The Omicron (B.1.1.529) variant of concern (VOC) has become the dominant variant in many parts of the United States.¹ The Omicron variant, which includes numerous mutations in the spike protein, is predicted to have markedly reduced susceptibility to several anti-SARS-CoV-2 monoclonal antibodies (mAbs), especially bamlanivimab plus etesevimab and casirivimab plus imdevimab. Sotrovimab appears to retain activity against the Omicron variant.

With the rapid rise in the prevalence of the Omicron VOC, it is anticipated there will be a limited supply of therapeutic agents that are active against the variant (e.g., the anti-SARS-CoV-2 mAb sotrovimab and small molecule antiviral agents, once they become available) for patients who are at high risk of progression to severe COVID-19 and who might benefit from these therapies.

Intravenous (IV) remdesivir is approved by the Food and Drug Administration (FDA) for the treatment of COVID-19 in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). Remdesivir has also been studied in nonhospitalized patients with mild to moderate COVID-19. Results from the PINETREE trial showed that 3 consecutive days of IV remdesivir resulted in a significant reduction in hospitalizations and deaths compared to placebo.² Remdesivir is expected to be active against the Omicron VOC.

This statement provides guidance on the use of anti-SARS-CoV-2 mAbs or remdesivir when the Omicron VOC is the predominant circulating variant. Ritonavir-boosted nirmatrelvir and molnupiravir, 2 new oral antiviral therapies, have just received Emergency Use Authorizations for use in nonhospitalized patients at high risk of progression to severe COVID-19 (see the FDA EUAs for recommendations). The COVID-19 Treatment Guidelines Panel (the Panel) will provide further recommendations as soon as more treatment options become available for this patient population.

Recommendations

When the Omicron variant represents the majority (e.g., >80%) of infections in a region, it is expected that bamlanivimab plus etesevimab and casirivimab plus imdevimab will not be active for treatment or post-exposure prophylaxis (PEP) of COVID-19.

In this setting, the Panel recommends using 1 of the following options to treat non hospitalized patients with mild to moderate COVID-19 who are at high risk of clinical progression:

• Sotrovimab 500 mg IV as a single infusion (AIIa) administered as soon as possible and within 10 days of symptom onset; or
• Remdesivir 200 mg IV on Day 1, then 100 mg once daily on Days 2 and 3 (BIIa) initiated as soon as possible and within 7 days of symptom onset.
  • Because remdesivir requires IV infusion for 3 consecutive days, logistical constraints may make it difficult to administer the drug in some settings.
  • Remdesivir should be administered in a setting where management of severe hypersensitivity reactions, such as anaphylaxis, is possible. Patients should be monitored during the infusion and observed for at least 1 hour after the infusion.
  • Remdesivir is currently FDA-approved for hospitalized individuals; however, use of the drug for outpatient treatment would be an off-label indication.

If neither sotrovimab nor remdesivir are feasible to use, and the Delta VOC still represents a significant, but not dominant proportion (e.g., ≥20%) of infections in the region:

• Patients could be offered bamlanivimab plus etesevimab or casirivimab plus imdevimab with the understanding that treatment would be ineffective if they are infected with the Omicron variant.
• Consider the use of bamlanivimab plus etesevimab or casirivimab plus imdevimab for PEP on a case-by-case basis with the understanding that the drugs may be ineffective if the person has been exposed to the Omicron variant.

Rationale

The data that support the EUA for sotrovimab are from the Phase 3 COMET-ICE trial, which included outpatients with mild to moderate COVID-19 who were at high risk for progression to severe COVID-19 and within 5 days of symptom onset. The primary endpoint was the proportion of participants who were hospitalized for ≥24 hours or who died from any cause by Day 29. Endpoint events occurred in 3 of 291 participants (1%) in the sotrovimab arm and 21 of 292 participants (7%) in the placebo arm (P = 0.002), resulting in a 6% absolute reduction and an 85% relative reduction (95% CI, 44–96) in hospitalizations or death associated with sotrovimab.^3,4 In vitro studies indicate sotrovimab remains active against the Omicron variant.⁵

Data supporting the clinical benefit of early outpatient treatment with remdesivir emerged from PINETREE, a randomized placebo-controlled trial in nonhospitalized patients with COVID-19 who were at high risk of clinical progression and within 7 days of symptom onset. The primary outcome was the proportion of participants who were hospitalized for ≥24 hours (defined as ≥24 hours of acute care) or who died from any cause by Day 28. Participants were randomized to receive 3 days of IV remdesivir or placebo as outpatients. At treatment initiation, the median duration of symptoms was 5 days. By Day 28, there was a significant decrease in hospitalizations and/or death among those who received remdesivir: the primary endpoint occurred in 2 of 279 (0.7%) remdesivir recipients versus 15 of 283 (5.3%) placebo recipients, resulting in a 4.6% absolute reduction and an 87% relative reduction in hospitalizations and/or death for remdesivir (HR 0.13; 95% CI, 0.03–0.59; P = 0.008).²

Here are the other recommendations for the treatment of Covid 19 from infectious disease specialists.  It also contains what is not recommended like oral steroids and azithromycin which I see prescribed frequently by emergency room physicians.  And yes, Ivermectin and hydroxychloroquine are on the do not prescribe list.

https://www.strac.org/files/Incident%20Specific/2019nCoV/Outpt_Strategies_ID_Leads_4Aug21rev.pdf

STRAC ID Leads Outpatient Strategies for COVID-19 Infection
• This is a summary of recommendations from STRAC ID Leads for outpatient
management of COVID-19.
• There are no oral FDA-approved or authorized therapies for COVID-19.
• NIH and Infectious Diseases Society of America (IDSA) guidelines do not recommend
non-FDA authorized or approved therapies for COVID-19 outside of a clinical trial.
Recommended by ID Leads
• Isolation – Persons diagnosed with COVID-19 should isolate at home
• For mild to moderate disease, CDC recommends discontinuing isolation 10 days
after the onset of symptoms and resolution of fever for at least 24 hours without
the use of fever-reducing medications.
• For severe disease (requiring hospitalization), CDC recommends discontinuing
isolation 20 days after the onset of symptoms and resolution of fever for at least
24 hours without the use of fever-reducing medications; for immunosuppressed
persons and those requiring intubation isolation should be continued for 28
days.
• For asymptomatic persons, isolation for 10 days after the first positive test for
SARS-CoV-2 is recommended.
https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/isolation.html
• General Recommendations
• Nutrition/hydration
• Adequate sleep
• Stop/limit smoking and vaping
• Limit alcohol use
• Acetaminophen or ibuprofen for fever
• Equipment
• Thermometer
• Pulse oximeter
• Home blood pressure cuff
• Warning Signals Warranting Presentation to Health Care Setting for Evaluation
• Oxygen saturation <94% at rest
• Significant desaturation into 85% range upon walking
• Persistent shortness of breath
• Persistent fever
• Decrease in mental status (e.g., confusion, lethargy)

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• Significant decrease in blood pressure
• Monoclonal Antibodies
• FDA authorized (under EUA) https://www.fda.gov/media/145611/download
▪ Casirivimab and imdevimab (REGEN-COV, Regeneron)
• Treatment (within 10 days of onset)
▪ Mild to moderate COVID-19 disease
▪ in adult and pediatric patients (12 years of age and older weighing at
least 40 kg)
▪ with positive results of direct SARS-CoV-2 viral testing,
▪ who are at high risk for progression to severe COVID-19, including
hospitalization or death
• Limitations of Authorized Use
▪ Not authorized for use in patients who:
• Are hospitalized due to COVID-19
• Require oxygen therapy due to COVID-19
• Require an increase in baseline oxygen flow rate due to COVID-19
in those on chronic oxygen therapy due to underlying non-COVID19 related comorbidity
▪ Monoclonal antibodies may be associated with worse clinical outcomes
when administered to hospitalized patients with COVID-19 requiring high
flow oxygen or mechanical ventilation.
• Criteria for identifying high risk individuals for monoclonal antibody administration:
The following medical conditions or other factors may place adults and pediatric patients (age
12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:
• Older age (for example, age ≥65 years of age)
• Obesity or being overweight (for example, BMI >25 kg/m2 ,
• or if age 12-17, have BMI ≥85th percentile for their age and gender based on CDC
growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm)
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppressive disease or immunosuppressive treatment
• Cardiovascular disease (including congenital heart disease) or hypertension
• Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma
[moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary
hypertension)
• Sickle cell disease
• Neurodevelopmental disorders (for example, cerebral palsy)
• Or other conditions that confer medical complexity (for example, genetic or
metabolic syndromes and severe congenital anomalies)
• Having a medical-related technological dependence (for example, tracheostomy,
gastrostomy, or positive pressure ventilation (not related to COVID 19)

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• Other factors may place individual patients at high risk for progression to severe COVID-19 and the
EUA is not limited to the medical conditions or factors listed above.
Not Recommended
• Oral corticosteroids – not recommended in outpatients not on oxygen for COVID-19
o RECOVERY trial showed benefit for hospitalized pts requiring supplemental
oxygen.
o Hospitalized pts who did not require oxygen had worse clinical outcomes on
steroids
The Recovery Collaborative Group. Dexamethasone in Hospitalized Patients with Covid19. New Eng J Med, 2020. doi:10.1056/NEJMoa2021436.
Often Recommended by ID Leads
• Zinc lozenges
o Antiviral activity
o Can decrease duration/severity of common cold
o Well-tolerated
o High doses over long term – GI side effects, copper deficiency
Prasad AS, Fitzgerald JT, Bao B, Beck FWJ, Chandrasekar PH. Duration of symptoms and
plasma cytokine levels in patients with the common cold treated with zinc acetate. Ann
Intern Med 2000;133:245-252.
• Vitamin D
o Important for immune function and an Immune modulator
o Vitamin D deficiency associated with worse outcomes
o Vitamin D supplementation can protect against acute (non-COVID) respiratory
infection
o Supplementation in hospitalized COVID-19 pts – no difference in LOS, intubation,
death
o Consider especially for those at risk for deficiency
▪ Elderly
▪ Persons with melanin-rich skin
▪ Persons with no or limited sun exposure
o Dose of 2000 IU daily
Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? The Lancet
Diabetes and Endocrinology. 2020;8(7):570.
https://www.thelancet.com/journals/landia/article/PIIS2213-8587%2820%2930183-
2/fulltext
Jain A, Chaurasia, Sengar NS, Singh M, Mahor S, Narain. Analysis of vitamin D level
among asymptomatic and critically ill COVID-19 patients and its correlation with
inflammatory markers. Nature Research 2020;10:20191.
https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-d/

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• Melatonin
o Antioxidant and anti-inflammatory
o Production decreased in older adults
o Good safety profile
o Reasonable dose is 3 mg nightly which is easily found in tablet form
o If a smaller dose is needed due to morning grogginess, use the liquid form at 0.3
mg nightly
Hardeland R. Melatonin and inflammation: story of a double-edged blade. J Pineal
Res. 2018;65(4):e12525.
Silvestri M, Rossi GA. Melatonin: its possible role in the management of viral infections:
a brief review. Ital J Pediatr. 2013;39:61.
Cross KM et al. Melatonin in early treatment for COVID-19: A narrative review of current
evidence and possible efficacy. Endocrine Practice 2021
https://doi.org/10.1016/j.eprac.2021.06.001
Sometimes Recommended by ID Leads
• Fluvoxamine
o SSRI that is an immunomodulator
o Potential mechanisms
▪ Sigma-1 activation – reduces cytokine production
▪ Inhibits sphingomyelinase, relevant for viral entry
▪ Inhibits hyperactivation of platelets and mast cells
▪ Inhibits metabolism of melatonin
▪ Good safety profile
▪ Inexpensive and widely available
o Lenze EJ, Mattar C, Zorumski CF et al. Fluvoxamine vs. placebo and clinical
deterioration with symptomatic COVID-19. JAMA Published online November 12,
2020.
▪ Positive Phase 2 study in outpatients; Dose 100 mg TID
▪ Primary endpoint – clinical deterioration, N=152 outpatients
▪ 0% (0/80) in fluvoxamine group vs 8.3% (6/72) in the placebo group. 5/6
to hospital; 4 hospitalized; P=0.009
▪ SAEs – 1 in fluvoxamine group (hospitalization for dehydration) vs. 6 in
placebo group
o Seftel D, Boulware D. Prospective cohort of fluvoxamine for early treatment of
coronavirus disease 19. Open Forum ID 2021;8(2) ofab050
https://doi.org/10.1093/ofid/ofab050 1 Feb 2021
▪ Dose 50 mg twice daily
▪ 0/65 pts on fluvoxamine hospitalized; 0/65 residual sx
▪ 6/48 (12/5%) on observation hospitalized; 29/48 (60%) residual sx
o Phase 3 trial underway. Pts can be referred to trial
https://stopcovidtrial.wustl.edu/ Dose 100 mg twice daily

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• Inhaled budesonide
o Ramakrishnan S et al. Inhaled budesonide in the treatment of early COVID-19: a
phase 2, open label, RCT. Lancet Respiratory Medicine 2021;9(7):763-772. April
09, 2021 DOI:https://doi.org/10.1016/S2213-2600(21)00160-0
o Small study, n=146
o Early administration of inhaled budesonide reduced the likelihood of needing
urgent medical care and reduced time to recovery after early COVID-19.
• Famotidine
o Histamine-2 receptor antagonist may modulate cytokine storm
o Positive preliminary studies warrant further investigation
o Good safety profile
o Would not exceed approved dose of 40 mg daily
Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of
hospitalized patients with COVID-19. Am J Gastroenterol 2020
• Self-proning
o May be used in cooperative patients who have mild desaturation and are
comfortable in prone position
o Benefit usually noticed within 5-10 minutes
o Usual interval 30-120 minutes
o Sequence: prone, left lateral decubitus, right lateral decubitis, upright sitting
o Only maintain if comfortable for patient
o Avoid with pregnancy, spinal instability, face or neck trauma, hemoptysis
Telias I, Katira BH, Brochard L. Is the prone position helpful during spontaneous
breathing in patients with COVID-10? Jour Amer Med Assoc 2020;323:22:2265-2267.
No Recommendation
• Ivermectin
o Recent meta-analysis showed improved mortality but two large studies in
analysis had flawed data, and without them, no benefit
o Good safety profile
o Some concerns about neurotoxicity in inflammatory phase (due to decrease in
BBB)
o Animal preparations should not be used in humans
Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter J. Use of ivermectin is
associated with lower mortality in hospitalized patients with coronavirus disease 2019.
Chest: Oct. 12, 2020.
Hill A et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2
infection. Open Forum ID ofab358 https://doi.org/10.1093/ofid/ofab358 6 July 2021

6
• Aspirin (ASA)
o Preliminary observational study showed less complications in hospitalized
patients who had received ASA within 24 hours of admission or 7 days prior to
admission
o Risk of bleeding
o Avoid in children due to Reye’s Syndrome
Chow JH, Khanna, AK, Kethireddy, S, et al. Aspirin Use is Associated with Decreased
Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized
Patients with COVID-19 Anesthesia & Analgesia Pub ahead of print: Oct. 21, 2020
• Nasal irrigation with 1% povidone-iodine
o Iodine should not be used in thyroid conditions or pregnancy
o User must be competent in using irrigation device, including proper cleaning
Farrell NF et al. Benefits and safety of nasal saline irrigations in a pandemic—
washing COVID-19 away. JAMA Otolaryngology-Head & Neck Surgery.
2020;146;787
• Probiotic Lactobacillus rhamnosus
o Some evidence to suggest immunomodulatory effect in sepsis
o Clinical trial ongoing in COVID-19
https://sites.duke.edu/protectehc/about-our-study/
Not Recommended Until More Information is Available
• Colchicine
o Preliminary positive study in hospitalized patients
o Side effects: GI (diarrhea, nausea/vomiting, abdominal pain), muscle weakness,
numbness/tingling, allergic reaction
Deftereos SG, Giannopoulos G, Vrachatis DA et al. Effect of colchicine vs. standard care
on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized
with coronavirus disease. JAMA Network Open 2020:3(6):e2013136
o Additional Information:
▪ COLCORONA Study
▪ https://www.medrxiv.org/content/10.1101/2021.01.26.21250494v1.full.
pdf
▪ Dose 0.5 mg BID x 3 days and once daily thereafter for total of 30 days
▪ Study in non-hospitalized pts. Primary endpoint death or hospitalization
▪ COVID dx by PCR or clinical criteria, N=4488
▪ Death or hospitalization decreased 1% (4.7% vs 5.8%; OR 0.79, p 0.08)
▪ PCR confirmed Covid, N=4159
▪ Death or hospitalization decreased 1.4% (4.6% vs 6.0%, p 0.04)
▪ Diarrhea more common in the colchicine group (13.7% vs 7.3%, p 0.0001)
▪ Pulmonary embolism more common in the colchicine group 0.5% vs.
0.1%, 11 vs 2 pts, p 0.01

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▪ Generic colchicine no longer available; based on our sources 30 days of
colchicine costs ~$250
Not Recommended
• Hydroxychloroquine
o Multiple well-conducted studies show negative results
o Side effects – GI and prolonged QT interval
Saag MS. Misguided use of hydroxychloroquine for COVID-19. Jour Amer Med Assoc
Published online November 9, 2020
• Azithromycin and Doxycycline
o Studies largely done with hydroxychloroquine
o Well-conducted trials have been negative
o Unnecessary use contributes to antimicrobial resistance
o Side effects – prolonged QT interval, GI, C. difficile colitis
• Vitamin C
o Antioxidant and anti-inflammatory
o Studied in sepsis with variable outcomes
o Few safety concerns
o COVID-19 studies have been IV doses in hospitalized patients
o Clinical trials ongoing
NIH Guidelines https://www.covid19treatmentguidelines.nih.gov/
IDSA Guidelines https://www.idsociety.org/practice-guideline/covid-19-guideline-treatmentand-management/