29. Sustained Recovery in Patients Admitted to Hospital With COVID-19

Abstract Background Several interventional Coronavirus Disease 2019 (COVID-19) studies assess outcomes at day 28, but this follow-up time can be too short, since COVID-19 often cause protracted disease. Further, data on mortality and readmissions after discharge are scarse. Methods Patients aged 18-100 years and hospitalized with COVID-19 in Eastern Denmark between March 18th, 2020 and January 12th, 2021, were followed for 91 days after admission. Patients were stratified in a first and second wave, by admissions before or after June 15th, 2020, app. when remdesivir and dexamethasone were introduced as standard of care. Sustained recovery was defined as the first date, achieving 14 consecutive days after hospital discharge without an event of readmission or death. Cumulative incidences of sustained recovery were estimated in both waves and in subgroups based on the patient’s maximum level of respiratory support in the first 14 days of admission as a proxy for disease severity. Risk factors for poor outcomes were assessed in a multivariable cox proportional hazards model. Results Overall 3,386 patients were included in the study; 1,137 and 2,249 patients were admitted in the first and second wave, respectively (Table 1). The cumulative incidence of sustained recovery at day 91 was higher in the second (0.79, 95% CI: 0.77,0.81) than in the first wave (0.72, 95% CI: 0.70, 0.75) (Fig. 1A). In both waves, those with more severe disease recovered at a slower rate (Fig. 2B). There were no differences in cumulative incidences of readmissions or deaths at day 91 after discharge between the two waves, cumulative incidence (0.20, 95% CI: 0.19,0.21) and (0.11, 95% CI: 0.09,0.12), respectively (Fig 1C, Fig 1D). Male sex, high age, cardiovascular disease, diabetes, chronic pulmonary disease, renal disease, malignancies and neurological disease were associated with lower rates of sustained recovery (Table 2). Conclusion A follow-up period of 28 days in clinical trials for COVID-19 treatments is too short, especially for patients with severe disease. Rates of adverse outcomes after hospital discharge are non-neglible. In-hospital mortality was reduced with improvements in treatment, but post discharge mortality and readmissions rates did not change significantly. Disclosures Carsten Utoft Niemann, PhD MD, Abbvie (Grant/Research Support, Advisor or Review Panel member)Astra Zeneca (Grant/Research Support, Advisor or Review Panel member, teaching)CSL Behring (Consultant)Genmab (Grant/Research Support)Gilead (Grant/Research Support)Janssen (Grant/Research Support, teaching)Novo Nordisk Foundation (Grant/Research Support)Roche (Grant/Research Support)Sunesis (Grant/Research Support)

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131. The Protective Role of Mucosal Interferons in Infants with Respiratory Syncytial Virus (RSV) Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.441 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S195-S196

Author(s):

Jeanette Taveras ◽

Cristina Garcia-Maurino ◽

Melissa Moore-Clingenpeel ◽

Sara Mertz ◽

Mark E Peeples ◽

...

Keyword(s):

Disease Severity ◽

Severe Disease ◽

Panel Member ◽

Type I ◽

Research Support ◽

Review Panel ◽

Duration Of Symptoms ◽

Lower Odds ◽

Rsv Infection ◽

Ifn Γ

Abstract Background Despite the high burden associated with RSV infection in young children the factors that determine disease severity are not well understood. The objective of this study was to assess the association of mucosal cytokine profiles, RSV loads (VL) and RSV disease severity. Methods Single-center, prospective study in previously healthy infants with mild (outpatients; OP), moderate (inpatient-IP; ward) or severe (IP-PICU) RSV infection. Mid-turbinate swabs were obtained to measure VL by PCR, and cytokine concentrations (conc.) using a 13-plex panel that included type I (IFN-α2), II (IFN-γ), and III (IFN-λ2/λ3) interferons (IFN), and inflammatory cytokines. Multivariable analyses were performed to identify factors predictive of disease severity. Results From 2014 to 2019 we enrolled 219 infants: 78 with mild RSV infection (OP; median [IQR] age, 6 [3.4–10.5] mo.), 101 with moderate disease (3.5 [1.3–8.3] mo.), and 40 with severe disease (2.3 [1.5–5.7] mo.). Duration of symptoms at enrollment was 4 (3–5) days and comparable between OP and IP, yet RSV VL in OP were significantly higher than in IP (8.1 [7.4–8.6] vs 7.4 [6.4–8.1] log10 copies/mL; p< 0.01) with no differences between ward and PICU infants. Median conc. of IFN-α2, IFN-γ, and IFN-λ2/λ3 were significantly higher in OP vs IP irrespective of hospitalization unit (Table 1). IP-10 conc. were also higher in OP and in ward patients vs PICU patients (p< 0.0001) and were independently associated with lower odds of supplemental O2 needs (OR, 95% CI: 0.4 [0.22–0.69]; p< 0.01) and PICU admission (0.4 [0.23–0.67]; p=0.001). In addition, higher IFN-λ2/λ3 conc. were nearly associated with lower odds of prolonged O2 use (OR: 0.35 [0.11–1.07]; p=0.07), and prolonged hospitalization (OR: 0.42 [0.16–1.03]; p=0.06). Conclusion Infants with mild RSV infection had higher RSV VL and higher conc. of IP-10 and type-I, III IFN than those hospitalized with severe disease. These findings suggest that IP-10 and mucosal IFNs are associated with protection against severe RSV disease and could be used as biomarkers for patient stratification in the clinical setting. Disclosures Octavio Ramilo, MD, Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Medimmune (Grant/Research Support)Merck (Advisor or Review Panel member)NIH/NIAID (Grant/Research Support)Pfizer (Consultant, Advisor or Review Panel member)Sanofi/Medimmune (Consultant, Advisor or Review Panel member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Advisor or Review Panel member)

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1643 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S807-S808

Author(s):

Teresa H Evering ◽

Mark Giganti ◽

Kara W Chew ◽

Michael Hughes ◽

Carlee Moser ◽

...

Keyword(s):

High Risk ◽

Symptom Onset ◽

Interim Analysis ◽

Neutralizing Antibodies ◽

Severe Disease ◽

Panel Member ◽

The Philippines ◽

Research Support ◽

Review Panel ◽

Research Grant

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

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1186. Increased Respiratory Syncytial Virus (RSV) Viral Replication Leads to Increased Cytokine Production and Polarized Interferon Response in Infant Mucosal Epithelium

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1378 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S684-S685

Author(s):

Rebecca M Glowinski ◽

Ki Wook Yun ◽

Asuncion Mejias ◽

Octavio Ramilo

Keyword(s):

Viral Replication ◽

Inflammatory Cytokines ◽

Cytokine Production ◽

Severe Disease ◽

Panel Member ◽

Interferon Response ◽

Research Support ◽

Review Panel ◽

Basolateral Side ◽

Rsv Infection

Abstract Background RSV is the most frequent etiology of pediatric lower respiratory tract infection. Most children hospitalized for RSV are previously healthy without known risk factors. Children with mild disease managed as outpatients (OP) have higher viral loads than those hospitalized with severe disease. OP children have higher concentrations of the mucosal interferon (IFN), IFNλ2/3, and IP-10, but no differences in IFNλ1. We examined how RSV replication impacts cytokine production kinetics in the nasal mucosa. Methods Primary infant human nasal epithelial (iHNE) cells were collected from nasopharyngeal swabs and cultured on an air-liquid interface. Cultures were infected with 0.1 or 0.001 multiplicity of infection (MOI) of RSV-A, or mock infected. Concentrations of IFN-related (IFNα2, β, γ, λ1, λ2/3, and IP-10) and inflammatory (IL-1β, -6, -12, and TNFα) cytokines secreted to the apical and basolateral surfaces were quantified via immunoassay. Kinetics according to viral inocula were compared by ANOVA with Dunn post-hoc testing of the area under the curve (AUC) for each cytokine. Peak concentrations were compared according to MOI and secretion surface by 2-way ANOVA. Results AUC of IFNs in both surfaces of RSV infected cells were significantly higher than those of mock infected. The 0.1 MOI RSV inoculum resulted in significantly higher AUCs for all IFN cytokines on both surfaces than the 0.001 MOI. Peak IFNλ1 concentrations were higher on the apical than basolateral side; peak IFNλ2/3 concentrations were higher on the basolateral side than apical. AUCs of inflammatory cytokines in RSV infection were significantly higher on the basolateral, but not apical, surfaces than mock; all basolateral inflammatory cytokines were higher in the 0.1 MOI than the 0.001 MOI. Conclusion Higher RSV inoculum induces higher concentrations of IFN-related cytokines on both sides of epithelial cells, and higher concentrations of inflammatory cytokines on the basolateral side. Differential secretion of IFNλ1 and IFNλ2/3 to the apical and basolateral surfaces suggests they may play different roles in immune response during RSV infection. These data support viral replication as an important factor influencing RSV pathogenesis and severity through cytokine production. Disclosures Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member)

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639. Time to Recurrence of Clostridioides difficile Infection (rCDI) is Rapid Following Completion of Standard of Care Antibiotics: Results from ECOSPOR-III, a Phase 3 Double-Blind, Placebo-Controlled Randomized Trial of SER-109, an Investigational Microbiome Therapeutic

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.836 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S422-S422

Author(s):

Thomas J Louie ◽

Matthew Sims ◽

Richard Nathan ◽

Steven O'Marro ◽

Princy N Kumar ◽

...

Keyword(s):

Panel Member ◽

Standard Of Care ◽

Oral Microbiome ◽

Research Support ◽

Independent Contractor ◽

Review Panel ◽

Material Support ◽

Time To Recurrence ◽

Study Population

Abstract Background The natural history of CDI recurrence after antibiotics may be helpful to understand the window of opportunity for microbiome repair. ECOSPOR III evaluated the efficacy of SER-109, an investigational microbiome therapeutic, compared to placebo with rates of rCDI as the primary endpoint. SER-109 was superior to placebo in reducing the rate of rCDI following standard-of-care antibiotics at 8 weeks (12.4% vs 39.8%, respectively; P < 0.001). Herein, we describe results from the secondary endpoint, time to recurrence, in this well-characterized study population. Methods A total of 182 C. difficile toxin+ adults with ≥ 3 CDI episodes and symptom resolution on CDI antibiotics were randomly assigned to SER-109 (4 capsules orally x 3 days) or placebo. Recurrence for this analysis was defined as ≥ 3 unformed stools/day for ≥ 48 hours, ± C. difficile stool toxin test, and an investigator decision to treat. Time to CDI recurrence was analyzed using observed data and Kaplan-Meier methods. Data were not imputed for subjects lost to follow-up or discontinued from study. Subjects who did not have a CDI recurrence were censored on the date of study completion, study discontinuation or death. Results Through 24 weeks, 11/89 (12.4%) SER-109 and 36/93 (38.7%) placebo subjects had rCDI (P < 0.001). Of all recurrence events in the study population, 16/47 (34.0%) were observed within 1 week; 30/47 (63.8%) within 2 weeks; and 34/47 (72.3%) within 4 weeks after randomization, highlighting the rapid onset of recurrence. On the other hand, 12/47 (25.5%) recurrences occurred between 4 and 12 weeks, highlighting late onset of recurrence in a subset of patients (Table). Significantly lower rates of recurrence in patients on SER-109 compared to placebo was maintained throughout the 24-week follow-up (Figure). Time of rCDI K-M Plot Conclusion SER-109, an investigational oral microbiome therapeutic, maintained significant efficacy in reducing rCDI vs placebo through 24 weeks. About two-thirds of all recurrences occurred within 14 days of antibiotic completion highlighting the need for rapid repair of the disrupted microbiome. However, the significant number of late recurrences in the placebo arm also highlights that rCDI trials limited to 4 weeks of follow-up after treatment completion may underestimate recurrences. Disclosures Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Richard Nathan, DO, none (Other Financial or Material Support, I am PI on several clinical trials. If you need that information, I would be happy to supply it.) Princy N. Kumar, MD, AMGEN (Other Financial or Material Support, Honoraria)Eli Lilly (Grant/Research Support)Gilead (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)GSK (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)Merck & Co., Inc. (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Robert Stevens, PharmD, Seres Therapeutics (Employee, Shareholder) Kelly Brady, MS, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder)

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46. Racial and Ethnic Disparities in COVID-19 Incidence among Persons with HIV in a Multisite-Cohort

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.046 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S33-S33

Author(s):

Edward R Cachay ◽

laura Bamford ◽

Adrienne Shapiro ◽

Bridget M Whitney ◽

Darcy Wooten ◽

...

Keyword(s):

Race And Ethnicity ◽

Cumulative Incidence ◽

Ethnic Disparities ◽

Panel Member ◽

Cd4 Count ◽

Research Support ◽

Structural Racism ◽

Cd4 Cell Count ◽

The Us

Abstract Background Little is known about how race and ethnicity, imperfect (albeit accessible) proxies for structural racism, impact COVID-19 incidence among people with HIV (PWH). We report the cumulative incidence and incidence rate ratios (IRR) for COVID-19 in a long-term multi-site cohort of PWH across the US Figure 1. Cumulative incidence of COVID-19 in the CNICS cohort Methods We examined COVID-19 cumulative incidence and IRR among PWH in care between 3/1/2020 and 12/31/2020 at seven sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort. We define COVID-19 incident case as having a laboratory-confirmed (RT-PCR/Ag) SARS-CoV-2 positive result or diagnosis verified by chart review. Reinfections were excluded. Results are presented as monthly and quarterly cumulative incidence and IRR with 95% CI stratified by CD4 count, self-reported race/ethnicity, and site. Follow-up was censored on the earliest of diagnosis of COVID-19 disease, loss to follow up, or 12/31/2020 Results Among 15,780 PWH in care in the CNICS cohort during the study period, 62% were non-white, with a median (IQR) age of 52 (IQR 40-59), 95% were on antiretroviral therapy, 17% had a CD4 count less than 350, and 6% less than 200. Overall, 651 PWH tested positive for COVID-19 for a cumulative incidence of 4.13%. COVID-19 cumulative incidence increased from 0.77% at the end of the first quarter to 4.12% by the end of December 2020. At the peak of the pandemic in December 2020, the cumulative incidence in Black PWH was 1.68 fold higher than in white PWH (p=.033) and 2.35 fold higher in Hispanics than in whites (P< .0001), figure 1. Similarly, the IRR for COVID-19 was 1.71 (95% CI 1.42-2.07) for Black and 2.40 (95% CI 1.91-3.01) for Hispanic PWH relative to white. Although there was variation across sites, reflecting geographic differences in pandemic waves and access to COVID-19 testing, overall individual trends remained the same. COVID-19 cumulative incidence was similar across CD4 cell count strata Conclusion Our results suggest effects of structural racial disparities on COVID-19 incidence in this diverse population of PWH across the US, with higher and disproportionate rates of COVID-19 in Black and Hispanic PWH. Incidence estimates are conservative because testing was not uniform, and no systematic testing was conducted Disclosures Edward R. Cachay, MD, MAS, Gilead Science (Grant/Research Support, Advisor or Review Panel member)Merck Sharp & Dohme Corp (Grant/Research Support) Adrienne Shapiro, MD, PhD, Vir Biotechnology (Scientific Research Study Investigator) Darcy Wooten, MD, MS, Nothing to disclose Rachel A. Bender Ignacio, MD MPH, Abbvie (Individual(s) Involved: Self): Consultant; SeaGen (Individual(s) Involved: Self): Consultant Greer A. Burkholder, MD, MSPH, Eli Lilly (Grant/Research Support) Heidi Crane, MD, MPH, ViiV (Grant/Research Support)

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127. Development of a Kinetic ELISA (kELISA) and Reactive B-cell Frequency (RBF) Assay to Detect Respiratory Syncytial Virus (RSV) Pre-Fusion F Protein-Specific Immune Responses in Infants

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.127 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S77-S78

Author(s):

Stephanie L Rolsma ◽

Sandy M Yoder ◽

Rachel S Nargi ◽

Eric Brady ◽

Natalia Jimenez-Truque ◽

...

Keyword(s):

Panel Member ◽

Multiple Time ◽

Research Support ◽

Review Panel ◽

Cell Frequency ◽

Material Support ◽

F Protein ◽

Multiple Time Points ◽

Research Grant

Abstract Background RSV is a major cause of pediatric respiratory disease. Antibodies to the prefusion conformation of the RSV fusion (pre-F) protein are needed for virus neutralization. Methods We measured RSV-specific responses in two groups of children < 3 years of age; subjects with laboratory-confirmed RSV (RSV-infected) or infants born in the period May to September and enrolled prior to their first RSV season (RSV-uninfected). RSV-infected infants had blood samples obtained at 1, 6, 9, and 12 months after infection. RSV-uninfected infants had blood samples obtained at enrollment, at the end of their first RSV season, and 6 months later. A kELISA to measure RSV pre-F-specific antibodies and an RBF assay to identify RSV F-specific B cells were developed. Results 102 subjects were enrolled; 11 were excluded due to missed visits or withdrawal. Of the 65 subjects in the RSV-uninfected group, all were kELISA positive at enrollment, consistent with maternal antibody transfer. 53 subjects had sufficient samples for analysis at multiple time points; 29 became seronegative and 24 remained seropositive. In the seronegative group, the kELISA value decreased rapidly to < 0.25 by 6 months after the RSV season in 27/29 (93%), (Figure 1a). In the persistently seropositive group, all 24 subjects maintained a positive kELISA value, with some developing higher values over time, consistent with asymptomatic infection (Figure 1b). An RBF assay was used to determine whether antibodies were due to persistent maternal antibodies or endogenous production (Figure 2). In the seronegative group, 24/29 (80%) had a negative RBF; in the seropositive group, 23/24 (96%) had a positive RBF during follow-up. There were 26 subjects in the RSV-infected group; 22 had sufficient samples for analysis at multiple time points. All were seropositive by kELISA at one month post-infection with variable kELISA values during follow-up (Figure 3). 17/22 (77%) had a positive RBF, although 4 of the subjects without a positive RBF had indeterminate results at ≥ 1 visit. Figure 1. kELISA values of baseline RSV-negative subjects, by subject age at time of sample. Panel A: Subjects classified as seronegative (n=29). Panel B: Subjects without known RSV classified as persistently seropositive (n=24). Figure 2. Reactive B-cell frequency assay. The first step in the RBF assay is growth of Lymphoblastoid Cell Lines (LCLs), as shown over days 1-3 (Left-Day 1, Middle-Day 2, Right-Day 3, magnification 200X). The cells circled in the figure indicate a single LCL’s growth over time. LCL supernatant is used to detect RSV F-protein specific antibodies using traditional ELISA, resulting in a positive, indeterminate, or negative result. Indeterminate results occur due to a lack of cell viability and/or failure to form LCLs, resulting in failure to exceed an optical density of 5x background. Figure 3. kELISA values of RSV-infected subjects, by subject age at time of sample. First sample was obtained at approximately one month after laboratory-confirmed RSV. Conclusion Assays measuring F-specific immune responses in infants will be critical for RSV vaccine development. A kELISA targeting RSV pre-F epitopes, with an RBF assay targeting RSV F-specific B cells, may allow discrimination for maternal and infant-derived antibodies. Disclosures Isaac Thomsen, MD, MSCI, Horizon Therapeutics (Individual(s) Involved: Self): Consultant James E. Crowe, Jr., MD, Astra Zeneca (Grant/Research Support)IDBiologics (Board Member, Grant/Research Support, Shareholder)Luna Biologics (Consultant)Meissa Vaccines (Advisor or Review Panel member)Takeda Vaccines (Grant/Research Support) Kathryn M. Edwards, MD, Bionet (Individual(s) Involved: Self): Consultant; CDC (Individual(s) Involved: Self): Research Grant or Support; IBM (Individual(s) Involved: Self): Consultant; Merck (Individual(s) Involved: Self): member DSMC, Other Financial or Material Support; Moderna (Individual(s) Involved: Self): member DSMC, Other Financial or Material Support; NIH (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): member DSMC, Other Financial or Material Support; Roche (Individual(s) Involved: Self): member of DSMB, Other Financial or Material Support; Sanofi Pasteur (Individual(s) Involved: Self): member DSMB, Other Financial or Material Support; Sequiras (Individual(s) Involved: Self): Member DSMB, Other Financial or Material Support; X4 Pharmaceuticals (Individual(s) Involved: Self): Consultant Buddy Creech, MD, MPH, Altimmune (Consultant)Astellas (Other Financial or Material Support, Data and Safety Monitoring Committee)Diotheris (Consultant)GSK (Consultant)Horizon (Consultant)Merck (Scientific Research Study Investigator)Premier Healthcare (Advisor or Review Panel member)Vir (Consultant)

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1187. Neurodevelopmental Outcomes of Children with Congenital Cytomegalovirus (cCMV) Infection: Does Antiviral Treatment Matter?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1379 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S685-S685

Author(s):

Margaret R Jia ◽

Alexandra K Medoro ◽

Traci Pifer ◽

Manish Rijal ◽

Teresa Borghese ◽

...

Keyword(s):

Antiviral Therapy ◽

Antiviral Treatment ◽

Panel Member ◽

Autism Spectrum ◽

Research Support ◽

Neurodevelopmental Outcomes ◽

Review Panel ◽

Neurodevelopmental Impairment ◽

Bayley Scales

Abstract Background cCMV infection is a major contributor to childhood neurologic and cognitive disabilities including sensorineural hearing loss (SNHL). Neonatal treatment with ganciclovir/valganciclovir improves hearing outcomes, but its impact on neurodevelopmental outcomes remains an important knowledge gap. We describe the neurodevelopmental outcomes of children with cCMV infection and evaluate the effect of neonatal antiviral therapy on outcomes. Methods Since 2013, infants with cCMV infection referred to Nationwide Children’s Hospital’s NEO-ID Clinic have had a complete evaluation at diagnosis as well as follow-up neurodevelopmental assessments. Pertinent demographic, clinical, laboratory, radiographic, and follow-up data were obtained and managed using REDCap. Neurodevelopmental assessments were performed using Bayley Scales of Infant and Toddler Development (BSID) III/IV (cognitive, language, motor domains) at ~ 24 months of age. The Gross Motor Function Classification System was used to classify functional motor impairment. Neurodevelopmental outcomes were compared by receipt of antiviral therapy in early infancy. Results 95 infants (mean ± SD; gestational age 35 ± 5 wk, birth weight 2121 ± 948 g; Table 1) with cCMV infection had follow-up neurodevelopmental assessments. 62% had central nervous system involvement, 37% had SNHL, 23% developed cerebral palsy (CP), and 6% were diagnosed with autism spectrum disorder. The majority had normal BSID scores (≥ 85) in cognitive and motor domains (65% and 54%, respectively) while 48% had normal scores in the language domain. 35% had severe impairment (< 70) in ≥ 1 domain (Table 2). 9 children had clinically inapparent cCMV infection; 2 (22%) had abnormalities on BSID testing (1, cognitive score: 80; 1, cognitive, language, and motor scores: 65, 68, 73, respectively). 11 (12%) children, including 6 who received antiviral therapy, had severe neurodevelopmental impairment, with CP and severe (< 70) BSID scores in both the cognitive and motor domains. Table 1. Demographic and Clinical Characteristics of 95 Children with Congenital CMV Infection by Receipt of Antiviral Treatment Table 2. Neurodevelopmental Outcomes Based on Testing with the Bayley Scales of Infant and Toddler Development (BSID) III/IV Conclusion A substantial proportion of children with cCMV infection had moderate (29%) or severe (33%) neurodevelopmental impairment, CP, or autism spectrum disorder, irrespective of antiviral treatment. Urgency exists for antenatal preventive strategies and vaccine development. Disclosures Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

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LB13. The Efficacy and Impact in Heathy Infants of Nirsevimab on Medically Attended RSV Lower Respiratory Tract Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1649 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S811-S812

Author(s):

Laura Hammitt ◽

Ron Dagan ◽

Yuan Yuan ◽

Manuel Baca Cots ◽

...

Keyword(s):

Research Study ◽

Scientific Research ◽

Panel Member ◽

Research Support ◽

Review Panel ◽

Term Infants ◽

Study Investigator ◽

Support Research ◽

Research Grant

Abstract Background Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in infants. Nirsevimab is a single-dose monoclonal antibody with extended half-life that was shown to protect preterm infants 29 to < 35 weeks gestation against RSV LRTI. However, most medically attended (MA) cases occur in otherwise healthy, term infants for whom there is currently no effective RSV prevention strategy. We report the primary analysis of efficacy and safety, along with the impact of nirsevimab in late preterm and term infants (≥ 35 weeks gestation) in the phase 3 MELODY study (NCT03979313). Methods Infants were randomized 2:1 to receive one intramuscular injection of nirsevimab (50 mg if < 5 kg; 100 mg if ≥ 5 kg at dosing) or placebo entering their first RSV season. The primary endpoint was the incidence of MA RSV LRTI over 150 days postdose. Cases met predefined clinical criteria of disease severity and were confirmed by real-time reverse-transcriptase PCR. Safety was evaluated through 360 days postdose. Enrollment started on 23 July 2019 and was suspended following the declaration of the COVID-19 pandemic by the WHO on 11 March 2020. Results Overall, 1490 infants were randomized and included in the intent-to-treat population; 1465 (98%) completed the 150-day efficacy follow-up, and 1367 (92%) completed the 360-day safety follow-up. The incidence of MA RSV LRTI was 1.2% (n=12/994) in the nirsevimab group and 5.0% (n=25/496) in the placebo group, giving nirsevimab an efficacy of 74.5% (95% confidence interval [CI]: 49.6, 87.1; p< 0.0001). Nirsevimab averted 93.6 (95% CI 63.0, 124.0) MA LRTIs per 1000 infants dosed. Nirsevimab was well tolerated, with similar rates of adverse events (87.4% nirsevimab; 86.8% placebo) and serious adverse events (6.8% nirsevimab; 7.3% placebo) between groups. Conclusion In this phase 3 study, a single dose of nirsevimab protected late preterm and term infants against MA RSV LRTI over an RSV season with a favorable safety profile. Approximately 11 infants need to be immunized to prevent 1 case of LRTI; nirsevimab has the potential to be an important intervention to reduce the burden of RSV LRTI in healthy infants. Disclosures Laura Hammitt, MD, MedImmune (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Merck & Co., Inc. (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Novavax (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Pfizer (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Laura Hammitt, MD, MedImmune (Individual(s) Involved: Self): Grant/Research Support, Research grant to my institution; Merck (Individual(s) Involved: Self): Grant/Research Support, Research grant to my institution; Pfizer (Individual(s) Involved: Self): Grant/Research Support, Research grant to my institution Ron Dagan, MD, Medimmune/AstraZeneca (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)MSD (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)Pfizer (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau) Yuan Yuan, PhD, AstraZeneca (Employee, Shareholder) Shabhir A. Mahdi, PhD, BMGF (Research Grant or Support)EDCTP (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melody (Research Grant or Support)Minervax (Research Grant or Support)Novavax (Research Grant or Support)SAMRC (Research Grant or Support) William J. Muller, MD, PhD, Ansun (Scientific Research Study Investigator)Astellas (Scientific Research Study Investigator)AstraZeneca (Scientific Research Study Investigator)Genentech (Scientific Research Study Investigator)Gilead (Scientific Research Study Investigator)Janssen (Scientific Research Study Investigator)Karius (Scientific Research Study Investigator)Melinta (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)Nabriva (Scientific Research Study Investigator)Seqirus (Scientific Research Study Investigator)Tetraphase (Scientific Research Study Investigator) William J. Muller, MD, PhD, Ansun (Individual(s) Involved: Self): Grant/Research Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; AstraZeneca (Individual(s) Involved: Self): Grant/Research Support; BD (Individual(s) Involved: Self): Research Grant or Support; Eli Lilly (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Karius, Inc. (Individual(s) Involved: Self): Grant/Research Support, Scientific Research Study Investigator; Melinta (Individual(s) Involved: Self): Grant/Research Support; Merck (Individual(s) Involved: Self): Grant/Research Support; Moderna (Individual(s) Involved: Self): Grant/Research Support; Nabriva (Individual(s) Involved: Self): Grant/Research Support; Seqirus (Individual(s) Involved: Self): Consultant; Tetraphase (Individual(s) Involved: Self): Grant/Research Support Heather J. Zar, PhD, AstraZeneca (Grant/Research Support)Novavax (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member) Dennis Brooks, MD, AstraZeneca (Employee) Amy Grenham, MSc, AstraZeneca (Employee, Shareholder) Ulrika Wählby Hamrén, PhD, AstraZeneca R&D (Employee, Shareholder) Vaishali S. Mankad, MD, AstraZeneca (Employee) Therese Takas, BSc, AstraZeneca (Employee, Other Financial or Material Support, Own stock in AstraZeneca) Jon Heinrichs, PhD, AstraZeneca (Shareholder)Bristol Myers Squibb (Shareholder)J&J (Shareholder)Merck (Shareholder)Organon (Shareholder)Procter & Gamble (Shareholder)Sanofi (Shareholder)Sanofi Pasteur (Employee) Amanda Leach, MRCPCH, AstraZeneca (Employee, Shareholder) M. Pamela Griffin, MD, AstraZeneca (Employee) Tonya L. Villafana, PhD, AstraZeneca (Employee)

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854. Long-term Outcomes of Participants on F/TAF for Pre-Exposure Prophylaxis: Results for 144 Weeks of Follow-Up in the DISCOVER Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1049 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S517-S518

Author(s):

Moti Ramgopal ◽

Peter Ruane ◽

Yongwu Shao ◽

Ramin Ebrahimi ◽

Alex Kintu ◽

...

Keyword(s):

Research Study ◽

Scientific Research ◽

Panel Member ◽

Mineral Density ◽

Research Support ◽

Review Panel ◽

Study Investigator ◽

Research Grant

Abstract Background In DISCOVER, a multinational randomized controlled trial, F/TAF demonstrated noninferior efficacy compared to F/TDF for HIV prevention with improved bone mineral density and renal safety biomarkers at the primary endpoint (when all participants had reached 48 weeks and 50% had reached 96 weeks) and at week (W) 96, the end of the blinded phase. We now report W144 outcomes for participants who were randomized to F/TAF and continued F/TAF in the open-label extension (OLE) phase. Methods All participants who completed the randomized blinded phase could opt to receive F/TAF for at least 48 weeks in the OLE phase. We evaluated HIV incidence in participants on F/TAF through W144 and assessed changes in hip and spine bone mineral density (BMD) and in glomerular function (eGFR) from baseline to W144. Results 2,080 of the 2,694 participants initially randomized to F/TAF opted into the OLE phase, and 1,933 were still on study drug through W144, thereby leading to a total of 7,885 person-years (PY) of follow-up on F/TAF. Eight participants taking F/TAF acquired HIV in the blinded phase and 3 in the OLE phase. Dried blood spot analyses on the 3 OL infections found tenofovir diphosphate levels consistent with low adherence. Genotypic resistance testing showed no relevant resistance mutations for the 3 new infections. Among participants taking F/TAF, HIV incidence was 0.16/100 PY (95% CI 0.06-0.33) at the primary endpoint, 0.16/100 PY (95% CI 0.07-0.31) through 96 weeks and 0.14/100 PY (95% CI 0.07-0.25) through 144 weeks. Participants taking F/TAF had increases in hip BMD (mean percentage change +0.54%) and in spine BMD (mean percentage change +1.02%) from baseline to W144 (Figure 1). Median eGFR increased over 144 weeks, with a median increase of 2.6 mL/min from baseline to week 144. Participants in the F/TAF arm gained a median 2.3 kg (IQR -0.9-5.8) over 3 years of follow up. Figure 1. Changes in hip and spine bone mineral density and in eGFR through Week 144 Conclusion The OLE of DISCOVER allowed for a long-term assessment (144 wks.) of F/TAF for PrEP. HIV incidence remained low with BMD and renal function parameters remaining stable through 144 weeks of follow-up. These findings demonstrate that F/TAF is a safe and effective option for long-term use in people who would benefit from PrEP. Disclosures Moti Ramgopal, MD FACP FIDSA, Abbvie (Scientific Research Study Investigator, Speaker’s Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker’s Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker’s Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker’s Bureau) Peter Ruane, MD, AbbVie (Consultant, Research Grant or Support)Allergan (Research Grant or Support)Gilead Sciences Inc. (Consultant, Research Grant or Support, Shareholder, Speaker’s Bureau)Merck (Consultant, Research Grant or Support)ViiV Healthcare (Consultant, Research Grant or Support) Yongwu Shao, PhD, Gilead Sciences Inc. (Employee, Shareholder) Ramin Ebrahimi, MSc, Gilead Sciences Inc. (Employee, Shareholder) Alex Kintu, MD, ScD, Gilead Sciences Inc. (Employee, Shareholder) Christoph C. Carter, MD, Gilead Sciences Inc. (Employee, Shareholder) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Jared Baeten, MD, PHD, Gilead Sciences Inc. (Employee, Shareholder) Cynthia Brinson, MD, Abbvie (Scientific Research Study Investigator)BI (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau, Personal fees)GSK (Scientific Research Study Investigator)Novo Nordisk (Scientific Research Study Investigator)ViiV Healthcare (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Peter Shalit, MD, PhD, Abbvie (Grant/Research Support)Gilead Sciences (Consultant, Grant/Research Support, Speaker’s Bureau)Glaxo Smithkline (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support, Speaker’s Bureau)Merck (Grant/Research Support, Speaker’s Bureau)Thera (Speaker’s Bureau)ViiV Healthcare (Speaker’s Bureau) Karam Mounzer, MD, Epividian (Advisor or Review Panel member)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker’s Bureau)Janssen (Consultant, Research Grant or Support, Speaker’s Bureau)Merck (Research Grant or Support, Speaker’s Bureau)ViiV Healthcare (Consultant, Speaker’s Bureau)

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21. Efficacy and Safety of Maribavir as a Rescue Treatment for Investigator Assigned Therapy in Transplant Recipients With Refractory or Resistant Cytomegalovirus Infections in the SOLSTICE Study: Phase 3 Trial Results

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.021 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S14-S15

Author(s):

Marcus Pereira ◽

Carlos Cervera ◽

Camille Kotton ◽

Joseph Sasadeusz ◽

...

Keyword(s):

Research Study ◽

Symptom Control ◽

Scientific Research ◽

Panel Member ◽

Cmv Infection ◽

Research Support ◽

Review Panel ◽

Material Support ◽

Study Investigator

Abstract Background Refractory or resistant (R/R) cytomegalovirus (CMV) infection after hematopoietic cell transplant (HCT) and solid organ transplant (SOT) cause serious, potentially fatal complications; therapeutic options are limited. In a Phase 3 study (NCT02931539), maribavir (MBV) was superior to investigator-assigned therapy (IAT; val/ganciclovir, foscarnet, cidofovir) for CMV clearance (Wk 8) and clearance plus symptom control (Wk 8 through Wk 16) in HCT/SOT recipients with R/R CMV infections. Here we present further study results on efficacy and safety of MBV in the rescue arm. Methods Patients (pts) were stratified and randomized 2:1 to MBV (400 mg/bid) or IAT for 8-wk treatment then 12-wk follow-up. After minimum 3 wks’ treatment, pts in the IAT group meeting criteria (worsening/lack of improvement of CMV infection or failure to achieve viremia clearance plus IAT intolerance) could enter a MBV rescue arm (8-wk treatment, 12-wk follow-up). In the rescue arm, efficacy was evaluated by confirmed CMV viremia clearance (plasma CMV DNA < 137 IU/mL in 2 consecutive tests ≥ 5 days apart) at end of Wk 8 and confirmed clearance with symptom control at Wk 8 through Wk 16. Safety was assessed. Results A total of 352 pts were randomized (MBV: 235, IAT: 117, randomized set). Confirmed CMV viremia clearance at Wk 8 was achieved in 131 (55.7%) and 28 (23.9%) pts, respectively, in the randomized set. Having met criteria, 22 (18.8%) pts entered the MBV rescue arm; at entry, 6 (27.3%) pts had developed neutropenia and 9 (40.9%) had increased serum creatinine (Table 1). At Wk 8 of rescue therapy, 11 (50.0%) pts achieved confirmed CMV viremia clearance; 6 (27.3%) pts had CMV clearance with symptom control at Wk 8 maintained through Wk 16 (Table 2). All 22 pts reported treatment-emergent adverse events (TEAEs; Table 3); most common TEAEs of special interest were nausea, vomiting, and diarrhea (54.5%), and taste disturbance (50.0%). Neutropenia and acute kidney injury TEAEs were reported by 0 and 3 pts in the rescue arm, respectively. Table 1. Summary of patients from IAT-randomized group meeting criteria for entry into MBV rescue arm* Table 2. Patients achieving confirmed CMV viremia clearance at end of Wk 8 (end of treatment) or achieving confirmed CMV viremia clearance and symptom control at end of Wk 8 maintained through Wk 16 Table 3. Treatment-emergent adverse events during the on-rescue observation period Conclusion Rescue arm data show MBV was efficacious for R/R CMV infection in HCT/SOT recipients inadequately responding to IAT with/without intolerance and had a similar safety profile to that reported for pts in the randomized MBV group. Disclosures Marcus Pereira, MD, Hologic (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)Takeda (Scientific Research Study Investigator, Advisor or Review Panel member) Carlos Cervera, MD, PhD, Avir Pharma (Consultant, Advisor or Review Panel member)Lilly (Consultant, Advisor or Review Panel member)Merck (Consultant, Advisor or Review Panel member, Research Grant or Support)Sunovion (Consultant, Advisor or Review Panel member)Takeda (Consultant, Advisor or Review Panel member)Veritas Pharma (Consultant, Advisor or Review Panel member) Camille Kotton, MD, Shire/Takeda (Advisor or Review Panel member) Camille Kotton, MD, UpToDate (Individual(s) Involved: Self): I write chapters on zoonoses for UpToDate., Independent Contractor Joseph Sasadeusz, MBBS, PhD, Abbvie (Grant/Research Support, Other Financial or Material Support, Consulting fee: speaker)Gilead (Other Financial or Material Support, Speaker)Merck (Grant/Research Support, Consulting fee: speaker)Takeda (Grant/Research Support) Jingyang Wu, MS, Shire Human Genetic Therapies, Inc., a Takeda company (Employee, Other Financial or Material Support, Holds stock/stock options) Martha Fournier, MD, Shire Human Genetic Therapies, Inc., a Takeda company (Employee, Other Financial or Material Support, Holds stock/stock options)Shire ViroPharma, a Takeda company (Other Financial or Material Support, This study was funded by Shire ViroPharma, a Takeda company)

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