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1. Deep-sequencing of viral genomes from a large and diverse cohort of treatment-naive HIV-infected persons shows associations between intrahost genetic diversity and viral load.

Author

Migle Gabrielaite, Marc Bennedbæk, Malthe Sebro Rasmussen, Virginia Kan, Hansjakob Furrer, Robert Flisiak, Marcelo Losso, Jens D Lundgren, INSIGHT START Study Group, and Rasmus L Marvig

Subjects
Biology (General), QH301-705.5
Abstract

BackgroundInfection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment.MethodsWe analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure.ResultsWe confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-valueConclusionsOur results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes.Trial registrationSamples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site.

Published
2023
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2. Metabolite profiles associated with disease progression in influenza infection.

Author

Chris H Wendt, Sandra Castro-Pearson, Jennifer Proper, Sarah Pett, Timothy J Griffin, Virginia Kan, Javier Carbone, Nikolaos Koulouris, Cavan Reilly, James D Neaton, and INSIGHT FLU003 Plus Study Group

Subjects
Medicine, Science
Abstract

BackgroundWe performed metabolomic profiling to identify metabolites that correlate with disease progression and death.MethodsWe performed a study of adults hospitalized with Influenza A(H1N1)pdm09. Cases (n = 32) were defined by a composite outcome of death or transfer to the intensive care unit during the 60-day follow-up period. Controls (n = 64) were survivors who did not require transfer to the ICU. Four hundred and eight metabolites from eight families were measured on plasma sample at enrollment using a mass spectrometry based Biocrates platform. Conditional logistic regression was used to summarize the association of the individual metabolites and families with the composite outcome and its major two components.ResultsThe ten metabolites with the strongest association with disease progression belonged to five different metabolite families with sphingolipids being the most common. The acylcarnitines, glycerides, sphingolipids and biogenic metabolite families had the largest odds ratios based on the composite endpoint. The tryptophan odds ratio for the composite is largely associated with death (OR 17.33: 95% CI, 1.60-187.76).ConclusionsIndividuals that develop disease progression when infected with Influenza H1N1 have a metabolite signature that differs from survivors. Low levels of tryptophan had a strong association with death.RegistryClinicalTrials.gov Identifier: NCT01056185.

Published
2021
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4. Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19:A Randomized Controlled Trial

Author

Christina, Barkauskas, Eleftherios, Mylonakis, Garyfallia, Poulakou, Barnaby E, Young, David M, Vock, Lianne, Siegel, Nicole, Engen, Greg, Grandits, Nilima R, Mosaly, Andrew M, Vekstein, Ralph, Rogers, Fadi, Shehadeh, Matthew, Kaczynski, Evangelia K, Mylona, Konstantinos N, Syrigos, Vasiliki, Rapti, David C, Lye, Diong Shiau, Hui, Lindsay, Leither, Kirk U, Knowlton, Mamta K, Jain, Rubria, Marines-Price, Alice, Osuji, J Scott, Overcash, Ioannis, Kalomenidis, Zafeiria, Barmparessou, Michael, Waters, Karla, Zepeda, Peter, Chen, Sam, Torbati, Francis, Kiweewa, Nicholus, Sebudde, Eyad, Almasri, Alyssa, Hughes, Sanjay R, Bhagani, Alison, Rodger, Uriel, Sandkovsky, Robert L, Gottlieb, Eriobu, Nnakelu, Barbara, Trautner, Vidya, Menon, Joseph, Lutaakome, Michael, Matthay, Philip, Robinson, Konstantinos, Protopapas, Nikolaos, Koulouris, Ivan, Kimuli, Amiran, Baduashvili, Dominique L, Braun, Huldrych F, Günthard, Srikanth, Ramachandruni, Robert, Kidega, Kami, Kim, Timothy J, Hatlen, Andrew N, Phillips, Daniel D, Murray, Tomas O, Jensen, Maria L, Padilla, Evan X, Accardi, Katy, Shaw-Saliba, Robin L, Dewar, Marc, Teitelbaum, Ven, Natarajan, Sylvain, Laverdure, Helene C, Highbarger, M Tauseef, Rehman, Susan, Vogel, David, Vallée, Page, Crew, Negin, Atri, Adam J, Schechner, Sarah, Pett, Fleur, Hudson, Jonathan, Badrock, Giota, Touloumi, Samuel M, Brown, Wesley H, Self, Crystal M, North, Adit A, Ginde, Christina C, Chang, Anthony, Kelleher, Stephanie, Nagy-Agren, Shikha, Vasudeva, David, Looney, Hien H, Nguyen, Adriana, Sánchez, Amy C, Weintrob, Birgit, Grund, Shweta, Sharma, Cavan S, Reilly, Roger, Paredes, Agnieszka, Bednarska, Norman P, Gerry, Abdel G, Babiker, Victoria J, Davey, Annetine C, Gelijns, Elizabeth S, Higgs, Virginia, Kan, Gail, Matthews, B Taylor, Thompson, Philippe, Legenne, Richa, Chandra, H Clifford, Lane, James D, Neaton, and Richard, Williams

Subjects
Adult, Treatment Outcome, Double-Blind Method, SARS-CoV-2, Recombinant Fusion Proteins, Internal Medicine, Humans, Designed Ankyrin Repeat Proteins, General Medicine, COVID-19/drug therapy, COVID-19 Drug Treatment
Abstract

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR

Published
2022

5. The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19

Author

Angela J, Rogers, Deborah, Wentworth, Andrew, Phillips, Katy, Shaw-Saliba, Robin L, Dewar, Neil R, Aggarwal, Abdel G, Babiker, Weizhong, Chang, Nila J, Dharan, Victoria J, Davey, Elizabeth S, Higgs, Norman, Gerry, Adit A, Ginde, J W Awori, Hayanga, Helene, Highbarger, Jeroen L, Highbarger, Mamta K, Jain, Virginia, Kan, Kami, Kim, Perrine, Lallemand, Bradley G, Leshnower, Joseph K, Lutaakome, Gail, Matthews, Ahmad, Mourad, Eleftherios, Mylonakis, Ven, Natarajan, Maria L, Padilla, Lavannya M, Pandit, Roger, Paredes, Sarah, Pett, Srikanth, Ramachandruni, M Tauseef, Rehman, Brad T, Sherman, D Clark, Files, Samuel M, Brown, Michael A, Matthay, B Taylor, Thompson, James D, Neaton, H Clifford, Lane, and Richard, Williams

Subjects
Adult, Male, Cross-Sectional Studies, SARS-CoV-2, Internal Medicine, COVID-19, Humans, General Medicine, Nucleocapsid, COVID-19/therapy
Abstract

Background: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19. Objective: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2. Design: Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge. Setting: 114 centers in 10 countries. Participants: Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms. Measurements: Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively. Results: Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity. Limitations: Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available. Conclusion: Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.

Published
2022

6. Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO):a randomised controlled trial

Author

Wesley H. Self, Uriel Sandkovsky, Cavan S. Reilly, David M. Vock, Robert L. Gottlieb, Michael Mack, Kevin Golden, Emma Dishner, Andrew Vekstein, Emily R. Ko, Tatyana Der, John Franzone, Eyad Almasri, Mohamed Fayed, Michael R. Filbin, Kathryn A. Hibbert, Todd W. Rice, Jonathan D. Casey, J. Awori Hayanga, Vinay Badhwar, Bradley G. Leshnower, Milad Sharifpour, Kirk U. Knowlton, Ithan D. Peltan, Elizieta Bakowska, Justyna Kowalska, Michael E. Bowdish, Jeffrey M. Sturek, Angela J. Rogers, D. Clark Files, Jarrod M. Mosier, Michelle N. Gong, David J. Douin, R. Duncan Hite, Barbara W. Trautner, Mamta K. Jain, Edward M. Gardner, Akram Khan, Jens-Ulrik Jensen, Michael A. Matthay, Adit A. Ginde, Samuel M. Brown, Elizabeth S. Higgs, Sarah Pett, Amy C. Weintrob, Christina C. Chang, Daniel D. Murrary, Huldrych F. Günthard, Ellen Moquete, Greg Grandits, Nicole Engen, Birgit Grund, Shweta Sharma, Huyen Cao, Rajesh Gupta, Suzette Osei, David Margolis, Qing Zhu, Mark N. Polizzotto, Abdel G. Babiker, Victoria J. Davey, Virginia Kan, B. Taylor Thompson, Annetine C. Gelijns, James D. Neaton, H. Clifford Lane, Jens D. Jundgren, John Tierney, Kevin Barrett, Betsey R. Herpin, Mary C. Smolskis, Susan E. Voge, Laura A. McNay, Kelly Cahill, Page Crew, Matthew Kirchoff, Ratna Sardana, Sharon Segal Raim, Joseph Chiu, Lisa Hensley, Josua Lorenzo, Rebecca Mock, Katy Shaw-Saliba, Judith Zuckerman, Stacey J. Adam, Judy Currier, Sarah Read, Eric Hughes, Laura Amos, Amy Carlsen, Anita Carter, Bionca Davis, Eileen Denning, Alain DuChene, Merrie Harrison, Payton Kaiser, Joseph Koopmeiners, Sue Meger, Thomas Murray, Kien Quan, Siu Fun Quan, Greg Thompson, Jamie Walski, Deborah Wentworth, Alan J. Moskowitz, Emilia Bagiella, Karen O'Sullivan, Mary E. Marks, Evan Accardi, Emily Kinzel, Gabriela Bedoya, Lopa Gupta, Jessica R. Overbey, Maria L. Padillia, Milerva Santos, Marc A. Gillinov, Marissa A. Miller, Wendy C. Taddei-Peters, Kathleen Fenton, Mezgebe Berhe, Clinton Haley, Christopher Bettacchi, Erin Duhaime, Madison Ryan, Sarah Burris, Felecia Jones, Samantha Villa, Samantha Want, Raven Robert, Tanquinisha Coleman, Laura Clariday, Rebecca Baker, Marian Hurutado-Rodriguez, Nazia Iram, Michelle Fresnedo, Allyson Davis, Kiara Leonard, Noelia Ramierez, Jon Thammavong, Krizia Duque, Emma Turner, Tammy Fisher, Dianna Robinson, Desirae Ransom, Erica Lusk, Aaron Killian, Adriana Palacious, Edilia Solis, Janet Jerrow, Matthew Watts, Heather Whitacre, Elizabeth Cothran, Peter K. Smith, Christina E. Barkauskas, Grace R. Dreyer, Marie Witte, Nilima Mosaly, Ahmad Mourad, Thomas L. Holland, Kathleen Lane, Andrew Bouffler, Lauren M. McGowan, Marry Motta, Gregory Tipton, Ben Stallings, Gennifer Stout, Beth McLendon-Arvik, Beth A. Hollister, Dana M. Giangiacomo, Sunil Sharma, Brian Pappers, Paul McCarthy, Troy Krupica, Arif Sarwari, Rebecca Reece, Lisa Fornaresio, Chad Glaze, Raquel Evans, Katarina Preamble, Lisa Giblin Sutton, Sabrina Buterbaugh, Elizabeth Berry Bartolo, Roger Williams, Robin Bunner, William Bender, Jeffrey Miller, Kim T. Baio, Mary K. McBride, Michele Fielding, Sonya Mathewson, Kristina Porte, Missy Maton, Chari Ponder, Elizabeth Haley, Christine Spainhour, Susan Rogers, Derrick Tyler, Noah Wald-Dickler, Douglass Hutcheon, Amytis Towfighi, May M. Lee, Meghan R. Lewis, Brad Spellberg, Linda Sher, Aniket Sharma, Anna P. Olds, Chris Justino, Edward Lozano, Chris Romero, Janet Leong, Valentina Rodina, Tammie Possemato, Jose Escobar, Charlene Chiu, Kevin Weissman, Andrew Barros, Kyle B. Enfield, Alexandra Kadl, China J. Green, Rachel M. Simon, Ashley Fox, Kara Thornton, Patrick E. Parrino, Stephen Spindel, Aditya Bansal, Katherine Baumgarten, Jonathan Hand, Derek Vonderhaar, Bobby Nossaman, Sylvia Laudun, DeAnna Ames, Shane Broussard, Nilmo Hernandez, Geralyn Isaac, Huan Dinh, Yiling Zheng, Sonny Tran, Hunter McDaniel, Nicolle Crovetto, Leslie Miller, Beth Schelle, Sherry McLean, Howard R. Rothbaum, Michael S. Alvarez, Shivam P. Kalan, Heather H. Germann, Jennifer Hendershot, Karen Maroney, Karen Herring, Sharri Cook, Pam Paul, Ronson J. Madathil, Joseph Rabin, Andrea Levine, Kapil Saharia, Ali Tabatabai, Christine Lau, James S. Gammie, Maya-Loren Peguero, Kimberley McKernan, Matthew Audette, Emily Fleischmann, Freshta Akbari, Maia Lee, Myounghee Lee, Andrew Chi, Hanna Salehi, Alan Pariser, Phuong Tran Nguyen, Jessica Moore, Adrienne Gee, Shelika Vincent, Richard A. Zuckerman, Alexander Iribarne, Sara Metzler, Samantha Shipman, Taylor Caccia, Haley Johnson, Crystallee Newton, Doug Parr, Vicente Rodriguez, Gordon Bokhart, Sharon M. Eichman, Crystal North, Cathryn Oldmixon, Nancy Ringwood, Laura Fitzgerald, Haley D. Morin, Ariela Muzikansky, Richard Morse, Roy G. Brower, Lora A. Reineck, Neil R. Aggarwal, Karen Bienstock, Peter Hou, Jay Steingrub, Mark A. Tidswell, Lori-Ann Kozikowski, Cynthia Kardos, Leslie DeSouza, Sherell Thornton-Thompson, Daniel Talmor, Nathan Shapiro, Valerie Banner-Goodspeed, Katherine L. Boyle, Sharon Hayes, Alan E. Jones, James Galbraith, Utsav Nandi, Rebekah K. Peacock, Blair Alden Parry, Justin D. Margolin, Kelsey Brait, Caroline Beakes, Kirsten N. Kangelaris, Kimberly J. Yee, Kimia Ashktorab, Alejandra E. Jauregui, Hanjing Zhuo, Gregory Hendey, Kinsley A. Hubel, Alyssa R. Hughes, Rebekah L. Garcia, Jennifer G. Wilson, Rosemary Vojnik, Jonasel Roque, Cynthia Perez, George W. Lim, Steven Y. Chang, Rebecca Beutler, Trisha Agarwal, Julia Vargas, Marc Moss, Amiran Baduashvili, Lakshmi Chauhan, Lani L. Finck, Michelle Howell, Robert C. Hyzy, Pauline K. Park, Kristine Nelson, Jake I. McSparron, Ivan N. Co, Bonnie R. Wang, Shijing Jia, Barbara Sullins, Sinan Hanna, Norman Olbrich, Lynne D. Richardson, Rahul Nair, Obiageli Offor, Brenda Lopez, Omowunmi Amosu, Hiwet Tzehaie, Thomas E. Terndrup, Herbert P. Wiedemann, Abhijit Duggal, Nirosshan Thiruchelvam, Kiran Ashok, Alexander H. King, Omar Mehkri, Kristin Hudock, Simra Kiran, Harshada More, Tammy Roads, Jamie Martinkovic, Sarah Kennedy, Bryce H. Robinson, Catherine L. Hough, Olivia F. Krol, Mistry Kinjal, Emmanuel Mills, Madeline McDougal, Rupali Deshmukh, Peter Chen, Sam S. Torbati, Yuri Matusov, June Choe, Niree A. Hindoyan, Susan E. Jackman, Emad Bayoumi, Timothy Wynter, Antonina Caudill, Ethan Pascual, Gregg J. Clapham, Lisa Herrera, Cristabelle Ojukwu, Shaunt Mehdikhani, D. Shane O'Mahony, Sonam T. Nyatsatsang, David M. Wilson, Julie A. Wallick, Chadwick Miller, Keven W. Gibbs, Lori S. Flores, Mary E. LaRose, Leigha D. Landreth, Peter E. Morris, Jamie L. Sturgill, Evan P. Cassity, Sanjay Dhar, Ashley A. Montgomery-Yates, Sara N. Pasha, Kirby P. Mayer, Brittany Bissel, Joseph Bledsoe, Samuel Brown, Michael Lanspa, Lindsey Leither, Brent P. Armbruster, Quinn Montgomery, Darrin Applegate, Naresh Kumar, Melissa Fergus, Erna Serezlic, Karah Imel, Ghazal Palmer, Brandon Webb, Valerie T. Aston, Jakea Johnson, Christopher Gray, Margaret Hays, Megan Roth, Adriana Sánchez, Laura Popielski, Heather Rivasplata, Melissa Turner, Michael Vjecha, Tianna Petersen, Dena Kamel, Laura Hansen, Claudia Sanchez Lucas, Natalie DellaValle, Sonia Gonzales, James Scott, David Wyles, Ivor Douglas, Jason Haukoos, Kevin Kamis, Caitlin Robinson, Jason V. Baker, Anne Frosch, Rachael Goldsmith, Hodan Jibrell, Melanie Lo, Jonathan Klaphake, Shari Mackedanz, Linh Ngo, Kelly Garcia-Myers, Norman Markowitz, Erika Pastor, Mayur Ramesh, Indira Brar, Emanuel Rivers, Princy Kumar, Maximiliano Menna, Kousick Biswas, Cristin Harrington, Alex Delp, Lavannya Pandit, Casey Hines-Munson, John Van, Laura Dillon, Yiqun Want, Paola Lichtenberger, Gio Baracco, Carol Ramos, Lauren Bjork, Melyssa Sueiro, Phyllis Tien, Heather Freasier, Theresa Buck, Hafida Nekach, Stephanie Nagy-Agren, Shikha Vasudeva, Tracy Ochalek, Brentin Roller, Chinh Nguyen, Amani Mikail, Dorthe Raben, Tomas O. Jensen, Bitten Aagaard, Charlotte B. Nielsen, Katharina Krapp, Bente Rosdahl Nykjær, Katja Lisa Kanne, Anne Louise Grevsen, Zillah Maria Joensen, Tina Bruun, Ane Bojesen, Frederik Woldbye, Nick E. Normand, Frederik V.L. Esmann, Clara Lundetoft Clausen, Nichlas Hovmand, Karen Brorup Pedersen, Louise Thorlacius-Ussing, Michaela Tinggaard, Dorthe S. Høgsberg, Ema Rastoder, Thobias Kamstrup, Christina Marisa Bergsøe, Lars Østergaard, Nina Breinholt Stærke, Isik S. Johansen, Fredrikke C. Knudtzen, Lykke Larsen, Mathias A. Hertz, Thilde Fabricius, Marie Helleberg, Jan Gerstoft, Tomas Østergaard Jensen, Birgitte Lindegaard, Thomas Ingemann Pedersen, Birgit Thorup Røge, Sandra Valborg Løfberg, Thomas Michael Hansen, Ariella Denize Nielsen, Sebastian Leicht von Huth, Henrik Nielsen, Rikke Krog Thisted, Daria Podlekareva, Stine Johnsen, Helle Frost Andreassen, Lars Pedersen, Cecilia Ebba Clara Ellinor Lindnér, Lothar Wiese, Lene Surland Knudsen, Nikolaj Julian Skrøder Nytofte, Signe Ravn Havmøller, Roger Paredes, Maria Exposito, Eduardo Fernández-Cruz, José Muñoz, Jose R. Arribas, Vicente Estrada, Juan P. Horcajada, Joaquin Burgos, Jose Luis Morales-Rull, Dominique L. Braun, Emily West, Khadija M'Rabeth-Bensalah, Mareile L. Eichinger, Manuela Grüttner-Durmaz, Christina Grube, Veronika Zink, Andrzej Horban, Agnieszka Bednarska, Natalia Jurek, Gerd Fätkenheuer, Jakob J. Malinm, Gail Matthews, Anthony Kelleher, Gesalit Cabrera, Catherine Carey, Sally Hough, Sophie Virachit, Amy Zhong, Barnaby E. Young, Po Ying Chia, Tau Hong Lee, Ray J. Lin, David Lye, Sean Ong, Ser Hon Puah, Tsin Wen Yeo, Shiau Hui Diong, Juwinda Ongko, Fleur Hudson, Mahesh KB Parmar, Anna Goodman, Jonathan Badrock, Adam Gregory, Nicola Harris, Giota Touloumi, Nikos Pantaz, Vicky Gioukari, Joseph Lutaakome, Cissy M. Kityo, Henry Mugerwa, Francis Kiweewa, Anu Osinusi, Craig Tipple, Angela Willis, Amanda Peppercorn, Helen Watson, Elizabeth Alexander, Erik Mogalian, Leo Lin, Xiao Ding, Li Yan, Jean-Luc Girardet, Ji Ma, Zhi Hong, Amy Adams, Sara Albert, Abby Balde, Michelle Baracz, Beth Baseler, Nancy Becker, Mona Bielica, Shere Billouin-Frazier, Jennifer Cash, Jay Choudhary, Suzanne Dolney, Mary Dixon, Carolyn Eyler, Leanna Frye, Michael Galcik, Jensen Gertz, Lisa Giebeig, Neelam Gulati, Liz Hankinson, Debbie Hissey, Debi Hogarty, Matt Hohn, H Preston Holley, Lisa Hoopengardner, Lynda Huber, Shirley Jankelevich, Gary Krauss, Eileen Lake, Jessica Linton, Leah MacDonald, Meryan Manandhar, Mary Spinelli-Nadzam, Charles Oluremi, Calvin Proffitt, Erin Rudzinski, Jen Sandrus, Marylu Schaffhauser, Adam Schechner, Connie Suders, Norman P. Gerry, Kenneth Smith, Courtney Solomon, Amanda Kubernac, Marium Rashid, Bhakti Patel, Robert Kubernac, Joseph Murphy, Marie L. Hoover, Craig Brown, Nadine DuChateau, Adam Flosi, Les Johnson, Amy Treagus, and Christine Wenner

Subjects
Adult, Male, Adolescent, SARS-CoV-2, Comment, COVID-19, Antibodies, Monoclonal, Articles, Middle Aged, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, COVID-19/drug therapy, COVID-19 Drug Treatment, Hospitalization, Infectious Diseases, Antineoplastic Agents, Immunological, Treatment Outcome, Antibodies, Monoclonal, Humanized/therapeutic use, Double-Blind Method, Humans, Female, Aged
Abstract

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Published
2022

7. Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Author

Thomas L. Holland, Adit A. Ginde, Roger Paredes, Thomas A. Murray, Nicole Engen, Greg Grandits, Andrew Vekstein, Noel Ivey, Ahmad Mourad, Uriel Sandkovsky, Robert L. Gottlieb, Mezgebe Berhe, Mamta K. Jain, Rubria Marines-Price, Barbine Tchamba Agbor Agbor, Lourdes Mateu, Sergio España-Cueto, Gemma Lladós, Eleftherios Mylonakis, Ralph Rogers, Fadi Shehadeh, Michael R. Filbin, Kathryn A. Hibbert, Kami Kim, Thanh Tran, Peter E. Morris, Evan P. Cassity, Barbara Trautner, Lavannya M. Pandit, Kirk U. Knowlton, Lindsay Leither, Michael A. Matthay, Angela J. Rogers, Wonder Drake, Beatrice Jones, Garyfallia Poulakou, Konstantinos N. Syrigos, Eduardo Fernández-Cruz, Marisa Di Natale, Eyad Almasri, Leire Balerdi-Sarasola, Sanjay R. Bhagani, Katherine L. Boyle, Jonathan D. Casey, Peter Chen, David J. Douin, D. Clark Files, Huldrych F. Günthard, R. Duncan Hite, Robert C. Hyzy, Akram Khan, Moses Kibirige, Robert Kidega, Ivan Kimuli, Francis Kiweewa, Jens-Ulrik Jensen, Bradley G. Leshnower, Joseph K. Lutaakome, Prasad Manian, Vidya Menon, Jose Luis Morales-Rull, D. Shane O'Mahony, J. Scott Overcash, Srikant Ramachandruni, Jay S. Steingrub, Hassan S. Taha, Michael Waters, Barnaby E. Young, Andrew N. Phillips, Daniel D. Murray, Tomas O. Jensen, Maria L. Padilla, David Sahner, Katy Shaw-Saliba, Robin L. Dewar, Marc Teitelbaum, Ven Natarajan, M. Tauseef Rehman, Sarah Pett, Fleur Hudson, Giota Touloumi, Samuel M. Brown, Wesley H. Self, Christina C. Chang, Adriana Sánchez, Amy C. Weintrob, Timothy Hatlen, Birgit Grund, Shweta Sharma, Cavan S. Reilly, Pedro Garbes, Mark T. Esser, Alison Templeton, Abdel G. Babiker, Victoria J. Davey, Annetine C. Gelijns, Elizabeth S. Higgs, Virginia Kan, Gail Matthews, B. Taylor Thompson, James D. Neaton, H. Clifford Lane, and Jens D. Lundgren

Subjects
Pulmonary and Respiratory Medicine, Adult, Treatment Outcome, Double-Blind Method, Antibodies, Monoclonal, Humans, COVID-19/drug therapy, Antibodies, Neutralizing, COVID-19 Drug Treatment
Abstract

BACKGROUND: Tixagevimab-cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab-cilgavimab versus placebo, in patients receiving remdesivir and other standard care.METHODS: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg-cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab-cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing.FINDINGS: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab-cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab-cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97-1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97-1·34]; p=0·13). Mortality was lower in the tixagevimab-cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50-0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab-cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68-1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab-cilgavimab group and 38 (5%) in the placebo group.INTERPRETATION: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab-cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.FUNDING: US National Institutes of Health (NIH) and Operation Warp Speed.

Published
2022

8. Tixagevimab/Cilgavimab for Treatment of Hospitalised COVID-19 Patients: A Randomised, Double-Blind, Phase 3 Trial

Author

Thomas L. Holland, Adit A. Ginde, Roger Paredes, Thomas A. Murray, Nicole Engen, Greg Grandits, Andrew Vekstein, Noel Ivey, Ahmad Mourad, Uriel Sandkovsky, Robert L. Gottlieb, Mezgebe Berhe, Mamta Jain, Rubria Marines-Price, Barbine Tchamba Agbor Agbor, Lourdes Mateu, Sergio Espana-Cueto, Gemma Llados, Eleftherios Mylonakis, Ralph Rogers, Fadi Shehadeh, Michael R. Filbin, Kathryn A. Hibbert, Kami Kim, Thanh Tran, Peter E. Morris, Evan P. Cassity, Barbara Trautner, Lavannya M. Pandit, Kirk U. Knowlton, Lindsay Leither, Michael A. Matthay, Angela J. Rogers, Wonder Drake, Beatrice Jones, Garyfallia Poulakou, Konstantinos N. Syrigos, Eduardo Fernandez-Cruz, Marisa Di Natale, Eyad Almasri, Leire Balerdi-Sarasola, Sanjay R. Bhagani, Katherine L. Boyle, Jonathan D. Casey, Peter Chen, David J. Douin, D. Clark Files, Huldrych F. Günthard, R. Duncan Hite, Robert C. Hyzy, Akram Khan, Moses Kibirige, Robert Kidega, Ivan Kimuli, Francis Kiweewa, Jens Ulrik Stæhr Jensen, Bradley G. Leshnower, Joseph K. Lutaakome, Prasad Manian, Vidya Menon, Jose Luis Morales-Rull, Darragh O'Mahony, J. Scott Overcash, Srikant Ramachandruni, Jay S. Steingrub, Hassan S. Taha, Michael Waters, Barnaby E. Young, Andrew N. Phillips, Daniel D. Murray, Tomas O. Jensen, Maria L. Padilla, David Sahner, Katy Shaw-Saliba, Robin L. Dewar, Marc Teitelbaum, Ven Natarajan, M. Tauseef Rehman, Sarah Pett, Fleur Hudson, Giota Touloumi, Samuel M. Brown, Wesley H. Self, Christina C. Chang, Adriana Sanchez, Amy C. Weintrob, Timothy Hatlen, Birgit Grund, Shweta Sharma, Cavan S. Reilly, Pedro Garbes, Mark T. Esser, Alison Templeton, Abdel G. Babiker, Victoria J. Davey, Annetine C. Gelijns, Elizabeth S. Higgs, Virginia Kan, Gail Matthews, B. Taylor Thompson, James D. Neaton, H. Clifford Lane, and Jens Lundgren

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2022

9. Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery

Author

David J. Douin, Lianne Siegel, Greg Grandits, Andrew Phillips, Neil R. Aggarwal, Jason Baker, Samuel M. Brown, Christina C. Chang, Anna L. Goodman, Birgit Grund, Elizabeth S. Higgs, Catherine L. Hough, Daniel D. Murray, Roger Paredes, Mahesh Parmar, Sarah Pett, Mark N. Polizzotto, Uriel Sandkovsky, Wesley H. Self, Barnaby E. Young, Abdel G. Babiker, Victoria J. Davey, Virginia Kan, Annetine C. Gelijns, Gail Matthews, B. Taylor Thompson, H. Clifford Lane, James D. Neaton, Jens D. Lundgren, Adit A. Ginde, Lee Kong Chian School of Medicine (LKCMedicine), Tan Tock Seng Hospital, and National Centre for Infectious Diseases, Singapore

Subjects
Pulmonary and Respiratory Medicine, SARS-CoV-2, Clinical Trials and Supportive Activities, Respiratory System, Antibodies, Monoclonal, Aftercare, COVID-19, Critical Care and Intensive Care Medicine, Medical and Health Sciences, Antibodies, Patient Discharge, outcomes assessment, Treatment Outcome, Good Health and Well Being, Clinical Research, Monoclonal, Humans, Medicine [Science], monoclonal antibodies, Aged
Abstract

Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach; 2) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P

Published
2022

10. Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

Author

Richard T Davey, Eduardo Fernández-Cruz, Norman Markowitz, Sarah Pett, Abdel G Babiker, Deborah Wentworth, Surender Khurana, Nicole Engen, Fred Gordin, Mamta K Jain, Virginia Kan, Mark N Polizzotto, Paul Riska, Kiat Ruxrungtham, Zelalem Temesgen, Jens Lundgren, John H Beigel, H Clifford Lane, James D Neaton, Jessica Butts, Eileen Denning, Alain DuChene, Eric Krum, Merrie Harrison, Sue Meger, Ross Peterson, Kien Quan, Megan Shaughnessy, Greg Thompson, David Vock, Julia Metcalf, Robin Dewar, Tauseef Rehman, Ven Natarajan, Rose McConnell, Emily Flowers, Kenny Smith, Marie Hoover, Elizabeth M Coyle, David Munroe, Bitten Aagaard, Mary Pearson, Adam Cursley, Helen Webb, Fleur Hudson, Charlotte Russell, Aminata Sy, Cara Purvis, Brooke Jackson, Yolanda Collaco-Moraes, Dianne Carey, Rosemary Robson, Adriana Sánchez, Elizabeth Finley, Donna Conwell, Marcelo H Losso, Luciana Gambardella, Cecilia Abela, Paco Lopez, Helena Alonso, Giota Touloumi, Vicky Gioukari, Olga Anagnostou, Anchalee Avihingsanon, Kanitta Pussadee, Sasiwimol Ubolyam, Bola Omotosho, Clemencia Solórzano, Tianna Petersen, Kranthi Vysyaraju, Stacey A Rizza, Jennifer A Whitaker, Raquel Nahra, John Baxter, Patricia Coburn, Edward M Gardner, James A Scott, Leslie Faber, Erica Pastor, Linda Makohon, Rodger A MacArthur, L Monique Hillman, Marti J Farrough, Hari M Polenakovik, Linda A Clark, Roberto J Colon, Ken M Kunisaki, Miranda DeConcini, Susan A Johnson, Cameron R Wolfe, Laura Mkumba, June Y Carbonneau, Alison Morris, Meghan E Fitzpatrick, Cathy J Kessinger, Robert A Salata, Karen A Arters, Catherine M Tasi, Ralph J Panos, Laura A Lach, Marshall J Glesby, Kirsis A Ham, Valery G Hughes, Robert T Schooley, Daniel Crouch, Leticia Muttera, Richard M Novak, Susan C Bleasdale, Ariel E Zuckerman, Weerawat Manosuthi, Supeda Thaonyen, Thaniya Chiewcharn, Gompol Suwanpimolkul, Sivaporn Gatechumpol, Sirikunya Bunpasang, Brian J Angus, Monique Anderson, Marcus Morgan, Jane Minton, Maria N Gkamaletsou, Joe Hambleton, David A Price, Martin J Llewelyn, Jonathan Sweetman, Javier Carbone, Jose R Arribas, Rocio Montejano, Jose L Lobo Beristain, Iñaki Z Martinez, Jose Barberan, Paola Hernandez, Dominic E Dwyer, Jen Kok, Alvaro Borges, Christian T Brandt, Lene S Knudsen, Nikolaos Sypsas, Costas Constantinou, Antonios Markogiannakis, Spyros Zakynthinos, Paraskevi Katsaounou, Ioannis Kalomenidis, Analia Mykietiuk, Maria F Alzogaray, Mora Obed, Laura M Macias, Juan Ebensrtejin, Patricia Burgoa, Esteban Nannini, Matias Lahitte, Santiago Perez-Patrigeon, José Arturo Martínez-Orozco, and Juan Pablo Ramírez-Hinojosa

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Oseltamivir, Influenzavirus B, Placebo-controlled study, Pilot Projects, Placebo, Antiviral Agents, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Internal medicine, Influenza, Human, Clinical endpoint, medicine, Humans, 030212 general & internal medicine, business.industry, Immunoglobulins, Intravenous, Odds ratio, Middle Aged, Clinical trial, Hospitalization, Treatment Outcome, 030228 respiratory system, chemistry, Influenza A virus, Drug Therapy, Combination, Female, business, Breast feeding
Abstract

Summary Background Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial. Methods This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013–14 to 2017–18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov , NCT02287467 . Findings 313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79–1·97; p=0·33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0·94 (0·55–1·59) and was 3·19 (1·21–8·42) for those with influenza B (interaction p=0·023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1·06, 95% CI 0·70–1·60; p=0·79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment. Interpretation When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted. Funding NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.

Published
2019

11. Influenza Immunoglobulin for Adults Hospitalized with Influenza

Author

Richard T. Davey, Jens D Lundgren, Fred M. Gordin, Norman Markowitz, Henry Clifford Lane, Sarah Pett, Paul F. Riska, Eduardo Fernandez-Cruz, John Beigel, Zelalem Temesgen, Virginia Kan, Deborah Wentworth, Mark N. Polizzotto, Nicole Engen, Mamta K Jain, Abdel Babiker, Surender Khurana, Kiat Ruxrungtham, and James D. Neaton

Subjects
Clinical trial, medicine.medical_specialty, Hemagglutination assay, business.industry, Internal medicine, medicine, Clinical endpoint, Odds ratio, Placebo, business, Institutional review board, Viral load, Confidence interval
Abstract

Background: Despite treatment with licensed antiviral agents, high rates of influenza-related morbidity and mortality occur worldwide. Methods: Adults hospitalized with laboratory-confirmed influenza were randomized (1:1) to a single double-blind infusion of high-titer anti-influenza intravenous immunoglobulin (hIVIG) or saline placebo. The primary endpoint was an ordered categorical outcome, ranging in severity from death to post-discharge resumption of normal activities, assessed at Day 7. The odds ratio (OR) (hIVIG versus placebo) of a favorable outcome was estimated with a proportional odds model. Findings: Of 308 randomized patients, 73% and 27% had influenza A and B, respectively; antiviral use was 95%. As expected, hIVIG produced a robust rise in influenza A hemagglutination inhibition (HAI) titers, and smaller rises in influenza B titers. Viral load declined after 3 days by 1.99 (hIVIG) versus 2.32 log10 copies/mL (placebo) (p=0.49). The OR for favorable outcome was 1.25 (95% confidence interval [CI] 0.79-1.97, p=0.33). ORs for influenza A and B were 0.94 (95% CI: 0.55-1.59) and 3.19 (95% CI: 1.21-8.42), respectively (p=0.02 for difference). This difference between influenza A and B was mirrored for secondary clinical outcomes, changes in viral load, and in sensitivity analyses, overall and by strain. To investigate this outcome further, anti-HA antibody affinities were measured in the hIVIG lots administered, and much stronger antibody affinities for B strains were observed than for A in hIVIG used. Interpretation: Overall, hIVIG was not superior to placebo for adults hospitalized with influenza. In contrast to our pre-study subgroup hypothesis based upon conventional HAI titers in hIVIG, benefit was evident for those with influenza B but not A. Consistent with findings of a contemporaneous anti-influenza plasma trial (IRC005), adjunctive immunotherapy appears ineffective for severe influenza A. The beneficial effect of hIVIG for influenza B is supported by antibody affinity analyses, but confirmation of clinical benefit is warranted. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02287467. Funding: NIAID, NIH. Declaration of Interest: There are no competing interests to declare in regard to this manuscript submission. Ethical Approval: The trial was approved by the institutional review board or ethics committee for each clinical site. All patients provided written informed consent.

Published
2019

12. Nomenclature and definitions for emergency department human immunodeficiency virus (HIV) testing: report from the 2007 conference of the National Emergency Department HIV Testing Consortium

Author

Michael S, Lyons, Christopher J, Lindsell, Jason S, Haukoos, Gregory, Almond, Jeremy, Brown, Yvette, Calderon, Eileen, Couture, Roland C, Merchant, Douglas A E, White, Richard E, Rothman, Chris, Aldridge, Gregory, Andrade, Christian, Arbelaez, Tom-meka, Archinard, Steven I, Aronin, Susan, Barrera, Moses, Bateganya, Joanna, Bell-Merriam, Bob, Bongiovanni, Kathleen, Brady, Bernard, Branson, Carol, Brosgart, Evan, Cadoff, Linda, Chaille-Arnold, Ben, Cheng, William, Chiang, Brittney, Copeland, Rosalyn L, Cousar, Maggie, Czarnogorski, Kit, Delgado, Emily, Erbelding, James, Feldman, Osvaldo, Garcia, Charlotte A, Gaydos, Nancy, Glick, Barbara, Gripshover, Jason, Haukoos, Alisa, Hayes, James, Heffelfinger, Laura, Herrera, Amy, Hilley, David, Holtgrave, Brooke, Hoots, Emily, Hopkins, Debra, Houry, Debra, Howell, Yu-Hsiang, Hsieh, Angela B, Hutchinson, Blanca, Jackson, Michael, Jaker, Kerin, Jones, Juliana, Jung, Linda, Kampe, Virginia, Kan, Nancy, Kass, Gabor D, Kelen, Karen, Kroc, Ann, Kurth, Margaret A, Lampe, Jason, Leider, Michael, Lemanski, Michael, Lyons, Sandra, McGovern, Seth, Mercer, Roland, Merchant, Nancy, Miertschin, Joan, Miller, Patricia, Mitchell, Sarah, Nelson, Linda, Onaga, David, Paltiel, Sindy, Paul, Harold, Pollack, Stephen, Raffanti, Liisa, Randall, Richard, Rothman, Akhter, Sabreen, Jeffrey, Sankoff, Vanessa, Sasso, Nathaniel Bernard, Saylor, Elissa, Schechter, Barbara, Schechtman, Steven, Schrantz, Alicia, Scribner, Judy, Shahan, Daniel, Skiest, Freya, Spielberg, Irijah S, Stennett, Patrick, Sullivan, Cathalene, Teahan, Susan, Thompson, Gretchen, Torres, Vicken, Totten, Krystn, Wagner, Rochelle, Walensky, Michael, Waxman, Andrea, Weddle, Douglas, White, Tom, Widell, James A, Wilde, Keith, Wrenn, and Juliet, Yonek

Subjects
medicine.medical_specialty, Mandatory reporting, media_common.quotation_subject, Human immunodeficiency virus (HIV), Guidelines as Topic, HIV Infections, Hiv testing, medicine.disease_cause, Article, Health services, Terminology as Topic, medicine, Humans, media_common, business.industry, Public health, Communication, Diagnostic test, General Medicine, Emergency department, Mandatory Reporting, Family medicine, Emergency medicine, Emergency Medicine, business, Emergency Service, Hospital, Diversity (politics)
Abstract

Early diagnosis of persons infected with human immunodeficiency virus (HIV) through diagnostic testing and screening is a critical priority for individual and public health. Emergency departments (EDs) have an important role in this effort. As EDs gain experience in HIV testing, it is increasingly apparent that implementing testing is conceptually and operationally complex. A wide variety of HIV testing practice and research models have emerged, each reflecting adaptations to site-specific factors and the needs of local populations. The diversity and complexity inherent in nascent ED HIV testing practice and research are associated with the risk that findings will not be described according to a common lexicon. This article presents a comprehensive set of terms and definitions that can be used to describe ED-based HIV testing programs, developed by consensus opinion from the inaugural meeting of the National ED HIV Testing Consortium. These definitions are designed to facilitate discussion, increase comparability of future reports, and potentially accelerate wider implementation of ED HIV testing.

Published
2008

13. Mycobacterium szulgai infection of the lung: case report and review of an unusual pathogen

Author

Virginia Kan, Fred M. Gordin, and Debra A. Benator

Subjects
Lung Diseases, Male, Microbial Sensitivity Tests, Histoplasmosis, Mycobacterium szulgai, Mycobacterium, Ciprofloxacin, medicine, Isoniazid, Humans, Ethambutol, Mycobacterium Infections, Lung, biology, business.industry, Respiratory disease, General Medicine, Middle Aged, medicine.disease, biology.organism_classification, Anti-Bacterial Agents, Radiography, medicine.anatomical_structure, Immunology, Nontuberculous mycobacteria, Drug Therapy, Combination, Rifampin, business, medicine.drug
Abstract

The nontuberculous mycobacteria are responsible for considerable morbidity in the immunocompromised and immunocompetent host, especially in the older patient with chronic fibrotic or cavitary disease of the lung. Mycobacterium szulgai is a slow growing mycobacterium infrequent in nature and man. Except from a snail and a tropical fish, it has been isolated only from humans and nearly always represents a true pathogen. Three-drug therapy using in vitro susceptibilities as a guide for 12 to 18 months increases the likelihood of success. We present a patient who developed M szulgai pulmonary infection 30 years after an episode of pulmonary tuberculosis. After successful therapy for his M szulgai infection, this patient developed chronic pulmonary histoplasmosis. We review the 25 years of clinical experience with this mycobacteria; particular emphasis is on the presentation and treatment of this very unusual infection.

Published
1997

14. Extension for Community Healthcare Outcomes Uruguay: A New Strategy to Promote Best Primary Care Practice for Autism

Author

Gustavo Giachetto MD, Ana Laura Casuriaga MD, Anabella Santoro MD, Virginia Kanopa MD, Gabriela Garrido MD, José Fernández, Henry Cohen MD, and Kristin Sohl MD

Subjects
Pediatrics, RJ1-570
Abstract

Introduction . In Uruguay, the special care required for children with neurodevelopmental disorders presents difficulties including lack of access to specialists and rehabilitation services. Project ECHO (Extension for Community Healthcare Outcomes) connects primary care clinicians from remote areas to specialists to enable them to treat complex conditions through ongoing education and mentoring. Objective . To share the experience of the ECHO Autism program during the first 2 years of implementation. Methods . Analysis of ECHO Autism clinics from June 2015 to June 2017 including clinical cases presented participants’ self-perception of changes in skills and competences. Results . Twenty clinical cases were presented: mean age 4.5 years; 15 were males; and 17 with medical and psychiatric comorbidities. After ECHO Autism implementation, a statistically significant improvement in participants’ self-perception of skills and competences was observed. Conclusions . ECHO Autism in Uruguay is a meaningful approach to autism care and offers improved access to best practice care.

Published
2019
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15. Hospitalizaciones por ALTE

Author

Virginia Kanopa, María Noel Cuadro, Alejandra de León, Lorena De León, Ana Milovidov, and Gustavo Giachetto

Subjects
evento de aparente amenaza a la vida infantil, hospitalización, Medicine, Medicine (General), R5-920
Abstract

Introducción: el ALTE (evento de aparente amenaza a la vida) genera ansiedad y preocupación en la familia y representa un desafío para el personal de salud. En Uruguay no se dispone de datos para evaluar la magnitud del problema. Objetivo: describir la prevalencia y características de los lactantes hospitalizados por ALTE en el Departamento de Pediatría del Centro Hospitalario Pereira Rossell (CHPR). Material y método: diseño descriptivo, retrospectivo. Período: 1°/12/2010 - 1°/12/2011. Criterios de inclusión: menores de un año hospitalizados en salas de cuidados moderados con diagnóstico de ALTE. Variables: edad, sexo, factores de riesgo (FR) para síndrome de muerte súbita (SMSL), estudios e interconsultas realizadas, evolución, duración de la estadía hospitalaria y diagnóstico al egreso. Fuente de datos: historias clínicas. Análisis: EpiInfo versión 2002. Resultados: fueron hospitalizados 2.695 menores de un año: 71 (2,6%) con ALTE. Tasa de hospitalización 26,3/1.000 (IC95% 20,2-32,3); 52,1% varones; 62% menores de dos meses. Se solicitaron estudios paraclínicos en 62 de los 71 niños con ALTE: en 8/8 c/ALTE mayor, en 46/50 con ALTE menor con FR, 8/13 con ALTE menor s/FR. El diagnóstico al egreso fue ALTE idiopático 36/71 (50,7%) y secundario 35/71 (49,3%). Se identificó causa digestiva en 21/35, respiratoria en 12/35 y neurológica en 2/35. La media de la estadía hospitalaria fue de 7 días (rango 1-51 días). Cuatro niños fueron hospitalizados en centro de tratamiento intensivo (CTI). Ninguno requirió soporte ventilatorio ni falleció. Conclusión: en el CHPR la mayoría de las hospitalizaciones por ALTE ocurren en niños menores de dos meses de edad que consultan por cambios de coloración y presentan factores de riesgo para SMSL. Se destaca la falta de criterios uniformes en el abordaje de estos niños y el bajo rendimiento de las pruebas diagnósticas.

Published
2014

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