key: cord-0993393-1i17kew3
authors: Razonable, Raymund R.; Ganesh, Ravindra; Bierle, Dennis M.
title: Clinical Prioritization of Anti-Spike Monoclonal Antibody Treatment of Mild to Moderate COVID-19
date: 2021-11-19
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2021.11.017
sha: d5f8066c5cab17b007fc43a208b4a9502d4a695e
doc_id: 993393
cord_uid: 1i17kew3

nan

The 2021 summer surge of coronavirus disease-19 in the United States is predominantly fueled by SARS-CoV-2 delta variant that is dominant in most communities 1 . The SARS-CoV-2 delta variant has increased transmissibility resulting in an uptick of cases with a corresponding increased rate of hospitalization across many locations, especially among communities with low COVID-19 vaccination rates. 1 Efforts to curtail this surge include vaccination and other public health mitigation strategies such as masking and social distancing. In addition, early outpatient treatment of mild to moderate COVID-19 is recommended to reduce the risk of progression to severe COVID-19 in patients at high risk in order to reduce the need for hospitalization.

Anti-spike monoclonal antibodies are authorized by the US FDA for early treatment of mild to moderate COVID-19 in high-risk patients. 2 In November 2020, the Mayo Clinic established a Monoclonal Antibody Treatment Program (MATRx) to provide these therapies to high-risk patients outside the hospital setting. 3 By October 22, 2021, the program had infused anti-spike monoclonal antibodies to over 13,800 patients. Analysis of the program's outcomes demonstrated significant reduction in hospital and intensive care unit admission, and mortality among 2335 patients who received bamlanivimab infusion compared to a propensity-matched cohort of 2335 untreated patients. 4 Given the emergence of SARS-CoV-2 delta and other variants with resistance to bamlanivimab and etesevimab, the MATRx program currently uses casirivimab-imdevimab for treatment, as it maintains efficacy against SARS-CoV-2 variants of concern including delta. 2 The hospitalization rate was significantly lower among 696 patients treated with casirivimab-imdevimab combination compared to 696 high-risk patients who did not receive monoclonal antibodies. 5 By leveraging the Electronic Health Record (EHR), the MATRx program developed the Monoclonal Antibody Screening Score (MASS), which is composed of the FDA EUA eligibility criteria issued in J o u r n a l P r e -p r o o f hospitalization. 6, 7 The clinical performance of MASS has been reported. 6, 7 There was a direct relationship between MASS and hospitalization rates -patients with higher MASS have higher rates of hospitalization. 6, 7 By stratifying patients into risk strata, MASS was originally designed to identify patients that will be prioritized for monoclonal antibody treatment during periods of scarcity. Resource scarcity may result from limited product supply, limited infusion capacity or staffing shortages. As it turned out, potential concern for scarcity -when the supply of the product or the capacity to infuse does not meet the increasing demand.

In this article, we offer our perspectives in addressing anti-spike monoclonal antibody allocation during periods of scarcity using the data gathered from MATRx program's clinical prioritization approaches. Specifically, we demonstrate that MASS and CAST scores can be used effectively to determine clinical priority and guide allocation -by identifying the subgroups of eligible patients who are at highest risk of hospitalization, and therefore would benefit most from prioritization for casirivimab-imdevimab treatment.

After IRB approval, we assessed the clinical outcomes of a total of 1141 patients in the Midwest who tested positive for COVID-19 and met the FDA EUA eligibility criteria for monoclonal antibody therapy in May and June 2021. The characteristics of this population are listed in Table 1 . The crude rate of allcause hospitalization was 5.3% among the 132 patients who were treated with casirivimab-imdevimab compared to 12.9% among 1009 patients who did not receive the therapy (p=0.015). This significant difference in the outcomes is even more clinically relevant because those who received casirivimabimdevimab treatment possessed more high-risk medical comorbidities, such as obesity, hypertension, diabetes and immunosuppression ( Table 1) . There was a significantly higher MASS (3.1 ± 2.6 vs. 1.3 ± 2.2; p<0.0001) and CAST (3.1 ± 1.9 vs. 1.8 ± 1.8; p<0.0001) scores among patients who received casirivimabimdevimab compared to those who did not receive monoclonal antibody. This data is similar to our previous report describing patients with higher comorbidity scores were more likely to consent to monoclonal antibody therapy, and likely reflects the patients' awareness of their multiple comorbidities as risk factors for COVID-19 complications. 6, 7 J o u r n a l P r e -p r o o f As shown in table 2, the rates of hospitalization among our patients increased directly with CAST and MASS, especially among those who did not receive monoclonal antibodies. CAST score of 1 or greater is more sensitive (sensitivity 96.9%, specificity of 26.5%) while a MASS of 1 or greater is more specific (sensitivity 73.1%, specificity 63.4%) for hospitalization. We further emphasize that patients with CAST score of 1 (without fulfilling any of stricter MASS eligibility criteria; i.e., MASS 0) were unlikely to require COVID-19 hospitalization; this latter group consists of the additional patients that were captured by the expanded EUA criteria enacted in May 2021. In our population of 218 untreated patients who belonged to this stratum (CAST 1, MASS 0), the all-cause and COVID-19 hospitalization rates were 7.8% and 0.1%, respectively; notably, 2/3 of all-cause hospitalizations in this group were for childbirth. Adjusting for pregnancy yields an all-cause hospitalization rate of only 1.8%, which compares favorably to the hospitalization rates among patients without any qualifying high-risk condition (i.e., CAST score of 0; 1.6% all-cause hospitalization, odds ratio 1.09, p=0.90; 0.4% COVID-19 related hospitalization, odds ratio 1.09, p=0.95). Accordingly, during periods when there is resource scarcity (i.e., when there is limited product supply or infusion appointment slots), this group of eligible but lower-risk patients may be given lower priority in order to ensure access for those with higher CAST and MASS scores.

These new data presented here add to our collective observations since the start of the MATRx Program in November 2020 that there is indeed a direct correlation between the number of medical comorbidities and the rate of hospitalization in high-risk patients with mild to moderate COVID-19.

Persons with multiple medical comorbidities (higher MASS and CAST scores) should therefore be given priority for monoclonal antibody allocation during periods of scarcity, as may occur during overwhelming surges of SARS-CoV-2 infection within the United States or in other countries where anti-spike monoclonal antibody supplies are far from abundant. This strategy is an effort to reduce the risk for disease J o u r n a l P r e -p r o o f progression thereby relieving the potential burden to the already overburdened hospital systems. This prioritization strategy should also be extended to patients with mild to moderate COVID-19 and were already admitted to the hospital for another cause in order to reduce their risk of disease progression that may lead to the need for intensive care unit admission.

We further propose that, during periods of scarcity, treatment of symptomatic high-risk COVID-19 patients should be given priority over post-exposure prophylaxis, with the exception of the exposed unvaccinated or immunocompromised essential or critical workers. High-risk patients who are already having mild to moderate COVID-19 have a limited time to receive these lifesaving monoclonal antibody therapies, and therefore should be prioritized over the exposed asymptomatic high-risk persons who will have a second chance at monoclonal antibody infusion, if they develop symptoms. For the eligible highrisk patients who were not given post-exposure prophylaxis due to scarcity, they should be monitored closely, and be treated early, only if they develop symptoms following their exposure. Because of society's dependence on our critical workers, they should be given priority for post-exposure prophylaxis if they remain at risk due to an underlying immunocompromised status or are not yet fully vaccinated.

While MASS and CAST scores are integral in the implementation of Mayo's MATRx Program, there was no period of resource scarcity since the program started in November 2020. There has always been sufficient supply of monoclonal antibody products from the federal government, and our institutional capacity for infusion had adequately met the overall demand for these lifesaving therapies. Nonetheless, the program remains at risk of resource scarcity since SARS-CoV-2 transmission and infection remains high in our communities and our product supply is not guaranteed as it remains dependent on the allocation provided by the federal and state governments. likelihood of benefit (defined by lack of clinical progression and hospitalization). In our program, we have found that MASS and CAST as paired screening tools are clinically useful in fulfilling this goal. 6, 7 We encourage the use of MASS and CAST to identify and stratify patients who would benefit the most from anti-spike monoclonal antibodies, thereby reducing COVID-19 related admissions and decompressing an already overwhelmed hospital system. As the SARS-CoV-2 delta variant continues to surge, and the demand for anti-spike monoclonal antibodies continues to increase, these two clinical tools for monoclonal antibody allocation should be strongly considered to complement other strategies that will also ensure equity among essential and critical workers and the underserved and under-represented populations. 6 J o u r n a l P r e -p r o o f , diabetes mellitus, hypertension, cardiovascular disease, pulmonary disease, dialysis or chronic kidney disease, bone marrow or organ transplant or immunosuppressive medication or disease, pregnancy, sickle cell disease, neurological or neurodevelopmental disorders, genetic or congenital metabolic disorder, liver disease, or use of medical devices. c Monoclonal Antibody Screening Score (MASS) assigned a score to each of the original US FDA EUA criteria (released November 2020), as follows: age ≥65 years (2), BMI ≥35 kg/m 2 (2), diabetes mellitus (2), chronic kidney disease (3), cardiovascular disease in a patient ≥55 years (2), chronic respiratory disease in a patient ≥55 years (3), hypertension in a patient ≥55 years (1), and immunocompromised status (3). Maximum score is 18.

Predicted COVID-19 positive cases, hospitalisations, and deaths associated with the Delta variant of concern

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

A Framework for Outpatient Infusion of Antispike Monoclonal Antibodies to High-Risk Patients with Mild-to-Moderate Coronavirus Disease-19: The Mayo Clinic Model

Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19

Casirivimab-Imdevimab Treatment is Associated with Reduced Rates of Hospitalization among High-Risk Patients with Mild to Moderate Coronavirus Disease-19

Influence of Social and Cultural Factors on the Decision to Consent for Monoclonal Antibody Treatment among High-Risk Patients with Mild-Moderate COVID-19

Real-World Clinical Outcomes of Bamlanivimab and Casirivimab-Imdevimab among High-Risk Patients with Mild to Moderate Coronavirus Disease