key: cord-0834921-eirlrb4j
authors: Bariola, J Ryan; McCreary, Erin K; Wadas, Richard J; Kip, Kevin E; Marroquin, Oscar C; Minnier, Tami; Koscumb, Stephen; Collins, Kevin; Schmidhofer, Mark; Shovel, Judith A; Wisniewski, Mary Kay; Sullivan, Colleen; Yealy, Donald M; Nace, David A; Huang, David T; Haidar, Ghady; Khadem, Tina; Linstrum, Kelsey; Seymour, Christopher W; Montgomery, Stephanie K; Angus, Derek C; Snyder, Graham M
title: Impact of bamlanivimab monoclonal antibody treatment on hospitalization and mortality among non-hospitalized adults with SARS-CoV-2 infection
date: 2021-05-17
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab254
sha: f978b0caee3294fa398b58d1b4cef26c338a122f
doc_id: 834921
cord_uid: eirlrb4j

BACKGROUND: Monoclonal antibody treatment may prevent complications of COVID-19. We sought to quantify the impact of bamlanivimab monoclonal antibody monotherapy on hospitalization and mortality among outpatients at high risk of COVID-19 complications. METHODS: In this observational study we compared outpatients who received bamlanivimab monoclonal antibody from December 9, 2020 to March 3, 2021 to non-treated patients with a positive polymerase chain reaction or antigen test for SARS-CoV-2 during the same period who were eligible for monoclonal antibody treatment. The primary outcome was 28-day hospitalization or all-cause mortality, and the secondary outcome was hospitalization or emergency department visit without hospitalization. The risk-adjusted odds of study outcomes comparing bamlanivimab treated and untreated patients was determined using 1:5 propensity matching and multivariable logistic regression. RESULTS: Among 232 patients receiving bamlanivimab matched with 1,160 comparator patients, the mean age was 67 years, 56% were female, and 196 (14%) of patients experienced hospitalization or mortality. After adjustment for propensity to receive treatment, bamlanivimab treatment was associated with a significantly reduced risk-adjusted odds of hospitalization or mortality within 28 days (OR 0.40, 95% confidence interval [95% CI] 0.24 to 0.69; p<.001). Bamlanivimab treatment was also associated with a significantly lower risk adjusted odds of hospitalization or emergency department visit without hospitalization (OR 0.54, 95% CI 0.35 to 0.82; p=.004). The results were most strongly associated with patients age 65 years and older. CONCLUSIONS: Bamlanivimab monoclonal antibody monotherapy was associated with reduced hospitalizations and mortality within 28 days among outpatients with mild-moderate COVID-19.

Monoclonal antibodies (mAb) bind to the SARS-CoV-2 spike (S) protein and block viral entry into host cells, neutralizing the virus. 1 currently evaluating mAb for prevention or treatment of COVID-19. However, real-world data are limited, and the role of mAb for patients with COVID-19 remains controversial. 3, 5, 6 Use of mAb therapy is low in the United States despite widespread drug availability due to lack of robust efficacy data, operational challenges with outpatient infusions, and patient access issues. 7 Our health system established a mAb program in November 2020 to decrease COVID-19-related complications for patients with mild-moderate illness. In its implementation, particular care was taken to expand access for underserved patients. Initially, only bamlanivimab monotherapy was available; the evaluation and distribution process is described elsewhere. 8 This study quantifies the risk-adjusted association between bamlanivimab monotherapy treatment and no bamlanivimab treatment on hospitalizations, mortality, and Emergency Department (ED) visits among outpatients at high risk of progressing to severe COVID-19. We also explored whether patient age, body mass index, and timing of treatment relative to initial diagnosis modified the association between mAB treatment and outcome.

This study was approved by the UPMC Quality Improvement Review Committee (Project ID 2882 and Project ID 3116).

UPMC is a 40-hospital integrated healthcare system providing care principally within central and western Pennsylvania (USA). After the November 2020 EUA was granted for bamlanivimab 700 mg infused once, UPMC established 16 outpatient infusion centers across all served geographical areas. In addition, infusions occurred in UPMC Senior Communities (i.e., long-term care facilities), patient homes (via collaboration with a home infusion company), and behavioral health units. Patients were referred via the electronic medical record systems for UPMC providers and by paper order for non-UPMC prescribers. A centralized team with pharmacists and physicians reviewed orders daily to confirm criteria for receipt (Supplemental Table 1 ). Decentralized nursing teams then contacted and scheduled eligible patients for infusions.

We used the EMR to access all key clinical data including detailed sociodemographic and medical history data, diagnostic and clinical tests conducted, surgical and other treatment A c c e p t e d M a n u s c r i p t procedures performed, prescriptions ordered, and billing charges on all outpatient and inhospital encounters, with diagnoses and procedures coded based on the International Classification of Diseases, Ninth and Tenth revisions (ICD-9 and ICD-10, respectively). We linked the deidentified primary data sources using common variables within the UPMC data systems aggregated in its Clinical Data Warehouse. 9

The study population was derived from patients who received bamlanivimab treatment from December 9, 2020 to March 3, 2021. During this time period at UPMC, bamlanivimab 700 mg was used exclusively and was administered over 1 hour per the initial EUA directives. Patients were candidates for bamlanivimab therapy based on criteria initially derived from and later matching EUA criteria including: recently diagnosed mild to moderate COVID-19 (with a positive polymerase chain reaction or antigen test for SARS-CoV-2 virus); symptom onset within 10 days prior to mAb treatment; body mass at least 40 kg; age ≥65 years or a medical condition conferring high risk of COVID-19 progression to severe disease and/or hospitalization (Supplemental Table 1 ). 10 A mild to moderate COVID-19 definition was consistent with EUA language and included patients not requiring hospitalization for COVID-19 or requiring new or increased oxygenation support. Patients were included if they completed bamlanivimab treatment and had at least 28 calendar days of follow-up, or if they experienced one of the study outcomes of interest within 28 days after treatment. No patients who met EUA eligibility for infusion were excluded simply due to any individual patient characteristics.

We also derived a comparator group from the same at-risk population by identifying non-hospitalized patients with a positive polymerase chain reaction or antigen test for SARS-A c c e p t e d M a n u s c r i p t CoV-2 during the same time period who were eligible for mAb treatment based on EUA criteria but were not treated.

For treated patients, the 28-day follow-up period began on the day of their treatment.

For comparator patients, the follow-up period began two days after their SARS-CoV-2 test result date, which corresponded to the earliest time from test positivity to initiation of treatment for treated patients.

The primary outcome was a composite of hospitalization or all-cause mortality during the follow-up windows. We assessed in-hospital mortality using the discharge disposition of "Ceased to Breathe" sourced from the inpatient EMR and out-of-hospital deaths from the Social Security Death Index. The secondary outcome was hospitalization or 28-day Emergency Department (ED) visit without hospitalization. To understand the contribution of individual elements of the primary and secondary composite outcomes, we also studied the frequency of individual events: ED visit without hospitalization, hospitalization, and mortality within 28 days.

In this observational study of outpatient eligible to receive bamlanivimab for COVID-19, we created within age strata propensity scores for receipt of mAb, matched those receiving bamlanivimab treatment to eligible patients not receiving treatment in a 1:5 ratio, and then calculated odds ratios (OR) of study outcomes.

First, we selected from the at-risk comparator population individuals matched by propensity score (Supplemental Figure 1) . 11, 12 Age is a strong predictor for complications A c c e p t e d M a n u s c r i p t of COVID-19 and the prevalence of high-risk medical conditions vary substantially by patient age. 13, 14 We anticipated that differences in patient profiles between treated and nontreated patients would vary by age because of the age-specific criteria for bamlanivimab contained in the EUA. Moreover, immunosenescence occurs with aging, so we anticipated age to be a potential effect modifier in the relationship between mAb receipt and study outcomes. 15 Therefore, we planned a priori to select non-treated patients using propensity scores within age strata consistent with the EUA criteria: less than 55 years, 55 years to less than 65 years, and 65 years of age and older. 10 Patients receiving bamlanivimab treatment and the selected comparator patients across all age strata were then combined to constitute the study population.

Propensity scores were derived using logistic regression models fit from covariates in age-stratified groups with treatment with mAb as the response variable and forward stepwise selection of measured pretreatment explanatory variables at p <0.15 (Supplemental Table   2 ). We included variables deemed biologically relevant into all models prior to stepwise selection. We used 1:5 propensity score matching with a maximum propensity score probability difference of 0.01 to construct matched treated and non-treated groups within age strata (Supplemental Figures 1 and 2) . We did not impute missing values for variables used in deriving the propensity scores but did compare characteristics of patients with propensity scores (i.e., full covariate data) to those without propensity scores.

We compared characteristics and unadjusted outcomes of treated versus non-treated patients using student t-tests for continuous variables and chi-square tests for categorical variables. The time at risk for non-treated patients was estimated starting at the time they would have received bamlanivimab had they been referred for care, conservatively using two days after SARS-CoV-2 testing. We compared the distribution of time from beginning of follow-up to study outcome among patients receiving treatment and those who did not, both A c c e p t e d M a n u s c r i p t in the matched and at-risk populations (Supplemental Table 3 ). For the propensity matched analysis of primary and secondary outcomes, as well as individual elements of the composite outcomes, we fit unconditional logistic regression models with bamlanivimab receipt as the primary exposure.

We also performed one sensitivity and three exploratory analyses. First, we used the propensity score (i.e., predicted probability of being treated with bamlanivimab) as a continuous variable to control for confounding and evaluate study outcomes in the unmatched cohort of patients who did and did not receive bamlanivimab. Second, because we postulated that treatment may have differential effects in potentially immunosenescent older population, we evaluated the association between bamlanivimab and study outcomes in the pre-defined age strata of the propensity score-matched cohort. Third, in the unmatched cohort, we tested for an interaction between treatment and body mass index because in one clinical trial higher BMI was associated with a more pronounced treatment effect. 16 Fourth, to identify a potential benefit of prompt (versus delayed) administration of bamlanivimab, among study patients receiving it we explored the frequency of treatment outcomes in four categories of time from diagnosis to treatment: 0 to 2 days, 3 to 4 days, 5 to 7 days, and 8 to 10 days. Treatment effects are reported as risk-adjusted OR with 95% confidence interval (95% CI). We set the alpha error at 0.05 for calculation of adjusted OR. All analyses were performed using the SAS System (Cary, NC), version 9.4. Methods and results are reported in accordance with

The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement (see Supplemental Table 4 ). 17 A c c e p t e d M a n u s c r i p t

Among 636 patients who received bamlanivimab during the study period, 463 (72.8%) patients achieved a study outcome or completed 28-day follow-up. The nonhospitalized at-risk population who met EUA criteria and did not receive bamlanivimab treatment included 11,311 patients, of whom 10,438 (92.2%) achieved study outcome or had sufficient follow-up time. The unmatched populations were significantly different on most characteristics with patients receiving bamlanivimab demonstrating higher frequencies of these medical conditions ( Table 1) . After propensity score matching within age strata, 232 patients receiving mAb treatment and 1,160 patients not receiving bamlanivimab were included in the study population. The mean age of the 1,392 patients in this cohort was 67 years and 56% were female. After propensity matching, nearly all matched and selected unmatched variables did not differ statistically and with minimal clinical differences between patients who received versus did not receive bamlanivimab treatment ( Table 1) 

Among the 232 propensity-matched patients receiving bamlanivimab treatment, 15 (6.4%) were hospitalized, 4 (1.7%) died, and 16 (6.9%) had an ED visit without hospitalization for any reason. Among the 1,160 propensity-matched patients not receiving bamlanivimab treatment, 172 (14.8%) were hospitalized, 33 (2.8%) died, and 83 (7.2%) had an ED visit without hospitalization (Table 2, Figure 1b) . The primary outcome of M a n u s c r i p t hospitalization or mortality occurred in 6.9% (16/232) of patients receiving bamlanivimab and 15.5% (180/1160) of patients not receiving bamlanivimab. The secondary outcome of hospitalization or ED visit without hospitalization occurred in 12.1% (28/232) of patients receiving bamlanivimab and 20.3% (235/1160) of patients not receiving bamlanivimab (Figure 1a) . In the propensity matched analyses, patients receiving bamlanivimab had an estimated 60% lower risk-adjusted odds of hospitalization or mortality (OR 0.40; 95% CI 0.24 to 0.69) and estimated 46% lower risk-adjusted odds of hospitalization or ED visit without hospitalization (OR 0.54; 95% CI 0.35 to 0.82) ( Table 2 ).

In an unmatched cohort of patients receiving bamlanivimab treatment and an at-risk population of patients not receiving the treatment, adjusted for propensity to receive bamlanivimab, bamlanivimab was associated with a 0.42 (95%CI 0.25 to 0.73) lower odds of hospitalization or mortality, and a 0.60 (95% CI 0.40 to 0.91) lower odds of hospitalization or ED visit (Supplemental Table 5 ). A post hoc parallel conditional logistic regression analysis yielded virtually identical results (Supplemental Table 6 ). In the age-stratified matched analysis, bamlanivimab treatment resulted in a 0.57 (95% CI 0.13 to 2.55), 0.42 (0.09 to 1.88), and 0.38 (0.20 to 0.70) lower odds of the primary outcome in the < 55 years, 55 to < 65 years, and 65 years and older age groups, respectively ( Table 2 ). In propensity score-adjusted analyses for the 28-day rate of hospitalization or mortality, there was no differential treatment effect by BMI for the association between bamlanivimab treatment and the primary outcomes 

In a propensity-matched cohort study, bamlanivimab treatment among outpatients with mild to moderate COVID-19 was associated with a significantly reduced risk-adjusted odds of hospitalization or death at 28 days. These results were robust to sensitivity analyses including an unmatched analysis controlled by propensity to receive treatment, and in age strata of the matched cohort.

In a previous randomized clinical trial, bamlanivimab 700mg in outpatients with mild to moderate COVID-19 showed improvement of symptoms at day 11 and fewer hospitalizations and ED visits at day 29 compared to placebo. 3, 18 A post hoc analysis of those 65 or older or with BMI of 35 kg/m 2 or greater in this trial demonstrated a larger potential benefit, 2.7% vs 13.5%. 3 In this study, we identified a similar association between bamlanivimab monotherapy and hospitalization or mortality, extending the trial findings to a generalizable population.

This study affirms the benefit of bamlanvimab treatment and expands our understanding of where the benefit may be greatest. Cumulatively our report shows benefit for patients across several possible outcomes, and we consider this highly relevant from a A c c e p t e d M a n u s c r i p t clinical standpoint. Rates of hospitalizations and ED visits in patients aged 65 years or older were higher than observed in the clinical trial, yet a reduction in primary and secondary outcomes was nonetheless observed. 3 Our exploratory analysis of benefit based on time to therapy warrants further investigation into how promptly this therapy should be administered for maximal benefit. Unlike the previous trial, this study did not identify an association between BMI and response to mAb therapy. 18 Future studies should continue to explore medical conditions and patient populations that may most benefit from mAb for the treatment of COVID-19.

Prevention of hospitalization is a highly relevant clinical metric for patients with COVID-19. Prior to mAb, no outpatient strategies resulted in decreased rates of hospitalization or death. These data support health systems' investment of resources in developing infrastructure for mAb infusions. Additionally, the potential benefits of mAb could be explored in patients cared for in the ED and those early in hospital admission without severe disease.

There are several limitations of our study. First, given the observational design, there were substantial differences between bamlanivimab treated and untreated populations. We mitigated measured confounding with propensity score modeling and a sensitivity analysis Department of Health and Human Services announced they would no longer supply sites with bamlanivimab alone due to concern about increased rates of resistant variants, and on April 16 th , 2021, the EUA for bamlanivimab monotherapy was rescinded by the FDA. 19 Many of our patients received bamlanvimab when the rate of resistant variants in this country was low, thus explaining why we still saw benefit with bamlanivimab monotherapy. More generally however, our findings provide early real-world experience that suggests neutralizing mAbs efficiently targeting common circulating strains of SARS-CoV-2 can lead to improved clinical outcomes. Our findings provide encouragement to providers still hesitant to provide COVID-19 mAbs in general and encourage further evaluation into the best patient groups to gain benefit from these treatments. It will be critical to show similar results for the other available mAb therapies and to define where each therapy may be best utilized, including possibly any continued role for bamlanivimab monotherapy. Similarly, it will be helpful to better define effectiveness by time to infusion from date of symptom onset. This would identify when patients receive the most benefit and inform operational considerations such as actual need for 7 days per week availability and other considerations.

In this propensity-matched observational study, bamlanivimab monotherapy was associated with reduced hospitalizations and mortality within 28 days among patients with mild-moderate COVID-19. This effect was most pronounced among those 65 years or older. M a n u s c r i p t 

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