectives: To test the hypothesis that Artesunate-mefloquine paediatric (AS+MEF) is as effective as Artemether-lumefantrine (AL) in treating acute uncomplicated malaria in children., Methods: In an open label, randomized controlled clinical trial, children aged 6-59 months were randomized to receive AS+MEF or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 28 days of follow-up., Results: One hundred and fifty-six patients with confirmed uncomplicated P. falciparum malaria were randomly assigned to receive AS+MEF (n = 77) or AL (n = 79). PCR-corrected day 28 cure rates for per protocol (PP) populations were 99% for AS+MEF and 97% (P = 1) for AL. For the intention to treat (ITT) population, cure rates were 96% for AS+MEF and 92% (P = 0.49) for AL. Both regimens were well tolerated., Conclusion: AS+MEF is as effective as AL, and both combinations were efficacious and safe., (© 2011 Blackwell Publishing Ltd.)

Published
2011
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4. A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire.

Author

Toure OA, Penali LK, Yapi JD, Ako BA, Toure W, Djerea K, Gomez GO, and Makaila O

Subjects
Adult, Artemether, Lumefantrine Drug Combination, Child, Cote d'Ivoire, Drug Administration Schedule, Drug Combinations, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Malaria, Falciparum parasitology, Male, Plasmodium falciparum isolation & purification, Polymerase Chain Reaction, Recurrence, Treatment Outcome, Antimalarials administration & dosage, Artemisinins administration & dosage, Ethanolamines administration & dosage, Fluorenes administration & dosage, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects
Abstract

Background: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL) is highly effective and well-tolerated. Artemisinin/naphtoquine (AN) is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast., Methods: We enrolled 122 participants aged 6 months or more with uncomplicated falciparum malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection., Results: Among 125 participants enrolled, 123 (98.4%) completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance., Interpretation: These data suggest that Arco could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.

Published
2009
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5. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

Author

WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, Adjuik, Martin A, Allan, Richard, Anvikar, Anupkumar R, Ashley, Elizabeth A, Ba, Mamadou S, Barennes, Hubert, Barnes, Karen I, Bassat, Quique, Baudin, Elisabeth, Björkman, Anders, Bompart, François, Bonnet, Maryline, Borrmann, Steffen, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Cot, Michel, Dahal, Prabin, D'Alessandro, Umberto, Deloron, Philippe, Desai, Meghna, Diap, Graciela, Djimde, Abdoulaye A, Dorsey, Grant, Doumbo, Ogobara K, Espié, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I, Faucher, Jean-François, Faye, Babacar, Flegg, Jennifer A, Gaye, Oumar, Gething, Peter W, González, Raquel, Grandesso, Francesco, Guerin, Philippe J, Guthmann, Jean-Paul, Hamour, Sally, Hasugian, Armedy Ronny, Hay, Simon I, Humphreys, Georgina S, Jullien, Vincent, Juma, Elizabeth, Kamya, Moses R, Karema, Corine, Kiechel, Jean R, Kremsner, Peter G, Krishna, Sanjeev, Lameyre, Valérie, Ibrahim, Laminou M, Lee, Sue J, Lell, Bertrand, Mårtensson, Andreas, Massougbodji, Achille, Menan, Hervé, Ménard, Didier, Menéndez, Clara, Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Ogutu, Bernhards R, Olliaro, Piero, Osorio, Lyda, Ouédraogo, Jean-Bosco, Penali, Louis K, Pene, Mbaye, Pinoges, Loretxu, Piola, Patrice, Price, Ric N, Roper, Cally, Rosenthal, Philip J, Rwagacondo, Claude Emile, Same-Ekobo, Albert, Schramm, Birgit, Seck, Amadou, Sharma, Bhawna, Sibley, Carol Hopkins, Sinou, Véronique, Sirima, Sodiomon B, Smith, Jeffery J, Smithuis, Frank, Somé, Fabrice A, Sow, Doudou, Staedke, Sarah G, Stepniewska, Kasia, Swarthout, Todd D, Sylla, Khadime, Talisuna, Ambrose O, Tarning, Joel, Taylor, Walter RJ, Temu, Emmanuel A, Thwing, Julie I, Tjitra, Emiliana, and Tine, Roger CK

Subjects
WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, Humans, Malaria, Falciparum, Recurrence, Artemisinins, Amodiaquine, Drug Combinations, Antimalarials, Treatment Outcome, Risk Factors, Dose-Response Relationship, Drug, Middle Aged, Africa, Female, Male, Malaria, Plasmodium falciparum, Drug resistance, Artesunate, Dosing, Efficacy, Falciparum, Dose-Response Relationship, Drug, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundArtesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.MethodsIndividual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.ResultsForty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P

Published
2015

6. Haematological consequences of acute uncomplicated falciparum malaria: a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data

Author

Mansoor, Rashid, Commons, Robert J, Douglas, Nicholas M, Abuaku, Benjamin, Achan, Jane, Adam, Ishag, Adjei, George O, Adjuik, Martin, Alemayehu, Bereket H, Allan, Richard, Allen, Elizabeth N, Anvikar, Anupkumar R, Arinaitwe, Emmanuel, Ashley, Elizabeth A, Ashurst, Hazel, Asih, Puji BS, Bakyaita, Nathan, Barennes, Hubert, Barnes, Karen I, Basco, Leonardo, Bassat, Quique, Baudin, Elisabeth, Bell, David J, Bethell, Delia, Bjorkman, Anders, Boulton, Caroline, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Burrow, Rebekah, Carrara, Verena I, Cot, Michel, D'Alessandro, Umberto, Das, Debashish, Das, Sabyasachi, Davis, Timothy ME, Desai, Meghna, Djimde, Abdoulaye A, Dondorp, Arjen M, Dorsey, Grant, Drakeley, Chris J, Duparc, Stephan, Espie, Emmanuelle, Etard, Jean-Francois, Falade, Catherine, Faucher, Jean Francois, Filler, Scott, Fogg, Carole, Fukuda, Mark, Gaye, Oumar, Genton, Blaise, Rahim, Awab Ghulam, Gilayeneh, Julius, Gonzalez, Raquel, Grais, Rebecca F, Grandesso, Francesco, Greenwood, Brian, Grivoyannis, Anastasia, Hatz, Christoph, Hodel, Eva Maria, Humphreys, Georgina S, Hwang, Jimee, Ishengoma, Deus, Juma, Elizabeth, Kachur, S Patrick, Kager, Piet A, Kamugisha, Erasmus, Kamya, Moses R, Karema, Corine, Kayentao, Kassoum, Kazienga, Adama, Kiechel, Jean-Rene, Kofoed, Poul-Erik, Koram, Kwadwo, Kremsner, Peter G, Lalloo, David G, Laman, Moses, Lee, Sue J, Lell, Bertrand, Maiga, Amelia W, Martensson, Andreas, Mayxay, Mayfong, Mbacham, Wilfred, McGready, Rose, Menan, Herve, Menard, Didier, Mockenhaupt, Frank, Moore, Brioni R, Muller, Olaf, Nahum, Alain, Ndiaye, Jean-Louis, Newton, Paul N, Ngasala, Billy E, Nikiema, Frederic, Nji, Akindeh M, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R, Ojurongbe, Olusola, Osorio, Lyda, Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Pareek, Anil, Penali, Louis K, Piola, Patrice, Plucinski, Mateusz, Premji, Zul, Ramharter, Michael, Richmond, Caitlin L, Rombo, Lars, Rosenthal, Philip J, Salman, Sam, Same-Ekobo, Albert, Sibley, Carol, Sirima, Sodiomon B, Smithuis, Frank M, Some, Fabrice A, Staedke, Sarah G, Starzengruber, Peter, Strub-Wourgaft, Nathalie, Sutanto, Inge, Swarthout, Todd D, Syafruddin, Din, Talisuna, Ambrose O, Taylor, Walter R, Temu, Emmanuel A, Thwing, Julie I, Tinto, Halidou, Tjitra, Emiliana, Toure, Offianan A, Tran, T Hien, Ursing, Johan, Valea, Innocent, Valentini, Giovanni, van Vugt, Michele, von Seidlein, Lorenz, Ward, Stephen A, Were, Vincent, White, Nicholas J, Woodrow, Charles J, Yavo, William, Yeka, Adoke, Zongo, Issaka, Simpson, Julie A, Guerin, Philippe J, Stepniewska, Kasia, Price, Ric N, Roper, Cally, Resistance, WorldWide Antimalarial, WorldWide Antimalarial Resistance Network Falciparum Haematology Study Group, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Epidémiologie des Maladies Chroniques en zone tropicale (EpiMaCT), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Group, WorldWide Antimalarial Resistance Network Falciparum Haematology Study, Mansoor, R, Ashley, EA, Ashurst, H, Burrow, R, Carrara, VI, Das, D, Dondorp, AM, Humphreys, GS, Lee, SJ, Mayxay, M, McGready, R, Newton, PN, Nosten, F, Richmond, CL, Sibley, C, Smithuis, FM, Taylor, WR, Tran, TH, von Seidlein, L, White, NJ, Woodrow, CJ, Guerin, PJ, Stepniewska, K, Price, RN, AII - Infectious diseases, Intensive Care Medicine, Infectious diseases, APH - Global Health, and APH - Quality of Care

Subjects
Infectious Medicine, Plasmodium falciparum, wh_120, Infektionsmedicin, Severe anaemia, Parasitemia, wa_530, Antimalarials, Non-artemisinin-based therapy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, qv_256, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Malaria, Falciparum, Child, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Pooled analysis of individual patient data, Anemia, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Artemisinin-based therapy, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Malaria, wc_750, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Haemoglobin
Abstract

Background Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. Results A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001). Conclusions In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.

Published
2022

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

Author

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

Subjects
Male, 0301 basic medicine, gametocytes, Plasmodium falciparum/drug effects, Artemisinins/therapeutic use, Amodiaquine/therapeutic use, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Malaria, Falciparum, Artemisinin, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Medicine(all), Microscopy, biology, Mefloquine, Malaria, Falciparum/drug therapy, Hazard ratio, General Medicine, Middle Aged, Artemisinins, 3. Good health, Drug Combinations, Child, Preschool, Drug Therapy, Combination, Research Article, medicine.drug, medicine.medical_specialty, plasmodium falciparum, Plasmodium falciparum, 030231 tropical medicine, Gametocyte, malaria, Malària, Amodiaquine, Host-Parasite Interactions, Antimalarials, 03 medical and health sciences, Internal medicine, parasitic diseases, medicine, Humans, Proportional Hazards Models, Resistència als medicaments, drug resistance, business.industry, medicine.disease, biology.organism_classification, Malaria, Logistic Models, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, chemistry, Host-Parasite Interactions/drug effects, Artesunate, Drug resistance, Antimalarials/therapeutic use, Immunology, business
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.

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