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1. Landscape drives zoonotic malaria prevalence in non-human primates

Author: Flegg, Jennifer, Johnson, Emilia, Sunil Kumar Sharma, Reuben, Ruiz Cuenca, Pablo, Byrne, Isabel, Salgado-Lynn, Milena, Suraya Shahar, Zarith, Col Lin, Lee, Zulkifli, Norhadila, Dilaila Mohd Saidi, Nor, Drakeley, Chris, Matthiopoulos, Jason, Nelli, Luca, Fornace, Kimberly, Soldati-Favre, Dominique, Flegg, Jennifer, Johnson, Emilia, Sunil Kumar Sharma, Reuben, Ruiz Cuenca, Pablo, Byrne, Isabel, Salgado-Lynn, Milena, Suraya Shahar, Zarith, Col Lin, Lee, Zulkifli, Norhadila, Dilaila Mohd Saidi, Nor, Drakeley, Chris, Matthiopoulos, Jason, Nelli, Luca, Fornace, Kimberly, and Soldati-Favre, Dominique
Abstract: Zoonotic disease dynamics in wildlife hosts are rarely quantified at macroecological scales due to the lack of systematic surveys. Non-human primates (NHPs) host Plasmodium knowlesi, a zoonotic malaria of public health concern and the main barrier to malaria elimination in Southeast Asia. Understanding of regional P. knowlesi infection dynamics in wildlife is limited. Here, we systematically assemble reports of NHP P. knowlesi and investigate geographic determinants of prevalence in reservoir species. Meta-analysis of 6322 NHPs from 148 sites reveals that prevalence is heterogeneous across Southeast Asia, with low overall prevalence and high estimates for Malaysian Borneo. We find that regions exhibiting higher prevalence in NHPs overlap with human infection hotspots. In wildlife and humans, parasite transmission is linked to land conversion and fragmentation. By assembling remote sensing data and fitting statistical models to prevalence at multiple spatial scales, we identify novel relationships between P. knowlesi in NHPs and forest fragmentation. This suggests that higher prevalence may be contingent on habitat complexity, which would begin to explain observed geographic variation in parasite burden. These findings address critical gaps in understanding regional P. knowlesi epidemiology and indicate that prevalence in simian reservoirs may be a key spatial driver of human spillover risk.
Published: 2024

2. Patient-specific Boolean models of signalling networks guide personalised treatments

Author: Barcelona Supercomputing Center, Flegg, Jennifer, Montagud, Arnau, Béal, Jonas, Tobalina, Luis, Traynard, Pauline, Subramanian, Vigneshwari, Valencia, Alfonso, Barcelona Supercomputing Center, Flegg, Jennifer, Montagud, Arnau, Béal, Jonas, Tobalina, Luis, Traynard, Pauline, Subramanian, Vigneshwari, and Valencia, Alfonso
Abstract: Prostate cancer is the second most occurring cancer in men worldwide. To better understand the mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model of prostate cancer which considers the major signalling pathways known to be deregulated. We personalised this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients. 488 prostate samples were used to build patient-specific models and compared to available clinical data. Additionally, eight prostate cell-line-specific models were built to validate our approach with dose-response data of several drugs. The effects of single and combined drugs were tested in these models under different growth conditions. We identified 15 actionable points of interventions in one cell-line-specific model whose inactivation hinders tumorigenesis. To validate these results, we tested nine small molecule inhibitors of five of those putative targets and found a dose-dependent effect on four of them, notably those targeting HSP90 and PI3K. These results highlight the predictive power of our personalised Boolean models and illustrate how they can be used for precision oncology., This work has been partially supported by the European Commission under the PrECISE project (H2020-PHC-668858), the INFORE project (H2020-ICT-825070) and the PerMedCoE (H2020-ICT-951773), Peer Reviewed, "Article signat per 12 autors/es: Arnau Montagud, Jonas Béal, Luis Tobalina, Pauline Traynard, Vigneshwari Subramanian, Bence Szalai, Róbert Alföldi, László Puskás, Alfonso Valencia, Emmanuel Barillot, Julio Saez-Rodriguez, Laurence Calzone", Postprint (author's final draft)
Published: 2022

3. A comparison of approximate versus exact techniques for Bayesian parameter inference in nonlinear ordinary differential equation models

Author: Alahmadi, Amani A., Flegg, Jennifer A., Cochrane, Davis G., Drovandi, Christopher C., Keith, Jonathan M., Alahmadi, Amani A., Flegg, Jennifer A., Cochrane, Davis G., Drovandi, Christopher C., and Keith, Jonathan M.
Abstract: The behaviour of many processes in science and engineering can be accurately described by dynamical system models consisting of a set of ordinary differential equations (ODEs). Often these models have several unknown parameters that are difficult to estimate from experimental data, in which case Bayesian inference can be a useful tool. In principle, exact Bayesian inference using Markov chain Monte Carlo (MCMC) techniques is possible; however, in practice, such methods may suffer from slow convergence and poor mixing. To address this problem, several approaches based on approximate Bayesian computation (ABC) have been introduced, including Markov chain Monte Carlo ABC (MCMC ABC) and sequential Monte Carlo ABC (SMC ABC). While the system of ODEs describes the underlying process that generates the data, the observed measurements invariably include errors. In this paper, we argue that several popular ABC approaches fail to adequately model these errors because the acceptance probability depends on the choice of the discrepancy function and the tolerance without any consideration of the error term. We observe that the so-called posterior distributions derived from such methods do not accurately reflect the epistemic uncertainties in parameter values. Moreover, we demonstrate that these methods provide minimal computational advantages over exact Bayesian methods when applied to two ODE epidemiological models with simulated data and one with real data concerning malaria transmission in Afghanistan.
Published: 2020

4. A Current Perspective on Wound Healing and Tumour-Induced Angiogenesis

Author: Flegg, Jennifer A., Menon, Shakti N., Byrne, Helen M., McElwain, D. L.Sean, Flegg, Jennifer A., Menon, Shakti N., Byrne, Helen M., and McElwain, D. L.Sean
Abstract: Angiogenesis, or capillary growth from pre-existing vasculature, is an essential component of several physiological processes, both vital and pathological. These include dermal wound healing and tumour growth that together pose some of the most significant challenges to healthcare systems worldwide. Over the last few decades, mathematical modelling has proven to be a valuable tool for unravelling the complex network of interactions that underlie such processes. Moreover, theoretical frameworks that describe some of the mechanical and chemical aspects of angiogenesis inherent in wound healing and tumour growth have revealed intriguing similarities between the two processes. In this review, we highlight some of the significant contributions made by mathematical models of tumour-induced and wound healing angiogenesis and illustrate how advances in each field have been made using insights from the other. We also detail some open problems that could be addressed through a combination of theoretical and experimental approaches.
Published: 2020

5. Numerical solution of a two dimensional tumour growth model with moving boundary

Author: Droniou, Jerome, Flegg, Jennifer A., Remesan, Gopikrishnan C., Droniou, Jerome, Flegg, Jennifer A., and Remesan, Gopikrishnan C.
Abstract: We consider a biphasic continuum model for avascular tumour growth in two spatial dimensions, in which a cell phase and a fluid phase follow conservation of mass and momentum. A limiting nutrient that follows a diffusion process controls the birth and death rate of the tumour cells. The cell volume fraction, cell velocity--fluid pressure system, and nutrient concentration are the model variables. A coupled system of a hyperbolic conservation law, \cred{a viscous fluid model}, and a parabolic diffusion equation governs the dynamics of the model variables. The tumour boundary moves with the normal velocity of the outermost layer of cells, and this time--dependence is a challenge in designing and implementing a stable and fast numerical scheme. We recast the model into a form where the hyperbolic equation is defined on a fixed extended domain and retrieve the tumour boundary as the interface at which the cell volume fraction decreases below a threshold value. This procedure eliminates the need to track the tumour boundary explicitly and the computationally expensive re--meshing of the time--dependent domains. A numerical scheme based on finite volume methods for the hyperbolic conservation law, Lagrange $\mathbb{P}_2 - \mathbb{P}_1$ Taylor--Hood finite element method for the \cred{viscous} system, and mass--lumped finite element method for the parabolic equations is implemented in two spatial dimensions, and several cases are studied. We demonstrate the versatility of the numerical scheme in catering for irregular and asymmetric initial tumour geometries. We present numerical simulations for both cases and the results are consistent with theoretical and heuristic expectations such as early linear growth rate and preservation of radial symmetry when the boundary conditions are symmetric., Comment: 24 pages, 51 figures, numerical solution without nre-meshing the time-depdendent domain
Published: 2020
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6. A simple history dependent remeshing technique to increase finite element model stability in elastic surface deformations

Author: Crawshaw, Jessica R., Flegg, Jennifer A., Osborne, James M., Crawshaw, Jessica R., Flegg, Jennifer A., and Osborne, James M.
Abstract: In this paper, we present and validate a simple adaptive surface remeshing technique to transfer history dependent variables from an old distorting mesh to a new mesh during finite element simulations of elastic surface deformation. This technique allows us to reduce the error arising from excessive mesh distortion whilst preserving information about the initial configuration of the mesh and the history dependent variables. The transfer technique presented here constructs the initial configuration of the new mesh by considering the distortion incurred by the elements of the old mesh and projecting backward in time. Using this new initial configuration, the stress and strain over the new mesh can be easily calculated. After presenting the necessary steps to reconstruct the initial configuration, we show that this relatively simple transfer technique adds stability to finite element simulations and reduces the spatial error and the strain error across the domain. The novel transfer technique presented in this paper is easy to implement and provides a simple strategy to add stability to simulations undergoing large deformations.
Published: 2020

7. A mathematical model of the use of supplemental oxygen to combat surgical site infection

Author: Jayathilake, Chathranee, Maini, Philip, Hopf, Harriet, McElwain, Sean, Byrne, Helen, Flegg, Mark, Flegg, Jennifer, Jayathilake, Chathranee, Maini, Philip, Hopf, Harriet, McElwain, Sean, Byrne, Helen, Flegg, Mark, and Flegg, Jennifer
Abstract: Infections are a common complication of any surgery, often requiring a recovery period in hospital. Supplemental oxygen therapy administered during and immediately after surgery is thought to enhance the immune response to bacterial contamination. However, aerobic bacteria thrive in oxygen-rich environments, and so it is unclear whether oxygen has a net positive effect on recovery. Here, we develop a mathematical model of post-surgery infection to investigate the efficacy of supplemental oxygen therapy on surgical-site infections. A 4-species, coupled, set of non-linear partial differential equations that describes the space-time dependence of neutrophils, bacteria, chemoattractant and oxygen is developed and analysed to determine its underlying properties. Through numerical solutions, we quantify the efficacy of different supplemental oxygen regimes on the treatment of surgical site infections in wounds of different initial bacterial load. A sensitivity analysis is performed to investigate the robustness of the predictions to changes in the model parameters. The numerical results are in good agreement with analyses of the associated well-mixed model. Our model findings provide insight into how the nature of the contaminant and its initial density influence bacterial infection dynamics in the surgical wound.
Published: 2019

8. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : an individual patient data meta-analysis

Author: Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., Winstanley, Peter A., Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., and Winstanley, Peter A.
Abstract: Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrude
Published: 2015
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9. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data

Author: Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, Zongo, Issaka, Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, and Zongo, Issaka
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
Published: 2015
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10. 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

Author: Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., Zongo, Issaka, Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., and Zongo, Issaka
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 degrees 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 (
Published: 2015
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11. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : an individual patient data meta-analysis

Author: Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., Winstanley, Peter A., Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., and Winstanley, Peter A.
Abstract: Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrude
Published: 2015
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12. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : an individual patient data meta-analysis

Author: Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., Winstanley, Peter A., Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., and Winstanley, Peter A.
Abstract: Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrude
Published: 2015
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13. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data

Author: Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, Zongo, Issaka, Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, and Zongo, Issaka
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
Published: 2015
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14. 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

Author: Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., Zongo, Issaka, Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., and Zongo, Issaka
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 degrees 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 (
Published: 2015
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15. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data

Author: Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, Zongo, Issaka, Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, and Zongo, Issaka
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
Published: 2015
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16. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data

Author: Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, Zongo, Issaka, Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, and Zongo, Issaka
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
Published: 2015
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17. 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, 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, Tine, Roger CK, WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, 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
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 < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a
Published: 2015

18. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis

Author: Abdulla, Salim, Ashley, Elizabeth, Bassat, Quique, Bethell, Delia, Björkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P. J., Diakite, Mahamadou, Djimde, Abdoulaye, Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abdul, Falade, Catherine, Flegg, Jennifer A., Price, Ric N., Abdulla, Salim, Ashley, Elizabeth, Bassat, Quique, Bethell, Delia, Björkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P. J., Diakite, Mahamadou, Djimde, Abdoulaye, Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abdul, Falade, Catherine, Flegg, Jennifer A., and Price, Ric N.
Abstract: BackgroundArtemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up.MethodsData from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive.ResultsPC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28–63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2–12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95–4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44–3.45 for tenfold increase, p < 0.001) were associated independently with an increased
Published: 2015

19. On the mathematical modeling of wound healing angiogenesis in skin as a reaction-transport process

Author: Flegg, Jennifer, Menon, Shakti, Maini, Philip, McElwain, Sean, Flegg, Jennifer, Menon, Shakti, Maini, Philip, and McElwain, Sean
Abstract: Over the last 30 years, numerous research groups have attempted to provide mathematical descriptions of the skin wound healing process. The development of theoretical models of the interlinked processes that underlie the healing mechanism has yielded considerable insight into aspects of this critical phenomenon that remain difficult to investigate empirically. In particular, the mathematical modeling of angiogenesis, i.e., capillary sprout growth, has offered new paradigms for the understanding of this highly complex and crucial step in the healing pathway. With the recent advances in imaging and cell tracking, the time is now ripe for an appraisal of the utility and importance of mathematical modeling in wound healing angiogenesis research. The purpose of this review is to pedagogically elucidate the conceptual principles that have underpinned the development of mathematical descriptions of wound healing angiogenesis, specifically those that have utilized a continuum reaction-transport framework, and highlight the contribution that such models have made toward the advancement of research in this field. We aim to draw attention to the common assumptions made when developing models of this nature, thereby bringing into focus the advantages and limitations of this approach. A deeper integration of mathematical modeling techniques into the practice of wound healing angiogenesis research promises new perspectives for advancing our knowledge in this area. To this end we detail several open problems related to the understanding of wound healing angiogenesis, and outline how these issues could be addressed through closer cross-disciplinary collaboration.
Published: 2015

20. 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, 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, Tine, Roger CK, WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, 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
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 < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment w
Published: 2015

21. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : an individual patient data meta-analysis

Author: Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., Winstanley, Peter A., Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., and Winstanley, Peter A.
Abstract: Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrude
Published: 2015
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22. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data

Author: Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, Zongo, Issaka, Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, and Zongo, Issaka
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
Published: 2015
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23. 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

Author: Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., Zongo, Issaka, Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., and Zongo, Issaka
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 degrees 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 (
Published: 2015
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24. 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

Author: Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., Zongo, Issaka, Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., and Zongo, Issaka
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 degrees 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 (
Published: 2015
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25. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : an individual patient data meta-analysis

Author: Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., Winstanley, Peter A., Abdulla, Salim, Ashley, Elizabeth A., Bassat, Quique, Bethell, Delia, Bjorkman, Anders, Borrmann, Steffen, D'Alessandro, Umberto, Dahal, Prabin, Day, Nicholas P., Diakite, Mahamadou, Djimde, Abdoulaye A., Dondorp, Arjen M., Duong, Socheat, Edstein, Michael D., Fairhurst, Rick M., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole, Gonzalez, Raquel, Greenwood, Brian, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, Htut, Ye, Juma, Elizabeth, Lim, Pharath, Mårtensson, Andreas, Mayxay, Mayfong, Mokuolu, Olugbenga A., Moreira, Clarissa, Newton, Paul, Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Onyamboko, Marie A., Owusu-Agyei, Seth, Phyo, Aung Pyae, Premji, Zul, Price, Ric N., Pukrittayakamee, Sasithon, Ramharter, Michael, Sagara, Issaka, Se, Youry, Suon, Seila, Stepniewska, Kasia, Ward, Stephen A., White, Nicholas J., and Winstanley, Peter A.
Abstract: Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrude
Published: 2015
Full Text: View/download PDF

26. 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

Author: Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., Zongo, Issaka, Abdulla, Salim, Adam, Ishag, Adjei, George O., Adjuik, Martin A., Alemayehu, Bereket, Allan, Richard, Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Berens-Riha, Nicole, Bjoerkman, Anders, Bompart, Francois, Bonnet, Maryline, Borrmann, Steffen, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Checchi, Francesco, Dahal, Prabin, D'Alessandro, Umberto, Desai, Meghna, Dicko, Alassane, Djimde, Abdoulaye A., Dorsey, Grant, Doumbo, Ogobara K., Drakeley, Chris J., Duparc, Stephan, Eshetu, Teferi, Espie, Emmanuelle, Etard, Jean-Francois, Faiz, Abul M., Falade, Catherine O., Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Faye, Oumar, Filler, Scott, Flegg, Jennifer A., Fofana, Bakary, Fogg, Carole, Gadalla, Nahla B., Gaye, Oumar, Genton, Blaise, Gething, Peter W., Gil, Jose P., Gonzalez, Raquel, Grandesso, Francesco, Greenhouse, Bryan, Greenwood, Brian, Grivoyannis, Anastasia, Guerin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hamour, Sally, Hay, Simon I., Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ibrahim, Maman L., Jima, Daddi, Jones, Joel J., Jullien, Vincent, Juma, Elizabeth, Kachur, Patrick S., Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kiechel, Jean-Rene, Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Krishna, Sanjeev, Lameyre, Valerie, Lell, Bertrand, Lima, Angeles, Makanga, Michael, Malik, ElFatih M., Marsh, Kevin, Mårtensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, Clara, Mens, Petra F., Meremikwu, Martin, Moreira, Clarissa, Nabasumba, Carolyn, Nambozi, Michael, Ndiaye, Jean-Louis, Ngasala, Billy E., Nikiema, Frederic, Nsanzabana, Christian, Ntoumi, Francine, Oguike, Mary, Ogutu, Bernhards R., Olliaro, Piero, Omar, Sabah A., Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Penali, Louis K., Pene, Mbaye, Peshu, Judy, Piola, Patrice, Plowe, Christopher V., Premji, Zul, Price, Ric N., Randrianarivelojosia, Milijaona, Rombo, Lars, Roper, Cally, Rosenthal, Philip J., Sagara, Issaka, Same-Ekobo, Albert, Sawa, Patrick, Schallig, Henk D. F. H., Schramm, Birgit, Seck, Amadou, Shekalaghe, Seif A., Sibley, Carol H., Sinou, Vronique, Sirima, Sodiomon B., Som, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Sutherland, Colin J., Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tine, Roger C. K., Tinto, Halidou, Tommasini, Silva, Toure, Offianan A., Ursing, Johan, Vaillant, Michel T., Valentini, Giovanni, Van den Broek, Ingrid, Van Vugt, Michele, Ward, Stephen A., Winstanley, Peter A., Yavo, William, Yeka, Adoke, Zolia, Yah M., and Zongo, Issaka
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 degrees 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 (
Published: 2015
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27. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data

Author: Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, Zongo, Issaka, Adjuik, Martin A., Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Ba, Mamadou S., Barennes, Hubert, Barnes, Karen I., Bassat, Quique, Baudin, Elisabeth, Bjorkman, Anders, Bompart, Francois, 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., Espie, Emmanuelle, Etard, Jean-Francois, Fanello, Caterina I., Faucher, Jean-Francois, Faye, Babacar, Flegg, Jennifer A., Gaye, Oumar, Gething, Peter W., Gonzalez, 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, Valerie, Ibrahim, Laminou M., Lee, Sue J., Lell, Bertrand, Martensson, Andreas, Massougbodji, Achille, Menan, Herve, Menard, Didier, Menendez, 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, Ouedraogo, 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, Veronique, Sirima, Sodiomon B., Smith, Jeffery J., Smithuis, Frank, Some, Fabrice A., Sow, Doudou, Staedke, Sarah G., Stepniewska, Kasia, Swarthout, Todd D., Sylla, Khadime, Talisuna, Ambrose O., Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel A., Thwing, Julie I., Tjitra, Emiliana, Tine, Roger C. K., Tinto, Halidou, Vaillant, Michel T., Valecha, Neena, Van den Broek, Ingrid, White, Nicholas J., Yeka, Adoke, and Zongo, Issaka
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
Published: 2015
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28. Students' approaches to learning a new mathematical model

Author: Flegg, Jennifer, Mallet, Dann, Lupton, Mandy, Flegg, Jennifer, Mallet, Dann, and Lupton, Mandy
Abstract: In this article, we report on the findings of an exploratory study into the experience of undergraduate students as they learn new mathematical models. Qualitative and quanti- tative data based around the students’ approaches to learning new mathematical models were collected. The data revealed that students actively adopt three approaches to under- standing a new mathematical model: gathering information for the task of understanding the model, practising with and using the model, and finding interrelationships between elements of the model. We found that the students appreciate mathematical models that have a real world application and that this can be used to engage students in higher level learning approaches.
Published: 2013

29. Growth of confined cancer spheroids: a combined experimental and mathematical modelling approach

Author: Loessner, Daniela, Flegg, Jennifer, Byrne, Helen, Clements, Judith, Hutmacher, Dietmar, Loessner, Daniela, Flegg, Jennifer, Byrne, Helen, Clements, Judith, and Hutmacher, Dietmar
Abstract: A critical step in the dissemination of ovarian cancer is the formation of multicellular spheroids from cells shed from the primary tumour. The objectives of this study were to apply bioengineered three-dimensional (3D) microenvironments for culturing ovarian cancer spheroids in vitro and simultaneously to build on a mathematical model describing the growth of multicellular spheroids in these biomimetic matrices. Cancer cells derived from human epithelial ovarian carcinoma were embedded within biomimetic hydrogels of varying stiffness and grown for up to 4 weeks. Immunohistochemistry, imaging and growth analyses were used to quantify the dependence of cell proliferation and apoptosis on matrix stiffness, long-term culture and treatment with the anti-cancer drug paclitaxel. The mathematical model was formulated as a free boundary problem in which each spheroid was treated as an incompressible porous medium. The functional forms used to describe the rates of cell proliferation and apoptosis were motivated by the experimental work and predictions of the mathematical model compared with the experimental output. This work aimed to establish whether it is possible to simulate solid tumour growth on the basis of data on spheroid size, cell proliferation and cell death within these spheroids. The mathematical model predictions were in agreement with the experimental data set and simulated how the growth of cancer spheroids was influenced by mechanical and biochemical stimuli including matrix stiffness, culture duration and administration of a chemotherapeutic drug. Our computational model provides new perspectives on experimental results and has informed the design of new 3D studies of chemoresistance of multicellular cancer spheroids.
Published: 2013

30. Modelling the interaction of keratinocytes and fibroblasts during normal and abnormal wound healing processes

Author: Menon, Shakti, Flegg, Jennifer, McCue, Scott, Schugart, Richard, Dawson, Rebecca, McElwain, Sean, Menon, Shakti, Flegg, Jennifer, McCue, Scott, Schugart, Richard, Dawson, Rebecca, and McElwain, Sean
Abstract: The crosstalk between fibroblasts and keratinocytes is a vital component of the wound healing process, and involves the activity of a number of growth factors and cytokines. In this work, we develop a mathematical model of this crosstalk in order to elucidate the effects of these interactions on the regeneration of collagen in a wound that heals by second intention. We consider the role of four components that strongly affect this process: transforming growth factor-beta, platelet-derived growth factor, interleukin-1 and keratinocyte growth factor. The impact of this network of interactions on the degradation of an initial fibrin clot, as well as its subsequent replacement by a matrix that is mainly comprised of collagen, is described through an eight-component system of nonlinear partial differential equations. Numerical results, obtained in a two-dimensional domain, highlight key aspects of this multifarious process such as reepithelialisation. The model is shown to reproduce many of the important features of normal wound healing. In addition, we use the model to simulate the treatment of two pathological cases: chronic hypoxia, which can lead to chronic wounds; and prolonged inflammation, which has been shown to lead to hypertrophic scarring. We find that our model predictions are qualitatively in agreement with previously reported observations, and provide an alternative pathway for gaining insight into this complex biological process.
Published: 2012

31. Wound healing angiogenesis: The clinical implications of a simple mathematical model

Author: Flegg, Jennifer, Byrne, Helen, Flegg, Mark, McElwain, Sean, Flegg, Jennifer, Byrne, Helen, Flegg, Mark, and McElwain, Sean
Abstract: Nonhealing wounds are a major burden for health care systems worldwide. In addition, a patient who suffers from this type of wound usually has a reduced quality of life. While the wound healing process is undoubtedly complex, in this paper we develop a deterministic mathematical model, formulated as a system of partial differential equations, that focusses on an important aspect of successful healing: oxygen supply to the wound bed by a combination of diffusion from the surrounding unwounded tissue and delivery from newly formed blood vessels. While the model equations can be solved numerically, the emphasis here is on the use of asymptotic methods to establish conditions under which new blood vessel growth can be initiated and wound-bed angiogenesis can progress. These conditions are given in terms of key model parameters including the rate of oxygen supply and its rate of consumption in the wound. We use our model to discuss the clinical use of treatments such as hyperbaric oxygen therapy, wound bed debridement, and revascularisation therapy that have the potential to initiate healing in chronic, stalled wounds.
Published: 2012

32. Students' perceptions of the relevance of mathematics in engineering

Author: Flegg, Jennifer, Mallet, Dann, Lupton, Mandy, Flegg, Jennifer, Mallet, Dann, and Lupton, Mandy
Abstract: In this paper, we report on the findings of an exploratory study into the experience of students as they learn first year engineering mathematics. Here we define engineering as the application of mathematics and sciences to the building and design of projects for the use of society (Kirschenman and Brenner 2010)d. Qualitative and quantitative data on students' views of the relevance of their mathematics study to their engineering studies and future careers in engineering was collected. The students described using a range of mathematics techniques (mathematics skills developed, mathematics concepts applied to engineering and skills developed relevant for engineering) for various usages (as a subject of study, a tool for other subjects or a tool for real world problems). We found a number of themes relating to the design of mathematics engineering curriculum emerged from the data. These included the relevance of mathematics within different engineering majors, the relevance of mathematics to future studies, the relevance of learning mathematical rigour, and the effectiveness of problem solving tasks in conveying the relevance of mathematics more effectively than other forms of assessment. We make recommendations for the design of engineering mathematics curriculum based on our findings.
Published: 2012

33. Communicating assessment criteria is not sufficient for influencing students' approaches to assessment tasks - Perspectives from a Differential Equations Class

Author: Brown, S, Larsen, S, Oehrtman, M, Marrongelle, K, Mallet, Dann, Flegg, Jennifer, Brown, S, Larsen, S, Oehrtman, M, Marrongelle, K, Mallet, Dann, and Flegg, Jennifer
Abstract: This report presents the findings of an exploratory study into the perceptions held by students regarding the use of criterion-referenced assessment in an undergraduate differential equations class. Students in the class were largely unaware of the concept of criterion referencing and of the various interpretations that this concept has among mathematics educators. Our primary goal was to investigate whether explicitly presenting assessment criteria to students was useful to them and guided them in responding to assessment tasks. Quantitative data and qualitative feedback from students indicates that while students found the criteria easy to understand and useful in informing them as to how they would be graded, the manner in which they actually approached the assessment activity was not altered as a result of the use of explicitly communicated grading criteria.
Published: 2011

34. Towards a classification of criterion referenced assessment models in mathematics courses - student and academic perspectives

Author: Barton, S, Suzuki, K, Hedberg, J, Mallet, Dann, Flegg, Jennifer, Barton, S, Suzuki, K, Hedberg, J, Mallet, Dann, and Flegg, Jennifer
Abstract: We present the findings of a study into the implementation of explicitly criterion- referenced assessment in undergraduate courses in mathematics. We discuss students' concepts of criterion referencing and also the various interpretations that this concept has among mathematics educators. Our primary goal was to move towards a classification of criterion referencing models in quantitative courses. A secondary goal was to investigate whether explicitly presenting assessment criteria to students was useful to them and guided them in responding to assessment tasks. The data and feedback from students indicates that while students found the criteria easy to understand and useful in informing them as to how they would be graded, it did not alter the way the actually approached the assessment activity.
Published: 2011

35. Mathematical model of hyperbaric oxygen therapy applied to chronic diabetic wounds

Author: Flegg, Jennifer, Byrne, Helen, McElwain, Sean, Flegg, Jennifer, Byrne, Helen, and McElwain, Sean
Published: 2010

36. Mathematical modelling of chronic wound healing

Author: Flegg, Jennifer Anne and Flegg, Jennifer Anne
Abstract: Chronicwounds fail to proceed through an orderly process to produce anatomic and functional integrity and are a significant socioeconomic problem. There is much debate about the best way to treat these wounds. In this thesis we review earlier mathematical models of angiogenesis and wound healing. Many of these models assume a chemotactic response of endothelial cells, the primary cell type involved in angiogenesis. Modelling this chemotactic response leads to a system of advection-dominated partial differential equations and we review numerical methods to solve these equations and argue that the finite volume method with flux limiting is best-suited to these problems. One treatment of chronic wounds that is shrouded with controversy is hyperbaric oxygen therapy (HBOT). There is currently no conclusive data showing that HBOT can assist chronic wound healing, but there has been some clinical success. In this thesis we use several mathematical models of wound healing to investigate the use of hyperbaric oxygen therapy to assist the healing process - a novel threespecies model and a more complex six-species model. The second model accounts formore of the biological phenomena but does not lend itself tomathematical analysis. Bothmodels are then used tomake predictions about the efficacy of hyperbaric oxygen therapy and the optimal treatment protocol. Based on our modelling, we are able to make several predictions including that intermittent HBOT will assist chronic wound healing while normobaric oxygen is ineffective in treating such wounds, treatment should continue until healing is complete and finding the right protocol for an individual patient is crucial if HBOT is to be effective. Analysis of the models allows us to derive constraints for the range of HBOT protocols that will stimulate healing, which enables us to predict which patients are more likely to have a positive response to HBOT and thus has the potential to assist in improving both the success rate and th
Published: 2009

37. A Three Species Model to Simulate Application of Hyperbaric Oxygen Therapy to Chronic Wounds

Author: Flegg, Jennifer, McElwain, Sean, Bryne, Helen, Turner, Ian, Flegg, Jennifer, McElwain, Sean, Bryne, Helen, and Turner, Ian
Abstract: Chronic wounds are a significant socioeconomic problem for governments worldwide. Approximately 15% of people who suffer from diabetes will experience a lower-limb ulcer at some stage of their lives, and 24% of these wounds will ultimately result in amputation of the lower limb. Hyperbaric Oxygen Therapy (HBOT) has been shown to aid the healing of chronic wounds; however, the causal reasons for the improved healing remain unclear and hence current HBOT protocols remain empirical. Here we develop a three-species mathematical model of wound healing that is used to simulate the application of hyperbaric oxygen therapy in the treatment of wounds. Based on our modelling, we predict that intermittent HBOT will assist chronic wound healing while normobaric oxygen is ineffective in treating such wounds. Furthermore, treatment should continue until healing is complete, and HBOT will not stimulate healing under all circumstances, leading us to conclude that finding the right protocol for an individual patient is crucial if HBOT is to be effective. We provide constraints that depend on the model parameters for the range of HBOT protocols that will stimulate healing. More specifically, we predict that patients with a poor arterial supply of oxygen, high consumption of oxygen by the wound tissue, chronically hypoxic wounds, and/or a dysfunctional endothelial cell response to oxygen are at risk of nonresponsiveness to HBOT. The work of this paper can, in some way, highlight which patients are most likely to respond well to HBOT (for example, those with a good arterial supply), and thus has the potential to assist in improving both the success rate and hence the costeffectiveness of this therapy.
Published: 2009

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