Clinical outcomes of COVID‐19 treated with remdesivir across the continuum of care

Abstract Introduction During the early phase of the coronavirus disease 2019 (COVID‐19), remdesivir was only approved for hospitalized patients. Our institution developed hospital‐based, outpatient infusion centers for selected hospitalized patients with COVID‐19 who had clinical improvement to allow for early dismissal. The outcomes of patients who transitioned to complete remdesivir in the outpatient setting were examined. Methods Retrospective study of all hospitalized adult patients with COVID‐19 who received at least one dose of remdesivir from November 6, 2020, to November 5, 2021, at one of the Mayo Clinic hospitals. Results Among 3029 hospitalized patients who received treatment with remdesivir for COVID‐19, the majority (89.5%) completed the recommended 5‐day course. Among them, 2169 (80%) patients completed treatment during hospitalization, whereas 542 (20.0%) patients were dismissed to complete remdesivir in outpatient infusion centers. Patients who completed the treatment in the outpatient setting had lower odds of death within 28 days (aOR 0.14, 95% CI 0.06–0.32, p < 0.001). However, their rate of subsequent hospital encounters within 30 days was higher (aHR 1.88, 95% CI 1.27–2.79, p = 0.002). Among patients treated with remdesivir only in the inpatient setting, the adjusted odds of death within 28 days were significantly higher among those who did not complete the 5‐day course of remdesivir (aOR 2.07, 95% CI 1.45–2.95, p < 0.001). Conclusions This study describes the clinical outcomes of a strategy of transitioning remdesivir therapy from inpatient to outpatient among selected patients. Mortality was lower among patients who completed the 5‐day course of remdesivir.


| INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 , continues to cause morbidity and mortality globally. 1 Evidence-supported treatment for COVID-19 includes small molecule antiviral drugs, anti-spike neutralizing monoclonal antibodies, and immunomodulatory agents. 2 Remdesivir, a direct-acting nucleotide inhibitor of SARS-CoV-2 RNAdependent RNA polymerase, was the first antiviral drug approved for clinical use and remains as the backbone for treatment of hospitalized patients with COVID-19. [3][4][5] Remdesivir has been demonstrated to be effective for the treatment of hospitalized patients with severe disease and high-risk outpatients with mild COVID-19. A phase 3 trial showed that a 5-day course of remdesivir shortened recovery time among hospitalized patients with COVID-19. 4,6,7 Among non-hospitalized outpatients with conditions that predispose to severe disease progression, a 3-day course of remdesivir reduced the rates of hospitalization or death by 87% compared to placebo. 8 Prior to 2022, remdesivir was only approved for clinical use in hospital settings. 9 At the Mayo Clinic, most patients remained hospitalized for a minimum of 5 days to complete the course of remdesivir treatment. Patients who improved clinically often expressed a desire to leave the hospital prior to completion of the 5-day course of remdesivir. However, the outcome of the abbreviated course of remdesivir was not known. In November 2021, our program developed hospital-based infusion therapy centers to allow for earlier dismissal of hospitalized patients who had achieved clinical improvement. Every patient who had clinical improvement, as assessed by the treating hospital providers, was offered an option to continue remdesivir treatment as an outpatient in the hospital-based infusion facilities. High-risk patients continued to be monitored using the remote monitoring program. By allowing early dismissal of stable improving hospitalized patients, the healthcare system would benefit by making hospital rooms and staff available for sicker patients.
In this study, we report the outcomes of patients with COVID-19 treated with remdesivir across the continuum of care. We aim to describe the characteristics and outcomes of patients who were transitioned to complete remdesivir in the hospital-based outpatient setting and assess their risk of mortality and 28-day re-admission rates.

| Study design and patient population
This is a retrospective multi-site cohort study of adult patients during a 1-year period from November 6, 2020, to November 5, 2021. All patients were admitted to one of the Mayo Clinic hospitals with COVID-19 diagnosis and received at least one dose of intravenous remdesivir. Per our standard practice, all patients hospitalized for COVID-19 were assessed for eligibility for a 5-day remdesivir course in the inpatient setting.
For this study, the patients were categorized into those who: 1) completed the 5-day remdesivir course entirely inpatient, 2) completed the remdesivir course after transitioning to the outpatient setting, 3) did not complete the remdesivir course but remained inpatient, and 4) did not complete remdesivir after discharge from the hospital. Determination of inpatient or outpatient status was based on patient classes, department, and manual review when unable to determine by other methods. The remdesivir treatment course was categorized as incomplete if <5 doses or <600 mg total was documented in the medication administration record.
Patients were eligible for this study if they were ≥18 years of age and received a first course of remdesivir. If there were >2 calendar days between doses of remdesivir, these were considered separate courses, and the subsequent course(s) were excluded. Other exclusion criteria included receipt of an anti-spike neutralizing monoclonal antibody or convalescent plasma, use of remdesivir under another study protocol, and patients transitioning from an outside facility during remdesivir treatment. Minnesota residents who declined research authorization were excluded. The Mayo Clinic Institutional Review Board deemed this study to be exempt (IRB 20-012975).

| Clinical variables and outcomes
All-cause mortality was defined as death within 28 days of the first dose of remdesivir. Death related to COVID-19 was determined by chart review by the study team physician or clinical pharmacist. The second review was performed by the study physician if the cause of death was unable to be determined by the clinical pharmacist.
Liver function tests (LFT, alanine, and aspartate aminotransferases) were reviewed for 10 days from the start of remdesivir treatment. Body mass index (BMI), World Health Organization (WHO) ordinal scale, Monoclonal Antibody Screening Score (MASS), and use of steroids, baricitinib, or tocilizumab were collected. MASS is a clinical risk prioritization score for the allocation of anti-spike monoclonal antibodies and includes age, BMI, chronic heart, kidney and lung diseases, diabetes mellitus, hypertension, pregnancy, and an immunosuppressed condition or treatment. 10 Primary diagnosis code was used to identify hospital and emergency care encounters related to COVID-19 within 30 days of the last administered dose of remdesivir and long COVID-related encounters within 180 days.

| Statistical analysis
Data are summarized using medians and interquartile ranges (IQRs) for continuous data and frequencies and percentages for categorical data. Patient characteristics were compared between groups using Kruskal-Wallis tests for continuous data and either Chi-square or

| Overall outcomes of the study population
Two hundred and sixty-five (8.7%) patients died within 28 days of starting remdesivir; 219 (82.6%) were COVID-19 related. Older age was significantly associated with higher rates of all-cause and COVID-19-related deaths ( Table 2). Higher all-cause and COVID-19-related death was also observed among patients who did not complete the 5-day course of remdesivir ( Figure 1). Patients who improved clinically and were dismissed to complete the remdesivir course in the outpatient setting had a lower risk of all-cause and COVID-19-related death ( There were no statistically significant differences in age, sex, and MASS between the inpatients who did and did not complete remdesivir in the hospital. However, the proportion of patients who required oxygen supplementation and received steroids or immunomodulators was significantly higher among patients who completed the remdesivir course for 5 days ( p < 0.001).
The adjusted odds of the abnormal liver panel were lower among hospitalized patients who did not complete versus those who completed the 5-day course of remdesivir (aOR 0.56; 95% CI 0.43-0.72, p < 0.001). There was no significant difference in subsequent ED visits or re-admission within 30 days, but the adjusted odds of 28-day mortality were two-fold higher among patients who did not complete remdesivir in the hospital (aOR 2.07, 95% CI 1.45-2.95, p < 0.001) ( Table 2). The results were similar, after excluding the patients who died in the hospital (Table S1). The all-cause and COVID-19 mortality among 22 patients who did not complete the remdesivir course in the outpatient setting was similar to those who remained hospitalized for the 5-day course of remdesivir. In contrast, the all-cause and COVID-19 mortality among those who completed the 5-day course of remdesivir in the outpatient was lower than those who remained in the hospital and those who were dismissed from the hospital but did not complete the course in the outpatient setting ( disease, and diabetes were the most common underlying conditions.

| Characteristics and outcomes of dismissed patients who completed versus did not complete remdesivir in the outpatient setting
Although medical comorbidities have been associated with severe outcomes from COVID-19, an older age was the most significant risk factor for all-cause and COVID-19-related death in this study. 13 The significant association between older age and severe outcome from COVID-19 is well described. [14][15][16] Since the conduct of our study, there have been increasing rates of vaccination among the population, whereas treatment options have expanded to reduce the risk of death and severe disease from COVID-19.
In our cohort, one in five patients who required hospitalization for COVID-19 improved early prior to completion of the standard 5-day remdesivir treatment. This is a novel observation that has This study observed that the rate of death by day 28 among patients who did not complete the 5-day course of remdesivir was higher compared to those who completed the treatment course. In particular, patients who did not complete the remdesivir course in the hospital and did not receive an additional dose of remdesivir as an outpatient had three-time higher odds of death within 28 days compared to patients who completed the treatment course. It is possible that this outcome could be accounted for by 22 patients who died during the treatment with remdesivir; however, these patients constitute only the minority of those who did not complete the treatment.
Moreover, it also appears that the survival rate of patients who completed the course in the outpatient setting was better than those who were dismissed from the hospital but did not complete the full 5-day remdesivir course. Our findings therefore imply that completion of a

ACKNOWLEDGMENTS
This work was supported by research funds from Gilead Sciences to RRR. The sponsor did not have any influence on data collection, analysis, interpretation, and drafting of the manuscript.

CONFLICT OF INTEREST STATEMENT
RRR received research funds from Regeneron and Roche on projects not related to this study, as a member of the DSMB for Novartis and is on the Board of Directors of the American Society of Transplantation. CGR is a member of an advisory board for Gilead. All other authors declare no potential conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.