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1. Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trialsResearch in context

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Ilias I. Siempos, Andre C. Kalil, Drifa Belhadi, Viviane Cordeiro Veiga, Alexandre Biasi Cavalcanti, Westyn Branch-Elliman, Eleni Papoutsi, Konstantinos Gkirgkiris, Nikoleta A. Xixi, Anastasia Kotanidou, Olivier Hermine, Raphaël Porcher, Xavier Mariette, Philippe Ravaud, Serge Bureau, Maxime Dougados, Matthieu Resche-Rigon, Pierre-Louis Tharaux, Annick Tibi, Elie Azoulay, Jacques Cadranel, Joseph Emmerich, Muriel Fartoukh, Bertrand Guidet, Marc Humbert, Karine Lacombe, Matthieu Mahevas, Frédéric Pene, Valerie Pourchet-Martinez, Frédéric Schlemmer, Yazdan Yazdanpanah, Gabriel Baron, Elodie Perrodeau, Damien Vanhoye, Cécile Kedzia, Lauren Demerville, Anne Gysembergh-Houal, Alexandre Bourgoin, Nabil Raked, Lakhdar Mameri, Claire Montlahuc, Lucie Biard, St.phanie Alary, Samir Hamiria, Thinhinane Bariz, Hala Semri, Dhiaa Meriem Hai, Moustafa Benafla, Mohamed Belloul, Pernelle Vauboin, Saskia Flamand, Claire Pacheco, Anouk Walter-Petrich, Emilia Stan, Souad Benarab, Corine Nyanou, Robin Charreteur, Céline Dupre, Kévin Cardet, Blandine Lehmann, Kamyl Baghli, Claire Madelaine, Eric D'Ortenzio, Oriane Puéchal, Caroline Semaille, Laurent Savale, Anatole Harrois, Samy Figueiredo, Jacques Duranteau, Nadia Anguel, Arthur Pavot, Xavier Monnet, Christian Richard, Jean-Louis Teboul, Philippe Durand, Pierre Tissieres, Mitja Jevnikar, David Montani, Stephan Pavy, Gaétane Nocturne, Samuel Bitoun, Nicolas Noel, Olivier Lambotte, Lelia Escaut, Stephane Jauréguiberry, Elodie Baudry, Christiane Verny, Edouard Lefevre, Mohamad Zaidan, Domitille Molinari, Gaël Leprun, Alain Fourreau, Laurent Cylly, Lamiae Grimaldi, Myriam Virlouvet, Ramdane Meftali, Soléne Fabre, Marion Licois, Asmaa Mamoune, Yacine Boudali, Clotilde Le Tiec, Céline Verstuyft, Anne-Marie Roques, Sophie Georgin-Lavialle, Patricia Senet, Gilles Pialoux, Angele Soria, Antoine Parrot, Helene François, Nathalie Rozensztajn, Emmanuelle Blin, Pascaline Choinier, Juliette Camuset, Jean-Simon Rech, Antony Canellas, Camille Rolland-Debord, Nadege Lemarié, Nicolas Belaube, Marine Nadal, Martin Siguier, Camille Petit-Hoang, Julie Chas, Elodie Drouet, Matthieu Lemoine, Audrey Phibel, Lucie Aunay, Eliane Bertrand, Sylviane Ravato, Marie Vayssettes, Anne Adda, Celine Wilpotte, Pélagie Thibaut, Julie Fillon, Isabelle Debrix, Soraya Fellahi, Jean-Philippe Bastard, Guillaume Lefévre, Jacques-Eric Gottenberg, Yves Hansmann, Frédéric Blanc, Sophie Ohlmann-Caillard, Vincent Castelain, Emmanuel Chatelus, Eva Chatron, Olivier Collange, François Danion, Frédéric De Blay, Pierre Diemunsch, Sophie Diemunsch, Renaud Felten, Bernard Goichot, Valentin Greigert, Aurelien Guffroy, Bob Heger, Charlotte Kaeuffer, Loic Kassegne, Anne Sophie Korganow, Pierrick Le Borgne, Nicolas Lefebvre, Paul-Michel Mertes, Eric Noll, Mathieu Oberlin, Vincent Poindron, Julien Pottecher, Yvon Ruch, François Weill, Nicolas Meyer, Emmanuel Andres, Eric Demonsant, Hakim Tayebi, Gabriel Nisand, Stéphane Brin, Cédric Sublon, Guillaume Becker, Anne Hutt, Tristan Martin, Sophie Bayer, Catherine Metzger, Arsene Mekinian, Noémie Abisror, Amir Adedjouma, Diane Bollens, Marion Bonneton, Nathalie Bourcicaux, Anne Bourrier, Maria Chauchard Thibault Chiarabiani, Doroth.e Chopin, Jonathan Cohen, Ines Devred, Bruno Donadille, Olivier Fain, Geoffrey Hariri, Vincent Jachiet, Patrick Ingliz, Marc Garnier, Marc Gatfosse, Etienne Ghrenassia, Delphine Gobert, Jessica Krause le Garrec, Cecilia Landman, Jean Remy Lavillegrand, Benedicte Lefebvre, Thibault Mahevas, Sandie Mazerand, Jean Luc Meynard, Marjolaine Morgand, Zineb Ouaz.ne, Jerome Pacanowski, S.bastien Riviere, Philippe Seksik, Harry Sokol, Heithem Soliman, Nadia Valin, Thomas Urbina, Chloé McAvoy, Maria Pereira Miranda, Gladys Aratus, Laurence Berard, Tabassome Simon, Anne Daguenel Nguyen, Elise Girault, Cl.mentine Mayala-Kanda, Marie Antignac, Céline Leplay, Jean-Benoit Arlet, Jean-Luc Diehl, Florence Bellenfant, Anne Blanchard, Alexandre Buffet, Bernard Cholley, Antoine Fayol, Edouard Flamarion, Anne Godier, Thomas Gorget, Sophie-Rym Hamada, Caroline Hauw-Berlemont, Jean-Sébastien Hulot, David Lebeaux, Marine Livrozet, Adrien Michon, Arthur Neuschwander, Marie-Aude Pennet, Benjamin Planquette, Brigitte Ranque, Olivier Sanchez, Geoffroy Volle, Sandrine Briois, Mathias Cornic, Virginie Elisee, Jesuthasan Denis, Juliette Djadi-Prat, Pauline Jouany, Ramon Junquera, Mickael Henriques, Amina Kebir, Isabelle Lehir, Jeanne Meunier, Florence Patin, Val.rie Paquet, Anne Tréhan, Véronique Vigna, Brigitte Sabatier, Damien Bergerot, Charléne Jouve, Camille Knosp, Olivia Lenoir, Nassim Mahtal, Léa Resmini, Xavier Lescure, Jade Ghosn, Antoine Bachelard, Anne Rachline, Valentina Isernia, Bao-chau, Phung, Dorothée Vallois, Aurelie Sautereau, Catherine Neukrich, Antoine Dossier, Raphaël Borie, Bruno Crestani, Gregory Ducrocq, Philippe Gabriel Steg, Philippe Dieude, Thomas Papo, Estelle Marcault, Marhaba Chaudhry, Charléne Da Silveira, Annabelle Metois, Ismahan Mahenni, Meriam Meziani, Cyndie Nilusmas, Sylvie Le Gac, Awa Ndiaye, Fran.oise Louni, Malikhone Chansombat, Zelie Julia, Solaya Chalal, Lynda Chalal, Laura Kramer, Jeniffer Le Grand, Kafif Ouifiya, Valentine Piquard, Sarah Tubiana, Yann Nguyen, Vasco Honsel, Emmanuel Weiss, Anais Codorniu, Virginie Zarrouk, Victoire de Lastours, Matthieu Uzzan, Naura Gamany, Agathe Claveirole, Alexandre Navid, Tiffanie Fouque, Yonathan Cohen, Maya Lupo, Constance Gilles, Roza Rahli, Zeina Louis, David Boutboul, Lionel Galicier, Yaël Amara, Gabrielle Archer, Amira Benattia, Anne Bergeron, Louise Bondeelle, Nathalie de Castro, Melissa Clément, Michaël Darmon, Blandine Denis, Clairelyne Dupin, Elsa Feredj, Delphine Feyeux, Adrien Joseph, Etienne Lenglin, Pierre Le Guen, Geoffroy Liégeon, Gwenaël Lorillon, Asma Mabrouki, Eric Mariotte, Grégoire Martin de Frémont, Adrien Mirouse, Jean-Michel Molina, Régis Peffault de Latour, Eric Oksenhendler, Julien Saussereau, Abdellatif Tazi, Jean-Jacques Tudesq, Lara Zafrani, Isabelle Brindele, Emmanuelle Bugnet, Karine Celli Lebras, Julien Chabert, Lamia Djaghout, Catherine Fauvaux, Anne Lise Jegu, Ewa Kozakiewicz, Martine Meunier, Marie-Thérèse Tremorin, Claire Davoine, Isabelle Madelaine, Sophie Caillat-Zucman, Constance Delaugerre, Florence Morin, Damien Sène, Ruxandra Burlacu, Benjamin Chousterman, Bruno Mégarbanne, Pascal Richette, Jean-Pierre Riveline, Aline Frazier, Eric Vicaut, Laure Berton, Tassadit Hadjam, Miguel Alejandro Vazquez-Ibarra, Clément Jourdaine, Olivia Tran, Véronique Jouis, Aude Jacob, Julie Smati, Stéphane Renaud, Claire Pernin, Lydia Suarez, Luca Semerano, Sébastien Abad, Ruben B. nainous, Nicolas Bonnet, Celine Comparon, Yves Cohen, Hugues Cordel, Robin Dhote, Nathalie Dournon, Boris Duchemann, Nathan Ebstein, Thomas Gille, Benedicte Giroux-Leprieur, Jeanne Goupil de Bouille, Hilario Nunes, Johanna Oziel, Dominique Roulot, Lucile Sese, ClaireTantet, Yurdagul Uzunhan, Coralie Bloch-Queyrat, Vincent Levy, Fadhila Messani, Mohammed Rahaoui, Myléne Petit, Sabrina Brahmi, Vanessa Rathoin, Marthe Rigal, Nathalie Costedoat-Chalumeau, Liem Binh Luong, Zakaria Ait Hamou, Sarah Benghanem, Philippe Blanche, Nicolas Carlier, Benjamin Chaigne, Remy Gauzit, Hassan Joumaa, Mathieu Jozwiak, Marie Lachétre, Hélène Lafoeste, Odie Launay, Paul Legendre, Jonathan Marey, Caroline Morbieu, Lola-Jade Palmieri, Tali-Anne Szwebel, Hendy Abdoul, Alexandra Bruneau, Audrey Beclin-Clabaux, Charly Larrieu, Pierre Montanari, Eric Dufour, Ada Clarke, Catherine Le Bourlout, Nathalie Marin, Nathalie Menage, Samira Saleh-Mghir, Mamadou Salif Cisse, Kahina Cheref, Corinne Guerin, Jérémie Zerbit, Marc Michel, Sébastien Gallien, Etienne Crickx, Benjamin Le Vavasseur, Emmanuelle Kempf, Karim Jaffal, William Vindrios, Julie Oniszczuk, Constance Guillaud, Pascal Lim, Elena Fois, Giovanna Melica, Marie Matignon, Maud Jalabert, Jean-Daniel Lelièvre, David Schmitz, Marion Bourhis, Sylia Belazouz, Laetitia Languille, Caroline Boucle, Nelly Cita, Agnés Didier, Fahem Froura, Katia Ledudal, Thiziri Sadaoui, Alaki Thiemele, Delphine Le Febvre De Bailly, Muriel Carvhalo Verlinde, Julien Mayaux, Patrice Cacoub, David Saadoun, Mathieu Vautier, Héléne Bugaut, Olivier Benveniste, Yves Allenbach, Gaëlle Leroux, Aude Rigolet, Perrine Guillaume-Jugnot, Fanny Domont, Anne Claire Desbois, Chloé Comarmond, Nicolas Champtiaux, Segolene Toquet, Amine Ghembaza, Matheus Vieira, Georgina Maalouf, Goncalo Boleto, Yasmina Ferfar, Jean-Christophe Corvol, C.line Louapre, Sara Sambin, Louise-Laure Mariani, Carine Karachi, Florence Tubach, Candice Estellat, Linda Gimeno, Karine Martin, Aicha Bah, Vixra Keo, Sabrine Ouamri, Yasmine Messaoudi, Nessima Yelles, Pierre Faye, Sebastien Cavelot, Cecile Larcheveque, Laurence Annonay, Jaouad Benhida, Aida Zahrate-Ghoul, Soumeya Hammal, Ridha Belilita, Fanny Charbonnier, Claire Aguilar, Fanny Alby-Laurent, Carole Burger, Clara Campos-Vega, Nathalie Chavarot, Benjamin Fournier, Claire Rouzaud, Damien Vimpére, Caroline Elie, Prissile Bakouboula, Laure Choupeaux, Sophie Granville, Elodie Issorat, Christine Broissand, Marie-Alexandra Alyanakian, Guillaume Geri, Nawal Derridj, Naima Sguiouar, Hakim Meddah, Mourad Djadel, Héléne Chambrin-Lauvray, Jean-Charles Duclos-vallée, Faouzi Saliba, Sophie-Caroline Sacleux, Ilias Kounis, Sonia Tamazirt, Eric Rudant, Jean-Marie Michot, Annabelle Stoclin, Emeline Colomba, Fanny Pommeret, Christophe Willekens, Rosa Da Silva, Valérie Dejean, Yasmina Mekid, Ines Ben-Mabrouk, Florence Netzer, Caroline Pradon, Laurence Drouard, Valérie Camara-Clayette, Alexandre Morel, Gilles Garcia, Abolfazl Mohebbi, Férial Berbour, Mélanie Dehais, Anne-Lise Pouliquen, Alison Klasen, Loren Soyez-Herkert, Jonathan London, Younes Keroumi, Emmanuelle Guillot, Guillaume Grailles, Younes El amine, Fanny Defrancq, Hanane Fodil, Chaouki Bouras, Dominique Dautel, Nicolas Gambier, Thierno Dieye, Boris Bienvenu, Victor Lancon, Laurence Lecomte, Kristina Beziriganyan, Belkacem Asselate, Laure Allanic, Elena Kiouris, Marie-Héléne Legros, Christine Lemagner, Pascal Martel, Vincent Provitolo, Félix Ackermann, Mathilde Le Marchand, Aurélie Chan Hew Wai, Dimitri Fremont, Elisabeth Coupez, Mireille Adda, Frédéric Duée, Lise Bernard, Antoine Gros, Estelle Henry, Claire Courtin, Anne Pattyn, Pierre-Grégoire Guinot, Marc Bardou, Agnes Maurer, Julie Jambon, Amélie Cransac, Corinne Pernot, Bruno Mourvillier, Eric Marquis, Philippe Benoit, Damien Roux, Coralie Gernez, Cécile Yelnik, Julien Poissy, Mandy Nizard, Fanette Denies, Helene Gros, Jean-Jacques Mourad, Emmanuelle Sacco, Sophie Renet, F. Ader, Y. Yazdanpanah, F. Mentre, N. Peiffer-Smadja, F.X. Lescure, J. Poissy, L. Bouadma, J.F. Timsit, B. Lina, F. Morfin-Sherpa, M. Bouscambert, A. Gaymard, G. Peytavin, L. Abel, J. Guedj, C. Andrejak, C. Burdet, C. Laouenan, D. Belhadi, A. Dupont, T. Alfaiate, B. Basli, A. Chair, S. Laribi, J. Level, M. Schneider, M.C. Tellier, A. Dechanet, D. Costagliola, B. Terrier, M. Ohana, S. Couffin-Cadiergues, H. Esperou, C. Delmas, J. Saillard, C. Fougerou, L. Moinot, L. Wittkop, C. Cagnot, S. Le Mestre, D. Lebrasseur-Longuet, V. Petrov-Sanchez, A. Diallo, N. Mercier, V. Icard, B. Leveau, S. Tubiana, B. Hamze, A. Gelley, M. Noret, E. D’Ortenzio, O. Puechal, C. Semaille, T. Welte, J.A. Paiva, M. Halanova, M.P. Kieny, E. Balssa, C. Birkle, S. Gibowski, E. Landry, A. Le Goff, L. Moachon, C. Moins, L. Wadouachi, C. Paul, A. Levier, D. Bougon, F. Djossou, L. Epelboin, J. Dellamonica, C.H. Marquette, C. Robert, S. Gibot, E. Senneville, V. Jean-Michel, Y. Zerbib, C. Chirouze, A. Boyer, C. Cazanave, D. Gruson, D. Malvy, P. Andreu, J.P. Quenot, N. Terzi, K. Faure, C. Chabartier, V. Le Moing, K. Klouche, T. Ferry, F, Valour, B. Gaborit, E. Canet, P. Le Turnier, D. Boutoille, F. Bani-Sadr, F. Benezit, M. Revest, C. Cameli, A. Caro, MJ Ngo Um Tegue, Y. Le Tulzo, B. Laviolle, F. Laine, G. Thiery, F. Meziani, Y. Hansmann, W. Oulehri, C. Tacquard, F. Vardon-Bounes, B. Riu-Poulenc, M. Murris-Espin, L. Bernard, D. Garot, O. Hinschberger, M. Martinot, C. Bruel, B. Pilmis, O. Bouchaud, P. Loubet, C. Roger, X. Monnet, S. Figueiredo, V. Godard, J.P. Mira, M. Lachatre, S. Kerneis, J. Aboab, N. Sayre, F. Crockett, D. Lebeaux, A. Buffet, J.L. Diehl, A. Fayol, J.S. Hulot, M. Livrozet, A Mekontso- Dessap, C. Ficko, F. Stefan, J. Le Pavec, J. Mayaux, H. Ait-Oufella, J.M. Molina, G. Pialoux, M. Fartoukh, J. Textoris, M. Brossard, A. Essat, E. Netzer, Y. Riault, M. Ghislain, L. Beniguel, M. Genin, L. Gouichiche, C. Betard, L. Belkhir, A. Altdorfer, V Fraipont Centro, S. Braz, JM Ferreira Ribeiro, R Roncon Alburqueque, M. Berna, M. Alexandre, B. Lamprecht, A. Egle, R. Greil, M. Joannidis, Thomas F. Patterson, Philip O. Ponce, Barbara S. Taylor, Jan E. Patterson, Jason E. Bowling, Heta Javeri, LuAnn Larson, Angela Hewlett, Aneesh K. Mehta, Nadine G. Rouphael, Youssef Saklawi, Nicholas Scanlon, Jessica J. Traenkner, Ronald P. Trible, Jr., Emmanuel B. Walter, Noel Ivey, Thomas L. Holland, Guillermo M. Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Lanny Hsieh, Alpesh N. Amin, Miki Watanabe, Helen S. Lee, Susan Kline, Joanne Billings, Brooke Noren, Hyun Kim, Tyler D. Bold, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Nicole Iovine, Lars K. Beattie, Rebecca Murray Wakeman, Matthew Shaw, Mamta K. Jain, Satish Mocherla, Jessica Meisner, Amneris Luque, Daniel A. Sweeney, Constance A. Benson, Farhana Ali, Robert L. Atmar, Hana M. El Sahly, Jennifer Whitaker, Ann R. Falsey, Angela R. Branche, Cheryl Rozario, Justino Regalado Pineda, José Arturo Martinez-Orozco, David Chien Lye, Sean WX. Ong, Po Ying Chia, Barnaby E. Young, Uriel Sandkovsky, Mezgebe Berhe, Clinton Haley, Emma Dishner, Valeria D. Cantos, Colleen F. Kelley, Paulina A. Rebolledo Esteinou, Sheetal Kandiah, Sarah B. Doernberg, Pierre-Cedric B. Crouch, Hannah Jang, Anne F. Luetkemeyer, Jay Dwyer, Stuart H. Cohen, George R. Thompson, 3rd, Hien H. Nguyen, Robert W. Finberg, Jennifer P. Wang, Juan Perez-Velazquez, Mireya Wessolossky, Patrick E.H. Jackson, Taison D. Bell, Miranda J. West, Babafemi Taiwo, Karen Krueger, Johnny Perez, Triniece Pearson, Catharine I. Paules, Kathleen G. Julian, Danish Ahmad, Alexander G. Hajduczok, Henry Arguinchona, Christa Arguinchona, Nathaniel Erdmann, Paul Goepfert, Neera Ahuja, Maria G. Frank, David Wyles, Heather Young, Myoung-don Oh, Wan Beom Park, Chang Kyung Kang, Vincent Marconi, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Eu Suk Kim, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Seow Yen Tan, Humaira Shafi, MF Jaime Chien, Raymond KC. Fong, Daniel D. Murray, Jens Lundgren, Henrik Nielsen, Tomas Jensen, Barry S. Zingman, Robert Grossberg, Paul F. Riska, Otto O. Yang, Jenny Ahn, Rubi Arias, Rekha R. Rapaka, Naomi Hauser, James D. Campbell, William R. Short, Pablo Tebas, Jillian T. Baron, Susan L.F. McLellan, Lucas S. Blanton, Justin B. Seashore, C. Buddy Creech, Todd W. Rice, Shannon Walker, Isaac P. Thomsen, Diego Lopez de Castilla, Jason W. Van Winkle, Francis X. Riedo, Surinder Kaur Pada, Alvin DY. Wang, Li Lin, Michelle Harkins, Gregory Mertz, Nestor Sosa, Louis Yi Ann Chai, Paul Anantharajah Tambyah, Sai Meng Tham, Sophia Archuleta, Gabriel Yan, David A. Lindholm, Ana Elizabeth Markelz, Katrin Mende, Richard Mularski, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Ryan C. Maves, Gregory C. Utz, Sarah L. George, Daniel F. Hoft, James D. Brien, Roger Paredes, Lourdes Mateu, Cora Loste, Princy Kumar, Sarah Thornton, Sharmila Mohanraj, Noreen A. Hynes, Lauren M. Sauer, Christopher J. Colombo, Christina Schofield, Rhonda E. Colombo, Susan E. Chambers, Richard M. Novak, Andrea Wendrow, Samir K. Gupta, Tida Lee, Tahaniyat Lalani, Mark Holodniy, Aarthi Chary, Nikhil Huprikar, Anuradha Ganesan, Norio Ohmagari, Ayako Mikami, D. Ashley Price, Christopher J.A. Duncan, Kerry Dierberg, Henry J. Neumann, Stephanie N. Taylor, Alisha Lacour, Najy Masri, Edwin Swiatlo, Kyle Widmer, James D. Neaton, Mary Bessesen, David S. Stephens, Timothy H. Burgess, Timothy M. Uyeki, Robert Walker, G. Lynn Marks, Anu Osinusi, Huyen Cao, Anabela Cardoso, Stephanie de Bono, Douglas E. Schlichting, Kevin K. Chung, Jennifer L. Ferreira, Michelle Green, Mat Makowski, Michael R. Wierzbicki, Tom M. Conrad, Jill Ann El-Khorazaty, Heather Hill, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, John H. Beigel, Kay M. Tomashek, Varduhi Ghazaryan, Tatiana Beresnev, Seema Nayak, Lori E. Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, Ruth Florese, Jocelyn D. Voell, Richard Davey, Ruth C. Serrano, Zanthia Wiley, Varun K. Phadke, Paul A. Goepfert, Carlos A. Gomez, Theresa A. Sofarelli, Laura Certain, Hannah N. Imlay, Cameron R. Wolfe, Emily R. Ko, John J. Engemann, Nora Bautista Felix, Claire R. Wan, Sammy T. Elmor, Laurel R. Bristow, Michelle S. Harkins, Nicole M. Iovine, Marie-Carmelle Elie-Turenne, Victor F. Tapson, Pyoeng Gyun Choe, Richard A. Mularski, Kevin S. Rhie, Rezhan H. Hussein, Dilek Ince, Patricia L. Winokur, Jin Takasaki, Sho Saito, Kimberly McConnell, PharmD, David L. Wyles, Ellen Sarcone, Kevin A. Grimes, Katherine Perez, Charles Janak, Jennifer A. Whitaker, Paulina A. Rebolledo, John Gharbin, Allison A. Lambert, Diego F. Zea, Emma Bainbridge, David C. Hostler, Jordanna M. Hostler, Brian T. Shahan, Evelyn Ling, Minjoung Go, Fleesie A. Hubbard, Melony Chakrabarty, Maryrose Laguio-Vila, Edward E. Walsh, Faheem Guirgis, Vincent C. Marconi, Christian Madar, Scott A. Borgetti, Corri Levine, Joy Nock, Keith Candiotti, Julia Rozman, Fernando Dangond, Yann Hyvert, Andrea Seitzinger, Kaitlyn Cross, Stephanie Pettibone, Seema U. Nayak, and Gregory A. Deye

Subjects
Acute respiratory distress syndrome, Acute hypoxemic respiratory failure, Pneumonia, Critically ill, Cancer, Medicine (General), R5-920
Abstract

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Published
2024
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2. Performance Analysis of the National Early Warning Score and Modified Early Warning Score in the Adaptive COVID-19 Treatment Trial Cohort

Author

Christopher J. Colombo, MD, MA, FACP, FCCM, Rhonda E. Colombo, MD, MHS, FACP, FIDSA, Ryan C. Maves, MD, FCCM, FCCP, FIDSA, Angela R. Branche, MD, Stuart H. Cohen, MD, Marie-Carmelle Elie, MD, Sarah L. George, MD, Hannah J. Jang, PhD, RN, CNL, PHN, Andre C. Kalil, MD, MPH, David A. Lindholm, MD, FACP, Richard A. Mularski, MD, MSHS, MCR, ATSF, FCCP, FACP, Justin R. Ortiz, MD, MS, FACP, FCCP, Victor Tapson, MD, C. Jason Liang, PhD, On behalf of the ACTT-1 Study Group, Aneesh K. Mehta, Nadine G. Rouphael, Jessica J. Traenkner, Valeria D Cantos, Ghina Alaaeddine, Barry S. Zingman, Robert Grossberg, Paul F. Riska, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Helen Y. Chu, Anna Wald, Margaret Green, Annie Luetkemeyer, Pierre-Cedric B. Crouch, Hannah Jang, Susan Kline, Joanne Billings, Brooke Noren, Diego Lopez de Castilla, Jason W. Van Winkle, Francis X. Riedo, Robert W. Finberg, Jennifer P. Wang, Mireya Wessolossky, Kerry Dierberg, Benjamin Eckhardt, Henry J Neumann, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Lanny Hsieh, Alpesh N. Amin, Thomas F. Patterson, Heta Javeri, Trung Vu, Roger Paredes, Lourdes Mateu, Daniel A. Sweeney, Constance A. Benson, Farhana Ali, William R. Short, Pablo Tebas, Jessie Torgersen, Giota Touloumi, Vicky Gioukari, David Chien Lye, Sean WX Ong, Norio Ohmagari, Ayako Mikami, Gerd Fätkenheuer, Jakob J. Malin, Philipp Koehler, Andre C. Kalil, LuAnn Larson, Angela Hewlett, Mark G. Kortepeter, C. Buddy Creech, Isaac Thomsen, Todd W. Rice, Babafemi Taiwo, Karen Krueger, Stuart H. Cohen, George R. Thompson, 3rd, Cameron Wolfe, Emmanuel B. Walter, Maria Frank, Heather Young, Ann R. Falsey, Angela R. Branche, Paul Goepfert, Nathaniel Erdmann, Otto O. Yang, Jenny Ahn, Anna Goodman, Blair Merrick, Richard M. Novak, Andrea Wendrow, Henry Arguinchona, Christa Arguinchona, Sarah L. George, Janice Tennant, Robert L. Atmar, Hana M. El Sahly, Jennifer Whitaker, D. Ashley Price, Christopher J. A. Duncan, Simeon Metallidis, Theofilos Chrysanthidis, F. McLellan, Myoung-don Oh, Wan Beom Park, Eu Suk Kim, Jongtak Jung, Justin R. Ortiz, Karen L. Kotloff, Brian Angus, Jack David Germain Seymour, Noreen A. Hynes, Lauren M. Sauer, Neera Ahuja, Kari Nadeau, Patrick E. H. Jackson, Taison D. Bell, Anastasia Antoniadou, Konstantinos Protopapas, Richard T Davey, Jocelyn D. Voell, Jose Muñoz, Montserrat Roldan, Ioannis Kalomenidis, Spyros G. Zakynthinos, Catharine I. Paules, Fiona McGill, Jane Minton, Nikolaos Koulouris, Zafeiria Barmparessou, Edwin Swiatlo, Kyle Widmer, Nikhil Huprikar, Anuradha Ganesan, Guillermo M. Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Justino Regalado Pineda, José Arturo Martinez-Orozco, Mark Holodniy, Aarthi Chary, Timo Wolf, Christoph Stephan, Jan-Christian Wasmuth, Christoph Boesecke, Martin Llewelyn, Barbara Philips, Christopher J. Colombo, Rhonda E. Colombo, David A. Lindholm, Katrin Mende, Tida Lee, Tahaniyat Lalani, Ryan C. Maves, Gregory C. Utz, Jens Lundgren, Marie Helleberg, Jan Gerstoft, Thomas Benfield, Tomas Jensen, Birgitte Lindegaard, Lothar Weise, Lene Knudsen, Isik Johansen, Lone W Madsen, Lars Østergaard, Nina Stærke, Henrik Nielsen, Timothy H. Burgess, Michelle Green, Mat Makowski, Jennifer L. Ferreira, Michael R. Wierzbicki, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Jing Wang, John H. Beigel, Kay M. Tomashek, Seema Nayak, Lori E. Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Peter Wolff, Rhonda PikaartTautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Dean Follmann, and H. Clifford Lane

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Published
2021
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3. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

Author

Cameron R Wolfe, Kay M Tomashek, Thomas F Patterson, Carlos A Gomez, Vincent C Marconi, Mamta K Jain, Otto O Yang, Catharine I Paules, Guillermo M Ruiz Palacios, Robert Grossberg, Michelle S Harkins, Richard A Mularski, Nathaniel Erdmann, Uriel Sandkovsky, Eyad Almasri, Justino Regalado Pineda, Alexandra W Dretler, Diego Lopez de Castilla, Angela R Branche, Pauline K Park, Aneesh K Mehta, William R Short, Susan L F McLellan, Susan Kline, Nicole M Iovine, Hana M El Sahly, Sarah B Doernberg, Myoung-don Oh, Nikhil Huprikar, Elizabeth Hohmann, Colleen F Kelley, Mark Holodniy, Eu Suk Kim, Daniel A Sweeney, Robert W Finberg, Kevin A Grimes, Ryan C Maves, Emily R Ko, John J Engemann, Barbara S Taylor, Philip O Ponce, LuAnn Larson, Dante Paolo Melendez, Allan M Seibert, Nadine G Rouphael, Joslyn Strebe, Jesse L Clark, Kathleen G Julian, Alfredo Ponce de Leon, Anabela Cardoso, Stephanie de Bono, Robert L Atmar, Anuradha Ganesan, Jennifer L Ferreira, Michelle Green, Mat Makowski, Tyler Bonnett, Tatiana Beresnev, Varduhi Ghazaryan, Walla Dempsey, Seema U Nayak, Lori E Dodd, John H Beigel, Andre C Kalil, Lana Wahid, Emmanuel B. Walter, Akhila G. Belur, Grace Dreyer, Jan E. Patterson, Jason E. Bowling, Danielle O. Dixon, Angela Hewlett, Robert Odrobina, Jakrapun Pupaibool, Satish Mocherla, Suzana Lazarte, Meilani Cayabyab, Rezhan H. Hussein, Reshma R. Golamari, Kaleigh L. Krill, Sandra Rajme, Paul F. Riska, Barry S. Zingman, Gregory Mertz, Nestor Sosa, Paul A. Goepfert, Mezgebe Berhe, Emma Dishner, Mohamed Fayed, Kinsley Hubel, José Arturo Martinez-Orozco, Nora Bautista Felix, Sammy T. Elmor, Amer Ryan Bechnak, Youssef Saklawi, Jason W. Van Winkle, Diego F. Zea, Maryrose Laguio-Vila, Edward E. Walsh, Ann R. Falsey, Karen Carvajal, Robert C. Hyzy, Sinan Hanna, Norman Olbrich, Jessica J. Traenkner, Colleen S. Kraft, Pablo Tebas, Jillian T Baron, Corri Levine, Joy Nock, Joanne Billings, Hyun Kim, Marie-Carmelle Elie-Turenne, Jennifer A. Whitaker, Anne F. Luetkemeyer, Jay Dwyer, Emma Bainbridge, Pyoeng Gyun Choe, Chang Kyung Kang, Nikolaus Jilg, Valeria D Cantos, Divya R. Bhamidipati, Srinivasa Nithin Gopalsamy, Aarthi Chary, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Constance A. Benson, Kimberly McConnell, Jennifer P. Wang, Mireya Wessolossky, Katherine Perez, Taryn A Eubank, Catherine Berjohn, Gregory C. Utz, Patrick E.H. Jackson, Taison D. Bell, Heather M. Haughey, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Christopher J. Colombo, Christina Schofield, Rhonda E. Colombo, Victor F. Tapson, Jonathan Grein, Fayyaz Sutterwala, Dilek Ince, Patricia L. Winokur, Monica Fung, Hannah Jang, David Wyles, Maria G. Frank, Ellen Sarcone, Henry Neumann, Anand Viswanathan, Sarah Hochman, Mark Mulligan, Benjamin Eckhardt, Ellie Carmody, Neera Ahuja, Kari Nadeau, David Svec, Jeffrey C. Macaraeg, Lee Morrow, Dave Quimby, Mary Bessesen, Lindsay Nicholson, Jill Adams, Princy Kumar, Allison A. Lambert, Henry Arguinchona, Radica Z. Alicic, Sho Saito, Norio Ohmagari, Ayako Mikami, David Chien Lye, Tau Hong Lee, Po Ying Chia, Lanny Hsieh, Alpesh N. Amin, Miki Watanabe, Keith A. Candiotti, Jose G. Castro, Maria A. Antor, Tida Lee, Tahaniyat Lalani, Richard M. Novak, Andrea Wendrow, Scott A. Borgetti, Sarah L. George, Daniel F. Hoft, James D. Brien, Stuart H. Cohen, George R. Thompson, Melony Chakrabarty, Faheem Guirgis, Richard T. Davey, Jocelyn Voell, Jeffrey R. Strich, David A. Lindholm, Katrin Mende, Trevor R. Wellington, Rekha R. Rapaka, Jennifer S. Husson, Andrea R. Levine, Seow Yen Tan, Humaira Shafi, Jaime M F Chien, David C. Hostler, Jordanna M. Hostler, Brian T. Shahan, David H. Adams, Anu Osinusi, Huyen Cao, Timothy H. Burgess, Julia Rozman, Kevin K. Chung, Christina Nieuwoudt, Jill A. El-Khorazaty, Heather Hill, Stephanie Pettibone, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, Gregory A. Deye, Effie Nomicos, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, and Ruth Florese

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, ACTT-4 Study Group, Adolescent, Clinical Trials and Supportive Activities, Clinical Sciences, Dexamethasone, Double-Blind Method, Clinical Research, Humans, Lung, Sulfonamides, Other Medical and Health Sciences, SARS-CoV-2, Prevention, Evaluation of treatments and therapeutic interventions, Middle Aged, COVID-19 Drug Treatment, Oxygen, Good Health and Well Being, Treatment Outcome, Purines, 6.1 Pharmaceuticals, Public Health and Health Services, Azetidines, Pyrazoles, Female
Abstract

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Published
2022

4. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial

Author

Andre C Kalil, Aneesh K Mehta, Thomas F Patterson, Nathaniel Erdmann, Carlos A Gomez, Mamta K Jain, Cameron R Wolfe, Guillermo M Ruiz-Palacios, Susan Kline, Justino Regalado Pineda, Anne F Luetkemeyer, Michelle S Harkins, Patrick E H Jackson, Nicole M Iovine, Victor F Tapson, Myoung-don Oh, Jennifer A Whitaker, Richard A Mularski, Catharine I Paules, Dilek Ince, Jin Takasaki, Daniel A Sweeney, Uriel Sandkovsky, David L Wyles, Elizabeth Hohmann, Kevin A Grimes, Robert Grossberg, Maryrose Laguio-Vila, Allison A Lambert, Diego Lopez de Castilla, EuSuk Kim, LuAnn Larson, Claire R Wan, Jessica J Traenkner, Philip O Ponce, Jan E Patterson, Paul A Goepfert, Theresa A Sofarelli, Satish Mocherla, Emily R Ko, Alfredo Ponce de Leon, Sarah B Doernberg, Robert L Atmar, Ryan C Maves, Fernando Dangond, Jennifer Ferreira, Michelle Green, Mat Makowski, Tyler Bonnett, Tatiana Beresnev, Varduhi Ghazaryan, Walla Dempsey, Seema U Nayak, Lori Dodd, Kay M Tomashek, John H Beigel, Angela Hewlett, Barbara S Taylor, Jason E Bowling, Ruth C Serrano, Nadine G Rouphael, Zanthia Wiley, Varun K Phadke, Laura Certain, Hannah N Imlay, John J Engemann, Emmanuel B Walter, Jessica Meisner, Sandra Rajme, Joanne Billings, Hyun Kim, Jose A Martinez-Orozco, Nora Bautista Felix, Sammy T Elmor, Laurel R Bristow, Gregory Mertz, Nestor Sosa, Taison D Bell, Miranda J West, Marie-Carmelle Elie-Turenne, Jonathan Grein, Fayyaz Sutterwala, Pyoeng Gyun Choe, Chang Kyung Kang, Hana M El Sahly, Kevin S Rhie, Rezhan H Hussein, Patricia L Winokur, Ayako Mikami, Sho Saito, Constance A Benson, Kimberly McConnell, Mezgebe Berhe, Emma Dishner, Maria G Frank, Ellen Sarcone, Pierre-Cedric B Crouch, Hannah Jang, Nikolaus Jilg, Katherine Perez, Charles Janak, Valeria D Cantos, Paulina A Rebolledo, John Gharbin, Barry S Zingman, Paul F Riska, Ann R Falsey, Edward E Walsh, Angela R Branche, Henry Arguinchona, Christa Arguinchona, Jason W Van Winkle, Diego F Zea, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Jay Dwyer, Emma Bainbridge, David C Hostler, Jordanna M Hostler, Brian T Shahan, Lanny Hsieh, Alpesh N Amin, Miki Watanabe, William R Short, Pablo Tebas, Jillian T Baron, Neera Ahuja, Evelyn Ling, Minjoung Go, Otto O Yang, Jenny Ahn, Rubi Arias, Rekha R Rapaka, Fleesie A Hubbard, James D Campbell, Stuart H Cohen, George R Thompson, Melony Chakrabarty, Stephanie N Taylor, Najy Masri, Alisha Lacour, Tida Lee, Tahaniyat Lalani, David A Lindholm, Ana Elizabeth Markelz, Katrin Mende, Christopher J Colombo, Christina Schofield, Rhonda E Colombo, Faheem Guirgis, Mark Holodniy, Aarthi Chary, Mary Bessesen, Noreen A Hynes, Lauren M Sauer, Vincent C Marconi, Abeer Moanna, Telisha Harrison, David C Lye, Sean W X Ong, Po Ying Chia, Nikhil Huprikar, Anuradha Ganesan, Christian Madar, Richard M Novak, Andrea Wendrow, Scott A Borgetti, Sarah L George, Daniel F Hoft, James D Brien, Susan L F McLellan, Corri Levine, Joy Nock, Seow Yen Tan, Humaira Shafi, Jaime M F Chien, Keith Candiotti, Robert W Finberg, Jennifer P Wang, Mireya Wessolossky, Gregory C Utz, Susan E Chambers, David S Stephens, Timothy H Burgess, Julia Rozman, Yann Hyvert, Andrea Seitzinger, Anu Osinusi, Huyen Cao, Kevin K Chung, Tom M Conrad, Kaitlyn Cross, Jill A El-Khorazaty, Heather Hill, Stephanie Pettibone, Michael R Wierzbicki, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, Gregory A Deye, Effie Nomicos, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Richard Davey, Tammy Yokum, Janice Arega, and Ruth Florese

Subjects
Male, Japan, Lung, Singapore, education.field_of_study, Alanine, Maintenance dose, ACTT-3 study group members, Hazard ratio, Rehabilitation, Middle Aged, Treatment Outcome, Infectious Diseases, 6.1 Pharmaceuticals, Public Health and Health Services, Female, Infection, Interferon beta-1a, medicine.drug, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Population, Clinical Trials and Supportive Activities, Clinical Sciences, Placebo, Antiviral Agents, Loading dose, Double-Blind Method, Clinical Research, Internal medicine, Republic of Korea, medicine, Humans, education, Adverse effect, Mexico, Aged, Other Medical and Health Sciences, SARS-CoV-2, business.industry, Comment, Evaluation of treatments and therapeutic interventions, Adenosine Monophosphate, United States, COVID-19 Drug Treatment, Oxygen, Oxygen Saturation, business, Breast feeding
Abstract

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

Published
2021

5. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

Author

Sabue, Mulangu, Lori E, Dodd, Richard T, Davey, Olivier, Tshiani Mbaya, Michael, Proschan, Daniel, Mukadi, Mariano, Lusakibanza Manzo, Didier, Nzolo, Antoine, Tshomba Oloma, Augustin, Ibanda, Rosine, Ali, Sinaré, Coulibaly, Adam C, Levine, Rebecca, Grais, Janet, Diaz, H Clifford, Lane, Jean-Jacques, Muyembe-Tamfum, Billy, Sivahera, Modet, Camara, Richard, Kojan, Robert, Walker, Bonnie, Dighero-Kemp, Huyen, Cao, Philippe, Mukumbayi, Placide, Mbala-Kingebeni, Steve, Ahuka, Sarah, Albert, Tyler, Bonnett, Ian, Crozier, Michael, Duvenhage, Calvin, Proffitt, Marc, Teitelbaum, Thomas, Moench, Jamila, Aboulhab, Kevin, Barrett, Kelly, Cahill, Katherine, Cone, Risa, Eckes, Lisa, Hensley, Betsey, Herpin, Elizabeth, Higgs, Julie, Ledgerwood, Jerome, Pierson, Mary, Smolskis, Ydrissa, Sow, John, Tierney, Sumathi, Sivapalasingam, Wendy, Holman, Nikki, Gettinger, David, Vallée, Jacqueline, Nordwall, and Marie Claire, Kolie

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, viruses, MEDLINE, macromolecular substances, Disease, 030204 cardiovascular system & hematology, medicine.disease_cause, Antiviral Agents, law.invention, Disease Outbreaks, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Humans, Single-Blind Method, 030212 general & internal medicine, Young adult, Child, Infusions, Intravenous, Ebola virus, Alanine, Extramural, business.industry, Infant, Newborn, virus diseases, Antibodies, Monoclonal, Infant, General Medicine, Hemorrhagic Fever, Ebola, Ribonucleotides, Ebolavirus, Adenosine Monophosphate, Multicenter study, Child, Preschool, Democratic Republic of the Congo, RNA, Viral, Female, business
Abstract

Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial.We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days.A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs.Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Published
2019

6. Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy

Author

Robert W. Coombs, Susan Cu-Uvin, Susan H. Eshleman, Irving F. Hoffman, Jonathan Uy, Donna Mildvan, David W. Haas, Thomas B. Campbell, Kelly Burke, David D. Celentano, Edith Swann, Ronald T. Mitsuyasu, Ann C. Collier, Beatriz Grinsztejn, Newton Kumwenda, Laurie Frarey, Breno Santos, Apsara Nair, Ann Walawander, David Chilongozi, Bartolo Santos, Taha E. Taha, Chiedza Maponga, Sima Berendes, S. Poongulali, M. P. Revuelta, Charles van der Horst, Robert C. Bollinger, Suniti Solomon, Jorge Sanchez, Francis Martinson, N. Kumarasamy, Joan Dragavon, James Hakim, Rosa Infante, Richard B. Pendame, Farida Amod, Roy M. Gulick, Jody Lawrence, P. Jan Geiseler, Joan Gormley, Judith S. Currier, Cynthia Firnhaber, Laura Moran, Larisa Zifchak, Myron S. Cohen, Keith A. Pappa, Beverly Putnam, Charles Flexner, David H. Haas, Sandra W. Cardoso, Karin L. Klingman, Ruben Lopez, Joel E. Gallant, James F. Rooney, Jabin Sharma, Edde Loeliger, Pablo Tebas, Beverly E. Sha, Barbara Brizz, Wendy Snowden, Scott M. Hammer, Johnstone Kumwenda, Javier R. Lama, Karin Nielsen, Christine Wanke, Steve Tabet, Alberto La Rosa, Wadzanai Samaneka, Joseph J. Eron, Michael K. Klebert, Renard S. Descallar, Bharat Ramratnam, Kenneth H. Mayer, Cheryl Marcus, Yvonne J. Bryson, Nikki Gettinger, Vicki L. Bailey, Adriana Andrade, David Shugarts, Robert T. Schooley, Ken Braun, David Currin, Eric S. Daar, Michael Hughes, Laura M. Smeaton, Vladimir Berthaud, Sharlaa Badal-Faesen, Victor De Gruttola, Cecelia Kanyama, Timothy P. Flanigan, Mark A. Winters, Yvette Delph, Smanga Ntshele, Peter N. Kazembe, Deise Lucia Faria, Mina C. Hosseinipour, Steven A. Safren, Ronald L. Barnett, Ana Martinez, Abel Tilahun Eshete, Beth D. Mullan, Henry H. Balfour, Ge-Youl Kim, Anthony Chisada, Yajing Bao, Ian Sanne, Virginia Kayoyo, Susan A. Fiscus, Janice M. Fritsche, and Nancy Webb

Subjects
Adult, Male, Microbiology (medical), Cart, medicine.medical_specialty, Sexual transmission, viruses, HIV Infections, Genitalia, Male, Gastroenterology, law.invention, Plasma, Randomized controlled trial, law, Internal medicine, Blood plasma, Humans, Medicine, business.industry, virus diseases, RNA, Genitalia, Female, Viral Load, Antiretroviral therapy, Infectious Diseases, Anti-Retroviral Agents, Genital tract, Immunology, HIV-1, HIV/AIDS, RNA, Viral, Female, business, Viral load
Abstract

Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

Published
2013

7. Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Author

David Chilongozi, Sharla Faesen, Breno Santos, Mamta K. Jain, Pablo Tebas, Apsara Nair, Cynthia Riviere, Beatriz Grinsztejn, Sima Berendes, Steve Tabet, Joan Gormley, M. Graham Ray, Johnstone Kumwenda, Judith Feinberg, Todd Stroberg, Kenneth H. Mayer, Nikki Gettinger, Vicki L. Bailey, James Hakim, Selvamuthu Poongulali, Sandra W. Cardoso, Marineide Gonçalves de Melo, Karin L. Klingman, Rosie Mngqibisa, Thomas B. Campbell, Amneris E. Luque, Beverly Putnam, Thira Sirisanthana, Janice M. Fritsche, Ann Walawander, Ge Youl Kim, Roberto Corales, Richard B. Pollard, Ronald T. Mitsuyasu, Martha Silberman, Rita Alves Lira, Janet Forcht, Norbert Bischofberger, Ana Martinez, Barbara Brizz, Laura M. Smeaton, Asmita Gaikwad, Farida Amod, Srikanth Tripathy, Babafemi Taiwo, Anthony Chisada, Chiedza Maponga, Charles van der Horst, Michael Wulfsohn, Javier R. Lama, Taha E. Taha, Manuel Revuelta, Christine Hurley, David Currin, Wendy Snowden, Keith A. Pappa, Rosa Infante, T. Petersen, Donna V. McGregor, Susan Cu-Uvin, Susan A. Fiscus, Eric S. Daar, Jody Lawrence, P. Jan Geiseler, Irving F. Hoffman, Luis Lopez-Detres, Karen T. Tashima, Larisa Zifchak, Victor De Gruttola, Timothy P. Flanigan, Laura Moran, Farideh Said, Alberto La Rosa, Raman R. Gangakhedkar, Maria Palmer, Michael F. Para, Joel E. Gallant, Nancy Webb, Cecilia Kanyama, Wadzanai Samaneka, Jabin Sharma, Yvonne J. Bryson, Mark A. Winters, Ian Sanne, David Shugarts, Yun Chen, Sampada Dhayarkar, Peter N. Kazembe, Scott M. Hammer, Adriana Andrade, Robert T. Schooley, Beth D. Mullan, Henry H. Balfour, Patrice Severe, Beverly E. Sha, Madeline Torres, Cathi Basler, Andrew K. Cheng, Jolene Noel-Connor, Vladimir Berthaud, Jonathan Uy, Michael K. Klebert, Virginia Kayoyo, Donna Mildvan, David W. Haas, Joseph J. Eron, Cheryl Mogridge, David D. Celentano, Ruben Lopez, Ronald L. Barnett, Karin Nielsen, Helen Patterson, Renard S. Descallar, Jenifer Baer, Deise Lucia Faria, Cheryl Marcus, Khuanchai Supparatpinyo, Mina C. Hosseinipour, Newton Kumwenda, Yvette Delph, Smanga Ntshele, Edith Swann, Steven A. Safren, David M. Asmuth, Kelly Burke, Laurie Frarey, Joseph Steele, Gary M. Cox, Umesh G. Lalloo, Richard B. Pendame, Mary Adams, Bharat Ramratnam, Christine Wanke, James F. Rooney, Francis Martinson, Edde Loeliger, Anjali A. Joglekar, John Martin, Myron S. Cohen, Sheela Godbole, Robert C. Bollinger, Roy M. Gulick, Cynthia Firnhaber, Charles Flexner, William A. O'Brien, Suniti Solomon, Jorge Sanchez, Yue Chen, Susan H. Eshleman, Kathy J. Watson, N. Kumarasamy, David H. Haas, Ann C. Collier, Bartolo Santos, Suwat Chariyalertsak, Michelle S. Cespedes, Howard Jaffe, Judith S. Currier, and Deeks, Steven G

Subjects
Male, Comparative Effectiveness Research, Time Factors, Internationality, HIV Infections, Medical and Health Sciences, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Pregnancy, law, 030212 general & internal medicine, 0303 health sciences, education.field_of_study, Coinfection, Hazard ratio, virus diseases, General Medicine, 3. Good health, Infectious Diseases, Treatment Outcome, 6.1 Pharmaceuticals, Combination, HIV/AIDS, Medicine, Female, Patient Safety, Infection, medicine.drug, medicine.medical_specialty, Efavirenz, Anti-HIV Agents, Clinical Trials and Supportive Activities, Population, Antiretroviral Therapy, Emtricitabine, 03 medical and health sciences, Drug Therapy, Clinical Research, General & Internal Medicine, Internal medicine, PEARLS study team of the ACTG, medicine, Humans, Highly Active, Dosing, education, 030306 microbiology, business.industry, Evaluation of treatments and therapeutic interventions, Mycobacterium tuberculosis, Surgery, Atazanavir, Regimen, Withholding Treatment, chemistry, HIV-1, business, Follow-Up Studies
Abstract

BackgroundAntiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and findings1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; pConclusionEFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial registrationwww.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

Published
2012

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