EM Lit Review: Monoclonal Antibody in Mild COVID Patients
By University of Virginia Health System emergency physicians and UVA School of Medicine associate professors Joshua Easter, MD, MSc and Robert Reiser, MD, MS
A 56 year old male with a history of hypertension presents with 4 days of cough and myalgias. His temperature is 38.1o C, heart rate is 90, blood pressure is 150/95, and oxygen saturation is 95% on room air. He has no respiratory distress, and his lungs are clear to auscultation. His SARS-CoV-2 test is positive. You anticipate the patient is safe for discharge from your ED. Should you administer a monoclonal antibody (such as bamlanivimab) to this patient?
A small proportion of patients (~10%) with initially mild SARS-CoV-2 infection will progress to more severe infections, requiring hospitalization. Studies in monkeys have shown that administration of neutralizing antibodies reduces the viral load of SARS-CoV-2 in the upper and lower respiratory tract when the antibodies are administered prior to infection. Eli Lilly and Company have manufactured a neutralizing antibody, bamlanivimab (LY-CoV555), that binds with high affinity to the receptor binding domain of SARS-CoV-2. A second antibody, etesevimab, also binds to SARS-CoV-2 and in preclinical studies neutralizes variants with mutations that prevent bamlanivimab binding. Based largely on the results of an industry sponsored trial, the FDA granted emergency use authorization to offer this monoclonal antibody to patients with SARS-CoV-2. The press has advocated increased utilization of this experimental therapy (NY Times; Washington Post).
Eli Lilly and Company performed a randomized, double-blind, placebo controlled trial of bamlanivimab at 49 medical centers in the United States. They recently published on the interim and final phases of their study, assessing the impact of bamlanivimab administration on 577 adult patients with SARS-CoV-2 and mild to moderate symptoms (Chen, 2020; Gottlieb, 2021). Patients with severe infection, requiring hospitalization or supplemental oxygen, as well as any patient deemed by the investigators to have a concomitant condition that “should preclude participation” were excluded. Patients were randomized to placebo or one of three doses of a single one hour infusion of bamlanivimab (700, 2800, or 7000 mg) or combination therapy of bamlanivimab and etesevimab within 3 days of a positive SARS-CoV-2 test. The primary outcome was the change in viral load at 11 days. Secondary outcomes were symptom burden, subsequent ED visits or hospitalization, and adverse reactions to bamlanivimab administration.
Most patients were young (mean age of 45 years) with mild disease (78%) early in their disease course (median of 4 days from symptom onset to treatment). All groups, including the placebo group, had substantial reductions in viral load by day 11 with a mean elimination of more than 99.97% of viral RNA.
Lilly examined the impact on viral load at 11 days and for 3 different doses, Compared with the placebo group, the change from baseline to day 11 in log viral load was not significantly different for any of the groups, except the combination of bamlanivimab and etesevimab. Viral clearance (defined as 2 consecutive negative test results for SARS-CoV-2) did not differ among any of the treatment groups at any time point.
In terms of symptoms, Lily assessed symptoms on a 24 point scale. Compared with the placebo group, the change in mean total symptom score from baseline to day 11 was significantly improved for patients receiving 700 mg of bamlanivimab or the combination of bamlanivimab and etesevimab, albeit by less than 1 point on a 24 point scale. The change in symptom score was not significantly different for patients receiving 2800 mg or 7000 mg compared to placebo. By day 11 all groups had minimal symptoms.
Regarding subsequent medical visits, at 1 month 1.4% of patients that received treatment had been to the ED or hospitalized compared to 5.8% of placebo patients. Only patients receiving receiving the combination of bamlanivimab and etesevimab had statistically significant reductions in subsequent medical care compared to placebo. A post hoc analysis limited to patients ³65 years or BMI ³35 foundthose who received bamlanivimab had a lower hospitalization rates; 2.7% in patients receiving 700 mg; 3.3% in those receiving 2800 mg, 5.9% in those receiving 7000 mg group, and 0% in those receiving combination therapy compared with 13.5% of those who received placebo. Only 1 patient in the study (in the placebo group) was admitted to the intensive care unit.
There were no significant differences in adverse events between groups. A small proportion (2.3%) of patients receiving bamlanivimab experienced mild infusion related events, such as pruritis, flushing, rash, or facial swelling.
While the FDA approved bamlanivimab as an experimental therapy and the press is encouraging increased utilization of it, this study provides very limited evidence to support its routine use. There were no consistent reductions in viral load across doses and time points with bamlanivimab monotherapy. All groups, including placebo, had substantial reductions in viral load by day 11. The clinical ramifications of the reduction in viral load with the combination of bamlanivimab and etesevimab is unclear. There is not currently robust evidence showing an association between viral load and symptoms, prognosis, or infectivity. As a result, routine administration of bamlanivimab does not appear to be justified based on the impact on viral load.
The reduction in symptom score of £1 point observed in this trial is also not of any clear clinical significance. Clinical symptoms were measured on a 24 point subjective symptom scale. A one point decrease in symptoms could represent resolution of a mild sore throat, or rating a cough as transitioning from moderate to mild. Moreover, by day 11 nearly all patients had minimal symptoms. Therefore, routine administration of monoclonal antibody does not appear to be justified based on the impact on symptoms.
The most robust evidence for monoclonal antibody administration is the potential effect on hospitalization, but this too is quite limited. First, seeking subsequent medical care in an imperfect measure of disease severity; there are numerous reasons patients might return to the ED or need hospitalization that do not necessarily reflect worsening disease. Notably, the investigators did not report on more objective measures of disease progression that they collected, such as need for supplemental oxygen or mechanical ventilation. While patients in the treatment groups did appear to return to the ED or hospital less for subsequent care, Lilly appears to have altered this outcome measure post-hoc. The initial protocol described differentiating between subsequent ED visits and hospitalizations ³24 hours. However, the investigators combined these outcome measures for unclear reasons, and discrete data have not been published. This has important implications, as often patients return to the ED and are discharged. Only 15 total patients in this trial returned to the ED or were hospitalized; if even a small number of these patients were ED visits only without admission to the hospital, it could drastically alter the results in terms of the impact of the drug on true hospitalizations.
Finally, the investigators examined a subgroup at high risk for severe infection. However, they only presented partial results for this subgroup; they selected a cohort with obesity or age ³65 years but notably excluded data they collected for other high risk groups, such as patients with significant co-morbidities. There is no explanation for this selection strategy. In addition, only 12% of their patients were ³65 years, making it difficult to draw any meaningful conclusions from this cohort.
Based on these limitations, the NIH and Infectious Disease Society of American guidelines do not consider bamlanivimab standard of care for SARS-CoV-2 (NIH, IDSA). Notably, a recent study of bamlanivimab for hospitalized patients was terminated early after it was found that the antibody did not improve outcomes (Lundgren, 2020). If monoclonal antibody is to be considered, it only should be for select patients, and when feasible it should be administered outside the ED (Table). In the absence of better evidence, we do not administer bamlanivimab routinely to our patients in the ED.
Your patient has early, mild SARS-CoV-2 infection and is at higher risk of severe disease based on his age coupled with hypertension. You discuss the significant limitations of the evidence with the patient regarding bamlanivimab, and you all decide not to administer it. The patient is discharged home and is asymptomatic after one week.
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