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1. ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

Author: Clare Shakeshaft, Carlo Giaquinto, Tim R. Cressey, Adeodata Kekitiinwa, David M. Burger, Pauline Amuge, Pablo Rojo, Cecilia L. Moore, Osee Behuhuma, Yacine Saϊdi, Linda Barlow-Mosha, James Hakim, Alexandra Compagnucci, Lorna Atwine, Diana M. Gibb, Ebrahim Variava, Hilda Mujuru, Mark F. Cotton, Victor Musiime, Moherndran Archary, Deborah Ford, Cissy Kityo, Thanyawee Puthanakit, Anna Turkova, Avy Violari, Abbas Lugemwa, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), University of Zimbabwe (UZ), Baylor College of Medicine Children's Foundation [Kampala, Uganda] (BCMCF), Joint Clinical Research Centre, MUJHU Research Collaboration [Kampala, Uganda] (MUJHURC), Chiang Mai University (CMU), Harvard T.H. Chan School of Public Health, University of Liverpool, Perinatal HIV Research Unit [Johannesburg, South Africa] (PHRU), University of the Witwatersrand [Johannesburg] (WITS), Klerksdorp Tshepong Hospital Complex [Matlosana, South Africa] (KTHC), Family Center for Research with Ubuntu [Cape Town, South Africa] (FCRU), Durban International Clinical Research Site [Durban, South Africa] (DICRS), Essais Thérapeutiques et Maladies Infectieuses, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chulalongkorn University [Bangkok], Africa Health Research Institute [Hlabisa, South Africa] (AHRI), Hlabisa Hospital [Hlabisa, South Africa] (HH), Radboud University Medical Center [Nijmegen], Università degli Studi di Padova = University of Padua (Unipd), Hospital Universitario 12 de Octubre [Madrid], ODYSSEY Trial Team: Shabinah Ali, Abdel Babiker, Chiara Borg, Anne-Marie Borges Da Silva, Joanna Calvert, Deborah Ford, Joshua Gasa, Diana M Gibb, Nasir Jamil, Sarah Lensen, Emma Little, Fatima Mohamed, Samuel Montero, Cecilia L Moore, Rachel Oguntimehin, Anna Parker, Reena Patel, Tasmin Phillips, Tatiana Sarfati, Karen Scott, Clare Shakeshaft, Moira Spyer, Margaret Thomason, Anna Turkova, Rebecca Turner, Nadine Van Looy, Ellen White, Kaya Widuch, Helen Wilkes, Ben Wynne, Carlo Giaquinto, Tiziana Grossele, Daniel Gomez-Pena, Davide Bilardi, Giulio Vecchia, Alexandra Compagnucci, Yacine Saidi, Yoann Riault, Alexandra Coelho, Laura Picault, Christelle Kouakam, Tim R Cressey, Suwalai Chalermpantmetagul, Dujrudee Chinwong, Gonzague Jourdain, Rukchanok Peongjakta, Pra-Ornsuda Sukrakanchana, Wasna Sirirungsi, Janet Seeley, Sarah Bernays, Magda Conway, Nigel Klein, Eleni Nastouli, Anita De Rossi, Maria Angeles Munoz Fernandez, David Burger, Pauline Bollen, Angela Colbers, Hylke Waalewijn, Cissy M Kityo, Victor Musiime, Elizabeth Kaudha, Annet Nanduudu, Emmanuel Mujyambere, Paul Ocitti Labeja, Charity Nankunda, Juliet Ategeka, Peter Erim, Collin Makanga, Esther Nambi, Abbas Lugemwa, Lorna Atwine, Edridah Keminyeto, Deogratiuos Tukwasibwe, Shafic Makumbi, Emily Ninsiima, Mercy Tukamushaba, Rogers Ankunda, Ian Natuhurira, Miriam Kasozi, Baker Rubinga, Adeodata R Kekitiinwa, Pauline Amuge, Dickson Bbuye, Justine Nalubwama, Winnie Akobye, Muzamil Nsibuka Kisekka, Anthony Kirabira, Gloria Ninsiima, Sylvia Namanda, Gerald Agaba, Immaculate Nagawa, Annet Nalugo, Florence Namuli, Rose Kadhuba, Rachael Namuddu, Lameck Kiyimba, Angella Baita, Eunice Atim, Olivia Kobusingye, Clementine Namajja, Africanus Byaruhanga, Rogers Besigye, Herbert Murungi, Geoffrey Onen, Philippa Musoke, Linda Barlow-Mosha, Grace Ahimbisibwe, Rose Namwanje, Monica Etima, Mark Ssenyonga, Robert Serunjogi, Hajira Kataike, Richard Isabirye, David Balamusani, Monica Nolan, Mark F Cotton, Anita Janese van Rensburg, Marlize Smuts, Catherine Andrea, Sumaya Dadan Sonja Pieterse, Vinesh Jaeven, Candice Makola, George Fourie, Kurt Smith, Els Dobbels, Peter Zuidewind, Hesti Van Huyssteen, Mornay Isaacs, Georgina Nentsa, Thabis Ncgaba, Candice MacDonald, Mandisa Mtshagi, Maria Bester, Wilma Orange, Ronelle Arendze, Mark Mulder, George Fourie, Avy Violari, Nastassja Ramsagar, Afaaf Liberty, Ruth Mathiba, Lindiwe Maseko, Nakata Kekane, Busi Khumlo, Mirriam Khunene, Noshalaza Sbisi, Jackie Brown, Ryphina Madonsela, Nokuthula Mbadaliga, Zaakirah Essack, Reshma Lakha, Aasia Vadee, Derusha Frank, Nazim Akoojee, Maletsatsi Monametsi, Gladness Machache, Yolandie Fourie, Anusha Nanan-Kanjee, Juan Erasmus, Angelous Mamiane, Tseleng Daniel, Fatima Mayat, Nomfundo Maduna, Patsy Baliram, Chaiwat Ngampiyasakul, Pisut Greetanukroh, Wanna Chamjamrat, Praechadaporn Khannak, Pornchai Techakunakorn, Thitiwat Thapwai, Patcharee Puangmalai, Ampai Maneekaew, Pradthana Ounchanum, Yupawan Thaweesombat, Areerat Kongponoi, Jutarat Thewsoongnoen, Suparat Kanjanavanit, Pacharaporn Yingyong, Thida Namwong, Rangwit Junkaew, Ussanee Srirompotong, Patamawadee Sudsaard, Siripun Nuanbuddee, Sookpanee Wimonklang, Sathaporn Na-Rajsima, Suchart Thongpaen, Pattira Runarassamee, Watchara Meethaisong, Arttasid Udomvised, Ebrahim Variava, Modiehi Rakgokong, Dihedile Scheppers, Tumelo Moloantoa, Abdul Hamid Kaka, Tshepiso Masienyane, Akshmi Ori, Kgosimang Mmolawa, Pattamukkil Abraham, Moherndran Archary, Rejoice Mosia, Sajeeda Mawlana, Rosie Mngqibisa, Rashina Nundlal, Elishka Singh, Penelope Madlala, Allemah Naidoo, Sphiwee Cebekhulu, Petronelle Casey, Collin Pillay, Subashinie Sidhoo, Minenhle Chikowore, Lungile Nyantsa, Melisha Nunkoo, Terence Nair, Enbavani Pillay, Sheleika Singh, Sheroma Rajkumar, Osee Behuhuma, Olivier Koole, Kristien Bird, Nomzamo Buthelezi, Mumsy Mthethwa, James Hakim, Hilda Mujuru, Kusum Nathoo, Mutsa Bwakura-Dangarembizi, Ennie Chidziva, Shepherd Mudzingwa, Themelihle Bafana, Colin Warambwa, Godfrey Musoro, Gloria Tinago, Shirley Mutsai, Columbus Moyo, Ruth Nhema, Misheck Nkalo Phiri, Stuart Chitongo, Joshua Choga, Joyline Bhiri, Wilber Ishemunyoro, Makhosonke Ndlovu, Thanyawee Puthanakit, Naruporn Kasipong, Sararut Chanthaburanun, Kesdao Nanthapisal, Thidarat Jupimai, Thornthun Noppakaorattanamanee, Torsak Bunupuradah, Wipaporn Natalie Songtaweesin, Chutima Saisaengjan, Stephan Schultze-Straber, Christoph Konigs, Robin Kobbe, Felicia Mantkowski, Steve Welch, Jacqui Daglish, Laura Thrasyvoulou, Delane Singadia, Sophie Foxall, Judith Acero, Gosia Pasko-Szcech, Jacquie Flynn, Gareth Tudor-Williams, Farhana Abdulla, Srini Bandi, Jin Li, Sean O'Riordan, Dominique Barker, Richard Vowden, Colin Ball Eniola Nsirim, Kathleen McClughlin, India Garcia, Pablo Rojo Conejo, Cristina Epalza, Luis Prieto Tato, Maite Fernandez, Luis Escosa Garcia, Maria José Mellado Peña, Talia Sainz Costa, Claudia Fortuny Guasch, Antoni Noguera Julian, Carolina Estepa, Elena Bruno, Alba Murciano Cabeza, Maria Angeles Muñoz Fernandez, Paula Palau, Laura Marques, Carla Teixeira, Alexandre Fernandes, Rosita Nunes, Helena Nascimento, Andreia Padrao, Joana Tuna, Helena Ramos, Ana Constança Mendes, Helena Pinheiro, Ana Cristina Matos, Flavia Kyomuhendo, Sarah Nakalanzi, Cynthia Mukisa Williams, Ntombenhle Ngcobo, Deborah Pako, Jacky Crisp, Benedictor Dube, Precious Chandiwana, Winnie Gozhora, Ian Weller, Elaine Abrams, Tsitsi Apollo, Polly Clayden, Valériane Leroy, Anton Pozniak, Jane Crawley, Rodolphe Thiébaut, Helen McIlleron, Alasdair Bamford, Hermione Lyall, Andrew Prendergast, Felicity Fitzgerald, Anna Goodman, Malbec, Odile, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Radboud University Medical Centre [Nijmegen, The Netherlands], and Universita degli Studi di Padova
Subjects: 0301 basic medicine, Male, Pediatrics, [SDV]Life Sciences [q-bio], HIV Infections, Basket trial, Dolutegravir, Efficacy, HIV, Paediatric, Pharmacokinetic, Randomized control trial, Safety, Adolescent, Body Weight, Child, Child, Preschool, Cohort Studies, Drug Dosage Calculations, Europe, Female, HIV Integrase Inhibitors, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Oxazines, Piperazines, Pyridones, RNA, Viral, South Africa, Thailand, Treatment Outcome, Uganda, Viral Load, World Health Organization, Zimbabwe, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Heterocyclic Compounds, law, Clinical endpoint, Medicine, Viral, 030212 general & internal medicine, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Viral load, Cohort study, Research Article, medicine.medical_specialty, 030106 microbiology, 3-Ring, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, lcsh:RC109-216, Dosing, Preschool, Pregnancy, business.industry, Clinical study design, medicine.disease, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, RNA, business
Abstract: Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children Methods ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children Results Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to Conclusions By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. Trial registration NCT, NCT02259127, registered 7th October 2014; EUDRACT, 2014–002632-14, registered 18th June 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES); ISRCTN, ISRCTN91737921, registered 4th October 2014.
Published: 2021
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2. Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group

Author: J. Islam, Céline Pulcini, Marlies E J L Hulscher, Paul Little, Martin Wolkewitz, Benedikt Huttner, M. van Smeden, Stéphan Juergen Harbarth, Evelina Tacconelli, J. F. Timsit, Anne-Sophie Walker, Marc J. M. Bonten, J Rodríguez Baño, M J Llewelyn, Valentijn A. Schweitzer, C.H. van Werkhoven, Alessia Savoldi, Julia Bielicki, NIHR Biomedical Research Centre (UK), University of Oxford, Public Health England, Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], Unit of Infectious Diseases, Clinical Microbiology and Preventive Medicine [Seville, Spain] (Department of Medicine), Universidad de Sevilla-Hospital Universitario Virgen Macarena [Seville, Spain]-Biomedicine Institute of Sevilla [Seville, Spain], Paediatric Infectious Diseases Research Group [London, UK], St George‘s, University of London-Institute for Infection and Immunity [London, UK], Divisions of Infectious Diseases and Infection Control [Geneva, Switzerland] (Faculty of Medicine), Geneva University Hospitals - HUG [Switzerland], Scientific Center for Quality of Healthcare [Nijmegen, The Netherlands], Radboud University Medical Center [Nijmegen]-Radboud Institute for Health Sciences [Nijmegen, the Netherlands], Department of Infectious Diseases and Infection Control [Geneva, Switzerland], Hôpitaux Universitaires de Genève (HUG), Department of Global Health and Infection [Falmer, U.K.], Brighton and Sussex Medical School (BSMS), Department of Primary Care Research [Southampton, U.K.], University of Southampton, Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Infectious Diseases [Verona, Italy], Department of Diagnostic and Public Health [Verona, Italy], Internal Medicine [Tuebingen, Germany], Tuebingen University [Germany], Department of Infectious Diseases, Università Cattolica del Sacro Cuore, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Department of Clinical Epidemiology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Institute for Medical Biometry and Statistics [Freiburg, Germany], University of Freiburg [Freiburg], Department of Medical Microbiology [Utrecht, The Netherlands], Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford], The presented work was supported by a grant (JPIAMRWG-010) from the Joint Programming Initiative on Antimicrobial Resistance. ASW is supported by the NIHR Oxford Biomedical Research Centre and the Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE) [HPRU-2012-10041], and is an NIHR Senior Investigator., Biomedicine Institute of Sevilla [Seville, Spain]-Universidad de Sevilla-Hospital Universitario Virgen Macarena [Seville, Spain], St George's, University of London-Institute for Infection and Immunity [London, UK], Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), University of Verona (UNIVR)-University of Verona (UNIVR), Università cattolica del Sacro Cuore [Milano] (Unicatt), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Sevilla. Departamento de Medicina, Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford, Joint Programming Initiative on Antimicrobial Resistance, NIHR Oxford Biomedical Research Centre, Public Health England (PHE), Vialaron, Sylvie, Universidad de Sevilla / University of Sevilla-Hospital Universitario Virgen Macarena [Séville]-Biomedicine Institute of Sevilla [Seville, Spain], Università degli studi di Verona = University of Verona (UNIVR)-Università degli studi di Verona = University of Verona (UNIVR), and Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Research design, Internationality, Appropriate antimicrobial use, Psychological intervention, Antimicrobial stewardship, Antimicrobial resistance, Antimicrobial Stewardship, 0302 clinical medicine, Surveys and Questionnaires, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, media_common, ddc:616, Clinical Trials as Topic, General Medicine, Quality, 3. Good health, Anti-Bacterial Agents, Europe, Methodology, Infectious Diseases, restrict, R852, Research Design, Psychology, Microbiology (medical), Statement of work, Consensus, media_common.quotation_subject, 030106 microbiology, antibiotic stewardship, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Humans, Quality (business), Antimicrobial Stewardship/organization & administration/standards, Medical education, Bacteria, Clinical study design, R1, Intervention (law), Anti-Bacterial Agents/therapeutic use, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Bacteria/drug effects, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) Working Group on Design of Antimicrobial Stewardship Evaluations., [Background] Antimicrobial stewardship interventions and programmes aim to ensure effective treatment while minimizing antimicrobial-associated harms including resistance. Practice in this vital area is undermined by the poor quality of research addressing both what specific antimicrobial use interventions are effective and how antimicrobial use improvement strategies can be implemented into practice. In 2016 we established a working party to identify the key design features that limit translation of existing research into practice and then to make recommendations for how future studies in this field should be optimally designed. The first part of this work has been published as a systematic review. Here we present the working group's final recommendations., [Methods] An international working group for design of antimicrobial stewardship intervention evaluations was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). The group comprised clinical and academic specialists in antimicrobial stewardship and clinical trial design from six European countries. Group members completed a structured questionnaire to establish the scope of work and key issues to develop ahead of a first face-to-face meeting that (a) identified the need for a comprehensive systematic review of study designs in the literature and (b) prioritized key areas where research design considerations restrict translation of findings into practice. The working group's initial outputs were reviewed by independent advisors and additional expertise was sought in specific clinical areas. At a second face-to-face meeting the working group developed a theoretical framework and specific recommendations to support optimal study design. These were finalized by the working group co-ordinators and agreed by all working group members., [Results] We propose a theoretical framework in which consideration of the intervention rationale the intervention setting, intervention features and the intervention aims inform selection and prioritization of outcome measures, whether the research sets out to determine superiority or non-inferiority of the intervention measured by its primary outcome(s), the most appropriate study design (e.g. experimental or quasi- experimental) and the detailed design features. We make 18 specific recommendation in three domains: outcomes, objectives and study design., [Conclusions] Researchers, funders and practitioners will be able to draw on our recommendations to most efficiently evaluate antimicrobial stewardship interventions., The presented work was supported by a grant (JPIAMRWG-010) from the Joint Programming Initiative on Antimicrobial Resistance. A.S.W. is supported by the NIHR Oxford Biomedical Research Centre and the Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE) [HPRU-2012-10041], and is an NIHR Senior Investigator.
Published: 2019
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3. Body composition and adipokines changes after initial treatment with darunavir-ritonavir plus either raltegravir or tenofovir disoproxil fumarate-emtricitabine: A substudy of the NEAT001/ANRS143 randomised trial

Author: Bernardino, Jose I., Mocroft, Amanda, Wallet, Cedrick, de Wit, Stéphane, Katlama, Christine, Reiss, Peter, Mallon, Patrick W., Richert, Laura, Molina, Jean-Michel, Knobel Freud, Hernando, Morlat, Philippe, Babiker, Abdel, Pozniac, Anton, Raffi, Francois, Arribas, José Ramón, NEAT001/ANRS143 Trial Study Group, UAM. Departamento de Medicina, Department of Internal Medicine [Madrid, Spain], Hospital Universitario La Paz [Madrid, Spain]-IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], University College of London [London] (UCL), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université libre de Bruxelles (ULB), CHU Saint-Pierre, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), University of Amsterdam [Amsterdam] (UvA), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University College Dublin [Dublin] (UCD), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), IMIM-Hospital del Mar, Generalitat de Catalunya, Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Medical Research Council Clinical Trials Unit (MRC CTU), Chelsea and Westminster Hospital, Service des maladies infectieuses et tropicales [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), NEAT is a project funded to the Instituto Superiori di Sanita-Rome, by the European Union under the Sixth Framework Programme, project number LSHP-CT-2006-037570. This analysis was also partially funded by a grant from the Ministerio de Sanidad y Asuntos Sociales de España (2009/TRA-054). The trial was also supported by Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories, and the French National Institute for Health and Medical Research-France Recherche Nord & Sud SIDA-HIV Hépatites (Inserm-ANRS) is the sponsor and a funder of the trial., Gestionnaire, Hal Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Global Health, and APH - Aging & Later Life
Subjects: Leptin, 0301 basic medicine, Male, Time Factors, Lipodystrophy, Physiology, Peptide Hormones, [SDV]Life Sciences [q-bio], Psychologie appliquée, Pathology and Laboratory Medicine, Biochemistry, Body Mass Index, Fats, 0302 clinical medicine, Bone Density, Immune Physiology, Medicine and Health Sciences, 030212 general & internal medicine, Musculoskeletal System, Immune Response, Innate Immune System, therapy HAART, Multidisciplinary, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination, Sida -- Tractament, Sciences bio-médicales et agricoles, Lipids, 3. Good health, [SDV] Life Sciences [q-bio], Arms, Adipose Tissue, Connective Tissue, Body Composition, Cytokines, Medicine, Female, Anatomy, Biologie, Research Article, medicine.drug, Adult, medicine.medical_specialty, Medicina, Science, Immunology, Urology, Adipokine, Emtricitabine, 03 medical and health sciences, Signs and Symptoms, Adipokines, Diagnostic Medicine, Raltegravir Potassium, medicine, Humans, Bone, Darunavir, Cos humà -- Composició, Inflammation, business.industry, Biology and Life Sciences, HIV, Molecular Development, Raltegravir, 030112 virology, Hormones, Fibroblast Growth Factor-23, Biological Tissue, Body Limbs, Immune System, Lean body mass, Ritonavir, business, Body mass index, Developmental Biology
Abstract: Background Comparison of changes in body composition, adipokines and inflammatory markers after initial therapy with a nucleos(t)ide reverse transcriptase inhibitor (N(t)RTI)- sparing or containing regimen are scarce. Design Randomised Clinical Trial. Methods This is the body composition substudy of NEAT 001/ANRS 143, a randomised trial comparing darunavir/ritonavir (DRV/r) plus either raltegravir (RAL) or tenofovir disoproxil fumarate/ emtricitabine (TDF/FTC) in 805 ART naïve HIV-infected adults. The primary endpoint was percentage change in limb fat at week 96. Secondary endpoints were associations among these changes and metabolic markers (IL-6, insulin, leptin, adiponectin, FGF-23). Results 126 subjects (61 DRV/r + RAL and 65 DRV/r + TDF/FTC) were included. The rate of change in BMI between groups for RAL versus TDF/FTC at week 96 was 1.5% per 48-week period (p = 0.015). The rate of change in limb fat mass, trunk fat mass, total body fat and total lean mass was for RAL versus TDF/FTC at week 96 was 2.5% (p = 0.38), 7.3% ((p = 0.021), 4.9% (p = 0.061) and 1.3% (p = 0.12) respectively. Baseline insulin and leptin levels were correlated with baseline limb fat and trunk fat mass [r = 0.31 (p = 0.0043)/r = 0.28 (p = 0.0011) for limb fat, and r = 0.63 (p, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019
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4. Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape

Author: Christian Lienhardt, Patrick P. J. Phillips, Carole D. Mitnick, James D. Neaton, Andrew J. Nunn, Payam Nahid, UCSF Center for Tuberculosis [San Francisco, CA, États-Unis], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Harvard Medical School [Boston] (HMS), School of Public Health [Minneapolis, MN, États-Unis], University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Institut de Recherche pour le Développement (IRD [France-Sud]), Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), University of California [San Francisco] (UCSF), University of California-University of California, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), and Bodescot, Myriam
Subjects: Bacterial Diseases, Extensively Drug-Resistant Tuberculosis, Antitubercular Agents, 030204 cardiovascular system & hematology, Medical and Health Sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Tuberculosis, Multidrug-Resistant, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Collection Review, Pharmaceutics, Multi-Drug-Resistant Tuberculosis, Multi-drug-resistant tuberculosis, General Medicine, Multidrug-Resistant, Phase III clinical investigation, 3. Good health, Phase III as Topic, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Tuberculosis Diagnosis and Management, Infection, medicine.medical_specialty, Drug Research and Development, Tuberculosis, Tuberculosis diagnosis and management, Treatment guidelines, Drug therapy, Clinical trials, Extensively drug-resistant tuberculosis, Research and Analysis Methods, 03 medical and health sciences, Pharmacotherapy, Drug Therapy, Diagnostic Medicine, General & Internal Medicine, Humans, Clinical Trials, Intensive care medicine, Pharmacology, Treatment Guidelines, Health Care Policy, business.industry, Clinical study design, Tropical Diseases, medicine.disease, Health Care, Clinical trial, Clinical Trials, Phase III as Topic, Clinical Medicine, business
Abstract: SUMMARY POINTS: (*) The landscape of tuberculosis (TB) treatment has evolved considerably over the last 10 years, necessitating careful consideration of various trial design aspects to ensure that TB phase III trials are still impactful at trial completion, often more than 4–5 years after initial design. (*) The choice of control is guided by the specific trial objectives, weighing the relative merits of internal validity and external generalizability alongside randomization in making the correct inference. A particular challenge occurs when international or national guidelines change during the trial. (*) Improved execution and relevance of noninferiority trials for TB require greater emphasis on study quality, especially maximizing treatment adherence and minimizing missing outcome data; preferred use of intention-to-treat rather than per-protocol analyses; more careful justification of the margin of noninferiority; and consideration of recent innovations such as a Bayesian approach to noninferiority. (*) Many adaptive trial designs are well suited to optimization of TB treatment. A thorough understanding of type I error rates and biases in treatment effect estimates is critical for regulatory approval and consideration in establishing World Health Organization (WHO) guidelines. (*) Treatment stratification is an area of limited experience for TB trials, and trialists must learn from well-established methodology in other disease areas. (*) Explanatory trials are important for evaluating the efficacy of an intervention under close to ideal conditions. However, no single trial can address all relevant questions about a given therapeutic intervention at one time, and pragmatic trials will be essential for public health and policy decision-making purposes. (*) TB treatment trials today should favor bold and creative approaches that can produce high-quality evidence for effective, patient-centered care made accessible to all 10 million new TB patients, including the half-million with drug-resistant TB (DR-TB), each year.
Published: 2019
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5. Patient-Reported Outcomes in First-Line Antiretroviral Therapy: Results From NEAT001/ANRS143 Trial Comparing Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine or Raltegravir

Author: George, Elizabeth C., Bucciardini, Raffaella, Richert, Laura, Dedes, Nikos, Fragola, Vincenzo, Nieuwkerk, Pythia, Spire, Bruno, Volny-Anne, Alain, West, Brian, Molina, Jean-Michel, Horban, Andrzej, Fox, Julie, Pozniak, Anton, Vella, Stefano, Termote, Monique, Raffi, François, Vandekerckhove, Linos, the NEAT 001/ANRS 143 Study Group, on behalf of, Medical Psychology, APH - Mental Health, APH - Personalized Medicine, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Istituto Superiore di Sanità (ISS), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), European AIDS Treatment Group [Bruxelles], Amsterdam School of Public Health [the Netherlands], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Medical University of Warsaw - Poland, NHS Foundation Trust [London], The Royal Marsden, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des maladies infectieuses et tropicales [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), the NEAT 001/ANRS 143 Study Group, Istituto Superiore di Sanita [Rome], and Richert, Laura
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Visual analogue scale, Anti-HIV Agents, 030106 microbiology, HIV Infections, treatment satisfaction, Emtricitabine, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, EQ-5D, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Antiretroviral Therapy, Highly Active, medicine, Medicine and Health Sciences, Humans, Pharmacology (medical), health improvement, 030212 general & internal medicine, Patient Reported Outcome Measures, ritonavir-boosted darunavir, Generalized estimating equation, business.industry, Middle Aged, medicine.disease, Raltegravir, humanities, 3. Good health, Regimen, Infectious Diseases, quality of life, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Major depressive disorder, Female, raltegravir, business, medicine.drug
Abstract: International audience; BACKGROUND:There are few data comparing patient reported outcomes (PROs) in randomized trials of initial antiretroviral therapy (ART). We present results from a substudy of the NEAT001/ANRS143 trial.METHODS:The randomized trial compared first-line DRV/r 800/100mg once daily plus RAL 400mg twice daily and DRV/r plus TDF/FTC 245/200mg once daily. Changes in PROs were assessed with 3 questionnaires: EuroQoL 5 domains (EQ-5D), Centre for Epidemiologic Studies Depression scale (CES-D), and HIV Treatment Satisfaction (HIVTSQ). Major Depressive Disorder (MDD) was defined as CES-d≥16. General estimating equations were used to model change over 96 weeks in PROs from baseline.RESULTS:Of the 805 participants, 797(99%) contributed to the substudy. Baseline PROs data were similar for the two randomized groups. Health status improved over time with a mean increase in EQ-5D visual analogue scale of 8.0 by W96 (95%CI 6.5-9.4; p
Published: 2018
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6. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

Author: A. Sarah Walker, Osamah Hamouda, Virginie Rondeau, Maria Dorrucci, Heiner C. Bucher, Maria Prins, Geneviève Chêne, Kholoud Porter, Caroline A. Sabin, Rodolphe Thiébaut, Benoît Marin, Dominique Costagliola, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Basel Institute for Clinical Epidemiology, University Hospital Basel [Basel], Epidémiologie Clinique et Traitement de l'Infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Malattie Infettive, Reparto di Epidemiologia, Istituto Superiore di Sanita [Rome], Department of Infectious Disease Epidemiology, Robert Koch Institute [Berlin] (RKI), Cluster Infectious Diseases, Amsterdam BioMed Cluster, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Research Department of Infection and Population Health [London], CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949., Istituto Superiore di Sanità (ISS), AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, and Infectious diseases
Subjects: Male, MESH: CD4 Lymphocyte Count, medicine.medical_treatment, CD4 cell count, Disease, MESH: Epidemiologic Methods, MESH: Antiretroviral Therapy, Highly Active, Hepatitis, Liver disease, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Neoplasms, Immunology and Allergy, MESH: Neoplasms, 030212 general & internal medicine, Causes of death, Immunodeficiency, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: AIDS-Related Opportunistic Infections, Liver Diseases, Immunosuppression, Middle Aged, Human Immunodeficiency Virus/AIDS, Antiretroviral therapy, 3. Good health, Infectious Diseases, Cardiovascular Diseases, MESH: Young Adult, Female, Viral disease, Adult, medicine.medical_specialty, MESH: Immune Tolerance, MESH: Liver Diseases, Adolescent, Immunology, Article, Young Adult, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Immune Tolerance, medicine, Humans, Seroconversion, highly active, Aged, MESH: Acquired Immunodeficiency Syndrome, MESH: Adolescent, Acquired Immunodeficiency Syndrome, MESH: Humans, AIDS-Related Opportunistic Infections, 030306 microbiology, business.industry, MESH: Cardiovascular Diseases, MESH: Adult, medicine.disease, MESH: Male, CD4 Lymphocyte Count, Neoplasm, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Bacterial infection, Epidemiologic Methods, business, MESH: Female
Abstract: International audience; OBJECTIVE: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). DESIGN: Observational multicentre cohorts. METHODS: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification. RESULTS: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. CONCLUSION: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.
Published: 2009
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7. An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012

Author: Joseph H. Perriëns, Intira Jeannie Collins, Jean-Paul Moatti, Janice Soo Fern Lee, Boniface Dongmo Nguimfack, Luis Sagaon Teyssier, Marc Lallemant, Drugs for Neglected Diseases Initiative, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), and BMC, BMC
Subjects: 0301 basic medicine, Multivariate analysis, Databases, Factual, [SDV]Life Sciences [q-bio], Developing country, Drug Costs, Competition (economics), 03 medical and health sciences, South Africa, 0302 clinical medicine, Procurement, Market segmentation, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pediatric antiretroviral prices, Income country, Medicine, Humans, Pediatrics, Perinatology, and Child Health, 030212 general & internal medicine, [SHS.ECO] Humanities and Social Sciences/Economics and Finance, Price trends, Child, Developing Countries, health care economics and organizations, business.industry, 1. No poverty, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, 030112 virology, Drug Utilization, 3. Good health, [SDV] Life Sciences [q-bio], Pediatric antiretroviral procurement, Anti-Retroviral Agents, Pediatrics, Perinatology and Child Health, Value (economics), Multivariate Analysis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Income level, Pediatrics antiretroviral market, Linear Models, Global Price Reporting Mechanism, business, Demography, Research Article
Abstract: Background The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors. Methods Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed. Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs)) Results Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p
Published: 2016
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8. The impact of transient combination antiretroviral treatment in early HIV infection on viral suppression and immunologic response in later treatment

Author: Pantazis, Nikos, Touloumi, Giota, Meyer, Laurence, Olson, Ashley, Costagliola, Dominique, Kelleher, Anthony D, Lutsar, Irja, Chaix, Marie-Laure, Fisher, Martin, Moreno, Santiago, Porter, Kholoud, Department of Hygiene, Epidemiology and Medical Statistics [Athens], University of Athens Medical School [Athens], Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Epidémiologie, Systèmes d'Information, Modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The Kirby Institute for Infection and Immunity in Society (UNSW), University of New South Wales [Sydney] (UNSW), Department of Microbiology, University of Tartu, Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), HIV/GUM Research [Brigton], Brighton and Sussex University Hospitals - NHS Trust (BSUH), Infectious Diseases Department [Madrid], Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain] (IRYCIS), Universidad de Alcalá - University of Alcalá (UAH)-Universidad de Alcalá - University of Alcalá (UAH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and d'Eggis, Gilles
Subjects: Adult, Male, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adolescent, Anti-HIV Agents, virus diseases, HIV, HIV Infections, Middle Aged, Viral Load, virologic response, CD4 Lymphocyte Count, Europe, Young Adult, Treatment Outcome, Withholding Treatment, Antiretroviral Therapy, Highly Active, immunologic response, Humans, Female, Longitudinal Studies, early/primary HIV infection, treatment reinitiation, transient combination antiretroviral treatment, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objective: Effects of transient combination antiretroviral treatment (cART) initiated during early HIV infection (EHI) remain unclear. We investigate whether this intervention affects viral suppression and CD4+ cell count increase following its reinitiation in chronic infection (CHI).Design: Longitudinal observational study.Methods: We identified adult patients from Concerted Action of Seroconversion to AIDS and Death in Europe who seroconverted after 1/1/2000, had a 12 months or less HIV test interval and initiated cART from naive. We classified individuals as ‘pretreated in EHI’ if treated within 6 months of seroconversion, interrupted for at least 12 weeks, and reinitiated during CHI. Statistical analysis was performed using survival analysis methods and mixed models.Results: Pretreated and initiated in CHI groups comprised 202 and 4263 individuals, with median follow-up after CHI treatment 4.5 and 3 years, respectively. Both groups had similar virologic response and relapse rates (P = 0.585 and P = 0.206) but pretreated individuals restarted treatment with higher baseline CD4+ cell count (~80 cells/µl; P < 0.001) and retained significantly higher CD4+ cell count for more than 3 years after treatment (re)initiation. Assuming common baseline CD4+ cell count, differences in CD4+ cell count slopes were nonsignificant. Immunovirologic response to CHI treatment was not associated with timing or duration of the transient treatment.Conclusion: Although treatment interruptions are not recommended, stopping cART initiated in EHI does not seem to reduce the chance of a successful outcome of treatment in CHI.
Published: 2016
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9. Validation of treatment escalation as a definition of atopic eczema flares

Author: Jochen Schmitt, Hywel C Williams, Sinead Langan, Kim S Thomas, Caroline O'Leary, Beth Stuart, Carle Paul, University of Nottingham, UK (UON), University of Southampton, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Medical Faculty - Carl Gustav Carus, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Faculty of Epidemiology and Population Health [London], and London School of Hygiene and Tropical Medicine (LSHTM)
Subjects: Male, Anti-Inflammatory Agents, lcsh:Medicine, MESH: Dermatitis, Atopic / pathology, Severity of Illness Index, Medical Records, law.invention, Continuous variable, law, Adrenal Cortex Hormones, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Dermatologic Agents / therapeutic use, MESH: Child, MESH: Anti-Inflammatory Agents / therapeutic use, lcsh:Science, Child, MESH: Treatment Outcome, Multidisciplinary, Atopic dermatitis, Symptom Flare Up, MESH: Infant, MESH: Administration, Cutaneous, 3. Good health, Treatment Outcome, Area Under Curve, Child, Preschool, MESH: Adrenal Cortex Hormones / therapeutic use, Female, MESH: Dermatitis, Atopic / diagnosis, Flare, Research Article, MESH: Medical Records, medicine.medical_specialty, MESH: Terminology as Topic, Adolescent, Calcineurin Inhibitors, MESH: Drug Administration Schedule, Administration, Cutaneous, Drug Administration Schedule, Dermatitis, Atopic, Internal medicine, Terminology as Topic, MESH: Severity of Illness Index, medicine, Humans, Asthma, MESH: Adolescent, MESH: Humans, MESH: Calcineurin Inhibitors / therapeutic use, Receiver operating characteristic, Binary outcome, business.industry, lcsh:R, MESH: Child, Preschool, Infant, Odds ratio, MESH: ROC Curve, medicine.disease, MESH: Male, Topical medication, Surgery, MESH: Dermatitis, Atopic / drug therapy, ROC Curve, MESH: Area Under Curve, lcsh:Q, Dermatologic Agents, business, MESH: Female, MESH: Symptom Flare Up
Abstract: Background Atopic eczema (AE) is a chronic disease with flares and remissions. Long-term control of AE flares has been identified as a core outcome domain for AE trials. However, it is unclear how flares should be defined and measured. Objective To validate two concepts of AE flares based on daily reports of topical medication use: (i) escalation of treatment and (ii) days of topical anti-inflammatory medication use (topical corticosteroids and/or calcineurin inhibitors). Methods Data from two published AE studies (studies A (n=336) and B (n=60)) were analysed separately. Validity and feasibility of flare definitions were assessed using daily global bother (scale 0 to 10) as the reference standard. Intra-class correlations were reported for continuous variables, and odds ratios and area under the receiver operator characteristic (ROC) curve for binary outcome measures. Results Good agreement was found between both AE flare definitions and change in global bother: area under the ROC curve for treatment escalation of 0.70 and 0.73 in studies A and B respectively, and area under the ROC curve of 0.69 for topical anti-inflammatory medication use (Study A only). Significant positive relationships were found between validated severity scales (POEM, SASSAD, TIS) and the duration of AE flares occurring in the previous week – POEM and SASSAD rose by half a point for each unit increase in number of days in flare. Smaller increases were observed on the TIS scale. Completeness of daily diaries was 95% for Study A and 60% for Study B over 16 weeks). Conclusion Both definitions were good proxy indicators of AE flares. We found no evidence that ‘escalation of treatment’ was a better measure of AE flares than ‘use of topical anti-inflammatory medications’. Capturing disease flares in AE trials through daily recording of medication use is feasible and appears to be a good indicator of long-term control. Trial registration Current Controlled Trials ISRCTN71423189 (Study A).
Published: 2015
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10. Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

Author: Rosmarin, D, Palles, C, Church, D, Domingo, E, Jones, A, Johnstone, E, Wang, H, Love, S, Julier, P, Scudder, C, Nicholson, G, Gonzalez-Neira, A, Martin, M, Sargent, D, Green, E, McLeod, H, Zanger, UM, Schwab, M, Braun, M, Seymour, M, Thompson, L, Lacas, B, Boige, V, Ribelles, N, Afzal, S, Enghusen, H, Jensen, SA, Etienne-Grimaldi, MC, Milano, G, Wadelius, M, Glimelius, B, Garmo, H, Gusella, M, Lecomte, T, Laurent-Puig, P, Martinez-Balibrea, E, Sharma, R, Garcia-Foncillas, J, Kleibl, Z, Morel, A, Pignon, JP, Midgley, R, Kerr, D, Tomlinson, I, University of Oxford [Oxford], Spanish National Cancer Research Center (CNIO), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Mayo Clinic [Rochester], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Molecular Mechanisms of Origin and Treatment of Breast Cancer, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University Hospital Tuebingen, The Christie NHS Foundation Trust [Manchester, Royaume-Uni], St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Hospital Universitario Virgen de la Victoria [Malaga, Espagne], Rigshospitalet [Copenhagen], Copenhagen University Hospital, Herlev and Gentofte Hospital, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Uppsala University, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Català d'Oncologia, Imperial College Healthcare NHS Trust [Londres, Royaume-Uni], Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Charles University [Prague] (CU), Cytokines : structure, signalisation et prolifération tumorale, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Paul Papin, and CRLCC Paul Papin
Subjects: Genetic Markers, Polymorphism, Genetic, Drug-Related Side Effects and Adverse Reactions, [SDV]Life Sciences [q-bio], ORIGINAL REPORTS, Thymidylate Synthase, Deoxycytidine, Predictive Value of Tests, Antineoplastic Combined Chemotherapy Protocols, Humans, Fluorouracil, Colorectal Neoplasms, Capecitabine, Dihydrouracil Dehydrogenase (NADP)
Abstract: International audience; Purpose Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.Patients and Methods We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10−6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
Published: 2014
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11. An evaluation of HIV elite controller definitions within a large seroconverter cohort collaboration

Author: Olson, Ad, Meyer, L, Prins, M, Thiebaut, R, Gurdasani, D, Guiguet, M, Chaix, Ml, Amornkul, P, Babiker, A, Sandhu, Ms, Porter, K, Giaquinto, Carlo, CASCADE Collaboration in EuroCoord, University College of London [London] ( UCL ), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Public Health Service of Amsterdam, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] ( CAM ), Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 ( UPD5 ), International AIDS Vaccine Initiative [San Francisco] ( AVI ), HAL UPMC, Gestionnaire, University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Cambridge [UK] (CAM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), International AIDS Vaccine Initiative [San Francisco] (AVI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Medical Research Council Clinical Trials Unit ( MRC CTU ), Statistics In System biology and Translational Medicine ( SISTM ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH [Paris], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], University of Texas Health Science Center, University of Texas at Houston [Houston] ( UTHealth ), Universitat de Barcelona, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Infectious diseases, Epidemiology and Data Science, Other departments, Experimental Immunology, and Global Health
Subjects: Time Factors, Epidemiology, Human immunodeficiency virus (HIV), lcsh:Medicine, HIV Infections, Communicable diseases, medicine.disease_cause, Men who have sex with men, Cohort Studies, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antiretroviral Therapy, Highly Active, HIV Seropositivity, Medicine, 030212 general & internal medicine, Cooperative Behavior, lcsh:Science, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Public health, Multidisciplinary, Statistics, Hazard ratio, Antiretrovirals, HIV diagnosis and management, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, 3. Good health, AIDS, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, HIV epidemiology, Cohort, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious diseases, RNA, Viral, HIV clinical manifestations, Research Article, Cohort study, medicine.medical_specialty, Clinical Research Design, Sida, Sexually Transmitted Diseases, Viral diseases, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Internal medicine, VIH (Virus), Humans, Retrospective Studies, Demography, Proportional Hazards Models, 030304 developmental biology, [ SDV ] Life Sciences [q-bio], business.industry, Proportional hazards model, HIV (Viruses), lcsh:R, HIV, Malalties infeccioses, medicine.disease, Clinical disease, Salut pública, Antiretroviral agents, CD4 Lymphocyte Count, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Immunology, AIDS (Disease), lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Mathematics, Follow-Up Studies
Abstract: for C A S C A D E Collaboration in EuroCoord; International audience; Background: Understanding the mechanisms underlying viral control is highly relevant to vaccine studies and elite control (EC) of HIV infection. Although numerous definitions of EC exist, it is not clear which, if any, best identify this rare phenotype.Methods: We assessed a number of EC definitions used in the literature using CASCADE data of 25,692 HIV seroconverters. We estimated proportions maintaining EC of total ART-naïve follow-up time, and disease progression, comparing to non-EC. We also examined HIV-RNA and CD4 values and CD4 slope during EC and beyond (while ART naïve).Results: Most definitions classify ∼1% as ECs with median HIV-RNA 43–903 copies/ml and median CD4>500 cells/mm3. Beyond EC status, median HIV-RNA levels remained low, although often detectable, and CD4 values high but with strong evidence of decline for all definitions. Median % ART-naïve time as EC was ≥92% although overlap between definitions was low. EC definitions with consecutive HIV-RNA measurements 90% of measurements
Published: 2014
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12. Natural history of HIV-control since seroconversion

Author: Madec, Y, Boufassa, F, Porter, K, Prins, M, Sabin, C, Monforte, AD, Amornkul, P, Bartmeyer, B, Sannes, M, Venet, A, Lambotte, O, Meyer, L, Garcia-de-Olalla, P, CASCADE Collaboration Eurocoord, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Infectious diseases, Epidemiology and Data Science, Other departments, Experimental Immunology, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Research Department of Infection and Population Health [London], Ospedale San Paolo, Partenaires INRAE, International AIDS Vaccine Initiative [San Francisco] (AVI), Robert Koch Institute [Berlin] (RKI), Ullevål University Hospital, Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], and AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
Subjects: Adult, Male, medicine.medical_specialty, Canada, Time Factors, Immunology, Viremia, HIV Infections, Kaplan-Meier Estimate, Biology, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Risk Factors, Internal medicine, HIV Seropositivity, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Seroconversion, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Proportional Hazards Models, HIV-control, seroconverters, 0303 health sciences, Proportional hazards model, Hazard ratio, Australia, Viral Load, duration of control, medicine.disease, loss of control, Confidence interval, 3. Good health, CD4 Lymphocyte Count, Natural history, Europe, Infectious Diseases, natural history, HIV-1, RNA, Viral, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Viral load
Abstract: OBJECTIVES HIV-controllers spontaneously maintain HIV viremia at an undetectable level. We aimed to describe the delay to control from seroconversion, the duration of control, and risk factors for losing control. METHODS HIV-controllers were identified from a pooled dataset of 24 seroconverter cohorts from Europe, Australia, and Canada (CASCADE). HIV-controllers had at least five consecutive viral loads less than 400/500 copies/ml, while antiretroviral therapy naive, for at least 5 years after seroconversion. End of control was defined as two consecutive viral loads above 2000 copies/ml. Duration of control was described using Kaplan-Meier estimates; factors associated with duration of control were identified using a Cox model. CD4⁺ cell count evolution during control was described using a mixed model. RESULTS Of 9896 eligible seroconverters, we identified 140 (1.4%) HIV-controllers, the largest database of HIV-controllers followed from seroconversion. For 64 with viral load measured within 24 months from seroconversion, median delay to control was 16.7 (interquartile range: 7.8-37.9) months. Probability of maintaining control 20 years after seroconversion was 0.74 [95% confidence interval (CI): 0.64-0.85]. Occurrence of blips followed by return to undetectability did not increase the risk of loss of control [hazard ratio: 0.81 (95% CI: 0.10-6.70)]. However, CD4⁺ cell loss during control was significantly accelerated in individuals with blips. CONCLUSION In most individuals, control occurred rapidly after seroconversion; however, more than 3 years were required to achieve control in 25% of HIV-controllers. Control may be sustained even when CD4⁺ cell levels are below 500 cells/μl, opening important new perspectives to understand the physiopathology underlying control.
Published: 2013
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13. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

Author: Marin, Benoît, Thiébaut, Rodolphe, Bucher, Heiner, Rondeau, Virginie, Costagliola, Dominique, Dorrucci, Maria, Hamouda, Osamah, Prins, Maria, Walker, A. Sarah, Porter, Kholoud, Sabin, Caroline, Chêne, Geneviève, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Basel Institute for Clinical Epidemiology, University Hospital Basel [Basel], Epidémiologie Clinique et Traitement de l'Infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Malattie Infettive, Reparto di Epidemiologia, Istituto Superiore di Sanita [Rome], Department of Infectious Disease Epidemiology, Robert Koch Institute [Berlin] (RKI), Cluster Infectious Diseases, Amsterdam BioMed Cluster, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Research Department of Infection and Population Health [London], and CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949.
Subjects: MESH: Immune Tolerance, MESH: Liver Diseases, MESH: CD4 Lymphocyte Count, CD4 cell count, MESH: Epidemiologic Methods, MESH: Antiretroviral Therapy, Highly Active, Hepatitis, MESH: Neoplasms, Causes of death, highly active, MESH: Acquired Immunodeficiency Syndrome, MESH: Adolescent, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: AIDS-Related Opportunistic Infections, MESH: Cardiovascular Diseases, MESH: Adult, Human Immunodeficiency Virus/AIDS, MESH: Male, Antiretroviral therapy, MESH: Young Adult, Neoplasm, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Bacterial infection, MESH: Female
Abstract: International audience; OBJECTIVE: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). DESIGN: Observational multicentre cohorts. METHODS: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification. RESULTS: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. CONCLUSION: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.
Published: 2009
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14. Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters

Author: Yoann Madec, Faroudy Boufassa, Kholoud Porter, Laurence Meyer, Epidémiologie, Démographie et Sciences Sociales: santé reproductive, sexualité et infection à VIH (Inserm U569), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d'études démographiques (INED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement d'épidémiologie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Immunology, HIV Infections, Viremia, Models, Biological, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Internal medicine, HIV Seropositivity, Humans, Immunology and Allergy, Medicine, 030212 general & internal medicine, Seroconversion, Sida, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Acquired Immunodeficiency Syndrome, 0303 health sciences, biology, business.industry, Mortality rate, virus diseases, Odds ratio, Middle Aged, Viral Load, biology.organism_classification, medicine.disease, CD4 Lymphocyte Count, 3. Good health, Infectious Diseases, Concomitant, Disease Progression, HIV-1, RNA, Viral, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Viral disease, business, Viral load
Abstract: OBJECTIVES To identify factors associated with sustained undetectable viraemia after HIV-1 seroconversion in treatment-naive patients, and to describe concomitant CD4 cell count progression. METHODS Seroconverters enrolled in CASCADE were assumed to control viraemia if at least two consecutive viral load measurements were < 400/500 copies/ml without treatment. Factors associated with undetectable viraemia were identified through a logistic regression. A joint model was used to describe simultaneously the CD4 cell count progression during and after that period and to identify factors associated with sustained undetectable viraemia. RESULTS Of 2176 seroconverters, 145 (6.7%) spontaneously controlled viraemia. Women were more likely than men to achieve undetectable viraemia [adjusted odds ratio (OR), 2.12; 95% confidence interval (CI), 1.49-3.12] unlike patients who reported a symptomatic primary infection (adjusted OR, 0.58; 95% CI, 0.36-0.94). AIDS and death rates were significantly lower in patients achieving undetectable viraemia than in the others. The median period of undetectable viraemia was 11.2 months; on average, CD4 cell counts remained stable during that period, and decreased with a mean rate of 5 cells/microl per month thereafter. High CD4 cell count at the beginning of undetectable viraemia and non-symptomatic primary infection favoured the preservation of undetectable viraemia. CONCLUSION A small proportion of seroconverters appeared to be able to control HIV viraemia spontaneously, mostly those without seroconversion illness and within a few years following seroconversion; this is associated with the benefits of slower CD4 cell count decline and improved long-term prognosis. Such persons should be targeted for in depth investigation.
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15. Legume-supplemented feed for children hospitalised with severe malnutrition: a phase II trial.

Author: Walsh K, Kiosa A, Olupot-Olupot P, Alaroker F, Okiror W, Nakuya M, Tssenyondo T, Aromut D, Okalebo BC, Muhindo R, Mpoya A, George EC, Frost GS, and Maitland K
Subjects: Humans, Infant, Child, Preschool, Male, Female, Uganda, Hospitalization, Dietary Supplements, Diarrhea, Child Nutrition Disorders diet therapy, Child Nutrition Disorders therapy, Weight Gain, Malnutrition diet therapy, Fabaceae
Abstract: Children hospitalised with severe malnutrition have high mortality and readmission rates post-discharge. Current milk-based formulations target restoring ponderal growth but not the modification of gut barrier integrity or microbiome which increases the risk of gram-negative sepsis and poor outcomes. We propose that legume-based feeds rich in fermentable carbohydrates will promote better gut health and improve overall outcomes. We conducted an open-label phase II trial at Mbale and Soroti Regional Referral Hospitals, Uganda, involving 160 children aged 6 months to 5 years with severe malnutrition (mid-upper arm circumference (MUAC) < 11·5 cm and/or nutritional oedema). Children were randomised to a lactose-free, chickpea-enriched legume paste feed (LF) ( n 80) v . WHO standard F75/F100 feeds ( n 80). Co-primary outcomes were change in MUAC and mortality to day 90. Secondary outcomes included weight gain (> 5 g/kg/d), de novo development of diarrhoea, time to diarrhoea and oedema resolution. Day 90 MUAC increase was marginally lower in LF v . WHO arm (1·1 cm (interquartile range (IQR) 1·1) v . 1·4 cm (IQR 1·40), P = 0·09); day 90 mortality was similar (11/80 (13·8 %) v . 12/80 (15 %), respectively, OR 0·91 (95 % CI 0·40, 2·07), P = 0·83). There were no differences in any of the other secondary outcomes. Owing to initial poor palatability of the LF, ten children switched to WHO feeds. Per-protocol analysis indicated a trend to lower day 90 mortality and readmission rates in the LF (6/60 (10 %) and 2/60(3 %)) v . WHO feeds (12/71(17·5 %) and 4/71(6 %)). Further refinement of LF and clinical trials are warranted, given the poor outcomes in children with severe malnutrition.
Published: 2024
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16. Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

Author: Dodd M, Carpenter J, Thompson JA, Williamson E, Fielding K, and Elbourne D
Subjects: Humans, Equivalence Trials as Topic, Antitubercular Agents therapeutic use, Antitubercular Agents administration & dosage, Tuberculosis drug therapy, Treatment Outcome, Bias, Models, Statistical, Assessment of Medication Adherence, Intention to Treat Analysis, Computer Simulation
Abstract: Background: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence., Methods: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator., Results: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power., Conclusions: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches., (© 2024 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)
Published: 2024
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17. Use of point-of-care haemoglobin tests to diagnose childhood anaemia in low- and middle-income countries: A systematic review.

Author: Brehm R, South A, and George EC
Subjects: Child, Child, Preschool, Humans, Anemia diagnosis, Anemia blood, Developing Countries, Hemoglobins analysis, Point-of-Care Testing economics
Abstract: Objectives: Anaemia is a major cause of mortality and transfusion in children in low- and middle-income countries (LMICs); however, current diagnostics are slow, costly and frequently unavailable. Point-of-care haemoglobin tests (POC(Hb)Ts) could improve patient outcomes and use of resources by providing rapid and affordable results. We systematically reviewed the literature to investigate what, where and how POC(Hb)Ts are being used by health facilities in LMICs to diagnose childhood anaemia, and to explore challenges to their use., Methods: We searched a total of nine databases and trial registries up to 10 June 2022 using the concepts: anaemia, POC(Hb)T, LMIC and clinical setting. Adults ≥21 years and literature published >15 years ago were excluded. A single reviewer conducted screening, data extraction and quality assessment (of diagnostic studies) using QUADAS-2. Outcomes including POC(Hb)T used, location, setting, challenges and diagnostic accuracy were synthesised., Results: Of 626 records screened, 41 studies were included. Evidence is available on the use of 15 POC(Hb)Ts in hospitals (n = 28, 68%), health centres (n = 9, 22%) and clinics/units (n = 10, 24%) across 16 LMICs. HemoCue (HemoCue AB, Ängelholm, Sweden) was the most used test (n = 31, 76%). Key challenges reported were overestimation of haemoglobin concentration, clinically unacceptable limits of agreement, errors/difficulty in sampling, environmental factors, cost, inter-observer variability and supply of consumables. Five POC(Hb)Ts (33%) could not detect haemoglobin levels below 4.5 g/dL. Diagnostic accuracy varied, with sensitivity and specificity to detect anaemia ranging from 24.2% to 92.2% and 70% to 96.7%, respectively., Conclusions: POC(Hb)Ts have been successfully utilised in health facilities in LMICs to diagnose childhood anaemia. However, limited evidence is available, and challenges exist that must be addressed before wider implementation. Further research is required to confirm accuracy, clinical benefits and cost-effectiveness., (© 2023 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)
Published: 2024
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18. Avoid re-interpreting fluid bolus recommendations for low-income settings.

Author: Kiguli S, Maitland K, and George E
Abstract: Competing Interests: We declare no competing interests.
Published: 2023
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19. Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT).

Author: Uyoga S, Olupot-Olupot P, Connon R, Kiguli S, Opoka RO, Alaroker F, Muhindo R, Macharia AW, Dondorp AM, Gibb DM, Walker AS, George EC, Maitland K, and Williams TN
Subjects: Blood Transfusion, Child, Child, Preschool, Hemoglobins metabolism, Humans, Infant, Anemia, Sickle Cell complications, Anemia, Sickle Cell epidemiology, Anemia, Sickle Cell therapy, Malaria epidemiology, Malaria, Falciparum epidemiology, Malaria, Falciparum parasitology
Abstract: Background: Sickle cell anaemia (SCA) has historically been associated with high levels of childhood mortality in Africa. Although malaria has a major contribution to this mortality, to date, the clinical pathology of malaria among children with SCA has been poorly described. We aimed to explore the relationship between SCA and Plasmodium falciparum malaria in further detail by investigating the burden and severity of malaria infections among children recruited with severe anaemia to the TRACT trial of blood transfusion in Africa., Methods: This study is a post-hoc secondary analysis of the TRACT trial data, conducted after trial completion. TRACT was an open-label, multicentre, factorial, randomised controlled trial enrolling children aged 2 months to 12 years who presented with severe anaemia (haemoglobin <6·0 g/dL) to four hospitals in Africa. This secondary analysis is restricted to Uganda, where the birth prevalence of SCA is approximately 1% and malaria transmission is high. Children were classified as normal (HbAA), heterozygous (HbAS), or homozygous (HbSS; SCA) for the rs334 A→T sickle mutation in HBB following batch-genotyping by PCR at the end of the trial. To avoid confounding from SCA-specific medical interventions, we considered children with an existing diagnosis of SCA (known SCA) separately from those diagnosed at the end of the trial (unknown SCA). The outcomes considered in this secondary analysis were measures of P falciparum parasite burden, features of severe malaria, and mortality at day 28 in malaria-positive children., Findings: Between Sept 17, 2014, and May 15, 2017, 3944 children with severe anaemia were enrolled into the TRACT trial. 3483 children from Uganda were considered in this secondary analysis. Overall, 1038 (30%) of 3483 Ugandan children had SCA. 1815 (78%) of 2321 children without SCA (HbAA) tested positive for P falciparum malaria, whereas the prevalence was significantly lower in children with SCA (347 [33%] of 1038; p<0·0001). Concentrations of plasma P falciparum histidine-rich protein 2 (PfHRP2), a marker of the total burden of malaria parasites within an individual, were significantly lower in children with either known SCA (median 8 ng/mL; IQR 0-57) or unknown SCA (7 ng/mL; 0-50) than in HbAA children (346 ng/mL; 21-2121; p<0·0001). In contrast to HbAA children, few HbSS children presented with classic features of severe and complicated malaria, but both the frequency and severity of anaemia were higher in HbSS children. We found no evidence for increased mortality at day 28 in those with SCA compared with those without SCA overall (hazard ratios 1·07 [95% CI 0·31-3·76] for known SCA and 0·67 [0·15-2·90] for unknown SCA)., Interpretation: The current study suggests that children with SCA are innately protected against classic severe malaria. However, it also shows that even low-level infections can precipitate severe anaemic crises that would likely prove fatal without rapid access to blood transfusion services., Funding: UK Medical Research Council, Wellcome, and UK National Institute for Health and Care Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Published: 2022
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20. A predictive algorithm for identifying children with sickle cell anemia among children admitted to hospital with severe anemia in Africa.

Author: Olupot-Olupot P, Connon R, Kiguli S, Opoka RO, Alaroker F, Uyoga S, Nakuya M, Okiror W, Nteziyaremye J, Ssenyondo T, Nabawanuka E, Kayaga J, Williams Mukisa C, Amorut D, Muhindo R, Frost G, Walsh K, Macharia AW, Gibb DM, Walker AS, George EC, Maitland K, and Williams TN
Subjects: Algorithms, Child, Hospitals, Humans, Malawi epidemiology, Uganda epidemiology, Anemia, Sickle Cell complications, Anemia, Sickle Cell diagnosis, Anemia, Sickle Cell therapy
Abstract: Sickle cell anemia (SCA) is common in sub-Saharan Africa where approximately 1% of births are affected. Severe anemia is a common cause for hospital admission within the region yet few studies have investigated the contribution made by SCA. The Transfusion and Treatment of severe anemia in African Children Trial (ISRCTN84086586) investigated various treatment strategies in 3983 children admitted with severe anemia (hemoglobin < 6.0 g/dl) based on two severity strata to four hospitals in Africa (three Uganda and one Malawi). Children with known-SCA were excluded from the uncomplicated stratum and capped at 25% in the complicated stratum. All participants were genotyped for SCA at trial completion. SCA was rare in Malawi (six patients overall), so here we focus on the participants recruited in Uganda. We present baseline characteristics by SCA status and propose an algorithm for identifying children with unknown-SCA. Overall, 430 (12%) and 608 (17%) of the 3483 Ugandan participants had known- or unknown-SCA, respectively. Children with SCA were less likely to be malaria-positive and more likely to have an affected sibling, have gross splenomegaly, or to have received a previous blood transfusion. Most outcomes, including mortality and readmission, were better in children with either known or unknown-SCA than non-SCA children. A simple algorithm based on seven admission criteria detected 73% of all children with unknown-SCA with a number needed to test to identify one new SCA case of only two. Our proposed algorithm offers an efficient and cost-effective approach to identifying children with unknown-SCA among all children admitted with severe anemia to African hospitals where screening is not widely available., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
Published: 2022
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21. Prevalence of evidence of inconsistency and its association with network structural characteristics in 201 published networks of interventions.

Author: Veroniki AA, Tsokani S, White IR, Schwarzer G, Rücker G, Mavridis D, Higgins JPT, and Salanti G
Subjects: Humans, Network Meta-Analysis As Topic, Prevalence, Regression Analysis, Reproducibility of Results
Abstract: Background: Network meta-analysis (NMA) has attracted growing interest in evidence-based medicine. Consistency between different sources of evidence is fundamental to the reliability of the NMA results. The purpose of the present study was to estimate the prevalence of evidence of inconsistency and describe its association with different NMA characteristics., Methods: We updated our collection of NMAs with articles published up to July 2018. We included networks with randomised clinical trials, at least four treatment nodes, at least one closed loop, a dichotomous primary outcome, and available arm-level data. We assessed consistency using the design-by-treatment interaction (DBT) model and testing all the inconsistency parameters globally through the Wald-type chi-squared test statistic. We estimated the prevalence of evidence of inconsistency and its association with different network characteristics (e.g., number of studies, interventions, intervention comparisons, loops). We evaluated the influence of the network characteristics on the DBT p-value via a multivariable regression analysis and the estimated Pearson correlation coefficients. We also evaluated heterogeneity in NMA (consistency) and DBT (inconsistency) random-effects models., Results: We included 201 published NMAs. The p-value of the design-by-treatment interaction (DBT) model was lower than 0.05 in 14% of the networks and lower than 0.10 in 20% of the networks. Networks including many studies and comparing few interventions were more likely to have small DBT p-values (less than 0.10), which is probably because they yielded more precise estimates and power to detect differences between designs was higher. In the presence of inconsistency (DBT p-value lower than 0.10), the consistency model displayed higher heterogeneity than the DBT model., Conclusions: Our findings show that inconsistency was more frequent than what would be expected by chance, suggesting that researchers should devote more resources to exploring how to mitigate inconsistency. The results of this study highlight the need to develop strategies to detect inconsistency (because of the relatively high prevalence of evidence of inconsistency in published networks), and particularly in cases where the existing tests have low power., (© 2021. The Author(s).)
Published: 2021
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22. Point-of-care haemoglobin testing in African hospitals: a neglected essential diagnostic test.

Author: Uyoga S, George EC, Bates I, Olupot-Olupot P, Chimalizeni Y, Molyneux EM, and Maitland K
Subjects: Child, Child, Preschool, Clinical Trials, Phase III as Topic, Female, Humans, Infant, Malawi, Male, Randomized Controlled Trials as Topic, Uganda, Algorithms, Anemia blood, Anemia diagnosis, Anemia therapy, Blood Transfusion, Hemoglobins metabolism, Point-of-Care Testing
Abstract: Owing to the rapid turnaround time in the assessment of haemoglobin level by point-of-care tests (POC Hb), these have grown in popularity and scope in large parts of the world. However, whilst POC testing for malaria and HIV remains has been integrated into patient management in Africa, the use of POC haemoglobin testing remains neglected by health services. The main users of transfusions (paediatric, maternity and trauma services) present largely as emergencies. Ward-based POC Hb could result in more rapid and accurate diagnosis of anaemia, contributing to saving of lives and at the same time reduce unnecessary transfusions which deplete the limited supplies of donated blood in Africa. Severe anaemia requiring transfusion is a major cause of paediatric admission in Africa. At a dissemination meeting to discuss the results of a large phase III paediatric transfusion trial and steps to implementation of the findings participants strongly recommended that one of the most pressing actions required was to prioritise the use of POC haemoglobin testing. This would facilitate implementation of the new transfusion algorithm, developed at the meeting, which refines patient management including blood transfusions. We present the rationale for the strongly recommended prioritisation of POC Hb, using paediatric transfusion as an exemplar., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Published: 2021
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23. Transfusion management of severe anaemia in African children: a consensus algorithm.

Author: Maitland K, Kiguli S, Olupot-Olupot P, Opoka RO, Chimalizeni Y, Alaroker F, Uyoga S, Kyeyune-Byabazaire D, M'baya B, Bates I, Williams TN, Munube D, Mbanya D, Molyneux EM, South A, Walker AS, Gibb DM, and George EC
Subjects: Africa epidemiology, Anemia, Sickle Cell epidemiology, Child, Child, Preschool, Humans, Malaria epidemiology, Male, Severity of Illness Index, Algorithms, Anemia, Sickle Cell therapy, Blood Transfusion, Consensus, Malaria therapy
Abstract: The phase III Transfusion and Treatment of severe anaemia in African Children Trial (TRACT) found that conservative management of uncomplicated severe anaemia [haemoglobin (Hb) 40-60 g/l] was safe, and that transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia (Hb <60 g/l) had strong but opposing effects on mortality, depending on fever status (>37·5°C). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all 3196 children receiving an initial transfusion there was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Published: 2021
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24. Mortality risk over time after early fluid resuscitation in African children.

Author: George EC, Kiguli S, Olupot PO, Opoka RO, Engoru C, Akech SO, Nyeko R, Mtove G, Mpoya A, Thomason MJ, Crawley J, Evans JA, Gibb DM, Babiker AG, Maitland K, and Walker AS
Subjects: Child, Humans, Resuscitation, Retrospective Studies, Time, Fluid Therapy, Infections
Abstract: Background: African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear., Methods: In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20-40 ml/kg 5% albumin or 0.9% saline over 1-2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other)., Results: Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death., Conclusions: The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration., Trial Registration: ISRCTN69856593. Date of registration 15 December 2008.
Published: 2019
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25. Implications for paediatric shock management in resource-limited settings: a perspective from the FEAST trial.

Author: Houston KA, George EC, and Maitland K
Subjects: Africa, Eastern epidemiology, Fever epidemiology, Fever etiology, Fluid Therapy adverse effects, Fluid Therapy methods, Humans, Pediatric Emergency Medicine standards, Pediatric Emergency Medicine trends, Prevalence, Resuscitation methods, Resuscitation standards, Survival Analysis, Developing Countries statistics & numerical data, Fluid Therapy standards, Health Resources supply & distribution, Pediatric Emergency Medicine methods, Shock therapy
Abstract: Background: Although the African "Fluid Expansion as Supportive therapy" (FEAST) trial showed fluid resuscitation was harmful in children with severe febrile illness managed in resource-limited hospitals, the most recent evidence reviewed World Health Organization (WHO) guidelines continue to recommend fluid boluses in children with shock according to WHO criteria "WHO shock", arguing that the numbers included in the FEAST trial were too small to provide reasonable certainty., Methods: We re-analysed the FEAST trial results for all international definitions for paediatric shock including hypotensive (or decompensated shock) and the WHO criteria. In addition, we examined the clinical relevance of the WHO criteria to published and unpublished observational studies reporting shock in resource-limited settings., Results: We established that hypotension was rare in children with severe febrile illness complicating only 29/3170 trial participants (0.9%). We confirmed that fluid boluses were harmful irrespective of the definitions of shock including the very small number with WHO shock (n = 65). In this subgroup 48% of bolus recipients died at 48 h compared to 20% of the non-bolus control group, an increased absolute risk of 28%, but translating to an increased relative risk of 240% (p = 0.07 (two-sided Fisher's exact test)). Examining studies describing the prevalence of the stringent WHO shock criteria in children presenting to hospital we found this was rare (~ 0.1%) and in these children mortality was very high (41.5-100%)., Conclusions: The updated WHO guidelines continue to recommend boluses for a very limited number of children presenting at hospital with the strict definition of WHO shock. Nevertheless, the 3% increased mortality from boluses seen across FEAST trial participants would also include this subgroup of children receiving boluses. Recommendations aiming to differentiate WHO shock from other definitions will invariably lead to "slippage" at the bedside, with the potential of exposing a wider group of children to the harm of fluid-bolus therapy.
Published: 2018
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26. Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa.

Author: Aramburo A, Todd J, George EC, Kiguli S, Olupot-Olupot P, Opoka RO, Engoru C, Akech SO, Nyeko R, Mtove G, Gibb DM, Babiker AG, and Maitland K
Subjects: Africa, Eastern, Child, Child, Preschool, Female, Humans, Infant, Malaria complications, Male, Prognosis, Risk Factors, Sepsis complications, Critical Illness mortality, Fever mortality, Lactic Acid metabolism, Malaria mortality, Sepsis mortality
Abstract: Background: Hyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas., Methods: In a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L)., Results: Of 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L). At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h (OR 4.62; 95% CI 2.7, 8.0; p < 0.001)., Conclusions: Independently of the underlying diagnosis, HL is a strong risk factor for death at 72 h in children admitted with severe febrile illnesses in Africa. Children able to clear lactate within 8 h had an improved chance of survival. These findings prompt the more widespread use of lactate and LC to identify children with severe disease and monitor response to treatment., Trial Registration: ISRCTN69856593 Registered 21 January 2009.
Published: 2018
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27. Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study.

Author: Pett SL, Kunisaki KM, Wentworth D, Griffin TJ, Kalomenidis I, Nahra R, Montejano Sanchez R, Hodgson SW, Ruxrungtham K, Dwyer D, Davey RT, and Wendt CH
Abstract: Background: Indoleamine-2,3-dioxygenase (IDO) mediated tryptophan (TRP) depletion has antimicrobial and immuno-regulatory effects. Increased kynurenine (KYN)-to-TRP (KT) ratios, reflecting increased IDO activity, have been associated with poorer outcomes from several infections., Methods: We performed a case-control (1:2; age and sex matched) analysis of adults hospitalized with influenza A(H1N1)pdm09 with protocol-defined disease progression (died/transferred to ICU/mechanical ventilation) after enrollment (cases) or survived without progression (controls) over 60 days of follow-up. Conditional logistic regression was used to analyze the relationship between baseline KT ratio and other metabolites and disease progression., Results: We included 32 cases and 64 controls with a median age of 52 years; 41% were female, and the median durations of influenza symptoms prior to hospitalization were 8 and 6 days for cases and controls, respectively ( P = .04). Median baseline KT ratios were 2-fold higher in cases (0.24 mM/M; IQR, 0.13-0.40) than controls (0.12; IQR, 0.09-0.17; P ≤ .001). When divided into tertiles, 59% of cases vs 20% of controls had KT ratios in the highest tertile (0.21-0.84 mM/M). When adjusted for symptom duration, the odds ratio for disease progression for those in the highest vs lowest tertiles of KT ratio was 9.94 (95% CI, 2.25-43.90)., Conclusions: High KT ratio was associated with poor outcome in adults hospitalized with influenza A(H1N1)pdm09. The clinical utility of this biomarker in this setting merits further exploration., Clinicaltrialsgov Identifier: NCT01056185.
Published: 2017
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28. Good-quality research: a vital step in improving outcomes in paediatric intensive care units in low- and middle-income countries.

Author: George EC
Subjects: Child, Preschool, Developing Countries, Humans, Infant, Infant, Newborn, Preceptorship, Treatment Outcome, Critical Care standards, Disease Management, Intensive Care Units, Pediatric, Quality of Health Care
Published: 2017
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29. Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score.

Author: George EC, Walker AS, Kiguli S, Olupot-Olupot P, Opoka RO, Engoru C, Akech SO, Nyeko R, Mtove G, Reyburn H, Berkley JA, Mpoya A, Levin M, Crawley J, Gibb DM, Maitland K, and Babiker AG
Subjects: Adolescent, Africa, Age Distribution, Child, Child, Preschool, Humans, Infant, Kenya, Male, Pediatrics organization & administration, Prognosis, Risk Assessment, Triage, Child Mortality trends, Emergency Service, Hospital trends, Hospitals, Pediatric organization & administration, Infant Mortality trends
Abstract: Background: Mortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality., Methods: Data collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors., Results: A risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0-10 and had an AUROC of 0.82 (95 % CI, 0.77-0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72-0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82-0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score., Conclusions: Eight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.
Published: 2015
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30. Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform.

Author: Treweek S, Altman DG, Bower P, Campbell M, Chalmers I, Cotton S, Craig P, Crosby D, Davidson P, Devane D, Duley L, Dunn J, Elbourne D, Farrell B, Gamble C, Gillies K, Hood K, Lang T, Littleford R, Loudon K, McDonald A, McPherson G, Nelson A, Norrie J, Ramsay C, Sandercock P, Shanahan DR, Summerskill W, Sydes M, Williamson P, and Clarke M
Subjects: Access to Information, Cooperative Behavior, Efficiency, Evidence-Based Medicine organization & administration, Humans, Information Dissemination, Interdisciplinary Communication, International Cooperation, Efficiency, Organizational, Evidence-Based Medicine methods, Randomized Controlled Trials as Topic methods, Research Design
Abstract: Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge ( www.trialforge.org ) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants' views on the processes in the life of a randomised trial that should be covered by Trial Forge.General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a 'go to' website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.
Published: 2015
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31. Sleep apnoea in the elderly - authors' reply.

Author: McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Nunn AJ, Stradling JR, Riha RL, and Morrell MJ
Subjects: Female, Humans, Male, Continuous Positive Airway Pressure, Sleep Apnea, Obstructive therapy
Published: 2014
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32. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.

Author: McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, and Morrell MJ
Subjects: Aged, Aged, 80 and over, Comorbidity, Cost-Benefit Analysis, Female, Humans, Male, Quality of Life, Sleep, Treatment Outcome, United Kingdom, Continuous Positive Airway Pressure economics, Sleep Apnea, Obstructive therapy
Abstract: Background: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap., Methods: This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927., Findings: Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use., Interpretation: In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome., Funding: National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London., (Copyright © 2014 McMillan et al. Open Access article distributed under the terms of CC BY. Published by .. All rights reserved.)
Published: 2014
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33. The impact of HIV on maternal quality of life in Uganda.

Author: Nuwagaba-Biribonwoha H, Mayon-White RT, Okong P, Carpenter LM, and Jenkinson C
Subjects: Adult, Female, HIV Infections epidemiology, Health Status, Humans, Pregnancy, Uganda epidemiology, HIV Infections psychology, Pregnancy Complications, Infectious psychology, Puerperal Disorders psychology, Quality of Life psychology
Abstract: To study the effect of HIV infection on quality of life (QOL) during pregnancy and puerperium, QOL was measured in a cohort study at St. Francis Hospital Nsambya, Kampala, Uganda. Dartmouth COOP charts were administered to 132 HIV-positive and 399 HIV-negative women at 36 weeks of pregnancy and six weeks post-partum. Responses were coded from 0 = best health-status to 4 = worst health-status and scores of 3-4 defined as poor. Odds ratios (OR) (95% confidence intervals(CI)) for poor scores were calculated and independent predictors of poor QOL examined using logistic regression. In pregnancy, HIV-positive women were more likely to have poor scores in feelings: OR = 3.2(1.9-5.3), daily activities: OR = 2.8(1.4-5.5), pain: OR = 2.1(1.3-3.5), overall health: OR = 1.7(1.1-2.7) and QOL: OR = 7.2(3.6-14.7), all p= 0.2). HIV infection was independently associated with poor QOL: OR = 8.5(3.8-19). Findings in puerperium were similar to those in pregnancy except more HIV-positive women had poor scores in social activities: OR = 2.5(1.4-4.7) and change in health: OR = 5.4(2-14.5) and infant death also predicted poor QOL: OR = 6.7(2.4-18.5). The findings reflect HIV's adverse impact on maternal QOL and the need for interventions to alleviate this infection's social and emotional effects.
Published: 2006
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33 results on '"Medical Research Council Clinical Trials Unit (MRC CTU)"'

1. ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

2. Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group

3. Body composition and adipokines changes after initial treatment with darunavir-ritonavir plus either raltegravir or tenofovir disoproxil fumarate-emtricitabine: A substudy of the NEAT001/ANRS143 randomised trial

4. Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape

5. Patient-Reported Outcomes in First-Line Antiretroviral Therapy: Results From NEAT001/ANRS143 Trial Comparing Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine or Raltegravir

6. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

7. An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012

8. The impact of transient combination antiretroviral treatment in early HIV infection on viral suppression and immunologic response in later treatment

9. Validation of treatment escalation as a definition of atopic eczema flares

10. Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

11. An evaluation of HIV elite controller definitions within a large seroconverter cohort collaboration

12. Natural history of HIV-control since seroconversion

13. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

14. Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters

15. Legume-supplemented feed for children hospitalised with severe malnutrition: a phase II trial.

16. Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

17. Use of point-of-care haemoglobin tests to diagnose childhood anaemia in low- and middle-income countries: A systematic review.

18. Avoid re-interpreting fluid bolus recommendations for low-income settings.

19. Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT).

20. A predictive algorithm for identifying children with sickle cell anemia among children admitted to hospital with severe anemia in Africa.

21. Prevalence of evidence of inconsistency and its association with network structural characteristics in 201 published networks of interventions.

22. Point-of-care haemoglobin testing in African hospitals: a neglected essential diagnostic test.

23. Transfusion management of severe anaemia in African children: a consensus algorithm.

24. Mortality risk over time after early fluid resuscitation in African children.

25. Implications for paediatric shock management in resource-limited settings: a perspective from the FEAST trial.

26. Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa.

27. Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study.

28. Good-quality research: a vital step in improving outcomes in paediatric intensive care units in low- and middle-income countries.

29. Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score.

30. Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform.

31. Sleep apnoea in the elderly - authors' reply.

32. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.

33. The impact of HIV on maternal quality of life in Uganda.

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