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1. Sirolimus reduces T cell cycling, immune checkpoint marker expression, and HIV-1 DNA in people with HIV

Author

Henrich, Timothy J, Bosch, Ronald J, Godfrey, Catherine, Mar, Hanna, Nair, Apsara, Keefer, Michael, Fichtenbaum, Carl, Moisi, Daniela, Clagett, Brian, Buck, Amanda M, Deitchman, Amelia N, Aweeka, Francesca, Li, Jonathan Z, Kuritzkes, Daniel R, Lederman, Michael M, Hsue, Priscilla Y, Deeks, Steven G, Team, the ACTG A5337, Campbell, Danielle, Cutler, Corey, Dorosh, Michael, Ha, Belinda, Hawkins, Elizabeth, Hensel, Christopher, Khairalla, Nayri, Knowles, Kevin, Lee, Sulggi A, Pedersen, Susan, Ritz, Justin, Ryder, Dylan, Sekaly, Rafick, Shugarts, David L, Straub, Becky, and Zolopa, Andrew

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Sexually Transmitted Infections, HIV/AIDS, Infectious Diseases, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Humans, HIV Infections, HIV-1, CD8-Positive T-Lymphocytes, CD4-Positive T-Lymphocytes, DNA, Viral, Sirolimus, Male, Female, Adult, Middle Aged, Immune Checkpoint Proteins, Cell Cycle, Programmed Cell Death 1 Receptor, ACTG A5337 Team, HIV curative strategies, HIV immunology, HIV persistence, HIV reservoirs, antiproliferative medications, immunotherapy, intact proviral HIV-1 DNA, mTOR inhibition, sirolimus, Biomedical and clinical sciences
Abstract

Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected T cells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20 weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 T cell responses but leads to a significant decrease in CD4+ T cell-associated HIV-1 DNA levels at 20 weeks of therapy in the primary efficacy population (n = 16; 31% decline, p = 0.008). This decline persists for at least 12 weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ T cell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.

Published
2024

2. 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 Trials and Supportive Activities, Prevention, Coronaviruses, Infectious Diseases, Clinical Research, Emerging Infectious Diseases, 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

3. Predictors of HIV rebound differ by timing of antiretroviral therapy initiation

Author

Li, Jonathan Z, Melberg, Meghan, Kittilson, Autumn, Abdel-Mohsen, Mohamed, Li, Yijia, Aga, Evgenia, Bosch, Ronald J, Wonderlich, Elizabeth R, Kinslow, Jennifer, Giron, Leila B, Di Germanio, Clara, Pilkinton, Mark, MacLaren, Lynsay, Keefer, Michael, Fox, Lawrence, Barr, Liz, Acosta, Edward, Ananworanich, Jintanat, Coombs, Robert, Mellors, John, Deeks, Steven, Gandhi, Rajesh T, Busch, Michael, Landay, Alan, Macatangay, Bernard, Smith, Davey M, and Team, for the AIDS Clinical Trials Group A5345 Study

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Pediatric, Infectious Diseases, Clinical Research, Clinical Trials and Supportive Activities, Pediatric AIDS, HIV/AIDS, Infection, Good Health and Well Being, Humans, HIV Infections, Proviruses, CD8-Positive T-Lymphocytes, Viral Load, DNA, AIDS Clinical Trials Group A5345 Study Team, AIDS vaccine, AIDS/HIV, Adaptive immunity, Biomedical and clinical sciences, Health sciences
Abstract

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Published
2024

4. Comparison Study of the Bio-Plex and Meso Scale Multiplexed SARS-CoV-2 Serology Assays Reveals Evidence of Diminished Host Antibody Responses to SARS-CoV-2 after Monoclonal Antibody Treatment

Author

Parikh, Urvi M, Heaps, Amy L, Moisi, Daniela, Gordon, Kelley C, Mellors, John W, Choudhary, Manish C, Deo, Rinki, Moser, Carlee, Klekotka, Paul, Landay, Alan L, Currier, Judith S, Eron, Joseph J, Chew, Kara W, Smith, Davey M, Li, Jonathan Z, Sieg, Scott F, and Study, Team ACTIV-2 A5401

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biodefense, Immunization, Prevention, Clinical Research, Vaccine Related, Emerging Infectious Diseases, Coronaviruses, Infectious Diseases, Biotechnology, Infection, Good Health and Well Being, Team ACTIV-2/A5401 Study, Bio-Plex, COVID, COVID-19, Meso Scale Discovery, SARS-CoV-2, bamlanivimab, monoclonal antibodies, Clinical sciences, Immunology, Medical microbiology
Abstract

BackgroundAssessing the breadth and duration of antigen-specific binding antibodies provides valuable information for evaluating interventions to treat or prevent SARS-CoV-2 infection. Multiplex immunoassays are a convenient method for rapid measurement of antibody responses but can sometimes provide discordant results, and antibody positive percent agreement for COVID-19 diagnosis can vary depending on assay type, disease severity, and population sampled. Therefore, we compared two assays marked for research applications, MSD and Bio-Plex Pro, to evaluate qualitative interpretation of serostatus and quantitative detection of antibodies of varying isotypes (IgG, IgM, and IgA) against receptor binding domain (RBD) and nucleocapsid (N) antigens.MethodsSpecimens from ACTIV-2/A5401, a placebo-controlled clinical trial of the SARSCoV-2 monoclonal antibody (mAb) bamlanivimab to prevent COVID-19 disease progression, were used to evaluate the concordance of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 Serology Assay and the Meso Scale Discovery (MSD) V-PLEX COVID-19 Panel 1 serology assay in detecting and quantifying IgG, IgA, and IgM binding anti-SARS-CoV-2 antibody responses against the RBD and N antigens. Data were disaggregated by study arm, bamlanivimab dose, days post-enrollment, and presence of emerging resistance.ResultsWe observed 90.5% (412 of 455 tests) concordance for anti-RBD IgG and 87% (396 of 455) concordance for anti-N IgG in classifying samples as negative or positive based on assay-defined cutoffs. Antibody levels converted to the WHO standard BAU/mL were significantly correlated for all isotypes (IgG, IgM, and IgA) and SARS-CoV-2 antigen targets (RBD and N) tested that were common between the two assays (Spearman r 0.65 to 0.92, P < 0.0001). Both assays uncovered evidence of diminished host-derived IgG immune responses in participants treated with bamlanivimab compared to placebo. Assessment of immune responses in the four individuals treated with the 700 mg of bamlanivimab with emerging mAb resistance demonstrated a stronger anti-N IgG response (MSD) at day 28 (median 2.18 log BAU/mL) compared to participants treated with bamlanivimab who did not develop resistance (median 1.55 log BAU/mL).ConclusionsThese data demonstrate the utility in using multiplex immunoassays for characterizing the immune responses with and without treatment in a study population and provide evidence that monoclonal antibody treatment in acute COVID-19 may have a modest negative impact on development of host IgG responses.

Published
2024

5. Impact of SARS-CoV-2 Resistance to Antiviral Monoclonal Antibody Therapy on Neutralizing Antibody Response

Author

Paul, Marc-Kendy, Choudhary, Manish C, Heaps, Amy L, Deo, Rinki, Moisi, Daniela, Gordon, Kelley C, Mellors, John W, Moser, Carlee, Klekotka, Paul, Landay, Alan, Currier, Judith S, Eron, Joseph J, Chew, Kara W, Smith, Davey M, Sieg, Scott F, Parikh, Urvi M, Li, Jonathan Z, and Team, on behalf of the ACTIV-2 A5401 Study

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Biotechnology, Clinical Research, Biodefense, Immunization, Coronaviruses Therapeutics and Interventions, Clinical Trials and Supportive Activities, Coronaviruses, Emerging Infectious Diseases, Antimicrobial Resistance, Infectious Diseases, Vaccine Related, Genetics, 5.2 Cellular and gene therapies, Infection, Good Health and Well Being, ACTIV-2/A5401 Study Team, COVID-19, SARS-CoV-2, bamlanivimab, monoclonal antibody, pseudovirus neutralization, Clinical sciences, Medical microbiology
Abstract

BackgroundAnti-SARS-CoV-2 monoclonal antibodies (mAbs) have played a key role as an anti-viral against SARS-CoV-2, but there is a potential for resistance to develop. The interplay between host antibody responses and the development of monoclonal antibody (mAb) resistance is a critical area of investigation. In this study, we assessed host neutralizing antibody (nAb) responses against both ancestral virus and those with treatment-emergent E484K bamlanivimab resistance mutations.MethodsStudy participants were enrolled in the ACTIV-2/Advancing Clinical Therapeutics Globally (ACTG) A5401 phase 2 randomized, placebo-controlled trial of bamlanivimab 700 mg mAb therapy (NCT04518410). Anterior nasal and nasopharyngeal swabs were collected for SARS-CoV-2 RNA testing and S gene next-generation sequencing to identify the E484K bamlanivimab resistance mutation. Serum nAb titers were assessed by pseudovirus neutralization assays.ResultsHigher baseline (pre-treatment) nAb titers against either ancestral or E484K virus was associated with lower baseline viral load. Participants with emerging resistance had low levels of nAb titers against either ancestral or E484K nAb at the time of study entry. Participants with emergent E484K resistance developed significantly higher levels of E484K-specific nAb titers compared to mAb-treated individuals who did not develop resistance. All participants who developed the E484K mAb resistance mutation were eventually able to clear the virus.ConclusionEmerging drug resistance after SARS-CoV-2-specific mAb therapy led to a heightened host neutralizing antibody response to the mAb-resistant variant that was associated with eventual viral clearance. This demonstrates the interplay between the antiviral treatment-directed viral evolution and subsequent host immune response in viral clearance.

Published
2024

6. 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

7. 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

9. Viral and host mediators of non-suppressible HIV-1 viremia

Author

Mohammadi, Abbas, Etemad, Behzad, Zhang, Xin, Li, Yijia, Bedwell, Gregory J, Sharaf, Radwa, Kittilson, Autumn, Melberg, Meghan, Crain, Charles R, Traunbauer, Anna K, Wong, Colline, Fajnzylber, Jesse, Worrall, Daniel P, Rosenthal, Alex, Jordan, Hannah, Jilg, Nikolaus, Kaseke, Clarety, Giguel, Francoise, Lian, Xiaodong, Deo, Rinki, Gillespie, Elisabeth, Chishti, Rida, Abrha, Sara, Adams, Taylor, Siagian, Abigail, Dorazio, Dominic, Anderson, Peter L, Deeks, Steven G, Lederman, Michael M, Yawetz, Sigal, Kuritzkes, Daniel R, Lichterfeld, Mathias D, Sieg, Scott, Tsibris, Athe, Carrington, Mary, Brumme, Zabrina L, Castillo-Mancilla, Jose R, Engelman, Alan N, Gaiha, Gaurav D, and Li, Jonathan Z

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, HIV/AIDS, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Humans, Male, Female, HIV-1, Viremia, Proviruses, HIV Seropositivity, HIV Infections, CD4-Positive T-Lymphocytes, RNA, Viral, Viral Load, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

Published
2023

10. 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

11. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Autologous neutralizing antibodies increase with early antiretroviral therapy and shape HIV rebound after treatment interruption

Author

Esmaeilzadeh, Elmira, Etemad, Behzad, Lavine, Christy L, Garneau, Lauren, Li, Yijia, Regan, James, Wong, Colline, Sharaf, Radwa, Connick, Elizabeth, Volberding, Paul, Sagar, Manish, Seaman, Michael S, and Li, Jonathan Z

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, Infectious Diseases, HIV/AIDS, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, Humans, Antibodies, Neutralizing, Anti-Retroviral Agents, HIV Infections, Proviruses, Immunoglobulin G, HIV Antibodies, Viral Load, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.

Published
2023

21. 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

22. HIV post-treatment controllers have distinct immunological and virological features

Author

Etemad, Behzad, Sun, Xiaoming, Li, Yijia, Melberg, Meghan, Moisi, Daniela, Gottlieb, Rachel, Ahmed, Hayat, Aga, Evgenia, Bosch, Ronald J, Acosta, Edward P, Yuki, Yuko, Martin, Maureen P, Carrington, Mary, Gandhi, Rajesh T, Jacobson, Jeffrey M, Volberding, Paul, Connick, Elizabeth, Mitsuyasu, Ronald, Frank, Ian, Saag, Michael, Eron, Joseph J, Skiest, Daniel, Margolis, David M, Havlir, Diane, Schooley, Robert T, Lederman, Michael M, Yu, Xu G, and Li, Jonathan Z

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, Sexually Transmitted Infections, Infectious Diseases, Genetics, HIV/AIDS, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Humans, CD8-Positive T-Lymphocytes, Killer Cells, Natural, Lymphocyte Activation, RNA, HIV Infections, Viremia, HIV, analytical treatment interruption, post-treatment controller, reservoir, T cell
Abstract

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Published
2023

23. 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

24. 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

25. Transcriptomic Signatures of Human Immunodeficiency Virus Post-Treatment Control

Author

Wedrychowski, Adam, Martin, Holly Anne, Li, Yijia, Telwatte, Sushama, Kadiyala, Gayatri Nikhila, Melberg, Meghan, Etemad, Behzad, Connick, Elizabeth, Jacobson, Jeffrey M, Margolis, David M, Skiest, Daniel, Volberding, Paul, Hecht, Frederick, Deeks, Steven, Wong, Joseph K, Li, Jonathan Z, and Yukl, Steven A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Minority Health, HIV/AIDS, Health Disparities, Infectious Diseases, Sexually Transmitted Infections, Genetics, Infection, Good Health and Well Being, Humans, HIV Infections, HIV-1, Interferons, Interleukin-7, RNA, Viral, Transcriptome, Tumor Suppressor Protein p53, ART, HIV DNA, HIV posttreatment controllers, RNA splicing, analytic treatment interruption, cell-mediated immune response, human immunodeficiency virus, noncontrollers, splicing, transcription, transcriptional completion, transcriptional profile, treatment interruption, viremic suppression, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract

Posttreatment controllers (PTCs) are rare HIV-infected individuals who can limit viral rebound after antiretroviral therapy interruption (ATI), but the mechanisms of this remain unclear. To investigate these mechanisms, we quantified various HIV RNA transcripts (via reverse transcription droplet digital PCR [RT-ddPCR]) and cellular transcriptomes (via RNA-seq) in blood cells from PTCs and noncontrollers (NCs) before and two time points after ATI. HIV transcription initiation did not significantly increase after ATI in PTCs or in NCs, whereas completed HIV transcripts increased at early ATI in both groups and multiply-spliced HIV transcripts increased only in NCs. Compared to NCs, PTCs showed lower levels of HIV DNA, more cell-associated HIV transcripts per total RNA at all times, no increase in multiply-spliced HIV RNA at early or late ATI, and a reduction in the ratio of completed/elongated HIV RNA after early ATI. NCs expressed higher levels of the IL-7 pathway before ATI and expressed higher levels of multiple cytokine, inflammation, HIV transcription, and cell death pathways after ATI. Compared to the baseline, the NCs upregulated interferon and cytokine (especially TNF) pathways during early and late ATI, whereas PTCs upregulated interferon and p53 pathways only at early ATI and downregulated gene translation during early and late ATI. In NCs, viral rebound after ATI is associated with increases in HIV transcriptional completion and splicing, rather than initiation. Differences in HIV and cellular transcription may contribute to posttreatment control, including an early limitation of spliced HIV RNA, a delayed reduction in completed HIV transcripts, and the differential expression of the IL-7, p53, and TNF pathways. IMPORTANCE The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways. These differences may represent correlates or mechanisms of posttreatment control and may provide insight into the development and/or monitoring of therapeutic strategies that are aimed at a functional HIV cure.

Published
2023

26. Despite regression of healthy lifestyle habits, weight loss after bariatric surgery is not affected during the COVID-19 pandemic

Author

Huang, Estella Y, Grunvald, Eduardo, Blitzer, Rachel R, Lee, Arielle M, Broderick, Ryan C, Li, Jonathan Z, Cheverie, Joslin N, Sandler, Bryan J, Horgan, Santiago, and Jacobsen, Garth R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Prevention, Nutrition, Clinical Research, Behavioral and Social Science, Digestive Diseases, Obesity, Evaluation of treatments and therapeutic interventions, 6.4 Surgery, Oral and gastrointestinal, Good Health and Well Being, Humans, Obesity, Morbid, Pandemics, Treatment Outcome, COVID-19, Communicable Disease Control, Gastric Bypass, Bariatric Surgery, Retrospective Studies, Weight Loss, Gastrectomy, Habits, Healthy Lifestyle, Coronavirus, Bariatric surgery, Weight loss, Surgery, Clinical sciences
Abstract

BackgroundThe coronavirus pandemic has caused a worldwide health crisis. Bariatric patients require extensive pre- and post-operative follow-up, which may be less feasible during public health social distancing mandates. We assessed the impact of the pandemic on the behaviors and weight loss outcomes of our pre- and post-operative bariatric patients.MethodsA retrospective review of a prospectively maintained database identified patients who underwent either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) at a single institution between March 2018 and May 2020. A cohort undergoing surgery within 12 months before the pandemic as well as a cohort undergoing a medically supervised diet prior to surgery was surveyed regarding pre- and post-COVID-19 lifestyle habits. Excess weight loss (EWL) outcomes from a group of pre-COVID surgical patients were compared to that of a group of post-COVID surgical patients. Primary outcome was whether the lockdown changed 1-year weight loss outcomes. Secondary outcome was whether patient lifestyle behaviors were changed during the pandemic.ResultsThere was no difference in 1-year EWL between pre- and post-COVID SG patients (51.7% versus 55.9%, p = 0.35), or between pre- and post-COVID RYGB patients (88.9% versus 80.4%, p = 0.42). Pre-stay-at-home order, 91.8% endorsed physical activity compared to 80.3% post-stay-at-home order (p = 0.0025). Mean physical activity decreased from 4.2 h/week to 2.7 h/week after the stay-at-home order (p

Published
2023

27. Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study

Author

Abraham, Rachael, Ager, Arijan, Aguilar, Franchesca A., Ahmadi-Izad, Ghazal, Ahmed, Dilshad R., Alvarez, Alicarmen, Anderson, Blake, Asencios, Walter D., Atha, Mary, Beaty, Casey L., Bedi, Brahmchetna, Berry, Jasmine A., Boone, Donchel, Bower, Mary, Bremner, James D., Brent, Corbin, Brown-Smith, Ke'Ara, Bull, Rachel, Bush, Patricia A., Capo, Gustavo, Carl-Igwe, Kelechi, Chitadze, Calista, Chukwumerije, Nachi, Clyburn, Erna, Collins, Shelby, Costello, Julie, Couture, Grace, Craft, Angel, Cribbs, Sushma K., Cui, Xiangqin, Dandy, Annette, Rio, Carlos del, Jasarevic, Rijalda, Detelich, Joshua F., Dixon, Cartia, Dow, Jeanne, Doyle, D'Andrea, Elchommali, Jannah, Ibeawuchi, Carmel, Elsey, Imani, Fineman, Rebecca, Francis, Anyssa G., Franks, Nicole, Gallini, Julia, Gander, Jennifer C., Gray, Natalie, Grimes, Ash, Gutter, Evan, Han, Jenny E., Hang, Tina P., Harding, Jess, Hernandez, Liliana, Hewitt, Lauren N., Holloway, Carla, Hudgins, Alex F., Huerta, Christopher, Ifejika, Cynthia, Ingram, Ketteria D., Javia, Vidhi N., Jeter, Mykayla, Johnson, Brandi, Joseph, Yasha, Juarez, Monica, Kajan, Dana, Khalil, Lana, Kirkpatrick, Caitlin M., Kleinhenz, Dean, Kolailat, Imanii, Koumanelis, Athena, Koumanelis, Alexandra, Kozoman, Rebecca, Krishnan, Shilpa, Lainez, Jordi, Lawrence, Brianna, Lee, Matthew A., Leon, Jose D., Lew, Valerie, Lewis, Kennedy C., Litvack, Matthew, Maroney, Mara, Maier, Cheryl L., Makkaoui, Nour, Marconi, Vincent C., Martin, Christopher F., Martinez, Monica, Mbogo, Loice, McCaslin, Atuarra, McIntyre, Jerrod, Moanna, Abeer, Montoya, Miranda, Morales, Elena, Moran, Caitlin A., Morgan-Billingslea, Jan, Murray, Calista, Nelson, Roslin, Neuman, Robert B., Nguyen, Tran, Ofotokun, Ighovwerha, Ojemakinde, Elizabeth I., Ojoawo, Bukkie, Osinski, Eileen, Oviedo, Sofia, Panganiban, Bernadine, Paredes-Gaitan, Yolanda, Patzer, Rachel E., Pemu, Priscilla, Prude, Michael, Rahman, Kazi, Ramakrishnan, Grace, Rebolledo, Paulina A., Roberts, Marjorie, Robinson, Keysha, Rogers, Chantrice, Rouphael, Nadine G., Searles, Charles, Shah, Anand, Segall, Marni, Shaw, Renata M., Silva, Ruvina, Simpson, Cheryl, Simpson-Derrell, Krystal, Sirajud-Deen, Talib, Smith, Veronica E., Stringer, Andre, Stroud, Jacob, Suthar, Mehul S., Sylber, Cory, Sylvera, Ashley, Tanner, Tehquin, Teunis, Larissa J., Tolbert, Maliya, Thomas, Kodasha M., Thompson, Sierra G., Titanji, Kehmia, Toy, Christopher, Traenkner, Jessica, Truong, Alex, Unterberger, Kristen, Vaccarino, Viola, Varney, Kris, Vyas, Kartavya, Vyas, Kurt, Walker, Tiffany A., Walkow, Max, Wang, Dongli, Wesley, Tamara, Wiley, Zanthia, Wimberly, Erika, Winston, Juton R., Winter, Terra J., Wongtrakool, Cherry, Aikawa, Masanori, Alba, George A., Aung, Taing N., Baden, Lindsey, Baslet, Gaston, Bassett, Ingrid V., Bennett, Lindsey, Bhattacharyya, Shamik, Blazey-Martin, Deborah, Buring, Julie, Cagnina, Rebecca E., Chen, Li Qing, Clark, Cheryl R., Cohen, Pieter, Collier, Ai-Ris, Czeisler, Charles, Duffy, Elizabeth, Estill, Peter, Fong, Tamara, Gay, Elizabeth, Ghamloush, Maher, Ginns, Leo C., Haack, Monika, Haas, Jennifer, Hamburg, Naomi, Hauser, Kristine S., John, Janice, Jordan, Michael, Juelg, Boris D., Kanjilal, Diane G., Kim, Arthur Y., Klerman, Elizabeth B., Kobayashi, Misaki ., Kogelman, Laura, Lamas, Daniela, Levy, Bruce D., Levy-Carrick, Nomi, Lewis, Gregory, Maley, Jason H., Manson, JoAnn, Marathe, Jai G., Mullington, Janet M., O'Connor, George T., Ojikutu, Bisola, Perlis, Roy, Quintana, Yuri, Redline, Susan, Remis, Elijah J., Rosand, Jonathan, Sesso, Howard D., Shaughnessy, Lynn, Shepherd, Fitzgerald M., Solomon, Scott, Sparks, Jeffrey A., Spencer, Lia L., Stephenson, Kathryn, Systrom, David, Thomas, Robert J., Min Thu, Phyo Phyo, Ticotsky, Amberly, Torres, Robert, Wallace, Zachary S., Walt, David, Ward, Honorine D., Washko, George, Whittelsey, Maureen, Wiener, Rebecca, Williams, Charles T., Xerras, Dean, Zhang, Haihua, Zionts, Danielle, Armstrong, Donna, Binkley, Susan E., Blackwell, Kenneth, Brown, Todd, Carton, Thomas W., Causey, Annalia, Cook, Felice, Daniel, Casey L., Datri, Paula, Domingo, Julio, Donahue, Conner, Eady, Maitlyn, Edberg, Jeffrey, Erdmann, Nathaniel, Fuloria, Jyotsna, Garcia-McClaney, Noah, Garner, Melissa, Gillespie, Mark, Gray, Brandon, Hagensee, Michael, Hall, Wanda, Hansel, Jamie, Hart, Cady, Hebson, Camden L., Hidalgo, Bertha, Holtzapfel, Kaylen, Jinright, Alexis, Judd, Suzanne E., Kennedy, Teri, Kirkwood, Leigh, Leggio, Cathryn, Levitan, Emily B., Maier, Megan, McCormack, Patricia, Miele, Lucio, Mitchell, Kevin, Montgomery, Aoyjai, Peralta-Carcelen, Myriam, Perkins, Allen, Pilco, Juan P., Powell, Leigh, Shevin, Rachael, Skipworth, Sidney, Spurgeon, Leah, Sutherland, Erica, Tita, Alan T., Trauth, Amber, Trotter, Siobhan, Van Deerlin, Alexander, Ware, Gregory, Weiser, Sharon, Wilson, Rosanne, Woodruff, Dana, Wu, Jing, Young, Madeline, Alemu, Mhret, Anderson, Jordan, Ashktorab, Hassan, Brim, Hassan, Chang, Linda, Chauhan, Mahak, Cho, Sung, Durrani, Saima, Gentil, Monique P., Goodman, Karli, Laiyemo, Adeyinka O., Lanke, Gandi, Lebron, Ralph, Maheshwari, Anurag, Mehari, Alem, Nezamloo, Ali, Ngwa, Julius, Njoku, Noelle, Ok, Jina, Sherif, Zaki A., Solemani, Akbar, Thuluvath, Paul, To, Chau, Spikes, Leslie A., James, Judith A., Luciano Roman, Carlos A., Chow, Dominic C., Marshall, Gailen D., Dickinson, John D., Hoover, Susan E., Warren, David E., Emery, Ivette F., Sukhera, Fatima I., Rosen, Clifford J., Greenway, Frank L., Hodder, Sally L., Shikuma, Cecilia M., VanWagoner, Timothy M., Bardes, James M., Kirwan, John P., Wood, Jeremy P., Whiteheart, Sidney W., Shellito, Judd, Roelke, Theresa, Black, Lora, Tjarks, Brian, Fonseca, Vivian, Gupta, Shaveeta, Longo, Michele, Yang, Mei, MarGangcuangco, Louis, Bengtson, Charles, Castro, Mario, Howard, Theresa, Garvy, Beth, Simmons, Christopher, Garla, Vishnu, Kuebler, Joy, Nandi, Utsav, Vasey, Andrew, Bogie, Amanda, Scott, James, Frontera, Sigrid Perez, Bagur, Jorge Santana, Dominique-Villanueva, Daphne, Juskowich, Joy, Reece, Rebecca, Sarwari, Arif, Aponte-Soto, Lisa, Adams, Dara, Baker, Aileen, Barbera, Sunni, Basu, Sanjib, Bleasdale, Susan, Bolliger, Dawn, Boyd, Andrew D., Boyineni, Jerusha, Breiter, Taylor, Brown, Daniel, Buhimschi, Irina A., Carrithers, Michael D., Certa, Marta, Chalamalla, Rashmika, Chebrolu, Praneeth, Chestek, David, Chessier, Erica, Cook, Judith A., Cranford, Savannah, Curry, Hannah L., Darbar, Dawood, Dasgupta, Raktima, Blakley, Felicia Davis, DeLisa, Julie A., Del Rios, Marina, Diaz, Maya Z., Diviak, Kathleen R., Dixon, Jennifer, Donlon, Meghan F., Donohue, Sarah E., Dworkin, Mark S., Edmonds, Sherrie, Ellison, Angela, Everett, Emily, Flanigan, Clarie, Freedman, Michael B., Gale, Lisa, Gerald, Lynn B., Giles, Wayne H., Gordon, Howard S., Hafner, John, Hammad, Bayan, Hanson, Keith A., Harris, Pastor C., Hartwig, Kimberly, Hasek, Sharon, Hasse, Wendy, Hendrickson, Monica, Hobbs, Brianna, Hryniewicka, Martyna, Hammerl, Savannah, Hutton, Robert, Ibanez, Alejandra L., Illendula, Sai D., Ismail, Nahed, Jain, Akash, Jennette, Kyle J., Kadubek, Grace, Kent, Denise, Kotini-Shah, Pavitra, Kelly, Sara W., Kent, Denise A., Kim, Keri S., Kindred, Elijah, Klein, Jonathan D., Krishnan, Jerry A., Large, Lucia, Lash, James ., Lin, Janet Y., Lu, Jun, Mahamed, Abeer M., Maholovich, Phoebe, Malchenko, Sergey, Martinez, Miriam, Mauntel-Medici, Cammeo, Madineni, Abhigna, McCauley, Mark, Menchaca, Martha, Mermelstein, Robin, Moreno, David J., Morrissy, Liam, Muramatsu, Naoko, Musick, Hugh, Noland, Seth, Norwick, Lourdes, Novak, Richard M., Olds, Lela, Ortiz, Marilyn, Patel, Khushboo, Perez, Nicolas L., Pliskin, Neil H., Pope, Sam, Prabhakar, Bellur S., Prasad, Bharati, Predki, Barbara, Prendergast, Heather M., Quigley, John G., Ramchandran, Ramaswamy, Ramirez, Ana, Rappe, Sarah, Rehman, Jalees, Rolon, Cesar, Rowley, Matthew, Rudraraju, Gowrisree, Rutherfoord, Melissa, Sader, Samer B., Sculley, Jennifer A., Smith-Mack, Jerisha, Swearingen, Peyton, Stewart de Ramirez, Sarah A., Sudhindra, Praveen, Sun, Jun, Tartt, Nancy, Terlinde, Tracy, Thompson, Tiffany, Vanden Hoek, Terry L., Kelly, Sara Warfield, Villanueva, Laura, Welter, Hannah, Woolley, Brittany, Yazici, Cemal, Charney, Alexander W., Kovatch, Patricia, Merad, Miriam, Nadkarni, Girish N., Wisnivesky, Juan P., Aberg, Judith A., Ascolillo, Steven, Assenso, Esther, Bagiella, Emilia, Bartram, Logan, Becker, Jacqueline, Beckmann, Noam D., Bendl, Ashley, Chen, Benjamin K., Civil, Alyssa, Dhar, Kaberi, Evo-Ortega, Lorraine, Fierer, Daniel, Gallagher, Emily J., Garcia-Sastre, Adolfo, Gnjatic, Sacha, Guliyeva, Sabina, Harvey-Ingram, Lori, Herrera-Moreno, Julia, Hill, Matthew, Horowitz, Carol R., Jackson, Rachel, Kastrat, Din, Lala-Trindade, Anu, Lin, Jenny, Macaluso, Nick, Marcon, Kathryn, Meyer, Dara, Morinigo, Janice, Natelson, Benjamin H., Nussenzweig, Maya, Padua, Tiffani, Putrino, David, Quazi, Nawreen, Ramos, Michelle, Richardson, Lynne, Russo, Scott, Seifert, Alan C., Serri, Abdullah, Walker, Jordan, Yee, Michell, Adolphi, Natalie L., Alekhina, Natalya, Archuleta, David A., Barlocker, Jackson, Bateman, Lucinda, Bradfute, Steven B., Brito, Rebecca, Bryan, Tanner W., Buck, Kaitlin E., Davis, Debra, Deakyne Davies, Sara J., Decker, Lauren A., Elifritz, Jamie, Erlandson, Kristine M., Facelli, Julio C., Fudge, Harrison Z., Tran, Huong, Pitch, Chloe, Feuerriegel, Elen M., Ford, Isaac, Friedman, Naomi P., Garcia-Soberanez, Noella D., Gardner, Edward M., Stringham, Caitlyn, Ling, Leah, Gebremariam, Tewodros H., Gentry, Frederick D., Gouripeddi, Ramkiran, Graham, Paige, Gronert, Eve G., Harkins, Michelle S., Hawkins, Kellie L., Hess, Rachel, Johnny, Jace D., Johnson, Brandon M., Jolley, Sarah E., Lloyd, Jennifer, Ludwig, Katelyn R., Martinez, Noah I., McCandless, Sean A., Montoya, Lorenzo A., Oakes, Judy L., Parada, Alisha N., Quinn, Davin K., Raissy, Hengameh, Ramos, Alfredo, Reid, Kayleigh M., Reusch, Jane E., Sheehan, Elyce B., Sokol, Ron J., Treacher, Irena S., Trinity, Joel D., Truong, Dongngan T., West, Shelby C., Molden, Joie, Sharareh, Nasser, Weaver, Lisa J., Spivak, Adam M., Brown, Jeanette P., Shah, Kevin S., Pace, Laura A., Scholand, Mary Beth, Velinder, Matt, Cortez, Melissa, Morimoto, Sarah Shizuko, Vernon, Suzanne D., Lu, Yue, Owen, Megan, Hermansen, Jessica A., Lindsay, Ashton M., Donohue, Dagny K., Garg, Lohit, Wodushek, Thomas, Higgins, Janine, Lockie, Tim, Brightman, Marisa, Thurman, Brook, Powell, Jenny M., Freston, Dylan C., Medina, Juliemar C., Aguirre, Bailee, Anderson, Jeff, Bair, Tami, Bosh, Lindsay, Evans, Lorlie, Garrett, Chase, Harris, Dixie, Herrera, Katherine, Horne, Benjamin D., Juan, James, Knight, Stacey, Knowlton, Kirk, Leither, Lindsay, Maestas, Heather, May, Heidi T., Najarian, Gabriel, Woller, Scott C., Zubal, Shyanne, Jensen, McKenna M., Webb, Tiaura, Iverson, Leslie, Ayache, Mirna, Baloi, Alexis, Barnboym, Emma, Boldt, Nicholas, Bukulmez, Hulya, Chesnick, Hailey, Conrad, Ann, Consolo, Mary, Curtis, Lynette, D’anza, Brian, DiFrancesco, Kathryn, Edminston, Marissa, Eteshola, Ebenezer, Gallagher, Michelle, Gibson, Kelly S., Gordesky, Larraine, Greenwood, Carla, Haghiac, Maricela, Harris, Paul, Hernandez, Carla, Iqbal, Shirin, Kaelber, David C., Kaufman, Elizabeth S., Kennedy, Olivia, Labbato, Danielle, Lengu, Ketrin, Levert, Antonio, Levin, Jennifer, Lowenthal, Rebecca, Mackin, Bridget, Malakooti, Shahdi K., McComsey, Grace A., Minium, Judy, Mouchati, Christian, Oleson, Christine, Pearman, Ann, Hershey, Morgan, Rivera, Amanda, Rodgers, Michael, Rodgers, Theresa, Roy, Arnab, Russ, Kris, Scott, Sarah, Sheth, Niyati, Singer, Nora G., Smith, Beth, Smith, Cheryl, Stancin, Terry, Temple, Daniel, Tribout, Megan, Weinberger, Elisheva, Zhang, David, Zisis, Sokratis N., Atieh, Ornina, Yendewa, George, Baissary, Jhony, Pettinato, KImberly, Lim, Joaquin, Jacob, Joshua, Adams, Cara, Tejani, Viral, Algren, Heather A., Alicic, Radica, Baxter, Joni, Brennan, Conor, Caudill, Antonina, Chen, Peter, Chopra, Tananshi, Chu, Helen Y., Del Alcazar, James, Duven, Alexandria M., Edmark, Rick, Emerson, Sarah, Goldman, Jason D., Gutierrez, Vanessa, Hadlock, Jennifer, Harteloo, Alex, Heath, James R., Hood, Susan, Jackman, Susan, Kaneko, John, Kemp, Megan, Kim, Christina, Kuykendall, Kelli, Li, Sarah, Logue, Jennifer K., Magis, Andrew T., Manner, Paula, Mason, Carly, McCaffrey, Kathryn, McDonald, Connor, McDonald, Dylan, Murray, Kim M., Nackviseth, Callista, Nguyen, Helen, Parimon, Tanyalak, Poussier, Rachel, Rowen, Lee, Satira, Richard, Torbati, Sam, Tuttle, Katherine R., Wallick, Julie A., Yuan, Dan, Watanabe, Kino, Wilcox, Lauren E., Contreras, Fatima, Dahlke, Lea, Gudipudi, Lasya, Modes, Matthew, Muttera, Nicole, Salinas, Nancy, Tadeo, Josie, White, Shane, Alvarado, Stephanie, Anderson, Reed, Arellanes, Azaneth, Barajas, Rose A., Chauhan, Suneet P., Clarke, Geoffrey D., Farner, Cheryl E., Fischer, Melinda S., Goldberg, Mark P., Hasbani, Keren, Hastings, Gabrielyd, Heard, Patricia, Herrera, Italia, Infante, Edgar, Johnson, Hillary, Jones, Johnnie, Kellogg, Dean L., Kraig, Ellen, Longoria, Lisa, Nambiar, Anoop M., Okafor, Emeka, Paredes, Claudia C., Patterson, Thomas F., Patterson, Jan E., Pinones, Alexis, Potter, Jennifer S., Reeves, W.B., Saade, George R., Salehi, Marzieh, Scholler, Irma, Seshadri, Sudha, Shah, Dimpy P., Shah, Pankil, Sharma, Kumar, Sharma, Kavita, Soileau, Bridgette, Solis, Pamela, Stoebner, Carmen, Sullivan, Michael, Taylor, Barbara S., Tragus, Robin, Tsevat, Joel, Verduzco-Gutierrez, Monica, Ahuja, Neera, Blish, Catherine A., Blomkalns, Andra L., Bonilla, Hector, Brotherton, Richard, Clinton, Kimberly, Dingankar, Vaidehi, Geng, Linda N., Go, Minjoung, Haddad, Francois, Jagannathan, Prasanna, Jamero, Christopher, Jee, Kathryn, Jia, Xiaolin K., Khurana, Naresh, Kumar, Andre, Maldonado, Yvonne, Miglis, Mitchell G., O'Conor, Ellen, Olszewski, Kelly, Pathak, Divya, Quintero, Orlando, Scott, Jake, Singh, Upinder, Urdaneta, Alfredo E., Utz, Paul J., Varkey, 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Ana, Huang, Weixing, Karlson, Elizabeth W., Kaufman, Daniel, Keogh, Diane, Kerr, James D., Klann, Jeffrey G., Krishnamoorthy, Aparna, Lasky-Su, Jessica A., Liao, Katherine P., MacFadden, Doug, Maram, Anupama, Martel, Megan W., Mendis, Michael, Metta, Reeta, Monteiro, Jonathan, Morales, Eduardo, Morse, Richard E., Murphy, Shawn, Nazaire, Marc-Danie, Neils, Gregory, Nguyen, Amber N., Norman, James, Paik, Henry H., Pant, Deepti, Park, HeeKyong, Rabideau, Dustin J., Reeder, Harrison T., Rossi-Roh, Kathleen, Santacroce, Leah M., Schlepphorst, Katherine, Schulte, Carolin, Selvaggi, Caitlin A., Shinnick, Daniel J., Simons, William, Simpson, Lynn A., St. Jean Flanders, Mary L., Strasser, Zachary, Thakrar, Mansi R., Thaweethai, Tanayott, Thorn, Madeleine, Trewett, Philip, Van Fleet, Dustin, Wagholikar, Kavishwar B., Wang, Taowei D., Wattanasin, Nich, Weber, Griffin, Williams, Michael A., Zhang, Ren Zhe, Cicek, Mine, Chang, Nancy, Wirkus, Samantha, Zahnle, Nicole, Flotte, Thomas J., Frisch, Erika, Boysen, Erik M., Welch, Gary, Akintonwa, Teresa, Blancero, Frank, Brown, Heather-Elizabeth, Carmilani, Megan, Cerda, Marta, Clash, Victor H., Copeland, Debra, Hall, Yvonka, kevin kondo, Lerma, Lydia, Lindsay, Jacqui, Marti, Heather, Maughan, Christine, Minor, Tony, Taylor, Brittany, Vincent, Hyatt, Zissis, Mike, Anderson, Brett, Bardhan, Sujata, Castro-Baucom, Leah, Chisolm, Deena, Corchado, Claudia, Damian, April Joy, Daniel, Casey, DasGupta, Soham, Dehority, Walter, Feldman, Candace, Fessel, Josh, Rosas, Lisa Goldman, Horowitz, Carol, Khullar, Dhruv, Lopez, Keila, McDonald Pinkett, Shelly, Myaskovsky, Larissa, Regino, Lidia, St John Thomas, Gelise, Stewart de Ramirez, Sarah, Vangeepuram, Nita, Walden, Anita, Williams, Neely, Yin, Shonna, Burton, Phoebe, Catallozzi, Marina, Clark, Cheryl, Dworetzky, Beth, Edwards, Belinda, Ferrer, Robert L., Judd, Suzanne, Rothman, Russell, Wagner, Laura, Wallace, Ann, Adams, Sonseeahray (Ray), Aragon, Leyna, Bander, Bryan, Bishof, Karyn, Brooks, Gail, Carignan, Etienne, Coombs, Krista, Davis, Hannah, Blakley, Felicia D., Diggs, Marissa, Brown, Heather E., Favors, Umar, Fields, Whitney, Fisher, Liza, Fitzgerald, Megan, Gaffney, Alicia, Witvliet, Margot Gage, Garcia, Roberto, Gustafson, Tyler, Guthe, Nick, Holmes, Verna, Hornig, Mady, Hornig, Maxwell, Jefferson, Wendy, Kochis, Nancy, Kondo, Kevin, Lam, Julie, Lawrence, Fadwa, Letts, Rebecca, Lewis, Juan, Lopez, Silcia, Martinez, Thomas, McCorkell, Lisa, McGrath, Rebecca, Minor, Thomas T., Moore, Charita, Nguyen, Kian, Nichols, Lauren, O'Brien, Lisa, Olson, Holly, Peddie, Aimee, Perlowski, Alice, Lorenzo, Elizabeth P., Prentiss, Lisa, Raytselis, Nadia, Rochez, Nitza, Rockwell, Megan, Rutter, Jacqueline, Seibert, Elle, Sekar, Anisha, Smith, Chimere, Stiles, Lauren, Taylor, Emily, Thompson, Julie, Trapp, Stephen, Valdiva, Stephen, Wilensky, Rochelle, Williams, Melissa, Dawson, Kay W., Wylam, Andrew, Swank, Zoe, Borberg, Ella, Chen, Yulu, Senussi, Yasmeen, Chalise, Sujata, Manickas-Hill, Zachary, Yu, Xu G., Li, Jonathan Z., Alter, Galit, Kelly, J. Daniel, Goldberg, Sarah A., Talla, Aarthi, Li, Xiaojun, Skene, Peter, Bumol, Thomas F., Torgerson, Troy R., Czartoski, Julie L., McElrath, M. Juliana, and Walt, David R.

Published
2024
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28. 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

29. 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

30. SARS-CoV-2 infection elucidates features of pregnancy-specific immunity

Author

Oh, Dong Sun, Kim, Eunha, Normand, Rachelly, Lu, Guangqing, Shook, Lydia L., Lyall, Amanda, Jasset, Olyvia, Demidkin, Stepan, Gilbert, Emily, Kim, Joon, Akinwunmi, Babatunde, Tantivit, Jessica, Tirard, Alice, Arnold, Benjamin Y., Slowikowski, Kamil, Goldberg, Marcia B., Filbin, Michael R., Hacohen, Nir, Nguyen, Long H., Chan, Andrew T., Yu, Xu G., Li, Jonathan Z., Yonker, Lael, Fasano, Alessio, Perlis, Roy H., Pasternak, Ofer, Gray, Kathryn J., Choi, Gloria B., Drew, David A., Sen, Pritha, Villani, Alexandra-Chloé, Edlow, Andrea G., and Huh, Jun R.

Published
2024
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31. Sirolimus reduces T cell cycling, immune checkpoint marker expression, and HIV-1 DNA in people with HIV

Author

Campbell, Danielle, Cutler, Corey, Dorosh, Michael, Ha, Belinda, Hawkins, Elizabeth, Hensel, Christopher, Khairalla, Nayri, Knowles, Kevin, Lee, Sulggi A., Pedersen, Susan, Ritz, Justin, Ryder, Dylan, Sekaly, Rafick, Shugarts, David L., Straub, Becky, Zolopa, Andrew, Henrich, Timothy J., Bosch, Ronald J., Godfrey, Catherine, Mar, Hanna, Nair, Apsara, Keefer, Michael, Fichtenbaum, Carl, Moisi, Daniela, Clagett, Brian, Buck, Amanda M., Deitchman, Amelia N., Aweeka, Francesca, Li, Jonathan Z., Kuritzkes, Daniel R., Lederman, Michael M., Hsue, Priscilla Y., and Deeks, Steven G.

Published
2024
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32. 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

33. 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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34. Participant Perspectives and Experiences Following an Intensively Monitored Antiretroviral Pause in the United States: Results from the AIDS Clinical Trials Group A5345 Biomarker Study

Author

Dubé, Karine, Eskaf, Shadi, Barr, Liz, Palm, David, Hogg, Evelyn, Simoni, Jane M, Sugarman, Jeremy, Brown, Brandon, Sauceda, John A, Henley, Laney, Deeks, Steven, Fox, Lawrence, Gandhi, Rajesh T, Smith, Davey, and Li, Jonathan Z

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Behavioral and Social Science, HIV/AIDS, Clinical Research, Infection, Acquired Immunodeficiency Syndrome, Anti-Retroviral Agents, Biomarkers, HIV Infections, Humans, Sexual Partners, United States, persons living with HIV, intensively monitored antiretroviral pause, analytical treatment interruption, social sciences, behavioral sciences, Virology, Clinical sciences
Abstract

The AIDS Clinical Trials Group A5345 study (NCT03001128) included an intensively monitored antiretroviral pause (IMAP), during which participants living with HIV temporarily stopped antiretroviral treatment (ART) in an effort to identify biomarkers that could predict HIV rebound. We evaluated the potential impact of the IMAP on A5345 study participants in the United States by questioning them immediately after the IMAP and at the end of the study. We administered longitudinal sociobehavioral questionnaires to participants following the IMAP when they resumed ART and at the end of the study. We summarized descriptive data from the post-IMAP and end-of-study questionnaires. Open-ended responses were analyzed using conventional content analysis. Reactions to pausing ART involved a mixture of curiosity and satisfaction from contributing to science. All participants indicated adherence with the ART interruption. About half (9/17) of post-IMAP questionnaire respondents reported having sexual partner(s) during the IMAP, and of those, nearly all (8/9) did not find it difficult to use measures to prevent HIV transmission to partners. The majority believed that they benefited from the study, yet some had elevated anxiety following the IMAP and at the end of the study. Most (24/29) respondents who completed the end-of-study questionnaire would recommend the study to other people living with HIV. Our findings underscore the relevance of the psychosocial aspects of participating in studies that involve interruptions of ART. Understanding how participants experience this research is invaluable for informing the design of future research aimed at sustained ART-free virologic suppression.

Published
2022

35. Time to Viral Rebound After Interruption of Modern Antiretroviral Therapies

Author

Li, Jonathan Z, Aga, Evgenia, Bosch, Ronald J, Pilkinton, Mark, Kroon, Eugène, MacLaren, Lynsay, Keefer, Michael, Fox, Lawrence, Barr, Liz, Acosta, Edward, Ananworanich, Jintanat, Coombs, Robert, Mellors, John W, Landay, Alan L, Macatangay, Bernard, Deeks, Steven, Gandhi, Rajesh T, and Smith, Davey M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Infectious Diseases, Clinical Research, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Anti-Retroviral Agents, HIV Infections, Humans, Viral Load, HIV treatment interruption, viral rebound, posttreatment controller, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

BackgroundDevelopment of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome.MethodsAIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies.ResultsThirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, P = .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation.ConclusionsEarly ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.

Published
2022

36. 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

37. Frequency of post treatment control varies by antiretroviral therapy restart and viral load criteria

Author

Fajnzylber, Jesse, Sharaf, Radwa, Hutchinson, John N, Aga, Evgenia, Bosch, Ronald J, Hartogensis, Wendy, Jacobson, Jeffrey M, Connick, Elizabeth, Volberding, Paul, Skiest, Daniel J, Margolis, David, Sneller, Michael C, Little, Susan J, Gulick, Roy M, Mellors, John W, Gandhi, Rajesh T, Schooley, Robert T, Henry, Keith, Tebas, Pablo, Deeks, Steve, Chun, Tae-Wook, Collier, Ann C, Hecht, Frederick M, and Li, Jonathan Z

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Sexually Transmitted Infections, HIV/AIDS, Clinical Research, Infectious Diseases, Clinical Trials and Supportive Activities, Infection, HIV Infections, Humans, Serologic Tests, Viral Load, CHAMP study team, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Virology, Biomedical and clinical sciences, Health sciences
Abstract

Clinical trials including an analytical treatment interruption (ATI) are vital for evaluating the efficacy of novel strategies for HIV remissions. We briefly describe an interactive tool for predicting viral rebound timing in ATI trials and the impact of posttreatment controller (PTC) definitions on PTC frequency estimates. A 4-week viral load threshold of 1000 cps/ml provides both high specificity and sensitivity for PTC detection. PTC frequency varies greatly based on the definition of a PTC.

Published
2021

40. 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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41. Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19

Author

Kuriakose, Safia, Singh, Kanal, Pau, Alice K, Daar, Eric, Gandhi, Rajesh, Tebas, Pablo, Evans, Laura, Gulick, Roy M, Lane, H Clifford, Masur, Henry, Aberg, Judith A, Adimora, Adaora A, Baker, Jason, Kreuziger, Lisa Baumann, Bedimo, Roger, Belperio, Pamela S, Cantrill, Stephen V, Coopersmith, Craig M, Davis, Susan L, Dzierba, Amy L, Gallagher, John J, Glidden, David V, Grund, Birgit, Hardy, Erica J, Hinkson, Carl, Hughes, Brenna L, Johnson, Steven, Keller, Marla J, Kim, Arthur Y, Lennox, Jeffrey L, Levy, Mitchell M, Li, Jonathan Z, Martin, Greg S, Naggie, Susanna, Pavia, Andrew T, Seam, Nitin, Simpson, Steven Q, Swindells, Susan, Tien, Phyllis, Waghmare, Alpana A, Wilson, Kevin C, Yazdany, Jinoos, Zachariah, Philip, Campbell, Danielle M, Harrison, Carly, Burgess, Timothy, Francis, Joseph, Sheikh, Virginia, Uyeki, Timothy M, Walker, Robert, Brooks, John T, Ortiz, Laura Bosque, Davey, Richard T, Doepel, Laurie K, Eisinger, Robert W, Han, Alison, Higgs, Elizabeth S, Nason, Martha C, Crew, Page, Lerner, Andrea M, Lund, Claire, and Worthington, Christopher

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Health Services, Clinical Research, Generic health relevance, Good Health and Well Being, Advisory Committees, COVID-19, Child, Data Interpretation, Statistical, Drug Approval, Evidence-Based Medicine, Female, Humans, Interprofessional Relations, National Institutes of Health (U.S.), Pandemics, Practice Guidelines as Topic, Pregnancy, SARS-CoV-2, Stakeholder Participation, United States, COVID-19 Drug Treatment, NIH COVID-19 Treatment Guidelines Panel, Medical and Health Sciences, General & Internal Medicine, Clinical sciences
Abstract

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Published
2021

42. Time to Viral Rebound After Interruption of Modern Antiretroviral Therapies.

Author

Li, Jonathan Z, Aga, Evgenia, Bosch, Ronald, Pilkinton, Mark, Kroon, Eugène, MacLaren, Lynsay, Keefer, Michael, Fox, Lawrence, Barr, Liz, Acosta, Edward, Anaworanich, Jintanat, Coombs, Robert, Mellors, John, Landay, Alan, Macatangay, Bernard, Deeks, Steven, Gandhi, Rajesh T, Smith, Davey M, and AIDS Clinical Trials Group A5345 Study Team

Subjects
AIDS Clinical Trials Group A5345 Study Team, HIV treatment interruption, posttreatment controller, viral rebound, Microbiology, Biological Sciences, Medical and Health Sciences
Abstract

BackgroundDevelopment of HIV remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern ART regimens and timing of ART initiation may impact this outcome.MethodsACTG A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon two successive viral loads ≥1,000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies.ResultsThirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of chronic-treated and none of early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens while 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at post-treatment interruption week 12 (chronic vs early: 2% vs 9%, P=0.0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants re-suppressed after ART re-initiation.ConclusionsEarly ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.

Published
2021

43. Participant Perspectives and Experiences Entering an Intensively Monitored Antiretroviral Pause: Results from the AIDS Clinical Trials Group A5345 Biomarker Study.

Author

Diepstra, Karen L, Barr, Liz, Palm, David, Hogg, Evelyn, Mollan, Katie R, Henley, Laney, Stover, Angela M, Simoni, Jane M, Sugarman, Jeremy, Brown, Brandon, Sauceda, John A, Deeks, Steven, Fox, Lawrence, Gandhi, Rajesh T, Smith, Davey, Li, Jonathan Z, and Dubé, Karine

Subjects
HIV cure-related research, analytical treatment interruption, behavioral sciences, intensively monitored antiretroviral pause, persons living with HIV, social sciences, Virology, Clinical Sciences
Abstract

The AIDS Clinical Trials Group (ACTG) A5345 study included an intensively monitored antiretroviral pause (IMAP), during which a cohort of participants temporarily stopped antiretroviral treatment during chronic HIV infection. We surveyed participant perceptions and understanding of A5345 using a cross-sectional sociobehavioral questionnaire. Participants completed the baseline questionnaire either before or after initiating the study's IMAP. Questionnaire responses were linked to existing demographic data. Quantitative responses were analyzed overall and stratified by IMAP status. Open-ended responses were analyzed using conventional content analysis. Thirty-two participants completed the baseline sociobehavioral questionnaire. Half (n = 16) completed it before (i.e., pre-IMAP initiation group) and half (n = 16) after IMAP initiation (i.e., post-IMAP initiation group). Eight pre-IMAP initiation respondents (50%) and 11 post-IMAP respondents (69%) responded "yes" when asked if they perceived any direct benefits from participating in A5345. Perceived societal-level benefits included furthering HIV cure-related research and helping the HIV community. Perceived personal-level benefits included the opportunity to learn about the body's response to IMAP and financial compensation. The majority of respondents-13 from each group (81% of each)-reported risks from participation, for example, viral load becoming detectable. A5345 participants perceived both societal- and personal-level benefits of study participation. While the majority of survey respondents perceived participatory risks, nearly one in five did not. Key messages pertaining to study-related risks and benefits may need to be clarified or reiterated periodically throughout follow-up in HIV cure-related studies with IMAPs. Clinical Trail Registration Number: NCT03001128.

Published
2021

44. 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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45. Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation

Author

Chen, Da-Yuan, Chin, Chue Vin, Kenney, Devin, Tavares, Alexander H., Khan, Nazimuddin, Conway, Hasahn L., Liu, GuanQun, Choudhary, Manish C., Gertje, Hans P., O’Connell, Aoife K., Adams, Scott, Kotton, Darrell N., Herrmann, Alexandra, Ensser, Armin, Connor, John H., Bosmann, Markus, Li, Jonathan Z., Gack, Michaela U., Baker, Susan C., Kirchdoerfer, Robert N., Kataria, Yachana, Crossland, Nicholas A., Douam, Florian, and Saeed, Mohsan

Published
2023
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47. Cell culture systems for isolation of SARS-CoV-2 clinical isolates and generation of recombinant virus

Author

Chen, Da-Yuan, Turcinovic, Jacquelyn, Feng, Shuchen, Kenney, Devin J., Chin, Chue Vin, Choudhary, Manish C., Conway, Hasahn L., Semaan, Marc, Close, Brianna J., Tavares, Alexander H., Seitz, Scott, Khan, Nazimuddin, Kapell, Sebastian, Crossland, Nicholas A., Li, Jonathan Z., Douam, Florian, Baker, Susan C., Connor, John H., and Saeed, Mohsan

Published
2023
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48. Diagnostic TR-FRET assays for detection of antibodies in patient samples

Author

Yue, Hong, Nowak, Radosław P., Overwijn, Daan, Payne, N. Connor, Fischinger, Stephanie, Atyeo, Caroline, Lam, Evan C., St. Denis, Kerri, Brais, Lauren K., Konishi, Yoshinobu, Sklavenitis-Pistofidis, Romanos, Baden, Lindsey R., Nilles, Eric J., Karlson, Elizabeth W., Yu, Xu G., Li, Jonathan Z., Woolley, Ann E., Ghobrial, Irene M., Meyerhardt, Jeffrey A., Balazs, Alejandro B., Alter, Galit, Mazitschek, Ralph, and Fischer, Eric S.

Published
2023
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