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1. Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial

Author

Evering, Teresa H, Moser, Carlee, Jilg, Nikolaus, Ritz, Justin, Wohl, David A, Li, Jonathan Z, Margolis, David, Javan, Arzhang Cyrus, Eron, Joseph J, Currier, Judith S, Daar, Eric S, Smith, Davey M, Hughes, Michael D, Chew, Kara W, Chew, Kara, Smith, David, Daar, Eric, Wohl, David, Currier, Judith, Eron, Joseph, Hughes, Michael, Giganti, Mark, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Li, Jonathan, Fletcher, Courtney, Fischer, William, Ignacio, Rachel Bender, Cardoso, Sandra, Corado, Katya, Jagannathan, Prasanna, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Singh, Upinder, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, Shahkolahi, Akbar, Lacal, Verónica, Salusso, Diego, Nuñez, Sebastian, Rodriguez, Marcelo Rodrigo, Laborde, Luciana, Papasidero, Marcelo, Wehbe, Luis, Gonzalez, Mariana, Voena, Felicitas Fernandez, Alvarez, Tomas, Lopez, Amaru, Huhn, Virginia, Nores, Ulises D'Andrea, Dieser, Pablo, Bordese, Fernando, Mussi, Marisa, de Carvalho Santana, Rodrigo, Bárbaro, Adriana Aparecida Tiraboschi, Santos, Breno, de Cássia Alves Lira, Rita, da Silva, Andre Luiz Machado, Cardoso, Sandra Wagner, Ribeiro, Maria Pia Diniz, Soliva, Nathália, Vasconcellos, Eduardo, Ribeiro, Jorge Eurico, Enéas, Miriam Amaral, Pinto, Jorge, de Morais Caporali, Julia Fonseca, Ferreira, Flávia Gomes Faleiro, Martinez, Norma Erendira Rivera, Lopez, Victor Casildo Bohorquez, Frias, Melchor Victor, Fetalvero, Krystle, Maranan, Alyxzza, Rosa, Jennifer, Coetzer, Thomas, Mohata, Maureen, Lalloo, Umesh, Madlala, Penelope, Pillay-Ramaya, Larisha, and Bennet, Jaclyn Ann

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, Prevention, Infectious Diseases, Emerging Infectious Diseases, Coronaviruses, 6.1 Pharmaceuticals, Good Health and Well Being, COVID-19, Monoclonal antibodies, Outpatient treatment, Clinical trial, Post COVID conditions, Long COVID, Post-acute sequelae of SARS-CoV-2 infection, ACTIV-2/A5401 Study Team, Clinical sciences, Health services and systems, Public health
Abstract

BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Published
2024

2. Expert Consensus Statement on an Updated Definition of Unintended Weight Loss Among Persons With Human Immunodeficiency Virus in the Modern Treatment Era.

Author

Bedimo, Roger, Hardy, David, Lee, Daniel, Palella, Frank, and Wohl, David

Subjects
AIDS, HIV-associated wasting, antiretroviral therapy, screening, unintentional weight loss, Humans, Weight Loss, HIV Infections, Anti-HIV Agents, HIV Wasting Syndrome, Consensus
Abstract

The era of modern antiretroviral therapy (ART) has markedly improved health and survival among persons with human immunodeficiency virus (HIV) (PWH). In the pre-ART era, wasting was associated with HIV disease progression to acquired immunodeficiency syndrome and death. Effective ART has reduced the prevalence and incidence of this pre-ART form of HIV-associated wasting. However, a subgroup of ART-treated virally suppressed PWH continue to lose weight, often accompanied by aging-related comorbidities and/or functional deficits. For this subgroup of patients, the older definition of HIV-associated wasting (HIVAW) cannot and should not be applied. An expert panel comprising the authors of this white paper convened to review the existing definition of HIVAW and to create an updated definition that they termed HIV-associated weight loss, based on clinically defined parameters among contemporary PWH receiving ART. Here, clinical features and laboratory biomarkers associated with HIV-associated weight loss are reviewed and approaches to screening and treatment are considered. Available management approaches, including the use of current US Food and Drug Administration-approved medications for HIVAW and other available therapies are discussed. The expert panel also identified knowledge gaps and provided recommendations for clinicians, payers, and researchers.

Published
2024

3. Safety and efficacy of inhaled interferon-β1a (SNG001) in adults with mild-to-moderate COVID-19: a randomized, controlled, phase II trial

Author

Jagannathan, Prasanna, Chew, Kara W, Giganti, Mark J, Hughes, Michael D, Moser, Carlee, Main, Mark J, Monk, Phillip D, Javan, Arzhang Cyrus, Li, Jonathan Z, Fletcher, Courtney V, McCarthy, Caitlyn, Wohl, David A, Daar, Eric S, Eron, Joseph J, Currier, Judith S, Singh, Upinder, Smith, Davey M, Fischer, William, Team, ACTIV-2 A5401 Study, Chew, Kara, Smith, David, Daar, Eric, Wohl, David, Currier, Judith, Eron, Joseph, Hughes, Michael, Giganti, Mark, Ritz, Justin, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Li, Jonathan, Fletcher, Courtney, Evering, Teresa, Ignacio, Rachel Bender, Cardoso, Sandra, Corado, Katya, Jilg, Nikolaus, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, Shahkolahi, Akbar, Pierone, Gerald, Elliott, Juliana, Jacobson, Jeffrey, Hojat, Leila, Pasternak, Julie, Berardi, Jonathan, Arar, Celine, Bukhman, Yevgeniy, Jain, Manish, Bukhman, Eugene, Shaik, Sadia, Hatlen, Timothy, Dooley, Kelly, Becker, Becky, Wilkins, Adaliah, Pérez, Jose, Roman, Eloy, Fernández, Heriberto, Hoover, Keila, Renfroe, James, Weldon, Mauney, Bougher, Genei, Malvestutto, Carlos, Harber, Heather, Cicarella, Robyn, Neytman, Gene, Herman, Jack, Herman, Craig, Aziz, Mariam, Swiatek, Joan, Pathak, Divya, Choudhary, Madhu, Sullivano, Jennifer, Osiyemi, Olayemi, Izquierdo, Myriam, Torna, Odelsey, Khodabakhshian, Aleen, and Fortier, Samantha

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, Coronaviruses, Infectious Diseases, Coronaviruses Therapeutics and Interventions, Emerging Infectious Diseases, Patient Safety, Prevention, Lung, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Inhaled interferon, SARS-CoV-2, COVID-19, ACTIV-2, Randomized clinical trial, ACTIV-2/A5401 Study Team, Clinical sciences, Health services and systems, Public health
Abstract

BackgroundWith the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need.MethodsSafety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.govNCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021.FindingsThe proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm.InterpretationIn this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia.FundingThe ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Published
2023

4. One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019: A Randomized Controlled Phase 2 Trial

Author

Jilg, Nikolaus, Chew, Kara W, Giganti, Mark J, Daar, Eric S, Wohl, David A, Javan, Arzhang Cyrus, Kantor, Amy, Moser, Carlee, Coombs, Robert W, Neytman, Gene, Hoover, Keila, Jana, Atasi, Hart, Phil A, Greninger, Alexander L, Szurgot, Bob, Eron, Joseph J, Currier, Judith S, Hughes, Michael D, Smith, Davey M, Li, Jonathan Z, Chew, Kara, Smith, David, Daar, Eric, Wohl, David, Currier, Judith, Eron, Joseph, Hughes, Michael, Giganti, Mark, Ritz, Justin, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Li, Jonathan, Fletcher, Courtney, Fischer, William, Evering, Teresa, Coombs, Robert, Ignacio, Rachel Bender, Cardoso, Sandra, Corado, Katya, Jagannathan, Prasanna, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Singh, Upinder, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, and Shahkolahi, Akbar

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Emerging Infectious Diseases, Infectious Diseases, Coronaviruses Therapeutics and Interventions, Coronaviruses, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Humans, Adult, COVID-19, SARS-CoV-2, RNA, Viral, Time Factors, Treatment Outcome, camostat, outpatient, phase 2, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

BackgroundCamostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults.MethodsWe conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28.ResultsOf 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA ConclusionsIn a phase 2 study of nonhospitalized adults with mild-to-moderate COVID-19, oral camostat did not accelerate viral clearance or time to symptom improvement, or reduce hospitalizations or deaths. Clinical Trials Registration. ClinicalTrials.gov identifier: NCT04518410.

Published
2023

5. Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial

Author

Corado, Katya C, Chew, Kara W, Giganti, Mark J, Mu, Ying, Fletcher, Courtney V, Currier, Judith S, Daar, Eric S, Wohl, David A, Li, Jonathan Z, Moser, Carlee B, Ritz, Justin, Javan, Arzhang Cyrus, Neytman, Gene, Caskey, Marina, Hughes, Michael D, Smith, Davey M, Eron, Joseph J, and Team, ACTIV-2 A5401 Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Coronaviruses, Biotechnology, Clinical Trials and Supportive Activities, Coronaviruses Therapeutics and Interventions, Immunization, Infectious Diseases, Emerging Infectious Diseases, Clinical Research, 6.1 Pharmaceuticals, ACTIV-2/A5401 Study Team, COVID-19, SARS-CoV-2, monoclonal antibodies, outpatient treatment, subcutaneous, Clinical sciences, Immunology, Medical microbiology
Abstract

BackgroundOutpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration.MethodsACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days.ResultsA total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA ConclusionsWhile safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.

Published
2024

6. Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

Author

Phan, Tin, Zitzmann, Carolin, Chew, Kara W, Smith, Davey M, Daar, Eric S, Wohl, David A, Eron, Joseph J, Currier, Judith S, Hughes, Michael D, Choudhary, Manish C, Deo, Rinki, Li, Jonathan Z, Ribeiro, Ruy M, Ke, Ruian, Perelson, Alan S, and Team, for the ACTIV-2 A5401 Study

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Coronaviruses Therapeutics and Interventions, Emerging Infectious Diseases, Coronaviruses, Infectious Diseases, Immunization, Biodefense, Biotechnology, 5.2 Cellular and gene therapies, Infection, Good Health and Well Being, Humans, SARS-CoV-2, Antibodies, Monoclonal, Spike Glycoprotein, Coronavirus, COVID-19, COVID-19 Drug Treatment, Antibodies, Viral, Drug Resistance, Viral, Viral Load, Antiviral Agents, Antibodies, Neutralizing, ACTIV-2/A5401 Study Team, Microbiology, Virology, Medical microbiology
Abstract

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

Published
2024

8. Immune Status and SARS-CoV-2 Viral Dynamics

Author

Li, Yijia, Moser, Carlee, Aga, Evgenia, Currier, Judith S, Wohl, David A, Daar, Eric S, Ritz, Justin, Greninger, Alexander L, Sieg, Scott, Parikh, Urvi M, Coombs, Robert W, Hughes, Michael D, Eron, Joseph J, Smith, Davey M, Chew, Kara W, Li, Jonathan Z, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Degli-Angeli, Emily, Goecker, Erin, Daza, Glenda, Harb, Socorro, Dragavon, Joan, Aldrovandi, Grace, Murtaugh, William, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bowman, Rachel, Erhardt, Bill, Warring, Lorraine, Hessinger, Diane, and Adams, Stacey

Subjects
Biomedical and Clinical Sciences, Immunology, Coronaviruses, Infectious Diseases, Emerging Infectious Diseases, Clinical Research, Clinical Trials and Supportive Activities, Infection, Good Health and Well Being, Humans, COVID-19, Immunocompromised Host, Immunosuppression Therapy, Kinetics, SARS-CoV-2, RNA, immunocompromise, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12-.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics. Clinical Trials Registration. NCT04518410.

Published
2023

9. Pooling Different Placebos as a Control Group in a Randomized Platform Trial: Benefits and Challenges From Experience in the ACTIV-2 COVID-19 Trial

Author

Moser, Carlee B, Chew, Kara W, Ritz, Justin, Newell, Matthew, Javan, Arzhang Cyrus, Eron, Joseph J, Daar, Eric S, Wohl, David A, Currier, Judith S, Smith, Davey M, Hughes, Michael D, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Aldrovandi, Grace, Murtaugh, William, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bowman, Rachel, Giganti, Mark, Erhardt, Bill, and Adams, Stacey

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Coronaviruses, Clinical Trials and Supportive Activities, Clinical Research, Coronaviruses Therapeutics and Interventions, Infectious Diseases, Emerging Infectious Diseases, 6.1 Pharmaceuticals, Generic health relevance, Humans, COVID-19, Control Groups, Pandemics, adaptive platform trials, pooled placebo, randomization, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410.

Published
2023

10. ACTIV-2: A Platform Trial for the Evaluation of Novel Therapeutics for the Treatment of Early COVID-19 in Outpatients

Author

Currier, Judith S, Moser, Carlee, Eron, Joseph J, Chew, Kara W, Smith, Davey M, Javan, Arzhang Cyrus, Wohl, David Alain, Daar, Eric S, Hughes, Michael D, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Science, Frontier, Erhardt, Bill, Waring, Lorraine, Hessinger, Diane, and Adams, Stacey

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Coronaviruses Therapeutics and Interventions, Clinical Research, Emerging Infectious Diseases, Infectious Diseases, Clinical Trials and Supportive Activities, Coronaviruses, Humans, COVID-19, Outpatients, COVID-19 Drug Treatment, Antiviral Agents, ACTIV-2, clinical trial, monoclonal antibodies, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410.

Published
2023

11. Validity and Characterization of Time to Symptom Resolution Outcome Measures in the ACTIV-2/A5401 Outpatient COVID-19 Treatment Trial

Author

Chew, Kara W, Moser, Carlee, Yeh, Eunice, Wohl, David A, Daar, Eric S, Ritz, Justin, Javan, Arzhang Cyrus, Eron, Joseph J, Currier, Judith S, Smith, Davey M, Hughes, Michael D, and Team, for the ACTIV-2 A5401 Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Clinical Trials and Supportive Activities, Coronaviruses, Clinical Research, 6.1 Pharmaceuticals, Good Health and Well Being, Female, Humans, Male, Middle Aged, Ambulatory Care, COVID-19, COVID-19 Drug Treatment, Outpatients, ACTIV-2, internal validity, patient-reported outcomes, symptom diary, symptom outcomes, symptom rebound, symptom recurrence, time to symptom resolution, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundTime to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation.MethodsACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo.ResultsThe analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences.ConclusionsThere was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms.Clinical trials registrationNCT04518410.

Published
2023

12. Association Between Anterior Nasal and Plasma SARS-CoV-2 RNA Levels and Hospitalization or Death in Nonhospitalized Adults With Mild-to-Moderate COVID-19

Author

Giganti, Mark J, Chew, Kara W, Eron, Joseph J, Li, Jonathan Z, Pinilla, Mauricio, Moser, Carlee, Javan, Arzhang Cyrus, Fischer, William A, Klekotka, Paul, Margolis, David, Wohl, David Alain, Coombs, Robert W, Daar, Eric S, Smith, Davey M, Currier, Judith S, Hughes, Michael D, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Greninger, Alexander, Degli-Angeli, Emily, Goecker, Erin, Daza, Glenda, Harb, Socorro, Dragavon, Joan, Aldrovandi, Grace, Murtaugh, William, Science, Frontier, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bowman, Rachel, Erhardt, Bill, Waring, Lorraine, Hessinger, Diane, and Adams, Stacey

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Emerging Infectious Diseases, Coronaviruses, Clinical Trials and Supportive Activities, Infectious Diseases, Good Health and Well Being, Adult, Humans, Antibodies, Monoclonal, COVID-19, Hospitalization, RNA, Viral, SARS-CoV-2, hospitalization, outpatient, SARS-CoV-2 RNA, surrogate marker, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundThere is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19).MethodsAnterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death.ResultsOne hundred two participants were hospitalized or died through 28 days of follow-up. Higher day 0 (pretreatment) AN RNA was associated with increasing risk of hospitalization/death (risk ratio [RR], 1.24 per log10 copies/mL [95% confidence interval {CI}, 1.04-1.49]) among placebo recipients, ranging from 3% to 16% for

Published
2023

13. Variant-Specific Viral Kinetics in Acute COVID-19

Author

Ribeiro, Ruy M, Choudhary, Manish C, Deo, Rinki, Giganti, Mark J, Moser, Carlee, Ritz, Justin, Greninger, Alexander L, Regan, James, Flynn, James P, Wohl, David A, Currier, Judith S, Eron, Joseph J, Hughes, Michael D, Smith, Davey M, Chew, Kara W, Daar, Eric S, Perelson, Alan S, Li, Jonathan Z, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Aldrovandi, Grace, Murtaugh, William, Science, Frontier, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bowman, Rachel, Erhardt, Bill, and Adams, Stacey

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Trials and Supportive Activities, Emerging Infectious Diseases, Infectious Diseases, Clinical Research, Coronaviruses, Infection, Humans, COVID-19, Half-Life, Kinetics, SARS-CoV-2, variant, viral kinetics, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410.

Published
2023

14. Statistical Challenges When Analyzing SARS-CoV-2 RNA Measurements Below the Assay Limit of Quantification in COVID-19 Clinical Trials

Author

Moser, Carlee B, Chew, Kara W, Giganti, Mark J, Li, Jonathan Z, Aga, Evgenia, Ritz, Justin, Greninger, Alexander L, Javan, Arzhang Cyrus, Ignacio, Rachel Bender, Daar, Eric S, Wohl, David A, Currier, Judith S, Eron, Joseph J, Smith, Davey M, Hughes, Michael D, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Aldrovandi, Grace, Murtaugh, William, Science, Frontier, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bosch, Ronald, Harrison, Linda, Erhardt, Bill, and Adams, Stacey

Subjects
Biological Sciences, Clinical Trials and Supportive Activities, Coronaviruses Therapeutics and Interventions, Emerging Infectious Diseases, Infectious Diseases, Genetics, Clinical Research, Coronaviruses, Generic health relevance, Good Health and Well Being, Humans, Antiviral Agents, Biological Assay, COVID-19, RNA, Viral, SARS-CoV-2, SARS-CoV-2 RNA, linear regression for censored data, randomized trial, ACTIV-2/A5401 Study Team, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Most clinical trials evaluating coronavirus disease 2019 (COVID-19) therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly imputed values can lead to biased estimates of treatment effects. In this article, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values

Published
2023

15. Long COVID After Bamlanivimab Treatment

Author

Evering, Teresa H, Moser, Carlee B, Jilg, Nikolaus, Yeh, Eunice, Sanusi, Busola, Wohl, David A, Daar, Eric S, Li, Jonathan Z, Klekotka, Paul, Javan, Arzhang Cyrus, Eron, Joseph J, Currier, Judith S, Hughes, Michael D, Smith, Davey M, Chew, Kara W, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Coombs, Robert, Greninger, Alexander, Degli-Angeli, Emily, Goecker, Erin, Daza, Glenda, Harb, Socorro, Dragavon, Joan, Aldrovandi, Grace, Murtaugh, William, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bowman, Rachel, Erhardt, Bill, Waring, Lorraine, Hessinger, Diane, Adams, Stacey, and Kallianpur, Asha R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Emerging Infectious Diseases, Clinical Research, Coronaviruses, Clinical Trials and Supportive Activities, Infectious Diseases, Respiratory, Good Health and Well Being, Female, Humans, Male, Middle Aged, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, COVID-19, Post-Acute COVID-19 Syndrome, bamlanivimab, clinical trial, long COVID, postacute sequelae of SARS-CoV-2 infection, symptom, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundProspective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401.MethodsData were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021. Long COVID was defined as the presence of self-assessed COVID symptoms at week 24. Self-assessed return to pre-COVID health was also examined. Associations were assessed by regression models.ResultsAmong 506 participants, median age was 51 years. Half were female, 5% Black/African American, and 36% Hispanic/Latino. At 24 weeks, 18% reported long COVID and 15% had not returned to pre-COVID health. Smoking (adjusted risk ratio [aRR], 2.41 [95% confidence interval {CI}, 1.34- 4.32]), female sex (aRR, 1.91 [95% CI, 1.28-2.85]), non-Hispanic ethnicity (aRR, 1.92 [95% CI, 1.19-3.13]), and presence of symptoms 22-28 days posttreatment (aRR, 2.70 [95% CI, 1.63-4.46]) were associated with long COVID, but nasal severe acute respiratory syndrome coronavirus 2 RNA was not.ConclusionsLong COVID occurred despite early, effective monoclonal antibody therapy and was associated with smoking, female sex, and non-Hispanic ethnicity, but not viral burden. The strong association between symptoms 22-28 days after treatment and long COVID suggests that processes of long COVID start early and may need early intervention.Clinical trials registrationNCT04518410.

Published
2023

16. Phase 2 Safety and Antiviral Activity of SAB-185, a Novel Polyclonal Antibody Therapy for Nonhospitalized Adults With COVID-19

Author

Taiwo, Babafemi O, Chew, Kara W, Moser, Carlee, Wohl, David Alain, Daar, Eric S, Li, Jonathan Z, Greninger, Alexander L, Bausch, Christoph, Luke, Thomas, Hoover, Keila, Neytman, Gene, Giganti, Mark J, Olefsky, Maxine, Javan, Arzhang Cyrus, Fletcher, Courtney V, Eron, Joseph J, Currier, Judith S, Hughes, Michael D, Smith, Davey M, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Coombs, Robert, Degli-Angeli, Emily, Goecker, Erin, Daza, Glenda, Harb, Socorro, Dragavon, Joan, Aldrovandi, Grace, Murtaugh, William, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Erhardt, Bill, Waring, Lorraine, Hessinger, Diane, Meintjes, Graeme A, Murray, Barbara E, Ray, Stuart Campbell, Rolla, Valeria Cavalcanti, Saloojee, Haroon, Tsiatis, Anastasios A, Volberding, Paul A, Kimmelman, Jonathan, Glidden, David, and Hunsberger, Sally

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, Infectious Diseases, Coronaviruses, Emerging Infectious Diseases, 6.1 Pharmaceuticals, Good Health and Well Being, Adult, Humans, COVID-19, SARS-CoV-2, Antiviral Agents, RNA, Viral, Immunoglobulin G, Double-Blind Method, SAB-185, antibody, polyclonal, transchromosomic, treatment, ACTIV-2/A5401 Study Team, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundSAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19).MethodsParticipants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.ResultsTwo-hundred thirteen participants received low-dose SAB-185/placebo (n = 107/106) and 215 high-dose SAB-185/placebo (n = 110/105). The proportions with SARS-CoV-2 RNA < LLOQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB-185 versus placebo only, relative risk 1.23 (95% confidence interval, 1.01-1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo: differences in medians of -0.78 log10 copies/mL (P = .08) and -0.71 log10 copies/mL (P = .10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (P = .24) for low-dose SAB-185/placebo and 8/10 days (P = .50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo.ConclusionsSAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk nonhospitalized adults with COVID-19. Clinical Trials Registration. NCT04518410.

Published
2023

17. Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial

Author

Chew, Kara, Smith, David (Davey), Daar, Eric, Wohl, David, Currier, Judith, Eron, Joseph, Javan, Arzhang Cyrus, Hughes, Michael, Moser, Carlee, Giganti, Mark, Ritz, Justin, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Li, Jonathan, Fletcher, Courtney, Fischer, William, Evering, Teresa H., Ignacio, Rachel Bender, Cardoso, Sandra, Corado, Katya, Jagannathan, Prasanna, Jilg, Nikolaus, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Singh, Upinder, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, Shahkolahi, Akbar, Margolis, David, Lacal, Verónica, Salusso, Diego, Nuñez, Sebastian, Rodriguez, Marcelo Rodrigo, Laborde, Luciana, Papasidero, Marcelo, Wehbe, Luis, Gonzalez, Mariana, Voena, Felicitas Fernandez, Alvarez, Tomas, Lopez, Amaru, Huhn, Virginia, D'Andrea Nores, Ulises, Dieser, Pablo, Bordese, Fernando, Mussi, Marisa, de Carvalho Santana, Rodrigo, Tiraboschi Bárbaro, Adriana Aparecida, Santos, Breno, de Cássia Alves Lira, Rita, Machado da Silva, Andre Luiz, Cardoso, Sandra Wagner, Diniz Ribeiro, Maria Pia, Soliva, Nathália, Vasconcellos, Eduardo, Ribeiro, Jorge Eurico, Enéas, Miriam Amaral, Pinto, Jorge, Fonseca de Morais Caporali, Julia, Faleiro Ferreira, Flávia Gomes, Rivera Martinez, Norma Erendira, Bohorquez Lopez, Victor Casildo, Frias, Melchor Victor, Fetalvero, Krystle, Maranan, Alyxzza, Rosa, Jennifer, Coetzer, Thomas, Mohata, Maureen, Sr., Lalloo, Umesh, Madlala, Penelope, Pillay-Ramaya, Larisha, Bennet, Jaclyn Ann, Mwelase, Noluthando, Mbhele, Nokuphiwa, Petrick, Frederick, Joubert, Leonard, Mbali, Rose, Sr., Joseph, Natasha, Manentsa, Mmatsie, van der Walt, Eugene, Lawrance Masilela, Mduduzi Sandile, Zwane, Zinhle, Chiperera, Tendai, Mohapi, Lerato, Moonsamy, Suri, Singh, Usha, McHarry, Kirsten, Snyman, Elizma, Lennox, Pieter, Innes, James Craig, Letlape, Oteng, Jonkane, Olebogeng, Brumskine, William, Adonis, Tania, Sein, Ni Ni, Sebe, Modulakgotla, Vahed, Yacoob, Hussen, Nazreen Jeewa, Mitha, Ismail, Cheekati, Vasundhara, Cheekati, Purna, Lummus, Christie, Idarraga, Samuel, Kim, Andrew, Pham, David N., Kao, Wei-Hsin, Pfeffer, Michael M., Dominguez, Miriam Batule, Malik, Anju, Bryan, Anna, Arnold, Melanie, Fernandez, Idania, Karpf, Cinzia, Ruiz, Aniuska, Taylor, David, Folkens, Eric, Manne, Jennifer, Yawetz, Sigal, Keenan, Cheryl, Eziri, Emeka, Fichtenbaum, Carl, Baer, Jenifer, Trentman, Sarah, Call, Robert, Vaughan, Leroy, Milstone, Aaron, Slandzicki, Jamie Alex, Wallan, Jessica, Guillory, Clinton, Andrews, Nancy, Hughes, Leslie, Berardi, Jonathan, Arar, Celine, Quinn, Randall, Amaya, Jorge P., Gomez-Martinez, Marissa, Cantu, Luis, Betancourt-Garcia, Monica, Okeke, Nwora Lance, Burns, Charles M., Haddad, Fadi, Haddad, Victoria, Focil, Augusto, Rosas, Griselda, Moyano, Susana, Rojas, Yaneicy Gonzalez, Aswad, Ahmad, Bukhman, Yevgeniy, Jain, Manish, Bukhman, Eugene, Farah, Humam, McClain, Rebekah, Shaik, Sadia, Hatlen, Timothy, Gotur, Deepa, Surber, Joseph, Kingsley, Jeffrey, Pixler, April, Zopo, Alex, Herman, Jack, Herman, Craig, Leon, Ramon, Nikolov, Boris, Vergara, Fernando Gonzalez, Gonzalez, Ana I., Gonzalez, Noemi, Gelman, Michael, Andriunas, Olga, Jagizarov, Zarema, Westerman, Jan, Davis, David, Sherer, Donna, Dooley, Kelly, Becker, Becky, Wilkins, Adaliah, Pérez, Jose, Roman, Eloy, Fernández, Heriberto, Mocherla, Bharat, Beck, Kelly, Maldonado, Valarie, Veltman, Jennifer, Gandhi, Rajesh, Shea, Katrina, Planchon, Matthew, Herpel, Laura Bogan, Tripathi, Kaushlendra K., Day, Donald C., Pullman, John, Sr., Williams-Leber, Erin, Johnson, Misty, Hecker, Michelle, Avery, Ann, Hoover, Keila, Monlux, George W., Juneja, Elizabeth, Jr., Wernick, Arthur, Ruiz, Karelia, Hernández, Maureen, Pérez, Yadilys, Taiwo, Babafemi O., Hawkins, Claudia, Berzins, Baiba, Malvestutto, Carlos, Harber, Heather, Cicarella, Robyn, DeJesus, Edwin, Rolle, Charlotte-Paige, Free, Almena L., Pulliam, Sallie D., Weinstein, Debra, Suarez, Rosa M., Socorro, Ezequiel, Socorro, Estefania, Neytman, Gene, Easley, Raymond, Aziz, Mariam, Swiatek, Joan, Nagpal, Avish, Kompelien, Breanna, McEvoy, Kathryn, Hoover, Susan E., Lutz, Allison, Just, Jessica, Hernandez, Manuel, Victoria, Yanly B., Rodriguez, Gabriel, Pathak, Divya, Ordway, Joshua J., Heffner, Megan, Weston, Patrick, Weston, Khalilah, Choudhary, Madhu, Sullivano, Jennifer, Osiyemi, Olayemi, Izquierdo, Myriam, Torna, Odelsey, Clemency, Brian, Varughese, Renoj, Lynch, Joshua, Khodabakhshian, Aleen, Fortier, Samantha, Coyne, Christopher, Cronin, Alexandrea, Benson, Constance, Hendrickx, Steven, Ramirez, Rosemarie, Luetkemeyer, Anne, Hendler, Suzanne, Dentoni-Lasofsky, Dennis, Rathore, Mobeen, Mahmoudi, Saniyyah, Riaz, Amna, Castro, Mario, Spikes, Leslie, Hall, Chase, Oakes, Jonathan, Loftis, Amy James, Tebas, Pablo, Short, William, Dube, Michael P., Khan, Saahir, Mendez, Luis M., McGuffin, Sarah, Jonsson, Chris, Jain, Mamta K., Senthil, Smruthi, Turner-Gray, Kimberly, Mehta, Sanjay, Lewinski, Mary, Azizad, Masoud, Chow, Christopher, Nakatani, Lisa, Williamson, Derrick, Atriss, Hisham, Caloura, Matthew, Malla, Midhun, Hazard-Jenkins, Hannah, Wilkin, Aimee, Fayssoux, Jamraus, Seagle, Hannah, Presti, Rachel, Haile, Alem, Wohl, David A., Li, Jonathan Z., Eron, Joseph J., Currier, Judith S., Daar, Eric S., Smith, Davey M., Hughes, Michael D., and Chew, Kara W.

Published
2024
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18. Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19

Author

Evering, Teresa H, Chew, Kara W, Giganti, Mark J, Moser, Carlee, Pinilla, Mauricio, Wohl, David Alain, Currier, Judith S, Eron, Joseph J, Javan, Arzhang Cyrus, Bender Ignacio, Rachel, Margolis, David, Zhu, Qing, Ma, Ji, Zhong, Lijie, Yan, Li, D’Andrea Nores, Ulises, Hoover, Keila, Mocherla, Bharat, Choudhary, Manish C, Deo, Rinki, Ritz, Justin, Fischer, William A, Fletcher, Courtney V, Li, Jonathan Z, Hughes, Michael D, Smith, Davey, Daar, Eric S, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Cardoso, Sandra, Corado, Katya, Jagannathan, Prasanna, Jilg, Nikolaus, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Singh, Upinder, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, Shahkolahi, Akbar, Lacal, Verónica, Salusso, Diego, Nuñez, Sebastian, Rodrigo Rodriguez, Marcelo, Laborde, Luciana, Papasidero, Marcelo, Wehbe, Luis, Gonzalez, Mariana, Fernandez Voena, Felicitas, Alvarez, Tomas, Lopez, Amaru, Huhn, Virginia, Dieser, Pablo, Bordese, Fernando, Mussi, Marisa, de Carvalho Santana, Rodrigo, Bárbaro, Adriana Aparecida Tiraboschi, Santos, Breno, de Cássia Alves Lira, Rita, da Silva, Andre Luiz Machado, Ribeiro, Maria Pia Diniz, Soliva, Nathália, Vasconcellos, Eduardo, Ribeiro, Jorge Eurico, Enéas, Miriam Amaral, and Pinto, Jorge

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Patient Safety, Infectious Diseases, Clinical Trials and Supportive Activities, Vaccine Related, Lung, Emerging Infectious Diseases, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Adult, Humans, Female, Middle Aged, Male, COVID-19, SARS-CoV-2, Antibodies, Monoclonal, Antibodies, Viral, Double-Blind Method, ACTIV-2/A5401 Study Team, Medical and Health Sciences, General & Internal Medicine, Clinical sciences
Abstract

BackgroundDevelopment of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life.ObjectiveTo assess the safety and efficacy of amubarvimab plus romlusevimab.DesignRandomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410).SettingNonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.PatientsAdults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.InterventionCombination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.MeasurementsNasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.ResultsEight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P

Published
2023

19. Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection

Author

Deo, Rinki, Choudhary, Manish C, Moser, Carlee, Ritz, Justin, Daar, Eric S, Wohl, David A, Greninger, Alexander L, Eron, Joseph J, Currier, Judith S, Hughes, Michael D, Smith, Davey M, Chew, Kara W, Li, Jonathan Z, Javan, Arzhang Cyrus, Giganti, Mark, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Fletcher, Courtney, Fischer, William, Evering, Teresa, Ignacio, Rachel Bender, Cardoso, Sandra, Corado, Katya, Jagannathan, Prasanna, Jilg, Nikolaus, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Singh, Upinder, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, and Shahkolahi, Akbar

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Clinical Trials and Supportive Activities, Clinical Research, Brain Disorders, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Humans, COVID-19, SARS-CoV-2, Retrospective Studies, RNA, Viral, ACTIV-2/A5401 Study Team, Medical and Health Sciences, General & Internal Medicine, Clinical sciences
Abstract

BackgroundAlthough symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described.ObjectiveTo characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19.DesignRetrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410).SettingMulticenter trial.Patients563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial.MeasurementsParticipants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log10 copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL to a viral load of 5.0 log10 copies/mL or higher.ResultsSymptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants.LimitationA largely unvaccinated population infected with pre-Omicron variants was evaluated.ConclusionSymptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

Published
2023

20. Nasal and Plasma Severe Acute Respiratory Syndrome Coronavirus 2 RNA Levels Are Associated With Timing of Symptom Resolution in the ACTIV-2 Trial of Nonhospitalized Adults With Coronavirus Disease 2019

Author

Li, Yijia, Harrison, Linda J, Chew, Kara W, Currier, Judy S, Wohl, David A, Daar, Eric S, Evering, Teresa H, Wu, Ryan, Giganti, Mark, Ritz, Justin, Javan, Arzhang Cyrus, Coombs, Robert W, Moser, Carlee, Hughes, Michael D, Eron, Joseph J, Smith, Davey M, and Li, Jonathan Z

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, Genetics, Lung, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Humans, COVID-19, RNA, SARS-CoV-2, Viral Load, symptom duration, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement. Clinical Trials Registration. https://clinicaltrials.gov/ct2/show/NCT04518410.

Published
2023

21. Bamlanivimab therapy for acute COVID-19 does not blunt SARS-CoV-2-specific memory T cell responses

Author

Ramirez, Sydney I, Grifoni, Alba, Weiskopf, Daniela, Parikh, Urvi M, Heaps, Amy, Faraji, Farhoud, Sieg, Scott F, Ritz, Justin, Moser, Carlee, Eron, Joseph J, Currier, Judith S, Klekotka, Paul, Sette, Alessandro, Wohl, David A, Daar, Eric S, Hughes, Michael D, Chew, Kara W, Smith, Davey M, Crotty, Shane, and Team, for the Accelerating COVID-19 Therapeutic Interventions and Vaccines–2 A5401 Study

Subjects
Biomedical and Clinical Sciences, Immunology, Vaccine Related, Infectious Diseases, Clinical Research, Biodefense, Emerging Infectious Diseases, Lung, Pneumonia, Pneumonia & Influenza, Prevention, Inflammatory and immune system, Good Health and Well Being, Humans, SARS-CoV-2, COVID-19, Memory T Cells, Antibodies, Monoclonal, Humanized, Antibodies, Viral, Accelerating COVID-19 Therapeutic Interventions and Vaccines–2/A5401 (ACTIV-2/A5401) Study Team, Adaptive immunity, Biomedical and clinical sciences, Health sciences
Abstract

Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2-specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity.

Published
2022

22. Comparative Pharmacokinetics of Tixagevimab/Cilgavimab (AZD7442) Administered Intravenously Versus Intramuscularly in Symptomatic SARS‐CoV‐2 Infection

Author

Ignacio, Rachel A Bender, Wohl, David A, Arends, Rosalin, Reddy, Venkatesh Pilla, Mu, Ying, Javan, Arzhang Cyrus, Hughes, Michael D, Eron, Joseph J, Currier, Judith S, Smith, Davey, Chew, Kara W, Gibbs, Michael, and Fletcher, Courtney V

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Biodefense, Infectious Diseases, Emerging Infectious Diseases, Immunization, Prevention, Vaccine Related, Humans, Adult, Male, Female, SARS-CoV-2, Antibodies, Monoclonal, COVID-19 Drug Treatment, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

AZD7442 (Evusheld) is a combination of two human anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs), tixagevimab (AZD8895) and cilgavimab (AZD1061). Route of administration is an important consideration to improve treatment access. We assessed pharmacokinetics (PKs) of AZD7442 absorption following 600 mg administered intramuscularly (i.m.) in the thigh compared with 300 mg intravenously (i.v.) in ambulatory adults with symptomatic COVID-19. PK analysis included 84 of 110 participants randomized to receive i.m. AZD7442 and 16 of 61 randomized to receive i.v. AZD7442. Serum was collected prior to AZD7442 administration and at 24 hours and 3, 7, and 14 days later. PK parameters were calculated using noncompartmental methods. Following 600 mg i.m., the geometric mean maximum concentration (Cmax ) was 38.19 μg/mL (range: 17.30-60.80) and 37.33 μg/mL (range: 14.90-58.90) for tixagevimab and cilgavimab, respectively. Median observed time to maximum concentration (Tmax ) was 7.1 and 7.0 days for tixagevimab and cilgavimab, respectively. Serum concentrations after i.m. dosing were similar to the i.v. dose (27-29 μg/mL each component) at 3 days. The area under the concentration-time curve (AUC)0-7d geometric mean ratio was 0.9 for i.m. vs. i.v. Participants with higher weight or body mass index were more likely to have lower concentrations with either route. Women appeared to have higher interparticipant variability in concentrations compared with men. The concentrations of tixagevimab and cilgavimab after administration i.m. to the thigh were similar to those achieved with i.v. after 3 days from dosing. Exposure in the i.m. group was 90% of i.v. over 7 days. Administration to the thigh can be considered to provide consistent mAb exposure and improve access.

Published
2022

23. Predictors of SARS-CoV-2 RNA From Nasopharyngeal Swabs and Concordance With Other Compartments in Nonhospitalized Adults With Mild to Moderate COVID-19

Author

Moser, Carlee, Li, Jonathan Z, Eron, Joseph J, Aga, Evgenia, Daar, Eric S, Wohl, David A, Coombs, Robert W, Javan, Arzhang Cyrus, Ignacio, Rachel A Bender, Jagannathan, Prasanna, Ritz, Justin, Sieg, Scott F, Parikh, Urvi M, Hughes, Michael D, Currier, Judith S, Smith, Davey M, Chew, Kara W, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Degli-Angeli, Emily, Goecker, Erin, Daza, Glenda, Harb, Socorro, Dragavon, Joan, Aldrovandi, Grace, Murtaugh, William, Cooper, Marlene, Gutzman, Howard, Knowles, Kevin, Bowman, Rachel, Erhardt, Bill, and Adams, Stacey

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Clinical Research, Prevention, Lung, Infectious Diseases, Vaccine Related, Good Health and Well Being, SARS-CoV-2 RNA, COVID-19, nasal swabs, nasopharyngeal swabs, predictors, serostatus, sex differences, ACTIV-2/A5401 Study Team, Clinical sciences, Medical microbiology
Abstract

BackgroundIdentifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission.MethodsParticipants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models.ResultsNasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27 log10 copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, -2.0 vs -1.3 log10 copies/mL, entry to day 3; P < .001).ConclusionsSARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes.

Published
2022

24. Emergence of SARS-CoV-2 escape mutations during Bamlanivimab therapy in a phase II randomized clinical trial

Author

Choudhary, Manish C, Chew, Kara W, Deo, Rinki, Flynn, James P, Regan, James, Crain, Charles R, Moser, Carlee, Hughes, Michael D, Ritz, Justin, Ribeiro, Ruy M, Ke, Ruian, Dragavon, Joan A, Javan, Arzhang Cyrus, Nirula, Ajay, Klekotka, Paul, Greninger, Alexander L, Fletcher, Courtney V, Daar, Eric S, Wohl, David A, Eron, Joseph J, Currier, Judith S, Parikh, Urvi M, Sieg, Scott F, Perelson, Alan S, Coombs, Robert W, Smith, Davey M, and Li, Jonathan Z

Subjects
Microbiology, Biological Sciences, Clinical Trials and Supportive Activities, Biotechnology, Vaccine Related, Infectious Diseases, Antimicrobial Resistance, Emerging Infectious Diseases, Biodefense, Prevention, Clinical Research, Lung, Pneumonia, Cancer, Pneumonia & Influenza, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Humans, SARS-CoV-2, Antibodies, Monoclonal, Humanized, Mutation, Antibodies, Monoclonal, COVID-19 Drug Treatment, ACTIV-2/A5401 Study Team, Medical Microbiology
Abstract

SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

Published
2022

25. Monoclonal antibody treatment drives rapid culture conversion in SARS-CoV-2 infection

Author

Boucau, Julie, Chew, Kara W, Choudhary, Manish C, Deo, Rinki, Regan, James, Flynn, James P, Crain, Charles R, Hughes, Michael D, Ritz, Justin, Moser, Carlee, Dragavon, Joan A, Javan, Arzhang C, Nirula, Ajay, Klekotka, Paul, Greninger, Alexander L, Coombs, Robert W, Fischer, William A, Daar, Eric S, Wohl, David A, Eron, Joseph J, Currier, Judith S, Smith, Davey M, team, the POSITIVES study, Li, Jonathan Z, Barczak, Amy K, and Team, the ACTIV-2 A5401 Study

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Research, Infectious Diseases, Vaccine Related, Biodefense, Biotechnology, Lung, Immunization, Prevention, Emerging Infectious Diseases, Pneumonia, Pneumonia & Influenza, Clinical Trials and Supportive Activities, Infection, Good Health and Well Being, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Humans, SARS-CoV-2, COVID-19 Drug Treatment, POSITIVES study team, ACTIV-2/A5401 Study Team, COVID, COVID therapies, COVID-19, mAbs, monoclonal antibodies, resistance, viral culture, Biomedical and clinical sciences
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410). Viral load by qPCR and viral culture are performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAbs results in rapid clearance of culturable virus. One day after treatment, 0 of 28 (0%) participants receiving mAbs and 16 of 39 (41%) receiving placebo still have culturable virus (p

Published
2022

26. Safety and efficacy of inhaled interferon-β1a (SNG001) in adults with mild-to-moderate COVID-19: a randomized, controlled, phase II trial

Author

Chew, Kara, Smith, David (Davey), Daar, Eric, Wohl, David, Currier, Judith, Eron, Joseph, Javan, Arzhang Cyrus, Hughes, Michael, Moser, Carlee, Giganti, Mark, Ritz, Justin, Hosey, Lara, Roa, Jhoanna, Patel, Nilam, Colsh, Kelly, Rwakazina, Irene, Beck, Justine, Sieg, Scott, Li, Jonathan, Fletcher, Courtney, Fischer, William, Evering, Teresa, Ignacio, Rachel Bender, Cardoso, Sandra, Corado, Katya, Jagannathan, Prasanna, Jilg, Nikolaus, Perelson, Alan, Pillay, Sandy, Riviere, Cynthia, Singh, Upinder, Taiwo, Babafemi, Gottesman, Joan, Newell, Matthew, Pedersen, Susan, Dragavon, Joan, Jennings, Cheryl, Greenfelder, Brian, Murtaugh, William, Kosmyna, Jan, Gapara, Morgan, Shahkolahi, Akbar, Main, Mark J., Pierone, Gerald, Elliott, Juliana, Jacobson, Jeffrey, Hojat, Leila, Pasternak, Julie, Berardi, Jonathan, Arar, Celine, Bukhman, Yevgeniy, Jain, Manish, Bukhman, Eugene, Shaik, Sadia, Hatlen, Timothy, Dooley, Kelly, Becker, Becky, Wilkins, Adaliah, Pérez, Jose, Roman, Eloy, Fernández, Heriberto, Hoover, Keila, Renfroe, James, Weldon, Mauney, Bougher, Genei, Malvestutto, Carlos, Harber, Heather, Cicarella, Robyn, Neytman, Gene, Herman, Jack, Herman, Craig, Aziz, Mariam, Swiatek, Joan, Pathak, Divya, Choudhary, Madhu, Sullivano, Jennifer, Osiyemi, Olayemi, Izquierdo, Myriam, Torna, Odelsey, Khodabakhshian, Aleen, Fortier, Samantha, Benson, Constance, Hendrickx, Steven, Ramirez, Rosemarie, Luetkemeyer, Anne, Hendler, Suzanne, Dentoni-Lasofsky, Dennis, Castro, Mario, Spikes, Leslie, Hall, Chase, Oakes, Jonathan, Loftis, Amy James, Tebas, Pablo, Short, William, McGuffin, Sarah, Jonsson, Chris, Presti, Rachel, Haile, Alem, Chew, Kara W., Giganti, Mark J., Hughes, Michael D., Monk, Phillip D., Li, Jonathan Z., Fletcher, Courtney V., McCarthy, Caitlyn, Wohl, David A., Daar, Eric S., Eron, Joseph J., Currier, Judith S., and Smith, Davey M.

Published
2023
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27. HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial

Author

Wohl, David A, Spinner, Christoph D, Flamm, Jason, Hare, C Bradley, Doblecki-Lewis, Susanne, Ruane, Peter J, Molina, Jean-Michel, Mills, Anthony, Brinson, Cynthia, Ramgopal, Moti, Clarke, Amanda, Crofoot, Gordon, Martorell, Claudia, Carter, Christoph, Cox, Stephanie, Hojilla, J Carlo, Shao, Yongwu, Das, Moupali, Kintu, Alexander, Baeten, Jared M, Grant, Robert M, Mounzer, Karam, and Mayer, Kenneth

Published
2024
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28. Antiviral and clinical activity of bamlanivimab in a randomized trial of non-hospitalized adults with COVID-19

Author

Chew, Kara W, Moser, Carlee, Daar, Eric S, Wohl, David A, Li, Jonathan Z, Coombs, Robert W, Ritz, Justin, Giganti, Mark, Javan, Arzhang Cyrus, Li, Yijia, Choudhary, Manish C, Deo, Rinki, Malvestutto, Carlos, Klekotka, Paul, Price, Karen, Nirula, Ajay, Fischer, William, Bala, Veenu, Ribeiro, Ruy M, Perelson, Alan S, Fletcher, Courtney V, Eron, Joseph J, Currier, Judith S, Hughes, Michael D, and Smith, Davey M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Emerging Infectious Diseases, Prevention, Lung, Clinical Research, Infectious Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Antibodies, Viral, Antiviral Agents, Humans, RNA, Viral, SARS-CoV-2, COVID-19 Drug Treatment, ACTIV-2/A5401 Study Team
Abstract

Anti-SARS-CoV-2 monoclonal antibodies are mainstay COVID-19 therapeutics. Safety, antiviral, and clinical efficacy of bamlanivimab were evaluated in the randomized controlled trial ACTIV-2/A5401. Non-hospitalized adults were randomized 1:1 within 10 days of COVID-19 symptoms to bamlanivimab or blinded-placebo in two dose-cohorts (7000 mg, n = 94; 700 mg, n = 223). No differences in bamlanivimab vs placebo were observed in the primary outcomes: proportion with undetectable nasopharyngeal SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28 (risk ratio = 0.82-1.05 for 7000 mg [p(overall) = 0.88] and 0.81-1.21 for 700 mg [p(overall) = 0.49]), time to symptom improvement (median 21 vs 18.5 days [p = 0.97], 7000 mg; 24 vs 20.5 days [p = 0.08], 700 mg), or grade 3+ adverse events. However, bamlanivimab was associated with lower day 3 nasopharyngeal viral levels and faster reductions in inflammatory markers and viral decay by modeling. This study provides evidence of faster reductions in nasopharyngeal SARS-CoV-2 RNA levels but not shorter symptom durations in non-hospitalized adults with early variants of SARS-CoV-2.

Published
2022

29. The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy

Author

Jacobson, Jeffrey M., Felber, Barbara K., Chen, Huichao, Pavlakis, George N., Mullins, James I., De Rosa, Stephen C., Kuritzkes, Daniel R., Tomaras, Georgia D., Kinslow, Jennifer, Bao, Yajing, Olefsky, Maxine, Rosati, Margherita, Bear, Jenifer, Heptinstall, Jack R., Zhang, Lu, Sawant, Sheetal, Hannaman, Drew, Laird, Gregory M., Cyktor, Joshua C., Heath, Sonya L., Collier, Ann C., Koletar, Susan L., Taiwo, Babafemi O., Tebas, Pablo, Wohl, David A., Belaunzaran-Zamudio, Pablo F., McElrath, M. Juliana, and Landay, Alan L.

Published
2024
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31. LB2. Safety and Efficacy of Combination SARS-CoV-2 Monoclonal Neutralizing Antibodies (mAb) BRII-196 and BRII-198 in Non-Hospitalized COVID-19 Patients

Author

Evering, Teresa H, Giganti, Mark, Chew, Kara W, Hughes, Michael, Moser, Carlee, Wohl, David Alain, Currier, Judith, Eron, Joseph J, Javan, Arzhang, Margolis, David A, Zhu, Qing, D’Andrea, Ulises, Hoover, Keila, Mocherla, Bharat R, Fletcher, Courtney, Li, Jonathan, Smith, Davey, and Daar, Eric

Subjects
Emerging Infectious Diseases, Prevention, Clinical Trials and Supportive Activities, Patient Safety, Infectious Diseases, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being
Abstract

Abstract Background SARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG. Methods ACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis. Results Between January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs. Conclusion BRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease. Disclosures Kara W. Chew, MD, MS, Amgen (Individual(s) Involved: Self): Grant/Research Support; Merck Sharp & Dohme (Individual(s) Involved: Self): Grant/Research Support David Alain Wohl, MD, Gilead Sciences (Individual(s) Involved: Self): Advisor or Review Panel member, Consultant, Research Grant or Support, Scientific Research Study Investigator; Janssen (Individual(s) Involved: Self): Advisor or Review Panel member; Merck (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support; ViiV (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) David A. Margolis, MD MPH, Brii Biosciences (Employee) Courtney Fletcher, Pharm.D., National Institute of Allergy and Infectious Diseases, NIH (Grant/Research Support) Davey Smith, M.D., Linear Therapies, Matrix Biomed, Bayer (Consultant, Shareholder) Eric Daar, Gilead (Consultant, Grant/Research Support)Merck (Consultant)ViiV (Consultant, Grant/Research Support)

Published
2021

32. Outpatient Treatment of SARS-CoV-2 Infection to Prevent COVID-19 Progression

Author

Cohen, Myron S, Wohl, David A, Fischer, William A, Smith, David J, and Eron, Joseph J

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Vaccine Related, Immunization, Prevention, Emerging Infectious Diseases, Biodefense, Lung, Biotechnology, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Humans, Outpatients, Pharmaceutical Preparations, SARS-CoV-2, COVID-19 Drug Treatment, antivirals, COVID-19, monoclonal antibodies, outpatients, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

As of March 2021, coronavirus disease 2019 (COVID-19) had caused more than 123 million infections and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and nonpharmaceutical interventions to stop the spread of infection. However, treatments to stop disease progression are limited. A wide variety of "repurposed" drugs evaluated for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US Food and Drug Administration for emergency use for outpatients with mild to moderate COVID-19 including some active against emerging severe acute respiratory syndrome coronavirus 2 variants of concern. Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19.

Published
2021

33. Outpatient Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection to Prevent Coronavirus Disease 2019 Progression.

Author

Cohen, Myron S, Wohl, David A, Fischer, William A, Smith, Davey M, and Eron, Joseph J

Subjects
Humans, Pharmaceutical Preparations, Outpatients, COVID-19, SARS-CoV-2, antivirals, monoclonal antibodies, outpatients, Infectious Diseases, Lung, Prevention, Vaccine Related, Emerging Infectious Diseases, Biotechnology, Biodefense, Immunization, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Infection, Microbiology, Biological Sciences, Medical and Health Sciences
Abstract

As of March 2021, coronavirus disease 2019 (COVID-19) had caused more than 123 million infections and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and nonpharmaceutical interventions to stop the spread of infection. However, treatments to stop disease progression are limited. A wide variety of "repurposed" drugs evaluated for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US Food and Drug Administration for emergency use for outpatients with mild to moderate COVID-19 including some active against emerging severe acute respiratory syndrome coronavirus 2 variants of concern. Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19.

Published
2021

35. Publisher Correction: Antiviral and clinical activity of bamlanivimab in a randomized trial of non-hospitalized adults with COVID-19

Author

Chew, Kara W., Moser, Carlee, Daar, Eric S., Wohl, David A., Li, Jonathan Z., Coombs, Robert W., Ritz, Justin, Giganti, Mark, Javan, Arzhang Cyrus, Li, Yijia, Choudhary, Manish C., Deo, Rinki, Malvestutto, Carlos, Klekotka, Paul, Price, Karen, Nirula, Ajay, Fischer, William, Bala, Veenu, Ribeiro, Ruy M., Perelson, Alan S., Fletcher, Courtney V., Eron, Joseph J., Currier, Judith S., Hughes, Michael D., and Smith, Davey M.

Published
2023
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36. Current and Past Immunodeficiency Are Associated With Higher Hospitalization Rates Among Persons on Virologically Suppressive Antiretroviral Therapy for up to 11 Years

Author

Davy-Mendez, Thibaut, Napravnik, Sonia, Eron, Joseph J, Cole, Stephen R, van Duin, David, Wohl, David A, Hogan, Brenna C, Althoff, Keri N, Gebo, Kelly A, Moore, Richard D, Silverberg, Michael J, Horberg, Michael A, Gill, M John, Mathews, W Christopher, Klein, Marina B, Colasanti, Jonathan A, Sterling, Timothy R, Mayor, Angel M, Rebeiro, Peter F, Buchacz, Kate, Li, Jun, Nanditha, Ni Gusti Ayu, Thorne, Jennifer E, Nijhawan, Ank, Berry, Stephen A, Benson, Constance A, Bosch, Ronald J, Kirk, Gregory D, Mayer, Kenneth H, Grasso, Chris, Hogg, Robert S, Montaner, Julio SG, Salters, Kate, Lima, Viviane D, Sereda, Paul, Trigg, Jason, Rodriguez, Benigno, Brown, Todd, Tien, Phyllis, D’Souza, Gypsyamber, Rabkin, Charles, Kroch, Abigail, Burchell, Ann, Betts, Adrian, Lindsay, oanne, Hunter-Mellado, Robert F, Martin, Jeffrey N, Brooks, John T, Saag, Michael S, Mugavero, Michael J, Willig, James, Mathews, William C, Kitahata, Mari M, Crane, Heidi M, Haas, David, Rebeiro, Peter, Turner, Megan, Tate, Janet, Dubrow, Robert, Fiellin, David, Gange, Stephen J, McKaig, Rosemary G, Freeman, Aimee M, Van Rompaey, Stephen E, Morton, Liz, McReynolds, Justin, Lober, William B, Lee, Jennifer S, You, Bin, Hogan, Brenna, Zhang, Jinbing, and Jing, Jerry

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Sexually Transmitted Infections, Clinical Research, Anti-HIV Agents, CD4 Lymphocyte Count, Canada, Cohort Studies, Female, HIV Infections, Hospitalization, Humans, Male, Viral Load, HIV/AIDS, 6.1 Pharmaceuticals, HIV, hospitalization, CD4 lymphocyte count, sustained virologic response, cohort studies, North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundPersons with HIV (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk.MethodsIn six US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005-2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by early (Years 2-5) and long-term (Years 6-11) suppression and lowest pre-suppression CD4 count 500 cells/μL had an aIRR of 1.44 during early suppression (95% CI 1.01-2.06), and 1.67 (1.03-2.72) during long-term suppression. Among patients with lowest pre-suppression CD4 ≥200 (56%), patients with current CD4 351-500 versus >500 cells/μL had an aIRR of 1.22 (0.93-1.60) during early suppression and 2.09 (1.18-3.70) during long-term suppression.ConclusionsVirologically suppressed patients with lower CD4 counts experienced higher hospitalization rates, and could potentially benefit from targeted clinical management strategies.

Published
2021

37. Hospitalization Rates and Causes Among Persons With HIV in the United States and Canada, 2005–2015

Author

Davy-Mendez, Thibaut, Napravnik, Sonia, Hogan, Brenna C, Althoff, Keri N, Gebo, Kelly A, Moore, Richard D, Horberg, Michael A, Silverberg, Michael J, Gill, M John, Crane, Heidi M, Marconi, Vincent C, Bosch, Ronald J, Colasanti, Jonathan A, Sterling, Timothy R, Mathews, W Christopher, Mayor, Angel M, Nanditha, Ni Gusti Ayu, Buchacz, Kate, Li, Jun, Rebeiro, Peter F, Thorne, Jennifer E, Nijhawan, Ank, van Duin, David, Wohl, David A, Eron, Joseph J, Berry, Stephen A, Benson, Constance A, Kirk, Gregory D, Mayer, Kenneth H, Grasso, Chris, Hogg, Robert S, Harrigan, P Richard, Montaner, Julio SG, Yip, Benita, Zhu, Julia, Salters, Kate, Gabler, Karyn, Carey, John T, Rodriguez, Benigno, Brown, Todd, Tien, Phyllis, D’Souza, Gypsyamber, Rabkin, Charles, Klein, Marina B, Kroch, Abigail, Burchell, Ann, Betts, Adrian, Lindsay, Joanne, Hunter-Mellado, Robert F, Martin, Jeffrey N, Brooks, John T, Saag, Michael S, Mugavero, Michael J, Willig, James, Mathews, William C, Kitahata, Mari M, Haas, David, Rebeiro, Peter, Turner, Megan, Tate, Janet, Dubrow, Robert, Fiellin, David, Gange, Stephen J, McKaig, Rosemary G, Freeman, Aimee M, Van Rompaey, Stephen E, Morton, Liz, McReynolds, Justin, Lober, William B, Lee, Jennifer S, and You, Bin

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Clinical Sciences, Medical Microbiology, Sexually Transmitted Infections, Aging, Infectious Diseases, Prevention, HIV/AIDS, Infection, Good Health and Well Being, Acquired Immunodeficiency Syndrome, Anti-HIV Agents, CD4 Lymphocyte Count, Canada, Comorbidity, HIV Infections, Hospitalization, Humans, Risk Factors, United States, Viral Load, HIV, hospitalization, cohort studies, North American AIDS Cohort Collaboration on Research and Design of IeDEA, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundTo assess the possible impact of antiretroviral therapy improvements, aging, and comorbidities, we examined trends in all-cause and cause-specific hospitalization rates among persons with HIV (PWH) from 2005 to 2015.MethodsIn 6 clinical cohorts, we followed PWH in care (≥1 outpatient CD4 count or HIV load [VL] every 12 months) and categorized ICD codes of primary discharge diagnoses using modified Clinical Classifications Software. Poisson regression estimated hospitalization rate ratios for calendar time trends, adjusted for demographics, HIV risk factor, and annually updated age, CD4, and VL.ResultsAmong 28 057 patients (125 724 person-years), from 2005 to 2015, the median CD4 increased from 389 to 580 cells/µL and virologic suppression from 55% to 85% of patients. Unadjusted all-cause hospitalization rates decreased from 22.3 per 100 person-years in 2005 (95% confidence interval [CI], 20.6-24.1) to 13.0 in 2015 (95% CI, 12.2-14.0). Unadjusted rates decreased for almost all diagnostic categories. Adjusted rates decreased for all-cause, cardiovascular, and AIDS-defining conditions, increased for non-AIDS-defining infection, and were stable for most other categories.ConclusionsAmong PWH with increasing CD4 counts and viral suppression, unadjusted hospitalization rates decreased for all-cause and most cause-specific hospitalizations, despite the potential effects of aging, comorbidities, and cumulative exposure to HIV and antiretrovirals.

Published
2021

38. Risk of COVID-19 after natural infection or vaccination

Author

Adams, Atoya, Miller, Eric, Rankin, Bruce G., Shinn, Steven, Nash, Marshall, Green, Sinikka L., Jacobsen, Colleen, Krishnankutty, Jayasree, Phungwayo, Sikhongi, Glover, Richard M., II, Slechta, Stacy, Holdeman, Troy, Hartvickson, Robyn, Grant, Amber, Poling, Terry L., Klein, Terry D., Klein, Thomas C., Klein, Tracy R., Smith, William B., Gibson, Richard L., Winbigler, Jennifer, Parker, Elizabeth, Wijewardane, Priyantha N., Bravo, Eric, Thessing, Jeffrey, Maxwell, Michelle, Horn, Amanda, Healy, Catherine Mary, Akamine, Christine, Chu, Laurence, Chouteau, R. Michelle, Cotugno, Michael J., Bauer, George H., Jr., Hachigian, Greg, Oshita, Masaru, Cancilla, Michael, Kiersey, Kristen, Seger, William, Antwi, Mohammed, Green, Allison, Kim, Anthony, Desjardins, Michael, Johnson, Jennifer A., Sherman, Amy, Walsh, Stephen R., Borger, Judith, Saleem, Nafisa, Solis, Joel, Medina, Martha Carmen, Keating, Westly, Garcia, Edgar, Bueno, Cynthia, Segall, Nathan, Denham, Douglas S., Weiss, Thomas, Avworo, Ayoade, Hedges, Parke, Strout, Cynthia Becher, Santiago, Rica, Davis, Yvonne, Howenstine, Patty, Bondell, Alison, Marks, Kristin, Wang, Tina, Wilkin, Timothy, Vogler, Mary, Johnston, Carrie, Andrasik, Michele P., Andriesen, Jessica G., Broder, Gail, Eaton, Niles, Gelderblom, Huub G., McClennen, Rachael, Michael, Nelson, Robb, Merlin, Sopher, Carrie, Miller, Vicki E., Santiago, Fredric, Gomez, Blanca, Valika, Insiya, Starr, Amy, Cantos, Valeria D., Kandiah, Sheetal, Rio, Carlos del, Rouphael, Nadine, Edupuganti, Srilatha, Anderson, Evan J., 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Mary, Whitaker, Jennifer A., Keitel, Wendy A., Atmar, Robert L., Horwith, Gary, Mason, Robin, Johnson, Lisa, Dora, Tambra, Murray, Deborah, Ledbetter, Logan, Ewing, Beverly, Stephenson, Kathryn E., Tan, Chen S., Zash, Rebecca, Ansel, Jessica L., Jaegle, Kate, Guiney, Caitlin J., Henderson, Jeffrey A., O'Leary, Marcia, Enright, Kendra, Kessler, Jill, Ducheneaux, Pete, Inniss, Asha, Brandon, Donald M., Davis, William B., Lawler, Daniel T., Oppong, Yaa D., Starr, Ryan P., Syndergaard, Scott N., Shelly, Rozeli, Majumder, Mashrur Islam, Sugimoto, Danny, Dugas, Jeffrey, Sr., Rijos, Dolores, Shelton, Sandra, Hong, Stephan, Schwartz, Howard, Sanchez-Crespo, Nelia, Schwartz, Jennifer, Piedra, Terry, Corral, Barbara, Medina, Carmen, Dever, Michael E., Shah, Mitul, Delgado, Michael, Scott, Tameika, Usdan, Lisa S., McGill, Lora J., Arnold, Valerie K., Scatamacchia, Carolyn, Anthony, Codi M., Merchant, Rajan, Yoon, Anelgine C., Hill, Janet, Ng-Price, Lucy, Thompson-Seim, Teri, Ackerman, Ronald, 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Nicholas A., Dellaero, David, Patel, Priti, Lisec, Kendra, Safirstein, Beth, Zapata, Luz, Gonzalez, Lazaro, Quevedo, Evelyn, Irani, Farah, Grillo, Joseph, Potts, Amy, White, Julie, Flume, Patrick, Headden, Gary, Taylor, Brandie, Warden, Ashley, Chamberlain, Amy, Jeanfreau, Robert, Jeanfreau, Susan, Matherne, Paul G., Caldwell, Amy, Stahl, Jessica, Vowell, Mandy, Newhouse, Lauren, Berthaud, Vladimir, Takizala, Zudi-Mwak, Beninati, Genevieve, Snell, Kimberly, Baker, Sherrie, Walker, James, Harrison, Tavane, Miller, Meagan, Otto, Janet, Gray, Roni, Wilson, Christine, Nemecek, Tiffany, Harrington, Hannah, Eppenbach, Sally, Lewis, Wendell, Bourgeois, Tana, Folsom, Lyndsea, Holt, Gregory, Mirsaeidi, Mehdi, Calderon, Rafael, Lichtenberger, Paola, Quintero, Jalima, Martinez, Becky, Immergluck, Lilly, Johnson, Erica, Chan, Austin, Fas, Norberto, Thomas-Seaton, LaTeshia, Khizer, Saadia, Staben, Jonathan, Beresnev, Tatiana, Jahromi, Maryam, Marovich, Mary A., Hutter, Julia, Nason, Martha, Ledgerwood, Julie, Mascola, John, Leibowitz, Mark, Morales, Fernanda, Delgado, Mike, Sanchez, Rosario, Vega, Norma, Áñez, Germán, Albert, Gary, Coston, Erin, Desai, Chinar, Dunbar, Haoua, Eickhoff, Mark, Garcia, Jenina, Kautz, Margaret, Lee, Angela, Lewis, Maggie, McGarry, Alice, McKnight, Irene, Nelson, Joy, Newingham, Patrick, Price-Abbott, Patty, Reed, Patty, Vegas, Diana, Wilkinson, Bethanie, Smith, Katherine, Woo, Wayne, Cho, Iksung, Glenn, Gregory M., Dubovsky, Filip, Fried, David L., Haughey, Lynne A., Stanton, Ariana C., Rameaka, Lisa Stevens, Rosenberg, David, Tomatsu, Lee, Gonzalez, Viviana, Manalo, Millie, Grunstra, Bernard, Quinn, Donald, Claybrook, Phillip, Olds, Shelby, Dye, Amy, Cannon, Kevin D., Chadwick, Mesha M., Jordan, Bailey, Hussey, Morgan, Nevarez, Hannah, Kelley, Colleen F., Chung, Michael, Moran, Caitlin, Rebolledo, Paulina, Bacher, Christina, Barranco-Santana, Elizabeth, Rodriguez, Jessica, Mendoza, Rafael, Ruperto, Karen, Olivieri, Odette, Ocaña, Enrique, Wylie, Paul E., Henderson, Renea, Jenson, Natasa, Yang, Fan, Kelley, Amy, Finkelstein, Kenneth, Beckmann, David, Hutchins, Tanya, Escallon, Sebastian Garcia, Johnson, Kristen, Sligh, Teresa S., Desai, Parul, Huynh, Vincent, Lopez, Carlos, Mendoza, Erika, Adelglass, Jeffrey, Naifeh, Jerome G., Kucera, Kristine J., Chughtai, Waseem, Jaffer, Shireen H., Davis, Matthew G., Foley, Jennifer, Burgett, Michelle L., Shlotzhauer, Tammi L., Ingalsbe-Geno, Sarah M., Duncanson, Daniel, Kush, Kelly, Nesbitt, Lori, Sonnier, Cora, McCarter, Jennifer, Butcher, Michael B., Fry, James, Percy, Donna, Freudemann, Karen, Gebhardt, Bruce C., Mangu, Padma N., Schroeck, Debra B., Davit, Rajesh K., Hennekes, Gayle D., Luft, Benjamin J., Carr, Melissa, Nachman, Sharon, Pellecchia, Alison, Smith, Candace, Valenti, Bruno, Bermudez, Maria I., Peraita, Noris, Delgado, Ernesto, Arrazcaeta, Alicia, Ramirez, Natalie, Amador, Carmen, Marafioti, Horacio, Dang, Lyly, Clement, Lauren, Berry, Jennifer, Allaw, Mohammed, 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Published
2023
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39. Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn’s Disease: A Pragmatic Randomized Trial

Author

Kappelman, Michael D., Wohl, David A., Herfarth, Hans H., Firestine, Ann M., Adler, Jeremy, Ammoury, Rana F., Aronow, Jeanine E., Bass, Dorsey M., Bass, Julie A., Benkov, Keith, Tobi, Catalina Berenblum, Boccieri, Margie E., Boyle, Brendan M., Brinkman, William B., Cabera, Jose M., Chun, Kelly, Colletti, Richard B., Dodds, Cassandra M., Dorsey, Jill M., Ebach, Dawn R., Entrena, Edurne, Forrest, Christopher B., Galanko, Joseph A., Grunow, John E., Gulati, Ajay S., Ivanova, Anastasia, Jester, Traci W., Kaplan, Jess L., Kugathasan, Subra, Kusek, Mark E., Leibowitz, Ian H., Linville, Tiffany M., Lipstein, Ellen A., Margolis, Peter A., Minar, Phillip, Molle-Rios, Zarela, Moses, Jonathan, Olano, Kelly K., Osaba, Lourdes, Palomo, Pablo J., Pappa, Helen, Park, K.T., Pashankar, Dinesh S., Pitch, Lisa, Robinson, Michelle, Samson, Charles M., Sandberg, Kelly C., Schuchard, Julia R., Seid, Michael, Shelly, Kimberly A., Steiner, Steven J., Strople, Jennifer A., Sullivan, Jillian S., Tung, Jeanne, Wali, Prateek, Zikry, Michael, Weinberger, Morris, Saeed, Shehzad A., and Bousvaros, Athos

Published
2023
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40. “My Death Will Not [Be] in Vain”: Testimonials from Last Gift Rapid Research Autopsy Study Participants Living with HIV at the End of Life

Author

Perry, Kelly E, Dubé, Karine, Concha-Garcia, Susanna, Patel, Hursch, Kaytes, Andy, Taylor, Jeff, Javadi, Sogol Stephanie, Mathur, Kushagra, Lo, Megan, Brown, Brandon, Sauceda, John A, Wohl, David A, Little, Susan, Hendrickx, Steven, Rawlings, Stephen A, Smith, Davey M, and Gianella, Sara

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Clinical Research, HIV/AIDS, Behavioral and Social Science, Autopsy, Cognition, Death, Female, HIV Infections, Humans, Male, Risk, HIV cure research, Last Gift, rapid research autopsy, end of life, altruism, sociobehavioral research, Virology, Clinical sciences
Abstract

End-of-life (EOL) HIV cure-related research provides a novel approach to studying HIV reservoirs. The Last Gift is a rapid autopsy research study at the University of California San Diego that enrolls terminally ill people living with HIV (PLWHIV) with a desire to contribute to HIV cure-related research. We conducted in-depth baseline and follow-up interviews with Last Gift study participants. We analyzed interview data applying conventional content analysis. Since summer 2017, 13 participants have been enrolled (n = 11 males and 2 females; aged 45-89 years) and 8 participants interviewed. Terminal illnesses included cancers, heart diseases, and neurodegenerative illnesses. Our analysis revealed five key themes: (1) The Last Gift study has tremendous meaning for participants at the end of their life. (2) HIV-specific altruism was a primary motivator to join the Last Gift study, nested within the context of community, scientific advancement, and moral obligation. (3) Participants did not expect physical benefits yet they perceived emotional/psychological, financial, and societal/scientific benefits. (4) There were minimal participant-perceived risks and concerns. (5) Last Gift participants expressed immense gratitude toward study staff. The Last Gift study provides a framework for ethical HIV cure-related research at EOL and highlighted participants' perspectives, motivations, and experiences. Knowing how PLWHIV understand and experience such studies will remain critical to designing ethical, fully informed HIV cure research protocols that are acceptable to PLWHIV.

Published
2020

41. The Dose Response: Perceptions of People Living with HIV in the United States on Alternatives to Oral Daily Antiretroviral Therapy

Author

Dubé, Karine, Eskaf, Shadi, Evans, David, Sauceda, John, Saberi, Parya, Brown, Brandon, Averitt, Dawn, Martel, Krista, Meija, Maria, Campbell, Danielle, Barr, Liz, Kanazawa, John, Perry, Kelly, Patel, Hursch, Luter, Stuart, Poteat, Tonia, Auerbach, Judith D, and Wohl, David A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Behavioral and Social Science, Clinical Research, HIV/AIDS, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adult, Aged, Anti-Retroviral Agents, Dose-Response Relationship, Drug, Drug Therapy, Female, HIV Infections, Humans, Male, Middle Aged, Patient Participation, Qualitative Research, Surveys and Questionnaires, United States, Young Adult, antiretroviral therapy, oral daily ART, long-acting ART, HIV cure research, HIV remission, people living with HIV, Clinical Sciences, Virology, Clinical sciences
Abstract

There are two concurrent and novel major research pathways toward strategies for HIV control: (1) long-acting antiretroviral therapy (ART) formulations and (2) research aimed at conferring sustained ART-free HIV remission, considered a step toward an HIV cure. The importance of perspectives from people living with HIV on the development of new modalities is high, but data are lacking. We administered an online survey in which respondents selected their likelihood of participation or nonparticipation in HIV cure/remission research based on potential risks and perceived benefits of these new modalities. We also tested the correlation between perceptions of potential risks and benefits with preferences of virologic control strategies and/or responses to scenario choices, while controlling for respondent characteristics. Of the 282 eligible respondents, 42% would be willing to switch from oral daily ART to long-acting ART injectables or implantables taken at 6-month intervals, and 24% to a hypothetical ART-free remission strategy. We found statistically significant gender differences in perceptions of risk and preferences of HIV control strategies, and possible psychosocial factors that could mediate willingness to switch to novel HIV treatment or remission options. Our study yielded data on possible desirable product characteristics for future HIV treatment and remission options. Findings also revealed differences in motivations and preferences across gender and other sociodemographic characteristics that may be actionable as part of research recruitment efforts. The diversity of participant perspectives reveals the need to provide a variety of therapeutic options to people living with HIV and to acknowledge their diverse experiential expertise when developing novel HIV therapies.

Published
2020

42. Comparing the Safety and Effectiveness of Medicines to Treat Crohn’s Disease in Children and Adolescents – The COMBINE Trial

Author

Kappelman, Michael, primary, Adler, Jeremy, additional, Ammoury, Rana, additional, Bass, Dorsey, additional, Bass, Julie, additional, Benkov, Keith, additional, Boccieri, Margie, additional, Bousvaros, Athos, additional, Boyle, Brendan, additional, Brinkman, William, additional, Cabera, Jose, additional, Colletti, Richard, additional, Dodds, Cassandra, additional, Dorsey, Jill, additional, Ebach, Dawn, additional, Firestine, Ann, additional, Forrest, Christopher, additional, Galanko, Joseph, additional, Grunow, John, additional, Gulati, Ajay, additional, Herfarth, Hans, additional, Ivanova, Anastasia, additional, Jester, Traci, additional, Kaplan, Jess, additional, Kugathasan, Subra, additional, Kusek, Mark, additional, Leibowitz, Ian, additional, Linville, Tiffany, additional, Lipstein, Ellen, additional, Margolis, Peter, additional, Minar, Phillip, additional, Molle Rios, Zarela, additional, Moses, Jonathan, additional, Olano, Kelly, additional, Park, K.T., additional, Palomo, Pablo, additional, Pappa, Helen, additional, Pashankar, Dinesh, additional, Pitch, Lisa, additional, Samson, Charles, additional, Sandberg, Kelly, additional, Schuchard, Julia, additional, Shelly, Kimberly, additional, Steiner, Steve, additional, Strople, Jennifer, additional, Sullivan, Jillian, additional, Tung, Jeanne, additional, Wali, Prateek, additional, Wohl, David, additional, Weinberger, Morris, additional, and Saeed, Shehzad, additional

Published
2023
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45. Serious Infections

Author

Hartman, Lauren, primary, Tiller, Rosanne, additional, Wohl, David Alain, additional, and van Duin, David, additional

Published
2022
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46. Safety and Efficacy of SAB-185 for Nonhospitalized Adults With COVID-19: A Randomized Clinical Trial.

Author

Chew, Kara W, Taiwo, Babafemi O, Moser, Carlee, Daar, Eric S, Wohl, David Alain, Ritz, Justin, Javan, Arzhang Cyrus, Li, Jonathan Z, Fischer, William, Greninger, Alexander L, Bausch, Christoph, Luke, Thomas, Call, Robert, Neytman, Gene, Giganti, Mark J, Fletcher, Courtney V, Hughes, Michael D, Eron, Joseph J, Currier, Judith S, and Smith, Davey M

Subjects
CLINICAL trial registries, CLINICAL trials, SARS-CoV-2 Omicron variant, DEATH rate, COVID-19
Abstract

Background We evaluated the fully human polyclonal antibody product SAB-185 in a phase 3 trial for COVID-19. Methods Nonhospitalized high-risk adults within 7 days of symptom onset were randomized 1:1 to open-label SAB-185 3840 units/kg or casirivimab/imdevimab 1200 mg. Noninferiority comparison was undertaken for pre-Omicron population (casirivimab/imdevimab expected to be fully active) and superiority comparison for the Omicron population (casirivimab/imdevimab not expected to be active). Primary outcomes were the composite of all-cause hospitalizations/deaths and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. A secondary outcome was time to sustained symptom resolution. Results Enrollment ended early due to low hospitalization/death rates upon Omicron emergence; 255 adults were in pre-Omicron and 392 in Omicron populations. Hospitalizations/deaths occurred in 6 (5.0%) and 3 (2.2%) of pre-Omicron SAB-185 and casirivimab/imdevimab arms (absolute difference 2.7%; 95% confidence interval [CI], −2.3%-8.6%); and 5 (2.5%) versus 3 (1.5%) (absolute difference 1.0%; 95% CI, −2.3%-4.5%) for Omicron. All risk ratios for grade ≥3 TEAEs were not significant. Time to symptom resolution was significantly shorter for SAB-185 for Omicron only: 18 versus >25 days; P =.006. Conclusions SAB-185 had an acceptable safety profile with faster symptom resolution in the Omicron population. Clinical Trials Registration NCT04518410. [ABSTRACT FROM AUTHOR]

Published
2024
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47. SARS-CoV-2 Monoclonal Antibody Treatment Followed by Vaccination Shifts Human Memory B-Cell Epitope Recognition, Suggesting Antibody Feedback.

Author

Bloom, Nathaniel, Ramirez, Sydney I, Cohn, Hallie, Parikh, Urvi M, Heaps, Amy, Sieg, Scott F, Greninger, Alex, Ritz, Justin, Moser, Carlee, Eron, Joseph J, Bajic, Goran, Currier, Judith S, Klekotka, Paul, Wohl, David A, Daar, Eric S, Li, Jonathan, Hughes, Michael D, Chew, Kara W, Smith, Davey M, and Crotty, Shane

Subjects
COVID-19, IMMUNOLOGIC memory, MEMORY, CORONAVIRUSES, SARS-CoV-2
Abstract

Therapeutic monoclonal antibodies (mAbs) have been studied in humans, but the impact on immune memory of mAb treatment during an ongoing infection remains unclear. We evaluated the effect of infusion of the anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2–infected individuals. Bamlanivimab treatment skewed the repertoire of MBCs targeting spike toward non-RBD epitopes. Furthermore, the relative affinity of RBD MBCs was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA coronavirus disease 2019 vaccination, MBC differences persisted and mapped to a specific reduction in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating MBC responses to infection, and single mAb administration can continue to impact MBC responses to additional antigen exposures months later. [ABSTRACT FROM AUTHOR]

Published
2024
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48. Antiretrovirals and Weight Change: Weighing the Evidence.

Author

Wohl, David Alain, Koethe, John R, Sax, Paul E, McComsey, Grace A, Kuritzkes, Daniel R, Moyle, Graeme, Kaplan, Lee, Wyk, Jean van, Campo, Rafael E, and Cohen, Calvin

Subjects
*HIV integrase inhibitors, *ANTIRETROVIRAL agents, *BODY weight, *CLINICAL trials, *HIV infections, *DECISION making in clinical medicine, *PRE-exposure prophylaxis, *WEIGHT gain
Abstract

Body weight is influenced by an interplay of individual and environmental factors. In people with human immunodeficiency virus (HIV), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy. Weight changes in comparative antiretroviral therapy trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors dolutegravir and bictegravir, particularly when coadministered with tenofovir alafenamide fumarate, compared with regimens that include agents such as tenofovir disoproxil fumarate that attenuate weight gain. We review weight changes in major randomized trials of preexposure prophylaxis and initial and switch HIV therapy, highlighting the challenges to assessing the role of antiretroviral therapy in weight change. This examination forms the basis for a model that questions assumptions regarding an association between integrase strand transfer inhibitors and tenofovir alafenamide fumarate and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions. [ABSTRACT FROM AUTHOR]

Published
2024
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49. Ebola Virus–Specific Neutralizing Antibody Persists at High Levels in Survivors 2 Years After Resolution of Disease in a Sierra Leonean Cohort.

Author

Bond, Nell G, Shore, Kayla R, Engel, Emily J, Coonan, Erin E, Al-Hasan, Foday, Gbakie, Michael A, Kamara, Fatima K, Kanneh, Lansana, Momoh, Mambu, Kanneh, Ibrahim M, Sandi, John D, Elliott, Debra, Ficenec, Samuel C, Smira, Ashley R, Fischer, William A, Wohl, David A, Robinson, James E, Shaffer, Jeffrey G, Garry, Robert F, and Samuels, Robert J

Subjects
EBOLA virus disease, HUMORAL immunity, EBOLA virus, SYMPTOMS, IMMUNE response
Abstract

Ebola virus (EBOV) infection results in Ebola virus disease (EVD), an often severe disease with a nonspecific presentation. Since its recognition, periodic outbreaks of EVD continue to occur in sub-Saharan Africa. The 2013–2016 West African EVD outbreak was the largest recorded, resulting in a substantial cohort of EVD survivors with persistent health complaints and variable immune responses. In this study, we characterize humoral immune responses in EVD survivors and their contacts in Eastern Sierra Leone. We found high levels of EBOV IgG in EVD survivors and lower yet substantial antibody levels in household contacts, suggesting subclinical transmission. Neutralizing antibody function was prevalent but variable in EVD survivors, raising questions about the durability of immune responses from natural infection with EBOV. Additionally, we found that certain discrete symptoms—ophthalmologic and auditory—are associated with EBOV IgG seropositivity, while an array of symptoms are associated with the presence of neutralizing antibody. [ABSTRACT FROM AUTHOR]

Published
2024
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50. The prevalence of Post-Ebola Syndrome hearing loss, Sierra Leone

Author

Ficenec, Samuel C., Grant, Donald S., Sumah, Ibrahim, Alhasan, Foday, Yillah, Mohamed S., Brima, Jenneh, Konuwa, Edwin, Gbakie, Michael A., Kamara, Fatima K., Bond, Nell G., Engel, Emily J., Shaffer, Jeffrey G., Fischer, William A., Wohl, David A., Emmett, Susan D., and Schieffelin, John S.

Published
2022
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