Evaluation of Monoclonal Antibodies in Preventing Hospitalizations, Emergency Department Visits, and Mortality in High-Risk COVID-19 Patients

Abstract

Background

The coronavirus disease 2019 (COVID-19) is a novel coronavirus that has caused an unprecedented global pandemic, with few treatment options currently available. Neutralizing monoclonal antibodies (mAbs) are a promising treatment approach to reduce hospitalizations in high-risk patients with mild-to-moderate COVID-19 infections.

Objective

The primary objective is to compare hospitalization rates of high-risk patients who tested positive for COVID-19 within 28 days between those who received mAb infusions versus those who did not. Secondary objectives were emergency department (ED) visits and mortality within 28 days of a positive test.

Methods

This single-center, institutional review board–approved, retrospective, observational cohort study included patients aged 19 years and older who tested positive for COVID-19 between December 2, 2020 and February 28, 2021. Patients who received the mAbs bamlanivimab or casirivimab/imdevimab were compared with patients who did not receive mAb infusions to examine hospitalization rates, ED visits, and mortality within 28 days of the positive COVID-19 test.

Results

A total of 2780 patients were evaluated for inclusion using electronic chart review via Cerner. Of the 1612 patients who met inclusion criteria, 568 received an mAb infusion (mAb group) and 1044 did not (non-mAb group). Baseline characteristics were similar between the 2 groups. Of the patients in the mAb group, 34 (6%) were hospitalized versus 397 (38%) in the non-mAb group. Patients with ED visits included 111 (20%) and 672 (64%) in the mAb and non-mAb groups, respectively. Finally, 5 patients in the mAb group experienced mortality (0.9%) versus 83 (8%) in the non-mAb group. Each endpoint achieved statistical significance with a P value of <0.0001.

Conclusion

Monoclonal antibody infusions are effective in preventing hospitalization, ED visits, and mortality in high-risk patients with mild-to-moderate COVID-19.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), first emerged in late 2019 and progressed into an unprecedented global pandemic. A wide range of symptoms have been reported, including fever and malaise, cough, sore throat, loss of taste and/or smell, diarrhea, respiratory failure, and death. ¹ Numerous medications from various drug classes have been tested as possible treatment agents for this novel virus, though few have shown efficacy. However, 1 promising approach is the use of neutralizing monoclonal antibodies (mAbs) early during infection.

Monoclonal antibodies are proteins produced by isolating genes of pathogen-specific B cells and are known to have direct pathogenic targets. Coronavirus disease 2019 attaches to human cells via spike proteins located on the virus surface. Monoclonal antibodies target and neutralize these spike proteins, thereby preventing the virus from attaching to and entering human cells. ² Two mAbs, bamlanivimab (BAM) and the combination casirivimab/imdevimab (CAS/IMD), were granted emergency use authorization (EUA) by the Food and Drug Administration (FDA) in November 2020.^3,4 Both EUAs were established for the treatment of mild-to-moderate COVID-19 in non-hospitalized, high-risk patients. The Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial first studied the effects of BAM monotherapy in the treatment of outpatients with mild-to-moderate COVID-19 during phase 2 of the trial. Although the primary endpoint of the study was viral load, a secondary endpoint evaluated hospitalization rates. The percentage of patients who received the BAM infusion, who were hospitalized at day 29, was 1.6% versus 6.3% of patients who received the placebo. A post hoc analysis examined the rates of hospitalization among patients who were 65 years of age or older and those with a body mass index (BMI) of 35 kg/m² or more. It was observed that 4% of patients in the treatment group were hospitalized versus 15% in the placebo group. ⁵ In addition, a post hoc analysis comparing BAM with and without etesevimab (ETE) reported a decreased hospitalization rate of 10.8% and 13.5%, respectively, for patients older than 65 years of age and a BMI of 35 kg/m². ⁶ Likewise, the interim analysis of a study using the cocktail of CAS/IMD showed COVID-19-related medical visits within 28 days of treatment for all patients receiving CAS/IMD was 6 of 182 (3%) versus 6 of 93 (6%) for placebo. ⁷ Among the participants who were serum antibody-negative at baseline, 5 of 80 (6%) in the CAS/IMD group had COVID-19-related medical visits compared with 5 of 33 (15%) in the placebo group. ⁷

Recently, the effectiveness of mAbs during the COVID-19 surge in the winter 2020-2021 has been evaluated. A real-world evaluation of the effectiveness of mAbs for COVID-19 was recently published evaluating 14-day hospitalization risk and mortality. This study included patients with high risk of emergency care hospitalization, and patients receiving mAb treatment had a decrease in both emergency care and/or hospitalization (odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.60-0.79). ⁸ A study by Bariola and colleagues found a substantial reduction in hospitalizations within 28 days between those receiving BAM and those who did not, 2.7% versus 13.5%, respectively, in high-risk patients. ⁹ A recent meta-analysis published in September 2021 included 8 studies conducted from December 1, 2019 to August 9, 2021. The combined total number of patients who were COVID-19 positive was 13 573, with 4191 treated with BAM and 9382 in the control group arm. Overall mortality and risk of hospitalization were statistically significantly lower in the BAM treatment arms: OR = 0.27, 95% CI = 0.15-0.49, P < 0.0001, I² = 0% and OR = 0.60, 95% CI = 0.49-0.73, P < 0.00001, I² = 31%, respectively. ¹⁰

To evaluate the effectiveness of mAb infusions during the winter peak of COVID-19 in 2020-2021, we conducted a retrospective cohort study to compare the rates of hospitalization, emergency department (ED) visits, and deaths in high-risk patients who received either BAM or CAS/IMD.

Methods

Study Setting and Design

This single-center, retrospective, observational cohort study conducted at the outpatient infusion center of a 314-bed community hospital in east-central Alabama was approved by the institutional review board. The study period was from December 2, 2020 to February 28, 2021, corresponding to the height of COVID-19 in the United States. During the study period, mAbs were supplied to the institution by the state and federal government, and thus the specific mAb available varied at different times. The 2 mAbs provided to our hospital included BAM dosed at 700 mg and the combination product of CAS 1200 mg and IMD 1200 mg, both given intravenously. Inclusion criteria were as follows: a positive COVID-19 test, at least 19 years of age, and at least 1 high-risk factor, defined by the FDA’s EUA for progression to severe COVID-19. These risk factors included being 65 years of age or older, BMI of 35 kg/m² or greater, type 1 or 2 diabetes mellitus, chronic kidney disease (CKD), immunosuppressive disease and/or therapy, and being at least 55 years old with heart disease, hypertension, or lung disease (LD). Certain patients were excluded due to the possible association of worse clinical outcomes when given an mAb infusion. Exclusion criteria were as follows: patients who were already hospitalized due to COVID-19, those who required oxygen therapy due to COVID-19, or those who required an increase in baseline oxygen flow rate due to COVID-19 if already on chronic oxygen therapy due to underlying non-COVID-19-related comorbidity. In addition, mentally disabled patients and pregnant patients were also excluded. Cerner Millennium, Version 2015.01.03 (Cerner Corp, Kansas City, MO, USA), was utilized to review electronic health records (EHRs), and study populations were selected following confirmation of eligibility to receive a mAb.

Study Outcomes

The primary outcome of our study was to compare hospitalization rates within 28 days of a positive COVID-19 test in patients who received an mAb infusion, either BAM or CAS/IMD (mAb group), with patients who received no mAb infusion (non-mAb group). Secondary outcomes included ED visits and mortality within 28 days.

Statistical Analysis

The primary and secondary outcome analyses were conducted using the Fisher exact test. The baseline characteristic comparison was performed using the Fisher exact test for categorical data and the Student t test for continuous data. Statistical significance was defined as P < 0.05. A post hoc OR was performed to describe the precision in the study. All statistical analyses were conducted in GraphPad (GraphPad Software, Inc, La Jolla, CA, USA).

Results

Patient Selection and Demographics

A total of 2780 patients who tested positive for COVID-19 between December 2, 2020 and February 28, 2021 were screened using electronic chart review. Of those 2780 patients, 1612 met inclusion criteria and had at least 1 high-risk factor. Of these, 568 patients received an mAb, BAM (514) or CAS/IMD (54). The demographic data between the 2 groups were similar based on sex, average age, type, and number of high-risk factors (Table 1). However, the mAb group contained more white patients, 71.1% versus 52.7%, and the non-mAb group had a higher number of African Americans, 42.2% versus 24.3%, as well as a higher number of patients with CKD and LD.

Table 1.

Patient Demographics.

	mAb (n = 568)	Non-mAb (n = 1044)	P value
Age (years), mean	62.8	60.7	0.0119
Gender, n (%)
Male	224 (39)	418 (40)	0.8314
Female	344 (61)	626 (60)
Race, n (%)
Asian	0 (0)	4 (0.4)	0.3040
Black	138 (24)	441 (42)	<0.0001
Hispanic	0 (0)	9 (1)	0.0313
Other	19 (3)	30 (3)	0.6492
White	404 (71)	550 (53)	<0.0001
Unknown	7 (1)	10 (1)	0.6161
Risk factors median	2	2
Age ≥65 years, n (%)	281 (49)	498 (48)	0.4982
BMI ≥35 kg/m2, n (%)	197 (35)	383 (37)	0.4471
CKD, n (%)	36 (6)	155 (15)	<0.0001
DM, n (%)	188 (33)	381 (36)	0.1904
Immunosuppressive disease, n (%)	65 (11)	143 (14)	0.2137
Immunosuppressive treatment, n (%)	54 (10)	94 (9)	0.7866
Age ≥55 cardiovascular disease, n (%)	158 (28)	321 (31)	0.2311
Age ≥55 hypertension, n (%)	325 (57)	557 (53)	0.1427
Age ≥55 chronic lung disease, n (%)	48 (8)	126 (12)	0.0287

Abbreviations: BMI, body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; mAb, monoclonal antibody.

Bolded values indicate a statistically significant result.

Study Outcomes

Regarding the primary outcome, 34 patients (6%) in the mAb group compared with 397 patients (38%) in the non-mAb group experienced hospitalization within 28 days of a positive COVID-19 test (OR = 0.01038, 95% CI = 0.0718-0.1500, P < 0.0001). For the secondary outcomes, 111 patients (20%) and 672 patients (64%) experienced an ED visit in the mAb and non-mAb groups, respectively (OR = 0.1345, 95% CI = 0.1054-0.1714, P < 0.0001). Finally, the 28-day mortality rate was 5 patients (0.9%) in the mAb group and 83 (8.%) in the non-mAb group (OR = 0.0128, 95% CI = 0.0415-0.2551, P < 0.0001; Table 2).

Table 2.

Clinical Outcomes.

Clinical outcomes within 28 days	mAb (n = 568)	Non-mAb (n = 1044)	Odds ratio (95% CI)	P value
Hospitalization, n (%)	34 (6)	397 (38)	0.01038 (0.0718-0.1500)	<0.0001
ED visitation, n (%)	111 (20)	672 (64)	0.1345 (0.1054-0.1714)	<0.0001
Mortality, n (%)	5 (0.9)	83 (8)	0.0128 (0.0415-0.2551)	<0.0001

Abbreviations: CI, confidence interval; ED; emergency department; mAb, monoclonal antibody.

Bolded values indicate a statistically significant result.

With regard to hospitalizations, there was no statistical difference in length of stay between those who received mAbs and those who did not (8.7 vs 10.5 days, P = 0.39). Likewise, there was also no difference in those requiring intensive care between mAb and non-mAb patients (24% vs 20%, P = 0.6582).

Discussion

Coronavirus disease 2019 infections have placed a tremendous strain on the health care system. ¹¹ Therapies that can prevent hospitalizations and decrease mortality are necessary to decrease the burden caused by COVID-19. During our study period, the Alabama Department of Public Health (ADPH) reported a vaccination rate of 6% of the state population. Monoclonal antibody therapy can play an important role in helping to ease the burden. This study adds to the existing literature and supports previous findings that mAbs can help prevent hospitalizations, ED visits, and mortality in patients with mild-to-moderate COVID-19 infections at high risk for disease progression.

The primary outcome of hospitalizations within 28 days of a positive COVID-19 test occurred significantly less in patients treated with a mAb (6%) compared to patients not treated with a mAb (38%), resulting in a number needed to treat of 3.1. Based on the non-mAb group rates, hospitalizations were reduced by 216 patients during the study period, and 2160 patient days were avoided based on an average hospitalization time at our facility of 10 days. This was reflected by both mAb and non-mAb patients having similar hospitalization length of stay and the need for intensive care.

This study has several limitations that must be considered. This was a retrospective study with limitations inherent to this type of study design. Information available was limited to what was available in patients’ EHRs. Many patients were tested for COVID-19 through drive-up services, so a full medical history was not obtained. Symptom onset was not obtained due to data collection discrepancies at both our testing center and hospital. Another limitation was in the inability to include patients who may have been tested through other community testing centers not affiliated with the study site. This would have potentially impacted the non-mAb group, because any patient receiving the mAb infusion, regardless of testing site, was documented, resulting in a greater risk reduction in the mAb group versus the non-mAb group. Information regarding patients’ onset of symptoms in relation to when they sought a COVID-19 test and/or mAb was also not available and could have led to a major difference in the risk of hospitalizations due to waiting too late to seek medical care. In addition, some COVID-19 variants have decreased susceptibility to mAbs. Our laboratory was unable to identify potential COVID-19 variants during this study period. However, according to the Centers for Disease Control and Prevention (CDC), B.1.1.7 (Alpha) increased from 0.6% to 15% in our region during the study period. ¹¹ Finally, a concerning observation of the study was the comparison of ethnicities and the number of mAbs between these groups. White patients were more likely to receive mAb treatment compared with African Americans and Hispanic patients. This is most likely due to health care disparities in the United States. According to a 2010 ADPH report on health care disparities, minorities in Alabama have lower access to health care. ¹² This is a multifactorial issue involving social and ecomonic concerns, lack of physician access, and health literacy. A physician-approved protocol was developed at our testing site to prescreen individuals for qualification for receiving mAb in an effort to reach as many in our community that met the EUA criteria.

The EUAs for both mAbs have changed several times since November 2020. The EUA for BAM alone was removed in April 2021 due to evidence of resistance with monotherapy, and a pause was announced on the combination BAM/ETE in June 2021.^13,14 However, as of September 2, 2021, BAM-ETE has been redistributed and is recommended in areas where the frequency of potentially resistant strains is low. Currently, CAS/IMD remains effective against variants of concern and interest. ¹¹ Since the time period examined for our study, the FDA has added that CAS/IMD may be administered as a subcutaneous injection. The dosage given is CAS 600 mg plus IMD 600 mg, regardless of the route. Infusion is still preferred, but administration of 4 subcutaneous injections (each containing 2.5 mL) is an acceptable alternative if it is not feasible to infuse or would delay treatment. ¹⁵ In addition, the FDA expanded the high-risk criteria in May 2021 to make it available to a larger percentage of the population. ¹⁶

Conclusion

The use of mAbs for the treatment of mild-to-moderate COVID-19 was highly effective in preventing hospitalizations within 28 days for high-risk patients, reducing ED visits, and preventing mortality. This study adds to the real-world evidence of mAbs for the treatment of COVID-19 and continues to show mAbs are extremely effective at reducing hospitalization and death. It is important to note that the dominant strains of COVID-19 have changed since the time of our study and continue to change, and this should be taken into consideration when selecting an mAb infusion.