bluuebunny/crossref_metadata_2025 huggingface dataset:
503. In vitro Evaluation of Sitagliptin-HIV-1 Trans-activator Transcription Peptide Nano-formula for Antiviral Activity Against SARS-CoV-2: Drug Repurposing Approach
Authors: Eljaaly Khalid , Asfour Hani , Ibrahim Tarek , Ahmed Osama , Alhakamy Nabil , Fahmy Usama , Al-Rabia Mohammed , Aloafi Ahmed , Tantawy Mohamed , Hussein Khulood , Aldarmani Ahmed , Elfaky Mahmoud
Published: December 2021

Background

The outbreak of COVID-19 pandemic in China regarded as a major health/economic hazard. The importance of coming up with mechanisms for preventing or treating COVID-19 has been felt across the world. This work aimed at examining the efficiency of Sitagliptin (SIT) and human immunodeficiency virus type 1 (HIV-1) trans-activator transcription peptide (TAT) against SARS-CoV-2.

Methods

SIT-TAT nano-conjugates were prepared according to a full three-factor bi-level (23) factorial design. SIT concentration (mM, X1), TAT concentration (mM, X2), and pH (X3) were selected as the factors. Particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for Fourier-transformed infrared (FTIR) and Transmission electron microscope was carried out. In addition, IC50 in Vero E6 cells, In vitro 3CL-protease inhibition and docking tests were investigated.

Results

The prepared complex’s formula was as follows 1: 1 SIT: TAT molar ratio, whereas zeta potential and particle size values were at 34.17 mV and 97.19 nm, respectively. This combination did exhibit its antiviral potentiality against SARS-CoV-2 via IC50 values of 9.083 5.415, and 16.14 µM for TAT, SIT-TAT, and SIT, respectively. In addition, the complex SIT-TAT showed a significant (P < 0.001) viral-3CL-protease inhibitory effect (IC50 = 3.959 µM ± 0.011) in comparison to isolated components (IC50 = 10.93 µM ± 0.25) and TAT (IC50 = 8.128 µM ± 0.42). This was further confirmed via in silico study. Molecular docking investigation has shown promising binding affinity of the formula components towards SARS-CoV-2 main protease (3-CL).

Conclusion

While offering significant binding interactions with protein’s key pocket residues, an optimized formulation of SIT-TAT could guarantee both the enhanced delivery to the target cells and the improved cellular uptake. The presented findings would guarantee further investigations regarding formula optimization against SARS-CoV-2.

Disclosures

All Authors: No reported disclosures
504. Case SEries: Nasal Antimicrobial Photodisinfection (APDT) as Treatment Protocol for Asymptomatic and Early Stage COVID-19 Patients
Authors: Kolenda Jack , Argemi Josepmaria
Published: December 2021

Background

Targeted reduction of SARS-CoV-2 viral load in the nose may mitigate the severity of lower tract respiratory disease as well as reduce hospitalization and mortality rates. Nasal Photodisinfection has been deployed for 10 years in Canadian hospitals reducing post-surgical infections. The objective of thiswork was to demonstrate effectiveness of APDT in early stage COVID-19 and asymptomatic carriers.

Methods

A cohort of 40 COVID-19 positive patients were treated with nasal photodisinfection (Steriwave) at a private clinic. All patients were previously identified by PCR as SARS-CoV-2 positive and admitted into the treatment cohort. BD rapid antigen nares testing was used before and after Photodisinfection treatment. Of the 40 patients, 13 were female and 27 were male. Age range was 9- 56 years of age. Treatment involved 3-4 applications of photosensitizer and 16-24 minutes per patient of treatment time. Patients were followed up within 24 hours, 48 hours as well as day 5 and 6 and day 10/11. Patients filled out a COVID-19 score card.

Results

Results demonstrated APDT was capable of significant and rapid viral load reduction in COVID-19 carriers. 100% of patients were converted from positive rapid antigen test to negative. 60% of patients reported fever resolution within 24 hours. Fever resolution occurred in 100% of patients within 48hours. Moreover, results demonstrated accelerated resolution of COVID-19 symptoms and significantly improved mental health benefits from reduction of COVID-19 related stress and anxiety. None of the patients experienced severe symptoms and no patients were hospitalized. Safety outcomes demonstrated no patient safety issues with only minor transient side effects (rhinorrhea, sneezing) observed. Moreover, the treatment procedure was pain-free and well tolerated by all patients.

Conclusion

Photodisinfection-based nasal decolonization anti-viral efficacy was demonstrated with improved outcomes for all patients treated in this case series. Significant rapid viral load reduction was confirmed by rapid antigen tests in all patients. More clinical studies are warranted in support of Photodisinfection based therapy for upper respiratory infections such as COVID-19.

Disclosures

All Authors: No reported disclosures
506. Outpatient Bamlanivimab, Casirivimab and Imdevimab for COVID-19: Single Center Feasibility Analysis
Authors: Chundi Vahini , Wenner Jennifer J , Scheib Christopher , Patel Yatin , snider Cynthia , Hatcher Jeffrey C , McQuaid Douglas B
Published: December 2021

Background

Monoclonal Antibodies directed at the spike protein of SARS-COV-2 are approved by the FDA for Emergency Use for outpatients with COVID- 19 who are at risk for severe complications. Here we present a single center experience using Bamlanivimab and Casirivimab/Imdevimab to prevent hospitalizations due to SARS-COV-2.

Methods

Adult patients who tested positive for SARS-COV-2 in our health system were offered outpatient monoclonal antibody infusion if: (1) testing was done within the previous 7 days, (2) the patient had fewer than 10 days of symptoms, (3) the patient was not currently hospitalized, and (4) met at least 1 of 8 criteria in the FDA EUA Fact Sheet for Bamlanivimab and Casirivimab/Imdevimab. Patients who met the criteria were offered the monoclonal antibody available at time of infusion. Those who declined antibody infusion were used as potential controls. The primary outcome was the discrepancy in hospitalization rates at 14-days past the infusion date for patients receiving the monoclonal antibody regimen versus 14-days past when those in control group would have been scheduled for infusion had they accepted. Secondary outcomes included emergency room visits, duration of hospitalization, and Intensive Care Unit stays. Coarsened exact matching (CEM) was used to obtain balance between treatment and control groups. A logistic regression model measured statistical differences between the groups.

Results

Between November 23, 2021 and February 8, 2021, 5567 patients were offered a monoclonal antibody infusion. A total of 894 patients completed infusion who were able to be matched with patients in the control group. Patients who received the infusion were statistically less likely to be hospitalized than those who did not receive the infusion (2.68% vs 6.70%, p< 0.001).

Conclusion

This feasibility study shows reduction in hospitalization in patients who received monoclonal antibody versus standard care. It provides real-world information regarding using monoclonal antibodies as a tertiary prevention strategy to limit the progression of SARS-CoV2 infections, which will lead to improved clinical outcomes and decreased healthcare costs.

Disclosures

All Authors: No reported disclosures
507. Impact of Baricitinib on Outcomes in Patients Treated with Remdesivir and Dexamethasone for SARS-CoV-2 Pneumonia: A Retrospective Cohort Study
Authors: Dea Lauren , Piwonka Hal , Gonzales Learned , Kerkar Shubha , Mdluli Xolani , Kim Yisu
Published: December 2021

Background

There is a lack of data specifically addressing the effects of triple therapy consisting of baricitinib plus remdesivir plus dexamethasone compared to dual therapy with remdesivir plus dexamethasone among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia.

Methods

This retrospective study enrolled hospitalized adults with SARS-CoV-2 receiving supplemental oxygen without invasive mechanical ventilation (IMV) being treated baricitinib (≤10 days) plus remdesivir (≤10 days) plus dexamethasone (≤10 days) or remdesivir (≤10 days) plus dexamethasone (≤10 days). The primary endpoint was 28-day mortality. Secondary objectives of this study were to measure progression to IMV, pulse oximetry (SpO2)/fraction of inspired oxygen (FiO2) from hospitalization to discharge, hospital length of stay (LOS), 14-day mortality, 14-day hospital readmissions, inflammatory markers, and safety outcomes.

Results

Among patients receiving supplemental oxygen without IMV, 28-day mortality for triple therapy vs. dual therapy was 20% and 24%, respectively (P=1.000). The effect of triple therapy compared to dual therapy on lung function was demonstrated by a 76% vs. 25% increase in SpO2/FiO2. This benefit must be contextualized by an increased progression to IMV among patients receiving triple therapy compared to dual therapy (10 patients [50%] vs. 7 patients [28%], respectively; P=0.130). The increased incidence of IMV translated to a significantly longer hospital LOS among patients receiving triple therapy compared to dual therapy (26 days vs. 17 days, respectively; P=0.001).

Conclusion

In patients receiving supplemental oxygen without IMV for SARS-CoV-2, triple therapy was not associated with a clinically meaningful reduction in 28-day mortality when compared to dual therapy.

Disclosures

All Authors: No reported disclosures
510. Reduced Mortality Rate in Critically Ill Patients with COVID-19 with the Implementation of a Treatment Protocol—Experience of a Tertiary Care Center in the Midwest During the Initial Surge of COVID-19
Authors: Kaushik Ashlesha , Gupta Sandeep , Gupta Jitendra
Published: December 2021

Background

COVID-19 has been an unprecedented pandemic resulting in high mortality. We report our experience of using a treatment protocol in the intensive care unit (ICU) during the first peak of the pandemic.

Methods

All patients diagnosed with SARS-CoV-2 infection admitted to the ICU between April 14-June 14, 2020 were included. Remdesivir was made available for use in our institution on May 14th 2020, and thereafter, a treatment protocol combining remdesivir, corticosteroids and tocilizumab was implemented in the ICU, with doses as follows: Remdesivir 200mg intravenously (I.V.) on day 1, then 100 mg for 4 days; tocilizumab 400 mg I.V. once a day for 2 days; dexamethasone 6 mg I.V. daily for 10 days followed by taper. During pre-protocol period, patients were receiving hydroxychloroquine (400 mg once on day 1 followed by 200 mg twice daily orally for 4 days). We compared the pre-protocol period (labeled as P1: April 14, 2020- May 13, 2020) with protocol period (P2: May 14, 2020 -June 14, 2020) for clinical outcomes.

Results

A total of 32 and 48 patients were included during P1 and P2 respectively. Both groups were similar in terms of demographic characteristics, mean (±SD) age [55(±10) and 54 (±12) years] and mean Charlson-Deyo risk score at admission [2.4(±0.8) and 2.5 (±0.9) respectively]. During both periods, a comparable number of patients needed mechanical ventilation (65% and 66% respectively), anticoagulation (74% and 76% respectively) and inotropes (41% and 40%). The mean duration of ICU stay during P1 was significantly longer than P2 [15.4 (±2.8) days versus 9.3 ± (3.8) days, p< 0.0001)]. During P1, mean duration of mechanical ventilation [10 (±1.6) days] was also significantly longer than P2 [7.1 (±2.7) days] (p= 0.0004). There was a significant reduction in mortality rate from 68% (22/32) during P1 to 10.4% (5/48) in P2 (p< 0.0001). Patients were 4.3 times more likely to die during P1 than P2 (95% CI= 2.47-7.86).

Conclusion

Our results showed a decrease in ICU mortality rate by 57.6% with the implementation of a treatment protocol combining remdesivir, tocilizumab and corticosteroids during the first months of the initial surge of the pandemic, with a significant decline in length of ICU stay and duration of mechanical ventilation; and support the therapeutic data endorsed by IDSA/NIH guidelines.

Disclosures

All Authors: No reported disclosures
512. Does Time From COVID-19 Symptom Onset to Administration of Anti-spike Protein Monoclonal Antibody Predict Response?
Authors: SanFilippo Savanna , Crovetto Brynna , Milano Marc , Bucek John , Nahass Ronald G , Brunetti Luigi
Published: December 2021

Background

Casirivimab/imdevimab is a monoclonal antibody (mAb) cocktail with emergency use authorization for mild-to-moderate coronavirus disease 2019 (Covid-19) in patients at high risk for severe disease progression and/or hospitalization. Little is known about the importance of early administration of this product. The objective of this study was to determine if early administration (within 3 days of symptom onset) of casirivimab/imdevimab is associated with better outcomes.

Methods

Single-center, retrospective cohort study including all consecutive patients who received casirivimab/imdevimab at our institution through May 2021. The primary outcome was 30-day post-infusion hospital admission rate in patients who received mAb ≥ 3 days (later) or < 3 days (early) in relation to patient reported symptom onset. Secondary outcomes included any hospital revisit within 30-days. Adverse events were also captured. Chi-square and independent samples t-test were used to compare categorical and continuous data, respectively. Multivariable logistic regression was used to adjust for confounders.

Results

270 patients met the inclusion criteria and were included in the analysis. There were 80 patients with early administration and 190 with later administration. Baseline characteristics for both groups were similar. Mean age was approximately 64 years and BMI 31 mg/m2. Table 1 provides a summary of patient characteristics. Late and early administration of casirivimab/imdevimab were similar in terms of hospital admission for any therapy related failure within 30 days of mAb administration after adjusting for age and Charlson comorbidity index (3.7% vs. 7.5%; adjusted odds ratio 0.69, 95% confidence interval, 0.20 – 2.39; p=0.561). Similarly, there were no significant differences in any hospital revisit.

Conclusion

We did not find any difference in outcomes between early and late administration of casirivimab/imdevimab.

Disclosures

Ronald G. Nahass, MD, Abbvie (Grant/Research Support, Speaker’s Bureau)Alkermes (Grant/Research Support)Gilead (Grant/Research Support, Speaker's Bureau)Merck (Grant/Research Support, Speaker's Bureau)
513. Use of Antimicrobial Stewardship Program in Operationalizing Monoclonal Antibody Therapy in SARS-CoV-2 Infection
Authors: Abrantes-Figueiredo Jessica , Nalewyko Stephanie , Wiskirchen Dora E
Published: December 2021

Background

Antimicrobial stewardship programs (ASP) have been essential during the coronavirus disease 2019 (COVID-19) pandemic response. Use of monoclonal antibodies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has proven difficult to operationalize, despite being available through emergency use authorization (EUA). Utilizing existing ASP and multidisciplinary approach to lead the effort, we aim to describe our experience in operationalizing monoclonal antibody therapy.

Methods

Retrospective study of SARS-CoV-2 infected adults receiving monoclonal antibody therapy under EUA (December 2020-April 2021). An algorithm developed by the ASP provided education and an interactive online tool allowing referring physicians and patients to assess eligibility prior to hospital arrival. Patients were screened and approved by existing ASP which included; Infectious Disease (ID) physicians, pharmacist, and ID Nurse. A multidisciplinary approach with ER staff and development of pharmacy workflow with order set were utilized as eligible patients received infusion in dedicated ER location. Data such as demographics, co-morbid condition, infusion related complications, hospitalization, and death were reviewed and collected regularly by the ASP team with frequent monitoring and regulatory reporting. Primary patient outcome was preventing hospitalization.

Results

107 patients received monoclonal antibody therapy. 47% patients were male, 50% White, and 79% non-Hispanic. 87% received monotherapy (bamlanivimab) and 13% received dual therapy (bamlanivimab/etesevimab). 17 patients required hospitalization post infusion. 1 death occurred. COVID-19 related hospitalization within 30-days was avoided in 84% of treated patients. No adverse event directly related to infusion were seen.

Conclusion

Use of monoclonal antibody therapy under EUA for patients for SARS-CoV-2 infection led to decrease in hospitalization in this cohort. An existing ASP using an algorithmic approval process, frequent monitoring, and multidisciplinary approach successfully operationalized the use of monoclonal antibody therapy. ASP’s provide benefit and versatility beyond monitoring of antimicrobials alone and should continue to receive support by hospital leadership.

Disclosures

All Authors: No reported disclosures
514. Anti-SARS-CoV-2 Monoclonal Antibodies for Early COVID-19: A Real World Experience
Authors: Belden Katherine , Hess Bryan , Brugger Caroline , Carr Rachel , Braun Todd , DeRose Joseph L , Zurlo John
Published: December 2021

Background

Anti-SARS-CoV-2 monoclonal antibodies afford prompt immunity, have demonstrated reduction in severe COVID-19 in high risk ambulatory patients, and are available through Emergency Use Authorization. Challenges exist, however, to widespread utilization.

Methods

This operations study 11/23/20-4/30/21 identified patients meeting monoclonal AB EUA criteria by test results or referral. Outreach to harder-hit neighborhoods included connecting with primary care teams and testing sites. Infusion centers with staff trained in infection control, rapid response and drug preparation were utilized. The primary study outcome was treatment of qualifying patients. Secondary outcomes included infusion complications, hospitalization/death, and symptom resolution. Investigational review board approval was obtained.

Results

367 patients were treated: mean age of 63, 201(55%) male, 276(75%) white, 54(15%) black. All patients had a first positive direct SARS-CoV-2 test within 10 days, 232(63%) had > 1 high-risk qualification, 32(9%) were vaccinated for SARS-CoV-2. Of patients with available zipcodes, 135(38%) had a Community Need Index >3.5 and 157(45%) a Social Vulnerability Index >0.5. 190(52%) received bamlanivimab, 93(25%) casirivimab/imdevimab, 84(23%) bamlanivimab/etesevimab. Four patients experienced infusion reaction, 1 with anaphylaxis. 172(73%) of 236 patients were symptom free at day 5. 20 patients (5%) were hospitalized for COVID-19 within 30 days with a median time from symptom onset to infusion of 7 days, 11(55%) were admitted within 24 hours, 1 died.

Patient Characteristics

COVID-19 course

Community Need Index and Social Vulnerability Index by Zipcode

Conclusion

Our study demonstrates that treatment with anti-SARS-CoV-2 monoclonal antibodies is feasible in a high resource setting. There were no related SARS-CoV-2 exposures and therapy was well tolerated. Trials of anti-SARS-CoV-2 monoclonal antibodies have reported lower rates of hospitalizations in treated patients than we found. This may reflect the expanded time frame for EUA therapy as compared to clinical trials, differences in real world patients or viral variants. Given potential benefit in unvaccinated patients or those at risk for poor vaccine response, the equitable utilization of anti-SARS-CoV-2 monoclonal antibody therapy in early COVID-19 should remain a focus for researchers and clinicians.

Disclosures

All Authors: No reported disclosures
515. Evolution of Treatment Patterns for Patients Hospitalized with COVID-19 in the United States
Authors: Zalocusky Kelly , Rizzo Shemra , Chawla Devika , Chia Yifeng , Kamath Tripthi , Tsai Larry
Published: December 2021

Background

COVID-19 remains a threat to public health, with over 30 million cases in the US alone. As understanding of optimal patient care has improved, treatment guidelines have continued to evolve. This study characterized real-world trends in treatment for US patients hospitalized with COVID-19, stratified by whether patients required invasive ventilation.

Methods

US patients diagnosed and hospitalized with COVID-19 between March 23 and December 31, 2020, in the Optum de-identified COVID-19 electronic health record (EHR) data set were identified. Both drug and procedure codes were used to ascertain medications, and both procedure and diagnostic codes were used to detect invasive ventilation during hospitalization. Medication trends were estimated by computing proportions of hospitalized patients receiving each drug weekly during the study period.

Results

In this cohort of 71,366 hospitalized patients, the largest observed change in care was related to chloroquine/hydroxychloroquine (HCQ) (Figure). HCQ usage peaked at 87% of patients receiving invasive ventilation (54% without ventilation) in the first week of this study (March 23-29), but declined to < 5% of patients, regardless of ventilation status, by the end of May. In contrast, dexamethasone usage was 10% at baseline in patients receiving ventilation (1% without ventilation) and increased to a steady state of >85% of patients receiving ventilation ( >50% without ventilation) by the end of June. Similarly, remdesivir usage increased sharply from a baseline of 2% of patients and continued to rise to a peak of 79% of patients receiving invasive ventilation (44% without ventilation) in November before declining.

Conclusion

Meaningful shifts in treatments for US patients hospitalized with COVID-19 were observed from March through December 2020. A dramatic decline was observed for HCQ use, likely owing to safety concerns, while usage of dexamethasone and remdesivir increased as evidence of their efficacy mounted. Across medications, usage was substantially more prevalent among patients requiring invasive ventilation compared with patients with less severe cases.

Disclosures

Kelly Zalocusky, PhD, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Shemra Rizzo, PhD, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Devika Chawla, PhD MSPH, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Yifeng Chia, PhD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee) Tripthi Kamath, PhD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee) Larry Tsai, MD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee)
517. Subcutaneous Sarilumab for the Treatment of Hospitalized patients with Moderate to Severe COVID19 Disease: A Pragmatic, Embedded, Multi-Center Randomized Clinical Trial
Authors: Branch-Elliman Westyn , Ferguson Ryan , Doros Gheorghe , Woods Patricia , Leatherman Sarah , Strymish Judith , Datta Rupak , Goswami Rekha , Jankowich Matthew , Shah Nishant , Taylor Thomas H , Page Sarah T , Schiller Sara , Shannon Colleen , Hau Cynthia , Flynn Maura , Holmberg Erika , Visnaw Karen , Dhond Rupali , Brophy Mary , Monach Paul
Published: December 2021

Background

The aim of this pragmatic, embedded adaptive trial was to measure the effectiveness of subcutaneous sarilumab in addition to an evolving standard of care for clinical management of inpatients with moderate to severe COVID-19 disease (NCT04359901). The study is also a real-world demonstration of the realization of a prospective learning healthcare system.

Methods

Two-arm, randomized, open-label controlled 5-center trial comparing standard care alone to standard care (SOC), which evolved over time, with addition of subcutaneous sarilumab (200 mg or 400 mg anti-IL6R) among hospitalized patients with moderate to severe COVID-19 not requiring mechanical ventilation. The primary outcome was 14-day incidence of intubation or death. The trial used a randomized play-the-winner design and was fully embedded within the EHR system, including the adaptive randomization process.

Results

Among 417 patients screened, 162 were eligible based on chart review, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death ( >30% of eligible patients enrolled) (Figure 1). After the second interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior.

Figure 1. Key Study Milestones, Outcomes, and Adaptations

Conclusion

This randomized trial of patients hospitalized with COVID-19 and requiring supplemental oxygen but not mechanical ventilation found no evidence of benefit from subcutaneous sarilumab in addition to an evolving standard-of-care. The numbers of patients and events were too low to allow independent conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6 inhibition in the treatment of patients hospitalized with COVID-19. The major innovation of this trial was the advancement of embedded, point-of-care clinical trials for FDA-approved drugs; this represents a realization of the learning healthcare system. Methods developed and piloted during the conduct of this trial can be used in future investigations to speed the advancement of clinical science.

Disclosures

Nishant Shah, MD, General Electric (Shareholder)Pfizer, Inc. (Research Grant or Support) Karen Visnaw, RN, Liquidia (Shareholder) Paul Monach, MD,PhD, Celgene (Consultant)ChemoCentryx (Consultant)Kiniksa (Advisor or Review Panel member)
519. Risk Factor Analysis for Hospital Admission Following Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Monoclonal Antibody Treatment
Authors: Abusalem Lana , Wood Cole , Crescencio Juan Carlos Rico , Dare Ryan K
Published: December 2021

Background

The FDA has issued emergency use authorization (EUA) for neutralizing monoclonal antibodies (mAb) for the treatment of mild-moderate coronavirus disease 2019 (COVID-19) in patients who are at high risk of disease progression. The EUA allows for COVID-19 mAb infusion to occur up to 10 days from symptom onset and due to logistics, mAb treatment typically occurs later in this 10 day window. Efficacy of early versus late mAb treatment is unknown

Methods

In this single center, retrospective case-control study, we performed a risk factor analysis of patients with mild COVID-19 infection treated with mAb on the composite outcome of subsequent evaluation in the Emergency Department (ED) or inpatient admission December 2020 through May 2021. Multivariate analysis of variables found to be significant in univariate analysis was performed using STATA 15 statistical software

Results

Two-hundred eighty-eight patients who received mAb treatment were included in analysis. The mean age was 58.6 years and 59.7% were female, 64.9% white, and 27.1% African American. Following mAb infusion, 31 (10.8%) had disease progression resulting in an ED encounter or inpatient admission. Patients who received early (days 1-5 of symptoms) mAb infusion were less likely to have progressive disease than patients with late (days 6-12 of symptoms) infusion; (6.1% vs 13.2%; P= 0.048). Zero of 21 patients who received mAb infusion on day 1-3 of symptoms had disease progression. Patients with CHF (7.4% vs 19.4%; P=0.038), cirrhosis (9.3% vs 25.8%; p=0.012), CKD (12.5% vs 35.5%; p=0.001) and hypertension (70.8% vs 90.3%; p=0.021) were more likely to have disease progression. There were no differences in sex, race, BMI, or symptoms between groups. Multivariate analysis revealed cirrhosis (OR 3.0; 95% CI 1.1-7.9) and CKD (OR 2.6; 95% CI 1.0-6.4) increased risk of disease progression while early mAb infusion was protective (OR 0.38; 95% CI 0.14-1.0)

Conclusion

Infusion of mAb for the treatment of mild to moderate Covid-19 within 5 days of symptom onset reduces rate of disease progression compared to delayed (day 6-12 of symptoms) infusion. This finding was significant when controlling for comorbidities. Efforts should be made to infuse high risk patients with COVID-19 mAb therapy within 5 days of symptom onset

Disclosures

All Authors: No reported disclosures
523. Use of Immune-Viral Dynamics Modeling to Understand Molnupiravir Drug Effect for COVID-19
Authors: Cao Youfang , Gao Wei , Birger Ruthie , Stone Julie
Published: December 2021

Background

Molnupiravir (MOV) is an orally administered ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) against SARS-CoV-2. Here we present viral dynamics analysis of Phase 2 clinical virology data to inform MOV Phase 3 study design and development strategy.

Methods

An Immune-Viral Dynamics Model (IVDM) was developed with mechanisms of SARS-CoV-2 infection, replication, and induced immunity, which together describe the dynamics of viral load (VL) during disease progression. Longitudinal virology data from ferret studies (Cox, et al. Nat. Microbiol 2021:6-11) were used to inform IVDM, which was further translated to human by adjusting parameter values to capture clinical data from MOVe-IN/MOVe-OUT studies. Different placements of drug effects (on viral infectivity vs. productivity) and representations of immune response were explored to identify the best ones to describe data. A simplified 95% drug effect was implemented to represent a highly effective dose of MOV.

Results

IVDM showed data were best described when MOV acts on viral infectivity, consistent with the error catastrophe mechanism of action. A cascade of innate and adaptive immune response and a basal level activation enabled durable immunity and continued viral decay after treatment end. IVDM reasonably describes VL and viral titer data from animals and humans. Influence of MOV start time was explored using simulations. Consistent with the ferret studies, simulations showed when treatment is started within the first week post infection, MOV reduces viral growth, resulting in a lower and shortened duration of detectable VL. When started later (e.g. >7 days since symptom onset), the magnitude of drug effect is substantially diminished in a typical patient with an effective immune response which reduces VL prior to treatment start. Further work is needed to model response in patients with longer term infection, where MOV drug effects may have more persistent utility.

Conclusion

A COVID-19 IVDM developed using multiscale MOV virology data supports drug action on viral infectivity and importance of interplay of treatment and immune response and can describe infection time course and drug effect. IVDM provided mechanistic interpretations for VL drug effect in clinical studies.

Disclosures

Youfang Cao, PhD, Merck & Co. (Employee) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Ruthie Birger, PhD, Merck (Employee) Julie Stone, PhD, Merck & Co., Inc. (Employee, Shareholder)
524. Assessing the Safety of an Outpatient Remdesivir Infusion Program for Patients with Severe COVID-19 in the Setting of a Pandemic Surge
Authors: Gee Benjamin , Cheruvanky Anita , Faiad Graciela , Li Aldon , Pham Huan , Quijada Earl , Sun Susan , Baghban Adam
Published: December 2021

Background

(i) Remdesivir (RDV) shortens recovery time among COVID-19 patients in an inpatient setting. (ii) Treatments for outpatients diagnosed with COVID-19 are limited. (iii) In early 2021, there was a national surge in COVID-19 hospitalizations, which resulted in hospital bed and staff shortages. (iv) In the face of this pandemic surge, we piloted a program to expand our RDV treatment capacity by establishing an off-label, outpatient infusion tent (OIT) for patients with severe COVID-19. (v) This is a retrospective, descriptive report examining the safety and efficacy of this program, with outcomes of interest being 30-day mortality and hospital admission within the subsequent 30 days

Methods

(i) The OIT, consisting of 11 chairs capable of treating 35 patients per day, was operational from January 1 to February 19, 2021. (ii) Patients were referred to the outpatient RDV program primarily from urgent care (UC) and the emergency department (ED), and from the inpatient setting to complete therapy. Patients received at least one dose prior to referral. (iii) Eligibility criteria included a confirmed COVID-19 diagnosis, radiographic evidence of viral pneumonia, and an oxygen saturation less than or equal to 94 on room air. (iv) Exclusion criteria included pregnancy, sepsis, end-stage renal disease or GFR < 30, hepatitis with transaminases 10 times the limit of normal. Patients with BMI > 40, age > 75, chronic lung disease, dementia, were considered on a case by case basis. (v) Patients received dexamethasone and deep vein thrombosis prophylaxis

Results

(i) A total of 88 patients received 258 infusions. The average number of outpatient infusions per participant was 2.9. (ii) Four out of 88 patients died (4.5%) within 30 days of first dose in the infusion tent. No deaths occurred in the outpatient setting. (iii) Fourteen out of 88 patients were admitted to the hospital within the subsequent 30 days (15.9%). (iv) 11/14 admissions (78.6%) were due to progression of COVID-19. There were no admissions due to adverse drug reactions

Table 1. Patient Characteristics

Table 2. Admissions Within Subsequent 30 Days

Conclusion

Mortality rate in outpatients with severe COVID-19 treated with RDV was similar to that reported in inpatients. In this cohort of patients with severe COVID, a majority (84.1%) avoided hospitalization while still receiving appropriate treatment. Results suggest RDV can be safely delivered to outpatients with severe COVID-19.

Disclosures

All Authors: No reported disclosures
526. Implementation of Use of Monoclonal Antibody Therapy in a Large Academic Center for the Outpatient Treatment of Covid-19: Impact on 30 Day Hospitalization Rates, ED Visits and Death
Authors: Bhimani Azra , Srinivasan Vinay , Weinstein Stacey , Clemons Nathan , Batiste Quanna , Yang Shangxin , Garner Omai , Vijayan Tara
Published: December 2021

Background

Monoclonal Antibody Therapy (MAbs) has been shown to reduce rates of ED visits and hospitalizations in patients at risk for severe Covid-19 infection in clinical trials. Since November, three Mabs received emergency use authorization: Bamlanivimab (Bam), Bamlanivimab/Etesevimab (Bam/Ete) and Casirivimab/Imdevimab (Casi/imdevi). We describe here the real-world effectiveness of implementing early MAb therapy in the outpatient setting for individuals with Covid-19 at high risk of progression.

Methods

We examined the records of 808 UCLA Health patients with a confirmed positive SARS-CoV2 PCR test who were either referred for outpatient Mab therapy or received Mab treatment in the emergency department (ED) between December 10, 2020, and May 3, 2021. The primary outcome of our analysis was the combined 30-day incidence of emergency department visits, hospitalizations, or death following the date of referral. SARS-CoV2 isolates of hospitalized patients who had received Mabs were sequenced to determine the presence of variants.

Results

Of 808 patients, 383 were referred for treatment but did not receive treatment, 109 received Mabs in the ED and 316 patients were treated in an outpatient setting. Composite 30-day mortality, ED visits and hospital admissions were significantly reduced in the combination therapy group (Bam/Ete or Cas/Imd) compared with monotherapy (Bam alone) or no treatment groups (aHR 0.16, 95% CI .038, .67). Significant factors associated with the composite outcome included: history of lung disease (HR 4.46, 95% CI 2.89-6.90), cardiovascular disease (HR 1.87, 95% CI 1.12-3.12), kidney disease (HR 2.04, 95% CI 1.27-3.25), and immunocompromised state (HR 3.24, 95% CI 1.02-10.26) as well as high social vulnerability index (HR 1.87, 95% CI 1.13-3.10). Over one-third of hospitalized patients who had received Mabs were confirmed to have the California variant (B.1.427/29) (Figure 1).

Figure 1. Covid-19 MAB Treatment Failure Lineages

Conclusion

Our data show that in a real-world setting, combination monoclonal antibody therapy, not monotherapy, significantly reduced ED visits and hospital admissions, likely due to the presence of the California variants. High socioeconomic vulnerability and certain medical conditions increased risk of treatment failure.

Disclosures

Omai Garner, PhD, D(ABMM), Beckman Coulter (Scientific Research Study Investigator)
527. Lower Risk of ICU Admission with Remdesivir in Patients Hospitalized with COVID-19 Pneumonia
Authors: Lim Sarah , Schreiner Pamela , Lifson Alan , Bye Erica , Como-Sabetti Kathryn , Lynfield Ruth , Lynfield Ruth
Published: December 2021

Background

Remdesivir (RDV) was approved by FDA in October 2020 for use in hospitalized patients with COVID-19. We examined the association between RDV treatment and ICU admission in patients hospitalized with COVID-19 pneumonia requiring supplemental oxygen (but not advanced respiratory support) in MN.

Methods

COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) is population-based surveillance of hospitalized laboratory confirmed cases of COVID-19. We analyzed COVID-NET cases ≥18 years hospitalized between Mar 23, 2020 and Jan 23, 2021 in MN for which medical record reviews were complete. On admission, included cases had evidence of COVID-19 pneumonia on chest imaging with oxygen saturation < 94% on room air or requiring supplemental oxygen. Cases were excluded if treated with RDV after ICU admission. Multivariable logistic regression was performed to assess the association between RDV treatment and ICU admission.

Results

Complete records were available for 8,666 cases (36% of admissions statewide). 1,996 cases were included in the analysis, of which 908 were treated with RDV. 83% of cases were residents of the 7-county metro area of Minneapolis-St. Paul. Mean age was 59.7 years (IQR 48-72), 55% were male, and the mean RDV treatment duration was 4.8 days (range 2-15). The proportion of cardiovascular disease (30.6% vs 23.9%, p=.003), renal disease (16.6% vs 7.6%, p< .001), and diabetes (34.7% vs 29.5%, p=0.01) was higher in the RDV untreated group, while obesity (22.3% vs 8.4%, p< .001) and dexamethasone use (54.7% vs 15%, p< .001) was more common in the RDV treated group. RDV untreated patients were more likely to be admitted to an ICU (18% vs 8.9%, p< .001) and had higher inpatient mortality than those treated with RDV (11% vs 4.4%, p< .001). After adjustment for dexamethasone use, age, sex and diabetes, treatment with RDV was associated with 48% lower odds of ICU admission (OR 0.52, 0.39-0.7, p< .001).

Conclusion

We found RDV treatment associated with a significantly lower risk of ICU admission in patients admitted to hospital requiring supplemental oxygen, suggesting that treatment may prevent disease progression in this group. Further studies should assess the potential benefit of RDV combination treatment with dexamethasone.

Disclosures

Ruth Lynfield, MD, Nothing to disclose
528. Hospital Course of Patients Receiving Bamalanivimab: A Real World Analysis
Authors: Belk Madeline , Edwards Jonathan , Hassoun Ali
Published: December 2021

Background

Monoclonal antibodies for the outpatient treatment of the novel Coronavirus Disease 2019 (COVID-19) first received emergency use authorization from the Food and Drug Administration in November 2020. These antibodies have been associated with a reduction in emergency department visits and hospitalization through randomized controlled trials. However, modest data is available to describe the outcomes of patients who were hospitalized despite treatment. This study describes real-world outcomes concerning the treatment of COVID-19 with the first approved monoclonal antibody for COVID-19, bamlanivimab, as well as hospital courses associated with patients admitting after receiving the therapy.

Methods

This single-center, retrospective study evaluated real-world data of patients treated with bamlanivimab. The primary endpoint was a composite of emergency department (ED) visits or hospitalization due to worsening COVID-19. Data was analyzed from November 23, 2020 to March 5, 2021. Descriptive statistics were used to analyze the primary endpoint. Secondary endpoints include reported symptoms 24-hours post-infusion and time to symptom resolution in days. Additionally, clinical course of patients hospitalized were analyzed and include average oxygen requirements, median length of stay, and mortality. A subgroup analysis was conducted between patients less than sixty-five years of age and those sixty-five and older.

Results

619 patients received bamlanivimab during the specified timeframe. The primary endpoint occurred in 34 patients; 11 ED visits and 23 hospitalizations. Baseline characteristics of the patients hospitalized include median age 69 years (IQR 55, 74), 56.5% male, and 82.6% Caucasian. The most common risk factors for severe disease among those hospitalized were age ≥ 65 years and history of diabetes. The clinical course of hospitalized patients varied but 52.9% required nasal cannula for respiratory support and the average length of stay was 4.5 + 4.5 days. Other COVID-19 therapies included dexamethasone in 76.5% of patients and remdesivir in 47.1% of patients. There were no major differences in the subgroup analysis.

Conclusion

Bamlanivimab appears to attenuate the clinical course of COVID-19 in patients who are hospitalized despite treatment.

Disclosures

All Authors: No reported disclosures
529. Systematic Review and Meta-Analysis of Ivermectin Safety Profile in COVID-19 Trials
Authors: Wentzel Hannah , Wang Junzheng , Dayanamby Abbienaya , Pilkington Victoria , Levi Jacob , Hill Andrew , Ellis Leah
Published: December 2021

Background

There is a continued and pressing need for safe and effective treatment of COVID-19. Significant survival benefits have been shown by dexamethasone, tocilizumab and sarilumab, however they are only recommended in hospitalised COVID-19 patients. Ivermectin is a well-established and readily available antiparasitic drug which may be suitable for treatment in mild and moderate disease stages. It recently demonstrated anti-viral properties in vitro and now over 80 clinical trials have been registered worldwide to test its effectiveness in COVID-19 patients. This meta-analysis aims to collect data on adverse events reported in new COVID-19 treatment trials for the use of ivermectin as a repurposed medication.

Methods

Data was extracted from randomised trials of COVID-19 treatment trials identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. The primary outcome of this meta-analysis is the frequency of adverse events. Key safety events included serious, gastrointestinal, neurological, cardiovascular and dermatological adverse events.

Results

Overall, 18 trials investigating ivermectin for COVID-19 in a total of 2496 participants reported safety data and were included. There was no significant difference in the proportion of all adverse events between ivermectin and the comparator. There were 371/1261 (29%) adverse events recorded in the ivermectin containing arms and 376/1284 (29%) in the control arms (RR 1.02 [95% CI 0.77 - 1.34]; p = 0.91). There was no significant difference in the rate of serious adverse events across treatment arms (RR 1.95 [95% CI 0.75 - 5.11]; p = 0.18). No significant differences between ivermectin and the control were seen across different subcategories of adverse events. Figure 1 shows a summary of the results for all adverse events.

Forest plot comparing ivermectin and the control for all adverse events in COVID-19 trials, subdivided into single-day dosing trials and multi-day dosing trials.

Conclusion

The results of recent COVID-19 trials show that overall, ivermectin is safe and well-tolerated. No significant difference in adverse event reporting was found across all subgroups in single and multi-day treatment regimens for the studies analysed. Safety reporting methodologies often varied across trials. Future and ongoing trials should be encouraged to collect and monitor safety data systematically.

Disclosures

All Authors: No reported disclosures
531. Risk Factors and Therapeutic Interventions Associated with Mortality in Veterans Diagnosed With SARS-CoV-2 Infection (or COVID-19) Admitted to a Large Academic Medical Center
Authors: Welch Elwyn , Raheem Shazia , Hunter Andrew , Ayyala Uma , Bandi Venkata , Pandit Lavannya , Kao Christina
Published: December 2021

Background

Patient and treatment-related factors have been used to stratify COVID-19 outcomes; however, studies in the general population and specifically veterans have yielded variable results. This study was designed to assess how baseline characteristics and interventions correlate with clinical outcomes in patients admitted with COVID-19 at a large academic Veterans Affairs hospital.

Methods

Retrospective chart review was conducted on veterans admitted to the hospital with COVID-19 between March 1 to December 31, 2020. Veterans without respiratory symptoms attributed to COVID-19 or enrolled in a COVID-19 clinical trial were excluded. Primary outcome was in-hospital mortality up to 28 days. Secondary outcomes were 90-day mortality, discharge to higher level of care or remained in the hospital within 28 days, and discharge with new oxygen requirement within 28 days. Patient characteristics and therapeutic interventions were assessed for correlation with primary and secondary outcomes.

Results

Of 497 hospitalized patients reviewed, 293 were included for analysis; 94% were male; average age was 68 years with 64.9% of veterans greater than 65 years of age; 43.7% were Black; 17.4% were Hispanic. In-hospital mortality at 28-days and 90-day mortality were 18.1% and 21.5%, respectively. At discharge, 34.1% had a new oxygen requirement and 17.5% went to a higher level of care. Patients that died in-hospital were more likely to be greater than 65 years of age (p< 0.001), Hispanic (p=0.007), have chronic kidney disease (CKD) (p=0.005), be admitted to ICU (p< 0.001); receive dexamethasone (p< 0.001), convalescent plasma (p< 0.001), or antibiotics (p< 0.001); require mechanical ventilation (p< 0.001); or have new onset atrial fibrillation (p< 0.001). Veterans also had higher levels of inflammatory markers within 48 hours of hospital admission (see Table 2) and longer length of hospital stay (< 0.001). There was a trend for patients that died in the hospital within 28-days to be less likely to be Black (p=0.06).

Table 1. Primary and Secondary Outcomes of Study Population (n=293)

Table 2. Patient Characteristics Stratified by Primary Outcome

Table 3. Characteristics of the Patients that Survived to Discharge Stratified by Secondary Outcome Measures

Conclusion

Patients were more likely to die in-hospital within 28-days if they were greater than 65 years of age, Hispanic and had CKD. Veterans that died in-hospital within 28-days had higher inflammatory marker levels and were more likely to receive COVID-19 treatments.

Disclosures

All Authors: No reported disclosures