IDSA Guidelines on the Treatment and Management of Patients with COVID-19

How to Approach a Patient When Considering Pharmacologic Treatments for COVID-19

In this section, we discuss how to approach a patient suspected to have COVID-19 and how to apply the IDSA COVID-19 treatment guidelines to specific clinical syndromes. The detailed evidence appraisals and recommendations for each therapeutic agent can be found in the individual sections. The certainty of supporting evidence is low to moderate for most recommendations; therefore, the guideline panel made conditional suggestions rather than strong recommendations for or against most of the agents. Though substantial progress was made with COVID-19 therapies in such a short period, there still remain many unanswered questions in the management of COVID-19. Therefore, the approach outlined here and in the guidelines are based on some assumptions and extrapolations. Despite limited evidence, to give actionable and timely guidance to frontline clinicians, we provide recommendations for use of combinations of agents, recommend some agents over others or extrapolate to sub populations not evaluated in trials.

Some of the critical unanswered questions in COVID-19 treatment trials are:

• Which sub-populations or specific clinical types of patients with COVID-19 benefit most from specific therapeutic agents?
• What is the efficacy and safety of COVID-19 therapies in populations that are immune from prior SARS-CoV-2 infections and vaccination?
• What is the efficacy and safety of treatments in infections with specific SARS-CoV-2 variants and sub-variants?
• How do therapeutic agents perform when compared to each other to allow a tiered approach to treating patients with COVID-19?
  • What is the comparative efficacy and safety of nirmatrelvir/ritonavir versus remdesivir, molnupiravir, and different anti-SARS-CoV-2 antibodies in mild-to-moderate disease?
  • What is the efficacy and safety of IL-6 inhibitors when compared to JAK inhibitors in severe disease?
• What is the comparative efficacy and safety of combinations of different drugs in treating different severities and clinical phenotypes of COVID-19?
• Which biomarkers can be used as predictors of therapeutic response to specific agents?

We hope future studies and trials address these uncertainties so we can give a more definitive treatment approach to COVID-19.

General Principles of COVID-19 Pharmacotherapy

During the early phase of the infection, when viral load is high and the host’s adaptive immune system has not mounted an adequate response, treatments targeting viral replication are most likely to be effective. These include both the direct antiviral therapies nirmatrelvir/ritonavir, molnupiravir, and remdesivir; and the passive immunity therapies of anti-SARS-CoV-2 antibodies and donor convalescent plasma. Timely initiation of antiviral therapies is critical as they are more efficacious when given within 5 to 7 days of symptom onset. Most patients do not progress to severe or critical disease, but some with risk factors do.  Later in the disease process, in patients with severe and especially critical disease, an excessive and aberrant inflammatory response is implicated to be the primary cause of immunopathological damage. At this stage anti-inflammatory therapies like corticosteroids, IL-6 inhibitors or JAK inhibitors have been shown to be beneficial.

Clinical Evaluation

Clinical evaluation should consider patient and pathogen specific factors that can influence choice of COVID-19 treatments. The evaluation should at least include assessment of:

• Severity of COVID-19
• Date of onset of symptoms
• Risk factors for progression to severe disease or death (see further discussion below, under Pharmacologic treatment of mild-to-moderate COVID-19 with risk factors for progression)
• Degree of chronic and acute end-organ dysfunction (including, but not limited to, pulmonary, cardiovascular, renal, and hepatic)
• Age and pregnancy status
• Virus-specific factors that may influence the choice of pharmacotherapy (e.g., variant specific susceptibility to certain drugs)
• Risk factors for progression are changing as the epidemic evolves with new variants, vaccination, and previous infection rates.

Diagnostic classification of severity of COVID-19 helps target specific treatments to patient populations that have been demonstrated to benefit in COVID-19 treatment trials. The clinician should identify which of the severity categories in Table 35 the patient falls into.

It is also important to identify factors that preclude the use of COVID-19 treatments or warrant their use with caution. Patients with low estimated GFR were not included in the trials for remdesivir and tocilizumab. Elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels are a contraindication for IL-6 inhibitors and remdesivir. Patients who were neutropenic, had an active bacterial, fungal or parasitic infection, or were hypercoagulable were eliminated from some of the JAK inhibitor trials. It is also important to identify if the patients have other acute disease that either mimic COVID-19 or present concomitantly with COVID-19. Patients can have a positive SARS-CoV-2 by RT-PCR from a nasopharyngeal sample, and present with pulmonary disease caused by a bacterial pneumonia or pulmonary edema. Patients with COVID-19 can also have pulmonary embolism contributing to their symptoms and hypoxemia. It is important to avoid anchoring bias to the diagnosis of COVID-19 and be attentive to considering and evaluating other etiologies. Many of the COVID-19 therapies are not FDA-approved and have instead received FDA EUA, so it is necessary to follow the regulatory processes and protocols for these agents.

Pharmacologic Treatment of Mild-to-Moderate COVID-19 with Risk Factors for Progression

COVID-19 is considered mild when there are clinical features suggestive of upper res-piratory tract involvement without features of lung or other end organ involvement. Moderate COVID-19 is pulmonary involvement with no hypoxia. Most patients improve with supportive care at this stage, but patients with risk factors can progress to more severe or critical disease or death; such individuals may benefit from pharmacotherapies. There are no validated clinical prediction rules or risk calculators, but the FDA EUA and CDC mention a few of these risk fac-tors to consider for treatment with anti-SARS-CoV-2 antibodies [276]. More research is needed to identify prediction instruments and determinants that both increase or decrease the risk of severe disease and how potentially protective factors influence risk stratification. Most of these treatments are effective only when given early, within 5-7 days of symptom onset.

Patients who have these risk factors should be offered treatment with nirma-trelvir/ritonavir for 5 days (oral) or remdesivir for 3 days (intravenous). If these agents  are not available or cannot be used then consider molnupiravir for 5 days (oral) or, if immunocompro-mised, high-titer convalescent plasma (intravenous) with activity against circulating variant. Convalescent plasma obtained from people who have recovered from COVID-19 due to Omi-cron and have been vaccinated is expected to be active against Omicron.

arenteral anti-SARS-CoV-2 monoclonal antibodies can be used to treat if the circulating SARS CoV-2 variants in that region are susceptible to the specific agent, given trials have shown a reduction in the need for hospitalizations, ER visits or medically attended visit. At present (2/2/2023) a significant proportion of the circulating SARS CoV-2 variants in the US are not sus-ceptible to most of the neutralizing antibodies. There are no neutralizing antibodies that are currently (2/2/2023) authorized or approved by US FDA. 

There are logistical issues related to administration of parenteral agents in ambulatory settings which may preclude their use. Oral antivirals like nirmatrelvir/ritonavir and mol-nupiravir have an advantage as they are easy to prescribe in outpatient settings, but there are significant limitations and unique considerations that need to be addressed by providers, which might be a barrier to their timely use. In the United States, many of the antiviral treatments do not have authorization for use in patients admitted to the hospital for mild-to-moderate COVID-19 but can be used if they are admitted for another reason and found to have mild-to-moderate COVID-19. We do not recommend using hydroxychloroquine, azithromycin, or lop-inavir/ritonavir as trials have shown no evidence of benefit.

We recommend against the use of ivermectin outside of the context of a clinical trial given the low certainty of evidence for its benefit. We also do not recommend the use of sys-temic corticosteroids in mild-to-moderate COVID-19. Though the RECOVERY trial was complet-ed in hospitalized patients and not ambulatory patients, it demonstrated a trend to increase mortality when used in patients with mild-to-moderate COVID-19 (relative risk 1.22; 95% CI 0.86, 1.75) [95].

Pharmacologic Treatment of Severe COVID-19

Patients with severe COVID-19 are those whose infection has pulmonary involvement resulting in hypoxia while breathing room air and/or needing treatment with low flow oxygen. Most existing criteria for trials consider either a SpO2 level less than 94% or 90% or tachypnea (respiratory rate >30 breaths per minute) as severe COVID-19. Clinical judgment of individual cases should supplement these criteria.

Corticosteroids, especially dexamethasone, has demonstrated a mortality benefit are recommended as the cornerstone of therapy in severe COVID-19. Remdesivir may be consid-ered as it has shown to decrease time to recovery or discharge, though it has not been shown to improve mortality [32, 159].

The IL-6 inhibitors tocilizumab and sarilumab [111, 277] and JAK inhibitors baricitinib and tofacitinib [182] have shown a benefit in severe, but non-critical COVID-19 when used with corticosteroids. The trials did not identify specific sub-populations of patients with severe COVID-19 already being treated with corticosteroids who would benefit most with additional treatment with IL-6 or JAK inhibitors. We recommend using either IL-6 inhibitors or JAK inhibi-tors (baricitinib preferred over tofacitinib) in those patients who have elevated inflammatory markers like CRP and progressive severe COVID-19. Since there is greater supportive data for tocilizumab and baricitinib we recommend them preferentially over sarilumab and tofacitinib, though the latter agents are suitable alternatives if the former are not available. We do not recommend using hydroxychloroquine, azithromycin, lopinavir/ritonavir, or convalescent plas-ma as trials have not shown a benefit in patients with severe disease. We also recommend against the use of ivermectin outside of the context of a clinical trial given the low certainty of evidence for its benefit.

Pharmacologic Treatment of Critically ill COVID-19 Requiring Non-Invasive Ventilation or Oxygen by High-Flow Nasal Cannula

Critically ill patients with COVID-19 need more ventilatory or oxygenation support either with high-flow oxygen or with noninvasive ventilation. High-flow oxygen therapy involves deliv-ery of oxygen via special devices at rates greater than those possible via a simple nasal canula.

We strongly recommend systemic corticosteroids in critically ill patients with COVID-19 as they have shown a mortality benefit in this population (OR: 0.66; 95% CI: 0.54; 0.82) [79]. In critically ill patients, dexamethasone 6mg/day is preferred but doses up to 20 mg/day can be used if indicated for other reasons. Hydrocortisone 50 mg IV Q6 hours is an alternative that has also been studied. Methylprednisolone and prednisone have less supporting data but are rea-sonable pharmacologic alternatives at equipotent doses. In addition to corticosteroids, we rec-ommend using either IL-6 inhibitors (tocilizumab preferred over sarilumab) or JAK inhibitors (baricitinib preferred over tofacitinib) in patients who have elevated inflammatory markers (e.g., CRP), which most critically ill COVID-19 patients have. The trials done so far have not identified specific sub-populations of critically ill patients already being treated with cortico-steroids who would benefit with additional treatment with IL-6 or JAK inhibitors. We do not rec-ommend remdesivir since it has not shown a benefit in this sub-population [159].

Pharmacologic Treatment of Critically ill COVID-19, Needing Invasive Mechanical Ventilation or ECMO

Patients who are critically ill with COVID-19 pulmonary disease and dysfunction needing significant ventilatory support with invasive mechanical ventilation or ECMO have the highest risk of mortality. Pharmacologically, we recommend treating them similarly to those on non-invasive ventilation or high-flow nasal cannula. Corticosteroids are strongly recommended in this category of critically ill patients as trials have demonstrated a mortality benefit [79]. In ad-dition to steroids, the panel recommends using either IL-6 inhibitors (tocilizumab is preferred over sarilumab) in critically ill patients who have elevated inflammatory markers like CRP. In situations where IL-6 inhibitors are not available, baricitinib can be used in mechanically venti-lated patients as a small trial showed a mortality benefit in this population [278]. Most other COVID-19 therapies studied in other severities have either not demonstrated benefit or not been studied in this population.

Executive Summary and Background

Executive Summary

Coronavirus disease 2019 (COVID-19) is a pandemic with a rapidly increasing incidence of infections and deaths. Many pharmacologic therapies are being used or considered for treatment. Given the rapidity of emerging literature, the Infectious Diseases Society of America (IDSA) identified the need to develop living, frequently updated evidence-based guidelines to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19. Please refer to the IDSA website for the latest version of the guidelines: https://idsociety.org/COVID19guidelines.

Summarized below are the recommendations with comments related to the clinical practice guideline for the treatment and management of COVID-19. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and research needs can be found online in the full text. In brief, per Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, recommendations are labeled as “strong” or “conditional”. The word “recommend” indicates strong recommendations and “suggest” indicates conditional recommendations. In situations where promising interventions were judged to have insufficient evidence of benefit to support their use and with potential appreciable harms or costs, the expert panel recommended their use in the context of a clinical trial. These recommendations acknowledge the current “knowledge gap” and aim at avoiding premature favorable recommendations for potentially ineffective or harmful interventions.

Hydroxychloroquine/Chloroquine + Azithromycin

• Recommendation 1: Among patients with COVID-19, the IDSA guideline panel recommends against hydroxychloroquine. (Strong recommendation, Moderate certainty of evidence)
  • Remark: Chloroquine is considered to be class equivalent to hydroxychloroquine.
• Recommendation 2: Among hospitalized patients with COVID-19, the IDSA guideline panel recommends against hydroxychloroquine plus azithromycin. (Strong recommendation, Low certainty of evidence)
  • Remark: Chloroquine is considered to be class equivalent to hydroxychloroquine.

Hydroxychloroquine for Prophylaxis

• Recommendation 3: In persons exposed to COVID-19, the IDSA guideline panel recommends against hydroxychloroquine. (Strong recommendation, Moderate certainty of evidence)

Lopinavir/Ritonavir

• Recommendation 4: In persons exposed to COVID-19, the IDSA guideline panel recommends against post-exposure prophylaxis with lopinavir/ritonavir. (Strong recommendation, Moderate certainty of evidence)
• Recommendation 5: Among ambulatory patients with mild-to-moderate COVID-19, the IDSA guideline panel recommends against the use of lopinavir/ritonavir. (Strong recommendation, Moderate certainty of evidence)
• Recommendation 6: Among hospitalized patients with COVID-19, the IDSA guideline panel recommends against the use of the combination lopinavir/ritonavir. (Strong recommendation, Moderate certainty of evidence)

Glucocorticoids

• Recommendation 7: Among hospitalized critically ill patients* with COVID-19, the IDSA guideline panel recommends dexamethasone rather than no dexamethasone. (Strong recommendation, Moderate certainty of evidence)
  • Remark: If dexamethasone is unavailable, equivalent total daily doses of alternative glucocorticoids may be used. Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent glucocorticoid dose may be substituted if dexamethasone is unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
• Recommendation 8: Among hospitalized patients with severe**, but non-critical, COVID-19, the IDSA guideline panel suggests dexamethasone rather than no dexamethasone. (Conditional recommendation†, Moderate certainty of evidence)
  • Remark: Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent glucocorticoid dose may be substituted if dexamethasone is unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
• Recommendation 9: Among hospitalized patients with mild-to-moderate*** COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation††, Low certainty of evidence)

Severity definitions:

*Critical illness is defined as patients on mechanical ventilation and extracorporeal mechanical oxygenation (ECMO). Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is ARDS.

**Severe illness is defined as patients with SpO₂ ≤94% on room air, including patients on supplemental oxygen.

***Mild-to-moderate illness is defined as patient with a SpO₂ >94% not requiring supplemental oxygen.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Inhaled Corticosteroids

• Recommendation 10: Among ambulatory patients with mild-to-moderate COVID-19, the IDSA guideline panel suggests against inhaled corticosteroids. (Conditional recommendation††, Moderate certainty of evidence)
  • Remark: Patients who are on inhaled corticosteroids for other indications may continue them.

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Interleukin-6 Inhibitors

• Recommendation 11: Among hospitalized adults with progressive severe* or critical** COVID-19 who have elevated markers of systemic inflammation, the IDSA guideline panel suggests tocilizumab in addition to standard of care (i.e., steroids) rather than standard of care alone. (Conditional recommendation†, Low certainty of evidence)
  • Remarks:
    • Patients, particularly those who respond to steroids alone, who put a high value on avoiding possible adverse events of tocilizumab and a low value on the uncertain mortality reduction, would reasonably decline tocilizumab.
    • In the largest trial on the treatment of tocilizumab, criterion for systemic inflammation was defined as CRP ≥75 mg/L.
• Recommendation 12: When tocilizumab is not available, for patients who would otherwise qualify for tocilizumab, the IDSA guideline panel suggests sarilumab in addition to standard of care (i.e., steroids) rather than standard of care alone. (Conditional recommendation†, Very low certainty of evidence)
  • Remark: Patients, particularly those who respond to steroids alone, who put a high value on avoiding possible adverse events of sarilumab and a low value on the uncertain mortality reduction, would reasonably decline sarilumab.

Severity definitions:

*Severe illness is defined as patients with SpO₂ ≤94% on room air, including patients on supplemental oxygen.

**Critical illness is defined as patients on mechanical ventilation and ECMO. Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is ARDS.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Convalescent Plasma

• Recommendation 13(UPDATED 2/22/2023): Among immunocompetent patients hospitalized with COVID-19, the IDSA guideline panel recommends against COVID-19 convalescent plasma. (Strong recommendation, Moderate certainty of evidence).
•  Recommendation 14(NEW 2/22/2023): Among immunocompromised patients hospitalized with COVID-19, the IDSA guideline panel suggests against the routine use of COVID-19 convalescent plasma. (Conditional recommendation, very low certainty of evidence.
  • Remark: Patients, particularly those who do not qualify for other treatments, who place a higher value on the uncertain mortality reduction and a lower value on the potential adverse effects of convalescent plasma would reasonably select convalescent plasma.
• Recommendation 15(UPDATED 2/22/2023): Among ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease who have no other treatment options*, the IDSA guideline panel suggests FDA-qualified high-titer COVID-19 convalescent plasma within 8 days of symptom onset rather than no high-titer COVID-19 convalescent plasma. (Conditional recommendation†, Low certainty of evidence)
  • Remarks:
    • In the United States, FDA emergency use authorization (EUA) only authorizes use in patients with immunosuppressive disease or receiving immunosuppressive treatment.
    • Patients, particularly those who are not immunocompromised, who place a low value on the uncertain benefits (reduction in the need for mechanical ventilation, hospitalization, and death) and a high value on avoiding possible adverse events associated with convalescent plasma would reasonably decline convalescent plasma.
  • Other options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir and three-day treatment with remdesivir Patient-specific factors (e.g., symptom duration, renal insufficiency or other contraindications, drug interactions) as well as logistical challenges, infusion capacity, and product availability should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Remdesivir

• Recommendation 16: Among patients (ambulatory or hospitalized) with mild-to-moderate COVID-19 at high risk for progression to severe disease, the IDSA guideline panel suggests remdesivir initiated within seven days of symptom onset rather than no remdesivir. (Conditional recommendation†, Low certainty of evidence)
  • Remarks:
    • Dosing for remdesivir in mild-to-moderate COVID-19 is 200 mg on day one followed by 100 mg on days two and three. Pediatric dosing is 5 mg/kg on day 1 and 2.5 mg/kg on subsequent days.
    • Options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, three-day treatment with remdesivir, molnupiravir, and neutralizing monoclonal antibodies. Patient-specific factors (e.g., patient age, symptom duration, renal function, drug interactions), product availability, and institutional capacity and infrastructure should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.
• Recommendation 17: In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation†, Low certainty of evidence)
• Recommendation 18a: In hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation†, Moderate certainty of evidence)
• Recommendation 18b: In patients with COVID-19 on invasive ventilation and/or ECMO, the IDSA panel suggests against the routine initiation of remdesivir (Conditional recommendation††, Very low certainty of evidence)

Severity definition:

*Severe illness is defined as patients with SpO₂ ≤94% on room air.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Famotidine

• Recommendation 19: Among ambulatory patients with mild-to-moderate COVID-19, the IDSA panel suggests against famotidine for the treatment of COVID-19 (Conditional recommendation††, Low certainty of evidence).
• Recommendation 20: Among hospitalized patients with severe* COVID-19, the IDSA panel suggests against famotidine for the treatment of COVID-19. (Conditional recommendation††, Low certainty of evidence)

Severity definition:

* Severe illness is defined as patients with SpO₂ ≤94% on room air, including patients on supplemental oxygen.

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Neutralizing Antibodies for Pre-Exposure Prophylaxis 

As of 1/26/2023, based on CDC Nowcast data, fewer than 10% of circulating variants in the US are susceptible to tixagevimab/cilgavimab (Evusheld), the sole product that has been available for pre-exposure prophylaxis. Tixagevimab/cilgavimab is therefore no longer authorized for use in the US until further notice by FDA. 

Neutralizing Antibodies for Post-Exposure Prophylaxis 

The first two US FDA authorized anti-SARS-CoV-2 neutralizing antibody combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were found to be largely inactive against the Omicron BA.1 and BA.2 variants, rendering these products no longer useful for either treatment or post-exposure prophylaxis. As a result, Emergency Use Authorization was withdrawn by the US FDA for both bamlanivimab/etesevimab and casirivimab/imdevimab, leaving no available neutralizing antibody product for use in the United States for post-exposure prophylaxis.

Neutralizing Antibodies for Treatment

During 2022, multiple Omicron sub-variants with progressively greater in vitro reductions in susceptibility to multiple anti-SARS CoV-2 neutralizing antibodies emerged. On November 30, 2022, the US FDA withdrew Emergency Use Authorization for bebtelovimab, the one anti-SARS CoV-2 neutralizing antibody product that had retained in vitro activity against most previously circulating SARS-CoV-2 variants, leaving no available neutralizing antibody product in the United States for treatment of COVID-19.   

 Janus Kinase Inhibitors

• Recommendation 21: Among hospitalized adults with severe* COVID-19, the IDSA panel suggests baricitinib with corticosteroids rather than no baricitinib. (Conditional recommendation†, Moderate certainty of evidence)
  • Remarks:
    • Baricitinib 4 mg per day (or appropriate renal dosing) up to 14 days or until discharge from hospital.
    • Baricitinib appears to demonstrate the most benefit in those with severe COVID-19 on high-flow oxygen/non-invasive ventilation at baseline.
    • Limited additional data suggest a mortality reduction even among patients requiring mechanical ventilation.
• Recommendation 22: Among hospitalized patients with severe* COVID-19 who cannot receive a corticosteroid (which is standard of care) because of a contraindication, the IDSA guideline panel suggests use of baricitinib with remdesivir rather than remdesivir alone. (Conditional recommendation†, Low certainty of evidence)
  • Remark: Baricitinib 4 mg daily dose for 14 days or until hospital discharge. The benefits of baricitinib plus remdesivir for persons on mechanical ventilation are uncertain.
• Recommendation 23: Among hospitalized adults with severe** COVID-19 but not on non-invasive or invasive mechanical ventilation, the IDSA panel suggests tofacitinib rather than no tofacitinib. (Conditional recommendation†, Low certainty of evidence)
  • Remarks:
    • Tofacitinib appears to demonstrate the most benefit in those with severe COVID-19 on supplemental or high-flow oxygen.
    • Patients treated with tofacitinib should be on at least prophylactic dose anticoagulant.
    • Patients who receive tofacitinib should not receive tocilizumab or other IL-6 inhibitor for treatment of COVID-19.
    • The STOP-COVID Trial did not include immunocompromised patients.

Severity definitions:

* Severe illness is defined as patients with SpO2 ≤94% on room air, including patients on supplemental oxygen, oxygen through a high-flow device, or non-invasive ventilation.

**Severe illness is defined as patients with SpO2 ≤94% on room air, including patients on supplemental oxygen or oxygen through a high-flow device.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Ivermectin

• Recommendation 24: In hospitalized patients with COVID-19, the IDSA panel suggests against ivermectin. (Conditional recommendation††, Very low certainty of evidence)
• Recommendation 25: In ambulatory persons with COVID-19, the IDSA panel recommends against ivermectin. (Strong recommendation, Moderate certainty of evidence)

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Fluvoxamine

• Recommendation 26: Among ambulatory patients with COVID-19, the IDSA guideline panel recommends fluvoxamine only in the context of a clinical trial. (Knowledge gap)

Nirmatrelvir/Ritonavir

• Recommendation 27(UPDATED 4/12/2023): In ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease, the IDSA guideline panel suggests nirmatrelvir/ritonavir initiated within five days of symptom onset rather than no nirmatrelvir/ritonavir. (Conditional recommendation†, Low certainty of evidence)
  • Remarks:
    • Patients’ medications need to be screened for serious drug interactions
    • Dosing based on renal function:
      • Estimated glomerular filtration rate (eGFR) > 60 ml/min: 300 mg nirmatrelvir/100 ritonavir every 12 hours for five days
      • eGFR ≤60 mL/min and ≥30 mL/min: 150 mg nirmatrelvir/100 mg ritonavir every 12 hours for five days
      •  eGFR <30 mL/min: not recommended
    • Patients with mild-to-moderate COVID-19 who are at high risk of progression to severe disease admitted to the hospital may also receive nirmatrelvir/ritonavir
  • Options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, remdesivir for a 3-day course, molnupiravir, and neutralizing monoclonal antibodies. Patient-specific factors (e.g., symptom duration, renal function, drug interactions) as well as product availability should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Molnupiravir

• Recommendation 28: In ambulatory patients (≥18 years) with mild-to-moderate COVID-19 at high risk for progression to severe disease who have no other treatment options*, the IDSA guideline panel suggests molnupiravir initiated within five days of symptom onset rather than no molnupiravir. (Conditional recommendation†, Low certainty of evidence)

*Other options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, three-day treatment with remdesivir, Patient-specific factors (e.g., symptom duration, renal function, drug interactions) as well as product availability should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.

• Remarks:
• Patients who will most likely benefit from antivirals are those with risk factors for progression to severe disease (e.g., elderly, those with high-risk comorbidities, incomplete vaccination status, or immunocompromised). Those without risk factors are less likely to benefit.
• Patients who put a higher value on the putative mutagenesis, adverse events, or reproductive concerns and a lower value on the uncertain benefits would reasonably decline molnupiravir.
• Patients with mild-to-moderate COVID-19 who are at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19 may also receive molnupiravir.
• Molnupiravir is not authorized under the FDA EUA for use in patients <18 years because it may affect bone and cartilage growth.
• Molnupiravir is not recommended under the FDA EUA for use during pregnancy.
• Molnupiravir is not authorized under the FDA EUA for pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in patients hospitalized due to COVID-19 because benefit of treatment has not been observed in individuals when treatment is started after hospitalization due to COVID-19.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Colchicine

• Recommendation 29: In hospitalized patients with COVID-19, the IDSA panel recommends against colchicine for treatment of COVID-19. (Strong recommendation, Moderate certainty of evidence)
• Recommendation 30: In ambulatory persons with COVID-19, the IDSA panel suggests against colchicine for treatment of COVID-19. (Conditional recommendation††, Moderate certainty of evidence)

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Anakinra

• Recommendation 31(NEW 5/4/2023): In hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests against the routine use of anakinra. (Conditional recommendation, Low certainty of evidence)

Severity definitions:

*Severe illness is defined as patients with SpO₂ ≤94% on room air, including patients on supplemental oxygen.

At the inception of its work, the panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19. Since then, many trials were done which provided much needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved which we hope future trials can answer. The panel has determined that when an explicit trade-off between highly uncertain benefits and known putative harms of these therapeutic agents were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm). The panel acknowledges that enrolling patients in randomized controlled trials (RCTs) might not be feasible for many frontline providers due to limited access and infrastructure. Should lack of access to clinical trials exist, we encourage setting up local or collaborative registries to systematically evaluate the efficacy and safety of drugs to contribute to the knowledge base. Each clinician can play a role in advancing our understanding of this disease through a local registry or other data collection efforts.

Background

The first cases of COVID-19 were reported from Wuhan, China in early December 2019 [1], now known to be caused by a novel beta-coronavirus, named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a span of months, COVID-19 has become pandemic due to its transmissibility, spreading across continents with the number of cases and deaths rising daily [2]. The emergence of new variants as the pandemic evolved has added more challenges to the prevention and treatment of COVID-19. Although most infected individuals exhibit a mild illness (80%+), 14% have serious and 5% have critical illness. Approximately 10% will require hospital admission due to COVID-19 pneumonia, of which approximately 10% will require intensive care, including invasive ventilation due to acute respiratory distress syndrome (ARDS) [3]. While mortality appears to be more common in older individuals and those with comorbidities, such as chronic lung disease, cardiovascular disease, hypertension and diabetes, young people with no comorbidities also appear to be at risk for critical illness including multi-organ failure and death.

There has been an expanding number of studies rapidly published online and in academic journals; however, some of these may be of limited quality and are pre-published without sufficient peer-review. Critical appraisal of the existing studies is needed to determine if the existing evidence is sufficient to support currently proposed management strategies.

Given the rapid global spread of SARS-CoV-2 and the difficulty for the overburdened front-line providers and policymakers to stay up to date on emerging literature, IDSA has recognized the necessity of developing a rapid guideline for the treatment of COVID-19. The guideline panel is using a methodologically rigorous process for evaluating the best available evidence and providing treatment recommendations. These guidelines will be frequently updated as substantive literature becomes available and are accessible on an easy to navigate web and device interface at http://www.idsociety.org/covid19guidelines.

There continue to be several ongoing trials evaluating therapeutic agents for the treatment of COVID-19. As data becomes available from these trials and if there is a preponderance of evidence to suggest the use of a therapeutic agent even in the context of clinical trials is no longer warranted it will be removed from future updates of the guideline (and the removal will be noted in the updated guidelines). If there is emerging evidence on the efficacy or safety of a therapeutic agent not mentioned in the current version of the guideline it will be included in future updates of the guideline.

These recommendations are intended to inform patients, clinicians, and other health professionals by providing the latest available evidence.

Recommendation: Neutralizing Antibodies for Prophylaxis (Pemivibart)

Neutralizing Antibodies for Pre-Exposure Prophylaxis

PEMIVIBART

Section last reviewed on 08/12/2024

Last literature search conducted 05/30/2024

[View full manuscript here]

[View supplemental material here]

Resources:

As the pandemic evolves, new SARS-CoV-2 variants emerge with varying susceptibility to available anti-SARS-CoV-2 neutralizing antibodies. For current information, please refer to the CDC COVID-19 Data Tracker (Summary of Variant Surveillance). 

Information on pemivibart is included in the US Food and Drug Administration Emergency Use Authorization for pemivibart (Pemgarda).

In moderately or severely immunocompromised persons 12 years or older, should pemivibart compared to no pemivibart be used for pre-exposure prophylaxis?

Recommendation: 

In moderately or severely immunocompromised individuals 12 years or older at risk for progression to severe COVID-19, the IDSA guideline panel suggests pre-exposure prophylaxis with pemivibart when predominant regional variants are susceptible to the agent (conditional recommendation, low certainty of evidence).

Remarks:

•    The anticipated benefit is likely greatest in people who are the most immunocompromised because they have the highest risk of inadequate immune response and progression to severe disease. See Table 1 for examples of individuals with varying degrees of immunosuppression. See Figures 1 and 2 for information from the FDA EUA. 
•    The anticipated benefit may be lower in patients aged 12 to 17 years, who have less severe COVID-19 outcomes than adults, as reflected by lower rates of hospitalization.
•    As the evidence is based on immunobridging and circulating variant susceptibility is evolving, additional clinical and laboratory data may impact this recommendation.
•    Patients who place a higher value on potential harms, specifically, the observed 0.6% risk of anaphylaxis, and a lower value on the uncertain benefits of prevention of severe COVID-19 would reasonably decline pemivibart.
•    Per the FDA EUA, pemivibart is authorized to be given at 4,500 mg IV every 3 months. 
•    Per the FDA EUA, in individuals who have recently received a COVID-19 vaccine, pemivibart should be administered at least 2 weeks after vaccination.

*Conditional recommendations are made when the suggested course of action would apply to the majority of people with many exceptions, and shared decision-making is important.

Table 1. Broad categorization of example immunocompromised status based on medical condition or immunosuppressive treatment. Thresholds by which this categorization has been determined have been derived from cohort studies beginning in the Omicron era of COVID-19; however, this may not be representative of currently evolving variants.

The risk of progression to severe COVID-19 is a continuum influenced by various factors, including the degree of immunosuppression. The categorization of risk and the examples provided in the table below are illustrative, based on a few studies, and are not exhaustive or a thorough list of all conditions [Evans 2023, Solera 2024]. 

Why is pemivibart being considered for pre-exposure prophylaxis?

Monoclonal antibodies (mAbs) directed at the receptor-binding domain of SARS-CoV-2 spike protein have been employed as prophylactic and therapeutic agents for COVID-19. Animal models, including those using the parent mAb for pemivibart, adintrevimab, have demonstrated the ability of these antibodies to inhibit viral replication in the lower respiratory tract, thereby reducing virus-induced pathology [Loo 2022, Rappazzo 2021].

An advantage of an anti-SARS-CoV-2 mAb is its ability to provide protection for individuals who do not respond to vaccination. Additionally, this protection begins immediately after the infusion. The FDA previously issued an Emergency Use Authorization (EUA) for tixagevimab/cilgavimab (Evusheld) as pre-exposure prophylaxis for COVID-19 [prior Evusheld EUA, Levin 2022]. However, as the pandemic progressed, new SARS CoV-2 variants emerged with reduced neutralizing susceptibility to various anti-SARS-CoV-2 mAbs in assays performed using infectious (also referred to as authentic) and pseudotyped viruses. There is evidence that the results of these in vitro neutralization assays can predict the efficacy of prophylactic or therapeutic anti-SARS-CoV-2 mAb activity [Follmann 2023, Stadler 2023]. The FDA has employed these and other immunobridging studies to determine the withdrawal and authorization of anti-SARS CoV-2 mAbs [evusheld EUA withdrawal, pemivibart EUA]. The FDA defines immunobridging as a method to infer vaccine (or by extension, monoclonal antibody) effectiveness by comparing immune responses, such as antibody levels, from a new vaccine (or antibody) to those of an approved vaccine or antibody under different conditions. This approach is useful when direct efficacy trials are impractical due to low disease incidence or ethical issues. Immunobridging allows for quicker and more cost-effective vaccine (and monoclonal) approvals, which is critical during public health emergencies like the COVID-19 pandemic. It has been used for evaluating COVID-19 vaccines across different age groups and for booster doses. In the case of pemivibart immunobridging, serum neutralization titer was utilized to compare pemivibart to previous mAbs [pemivibart EUA, FDA Guidance on Development and Licensure of Vaccines to Prevent COVID-19, WHO Consultation on Immunobridging].

While vaccination remains the first-line approach for the prevention of COVID-19, there are some immunosuppressed individuals who may not mount an adequate protective response to COVID-19 vaccines. Certain immunocompromised patients (examples listed in Table 1) are at particularly high risk for complications of COVID-19. Immunosuppressed individuals may benefit from pre-exposure prophylaxis (PrEP). Anti-SARS-CoV-2 mAbs have track records of efficacy for both treatment and prevention of COVID-19. In March 2024, the FDA conferred emergency use authorization for pemivibart for the pre-exposure prophylaxis of COVID-19 in adults and adolescents (12 years of age and older weighing at least 40 kg) based on immunobridging data from the CANOPY study, which suggests pemivibart should have similar efficacy against the newer Omicron subvariants as was previously seen with adintrevimab (the parent mAb of pemivibart) in the setting of circulating Delta variants and other anti-SARS-CoV-2 mAbs (See Tables 1 and 2 on the FDA EUA Factsheet [pemivibart EUA]. FDA authorization was based on immunobridging; the serum neutralization titer was used to compare pemivibart to other anti-SARS CoV-2 mAbs that showed clinical efficacy.    

In this focused update to the 2023 guideline [Bhimraj 2024], a recommendation and remarks are provided for pemivibart as pre-exposure prophylaxis. The primary audience for this recommendation is clinicians managing moderately or severely immunocompromised persons 12 years or older.

SUMMARY OF EVIDENCE

One ongoing randomized controlled trial (RCT) was identified studying pre-exposure prophylaxis (PrEP) with a single dose of 4,500 mg IV pemivibart administration in adults ≥18 years of age at increased risk of SARS-CoV-2 infection or inadequate response to COVID-19 vaccination [CANOPY] (Supplementary Table 1). Results of the effect of pemivibart in preventing symptomatic COVID infections are expected later in 2024. In the interim, to inform anticipated clinical benefits of pemivibart, the panel relied on indirect evidence from an RCT of adintrevimab (see Table 2), the ancestral neutralizing antibody from which pemivibart was derived, previous studies evaluating other anti-SARS-CoV-2 mAbs, and immunobridging evidence [pemivibart EUA, Stadler 2023].

CI: confidence interval; RR: risk ratio
Explanations
a. No control group comparison (see Supplementary Table 2)
b. Not based on patient-important outcomes. Neutralizing activity only. 
c. Adintrevimab is the ancestral neutralizing antibody which is no longer active against circulating virus but was used to create pemivibart
d. Several layers of indirectness are present: 1) Indirect data from parent monoclonal antibody against SARS CoV-2 variant that is no longer in circulation; 2) indirectness whether JN.1 will be susceptible to pemivibart to the same degree, i.e. uncertainty of remaining effect estimate at currently circulating variants; 3) uncertainty of baseline risk: over time, the proportion of symptomatic infections have declined and whether the historical 5.5% symptomatic infection rate seen with adintrevimab (enrollment in 2021) within 3 months is still applicable is unknown. With declining baseline risk for symptomatic infections, the absolute risk difference of downstream patient important outcomes (hospital admission, severe COVID etc.) resulting from pemivibart declines as well and may become less clinically relevant over time. 
e. Fragility present; low number of events
f. Anaphylaxis was observed in 4/263 (0.6%) participants receiving pemivibart, 2 of which were described as life-threatening. 

BENEFITS

In the EVADE RCT conducted in unvaccinated individuals, symptomatic COVID infections occurred in 40/728 (5.5%) patients receiving placebo compared to 12/752 (1.6%) patients receiving adintrevimab (RR 0.29, 95% CI 0.15, 0.55) [Ison 2023]. Additionally, prior studies found that in vitro neutralizing titers of anti-SARS CoV-2 mAbs, including adintrevimab and other anti-SARS CoV-2 mAbs, were associated with clinical benefit [Stadler 2023, pemivibart EUA]. In vitro neutralizing activity of pemivibart appears retained with currently circulating variants as of June 2024 [Invyvid press release].

HARMS

In the CANOPY trial, serious adverse events included anaphylaxis, which was observed in 4/623 (0.6%) participants receiving pemivibart, 2 of which were described as life threatening (absolute risk increase of 6 more anaphylactic reactions in 1,000, 95% CI, from 0 more to 12 more) [pemivibart EUA].

OTHER CONSIDERATIONS

The panel’s suggestion for the use of pemivibart is based on the following lines of evidence: the track record of success of anti-SARS-CoV-2 mAbs for both treatment and prevention; the phase 2/3 randomized controlled trial of the parent mAb adintrevimab demonstrating a 71% protection from symptomatic COVID-19; and immunobridging data.

The panel agreed the overall certainty of evidence for this recommendation was low (Table 2) due to concerns about: indirectness of evidence, given that efficacy of pemivibart is derived from immunobridging studies compared to adintrevimab and other anti-SARS-CoV-2 mAbs; uncertainty that pemivibart is active against the currently circulating variants; uncertain risks of pemivibart, including anaphylaxis; uncertainty regarding likelihood of symptomatic infections leading to hospitalizations and severe COVID-19 because of a lower risk of progression in 2024 than earlier in the pandemic when the adintrevimab study was conducted; lack of peer review for the immunobridging study; study risk of bias (Supplementary Table 2) in the CANOPY results reported; and imprecision due to the low number of symptomatic infections in the indirect data from adintrevimab. An additional source of uncertainty in adolescents is indirectness related to the inclusion of just 9 participants <18 years of age in the pre-exposure prophylaxis cohort of the EVADE trial and no participants <18 years of age in the CANOPY trial, necessitating extrapolation from adult data.

In the CANOPY study, 4/623 (0.6%) of participants were diagnosed with anaphylaxis, including 2 who were considered to have a severe reaction requiring Emergency Department visit and/or hospitalization. Due to the small number of participants who have received pemivibart in this trial, the true frequency of severe anaphylaxis remains unclear.

EQUITY CONSIDERATIONS

Efforts should be made to provide equitable access to this therapy for patients who may benefit, including those from marginalized communities, underserved populations, and diverse socioeconomic backgrounds. These include addressing barriers such as geographical disparities, financial constraints, language accessibility, and cultural considerations to ensure that all individuals have fair and inclusive opportunities to receive this treatment. 

CONCLUSIONS AND RESEARCH NEEDS

The guideline panel issued a conditional recommendation for PrEP with pemivibart in moderately or severely immunocompromised individuals. Due to the limited clinical evidence, the resulting net benefit remains unknown for adults and may be clarified when final randomized trial evidence is available; it will remain unknown for patients aged 12 to 17 years since they were not included in the trial. Detailed data on the efficacy of pre-exposure prophylaxis specifically in immunocompromised individuals who have received COVID-19 vaccines are needed. Additionally, data regarding safety, serum neutralizing against emerging variants, clinical efficacy, and pharmacoeconomic analyses are needed.

References

Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 (September 2022). Clin Infect Dis 2024; 78(7): e250-e349. 

Evans RA, Dube S, Lu Y, et al. Impact of COVID-19 on immunocompromised populations during the Omicron era: insights from the observational population-based INFORM study. Lancet Reg Health Eur. 2023; 35:100747.  

Follmann D, O’Brien MP, Fintzi J, et al. Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration. Nat Commun 2023; 14(1): 3605. 

Ison MG, Weinstein DF, Dobryanska M, et al. (EVADE Study Group). Prevention of COVID-19 following a single intramuscular administration of adintrevimab: results from a phase 2/3 randomized, double-blind, placebo-controlled trial (EVADE). Open Forum Infect Dis 2023; 10: ofad314. 

Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of COVID-19. N Eng J Med 2022; 386(23): 2188-2200. 

Loo Y-M, Tamney PM, Arends RH, et al. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci Transl Med 2022; 14. 

Rappazzo, CG, Tse LV, Kaku C, Wrapp D, Sakharkar M, Huang D, et al. Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody. Science 2021; 371: 823-829. 

Solera JT, Árbol BG, Mittal A, et al. Longitudinal outcomes of COVID-19 in solid organ transplant recipients from 2020 to 2023. Am J Transplant 2024; epub ahead of print.  

Stadler E, Burgess MT, Schlub TE, et al. Monoclonal antibody levels and protection from COVID-19. Nat Commun 2023; 14(1): 4545.  

A study to evaluate the efficacy and safety of VYD222 for prevention of COVID-19 (CANOPY). Available at: https://clinicaltrials.gov/study/NCT06039449. Accessed 06/27/2024. 

FDA guidance document on development and licensure of vaccines to prevent COVID-19. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-and-licensure-vaccines-prevent-covid-19. Accessed 07/25/2024. 

Invivyd announces antiviral activity of VYD222 (pemivibart) against SARS-CoV-2 KP.1.1 FLIRT & KP.3 variants. Available at: https://investors.adagiotx.com/news-releases/news-release-details/invivyd-announces-antiviral-activity-vyd222-pemivibart-against. Accessed 06/27/2024. 

U. S. Food and Drug Administration. Evusheld Emergency Use Authorization. Available at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-long-acting-monoclonal-antibodies-pre-exposure. Accessed 06/27/2024. 

U. S. Food and Drug Administration. Evusheld Emergency Use Authorization withdrawal. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-evusheld-not-currently-authorized-emergency-use-us#:~:text=Based%20on%20this%20revision%2C%20Evusheld,SARS%2DCoV%2D2%20variants. Accessed 06/27/2024. 

U. S. Food and Drug Administration. Emergency Use Authorization (EUA) for pemivibart (Pemgarda) Center for Drug Evaluation and Research (CDER) review. Available at: https://www.fda.gov/media/177333/download?attachment. Accessed 06/27/2024.  

WHO consultation on immunobridging. Available at https://cdn.who.int/media/docs/default-source/blue-print/doran-fink_4_immunobridging_vrconsultation_6.12.2021.pdf. Accessed 07/25/2024 

EVUSHELD (Archived)

Section last reviewed and updated on 1/27/2023

Please see the archived versions of this section below:

As of 1/26/2023, based on CDC Nowcast data, fewer than 10% of circulating variants in the US are susceptible to tixagevimab/cilgavimab (Evusheld), the sole product that has been available for pre-exposure prophylaxis. Tixagevimab/cilgavimab is therefore no longer authorized for use in the US until further notice by FDA. 

SARS-CoV-2 is expected to continue to evolve. Although the general trend has been towards increasing resistance to neutralizing monoclonal antibodies, there have been instances in which new variants became more susceptible to existing anti-SARS CoV-2 neutralizing antibodies. Should this occur again, or should newly developed, more active neutralizing antibodies be authorized for prophylaxis, the panel will offer recommendations regarding use.

Please see the archived versions of this section below:

Last Updated 1/12/23 (PDF)
Last Updated 5/23/22 (PDF)

Neutralizing Antibodies for Post-Exposure Prophylaxis (Archived)

Section last reviewed and updated on 1/12/2023

As the pandemic progressed, new SARS CoV-2 variants emerged with reduced susceptibility to various anti-SARS-CoV-2 neutralizing antibodies in assays performed using infectious (also referred to as authentic) and pseudotyped viruses. The first two US FDA authorized anti-SARS-CoV-2 neutralizing antibody combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were found to be largely inactive against the Omicron BA.1 and BA.2 variants, rendering these products no longer useful for either treatment or post-exposure prophylaxis. As a result, Emergency Use Authorization was withdrawn by the US FDA for both bamlanivimab/etesevimab and casirivimab/imdevimab, leaving no available neutralizing antibody product for use in the United States for post-exposure prophylaxis. Should new variants become susceptible to an existing neutralizing antibody or should newly developed, more susceptible neutralizing antibodies be authorized for post-exposure prophylaxis, the panel will offer recommendations regarding use. 

For areas of the world where a significant proportion of circulating variants retain susceptibility to at least one neutralizing antibody authorized for post-exposure prophylaxis, use could be considered. However, data are scarce on how susceptibility reductions affect clinical efficacy, relative to that observed prior to emergence of novel variants. 

Recommendation: Nirmatrelvir/Ritonavir

Section last reviewed and updated 4/12/2023

Last literature search conducted 3/31/2023

Resources:

• University of Liverpool: COVID-19 drug interaction checker
• University of Liverpool: HIV drug interaction checker

Recommendation 27(UPDATED 4/12/2023): In ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease, the IDSA guideline panel suggests nirmatrelvir/ritonavir initiated within five days of symptom onset rather than no nirmatrelvir/ritonavir. (Conditional recommendation†, Low certainty of evidence)

Remarks:

• Patients’ medications need to be screened for serious drug interactions
• Dosing based on renal function:
  • Estimated glomerular filtration rate (eGFR) > 60 ml/min: 300 mg nirmatrelvir/100 ritonavir every 12 hours for five days
  • eGFR ≤60 mL/min and ≥30 mL/min: 150 mg nirmatrelvir/100 mg ritonavir every 12 hours for five days
  • eGFR <30 mL/min: not recommended
• Patients with mild-to-moderate COVID-19 who are at high risk of progression to severe disease admitted to the hospital may also receive nirmatrelvir/ritonavir

*Options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, remdesivir for a 3-day course, molnupiravir, and neutralizing monoclonal antibodies. Patient-specific factors (e.g., symptom duration, renal function, drug interactions) as well as product availability should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Why is Nirmatrelvir/Ritonavir Considered for Treatment?

Nirmatrelvir is an inhibitor to the main protease (Mpro) of SARS-CoV-2; inhibition of this enzyme blocks viral replication. Nirmatrelvir is a substrate of the cytochrome P450 3A4 isoenzyme system and is co-packaged with an HIV-1 protease inhibitor, ritonavir, a potent inhibitor of cytochrome P450 3A4. Coadministration results in higher concentrations and a longer half-life of nirmatrelvir, allowing for every-12-hour dosing. The FDA granted EUA to nirmatrelvir/ritonavir on December 22, 2021 for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (≥12 years of age and weighing ≥40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death [235].

Summary of the Evidence

Our search identified one RCT reporting on treatment of mild-to-moderate COVID-19 in patients at high risk for progression to severe disease [235]. In addition, the search identified one RCT reporting on treatment of mild-to-moderate COVID-19 in 264 hospitalized patients [236]. Some data used to prepare this recommendation were extracted from the FDA EUA document.

Benefits

Nirmatrelvir/ritonavir

All-cause mortality through day 28 may be lower in ambulatory patients receiving nirmatrelvir/ritonavir compared to no nirmatrelvir/ritonavir (RR: 0.04; 95% CI: 0.00, 0.69; low CoE). Patients treated with nirmatrelvir/ritonavir rather than no nirmatrelvir/ritonavir may have fewer COVID-19-related hospitalizations (RR: 0.12; 95% CI: 0.06, 0.26; low CoE). The composite endpoint of COVID-19-related hospitalizations or mortality was lower in patients receiving nirmatrelvir/ritonavir compared to no nirmatrelvir/ritonavir (RR: 0.12; 95% CI: 0.06, 0.25; low CoE).

In hospitalized patients receiving nirmatrelvir/ritonavir, all-cause mortality may be lower (RR: 0.63; 95% CI: 0.21, 1.86; low CoE); however, no benefit has been shown for need for invasive mechanical ventilation or length of hospital stay (RR: 1.67; 95% CI: 0.62, 4.45; low CoE and MD -0.38 days; 95% CI: -2.09, 1.32; low CoE, respectively.

Harms

Nirmatrelvir/ritonavir

Limited evidence from hospitalized patients with mild-to-moderate COVID-19 receiving nirmatrelvir/ritonavir suggest increased serious adverse events and adverse events (RR 1.20; 95% CI: 0.38, 3.84; low CoE and RR: 1.40; 95% CI: 0.65, 3.04; low CoE).

Serious treatment-emergent adverse events were not reported in the FDA EUA.

Given co-formulation with ritonavir as a pharmacokinetic booster, there is potential for significant drug interactions. Contraindications exist between agents that can have their levels increased or decreased by nirmatrelvir and/or ritonavir and agents that can increase the metabolism of the components of nirmatrelvir and/or ritonavir, resulting in a loss of virologic response and possible resistance. These drug interactions can result in treatment failure or serious adverse events, which may lead to severe, life-threatening, or fatal events from greater exposures (i.e., higher levels) of concomitant medications. See Figures 2 and 3.

Less severe but clinically meaningful drug interactions may also occur when nirmatrelvir/ritonavir is co-administered with other agents. Levels of immunosuppressive agents such as tacrolimus, cyclosporine, or sirolimus can be increased when administered with nirmatrelvir/ritonavir. Hormonal contraceptives containing ethinyl estradiol may possibly have reduced effectiveness due to lowered ethinyl estradiol levels when administered with nirmatrelvir/ritonavir. Women of childbearing potential should be counseled to use a back-up, non-hormonal method of contraception.

Patients with moderate renal impairment (eGFR <60 and ≥30 mL/min) must be counseled that they will only take one 150-mg nirmatrelvir tablet (oval shape, pink) with one 100-mg tablet of ritonavir twice daily, instead of the regular dose of two 150-mg nirmatrelvir (300 mg) tablets with one 100-mg tablet of ritonavir twice daily. Pharmacists need to adhere to the specific instructions when dispensing the product according to instructions provided in the EUA [237]. Given the lack of renal function/eGFR data at the point of dispensing, providers must specify the numeric dosage of each agent on the prescription to ensure the correct dose is provided to the patient at the point of dispensing. There are no data in patients with severe renal disease (eGFR ≤ 30 mL/min); this medication is currently not recommended in patients with severe renal disease until more data on dosing in this population are available. 

There are no dose adjustments needed for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, however, data are lacking in patients with Child-Pugh C, and nirmatrelvir/ritonavir is therefore not recommended in this population. 

According to the EUA, nirmatrelvir/ritonavir use may be associated with a risk of developing HIV resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Supplementary Information

Study characteristics:

• Table s30. Should nirmatrelvir/ritonavir vs. no nirmatrelvir/ritonavir be used for ambulatory or hospitalized patients with mild to moderate COVID-19 at high risk for progression to severe disease? 

Risk of bias:

• Table s31. Risk of bias for randomized controlled studies (nirmatrelvir/ritonavir vs. no nirmatrelvir/ritonavir in ambulatory patients with mild to moderate COVID-19 at high risk for progression to severe disease)

Recommendation: Molnupiravir

Section last reviewed and updated 2/23/2023

Last literature search conducted 1/31/2023

Recommendation 28: In ambulatory patients (≥18 years) with mild-to-moderate COVID-19 at high risk for progression to severe disease who have no other treatment options*, the IDSA guideline panel suggests molnupiravir initiated within five days of symptom onset rather than no molnupiravir. (Conditional recommendation†, Low certainty of evidence)

*Other options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, three-day treatment with remdesivir, Patient-specific factors (e.g., symptom duration, renal function, drug interactions) as well as product availability should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.

Remarks:

• Patients who will most likely benefit from antivirals are those with risk factors for progression to severe disease (e.g., elderly, those with high-risk comorbidities, incomplete vaccination status, or immunocompromised). Those without risk factors are less likely to benefit.
• Patients who put a higher value on the putative mutagenesis, adverse events, or reproductive concerns and a lower value on the uncertain benefits would reasonably decline molnupiravir.
• Patients with mild-to-moderate COVID-19 who are at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19 may also receive molnupiravir.
• Molnupiravir is not authorized under the FDA EUA for use in patients <18 years because it may affect bone and cartilage growth.
• Molnupiravir is not recommended under the FDA EUA for use during pregnancy.
• Molnupiravir is not authorized under the FDA EUA for pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in patients hospitalized due to COVID-19 because benefit of treatment has not been observed in individuals when treatment is started after hospitalization due to COVID-19.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Why is Molnupiravir Considered for Treatment?

Molnupiravir is an oral antiviral that targets the genetic machinery that is responsible for SARS COV-2 replication. Molnupiravir is an oral pro-drug that is converted to β-D-N4-hydroxycytidine, which acts as a substrate for RNA-dependent RNA polymerase. After it is incorporated into the viral RNA, serial mutations develop, resulting in a virus that is less fit for ongoing viral replication. One phase I RCT evaluated the safety and tolerability of molnupiravir in healthy adults without COVID-19 [235]. The study reported molnupiravir to be well tolerated, with no increased reports of serious adverse events among persons in the molnupiravir arm compared to those receiving placebo. The FDA granted EUA to molnupiravir on December 23, 2021, for the treatment of mild-to-moderate COVID-19 in adults (≥18 years) who are at high risk for progression to severe COVID-19, including hospitalization or death.

Summary of the Evidence

Five RCTs informed the recommendation for molnupiravir [245-249]. Three RCTs re-ported on treatment of at least partially vaccinated participants with COVID-19 with either 800 mg of molnupiravir or placebo on outcomes of mortality, hospitalization, and serious adverse events [246, 247, 249]. In the largest trial (N=26,411), PAMORAMIC, 99% of participants had at least one COVID-19 vaccine dose with 92%-93% having received three doses [246]. Two RCTs reported on treatment of unvaccinated patients with COVID-19 with either 800 mg of mol-nupiravir or placebo for five days [245, 248]. In one phase III trial (MOVe-OUT trial) reporting on the outcomes of death, hospitalization and serious adverse events, patients with mild-to-moderate COVID-19 received either molnupiravir or placebo within five days after the onset of symptoms. In the phase IIa trial reporting on the outcomes of death and serious adverse events in patients with symptom duration <7 days received molnupiravir or placebo. 

Benefits

COVID-19-related mortality may be lower in patients receiving molnupiravir rather than placebo (RR: 0.28; 95% CI: 0.09, 0.86; low CoE); however, given the small baseline risk of mortality across the available evidence, the reduction in mortality may not be clinically meaningful (Absolute effect: 1 fewer per 1,000 persons; 95% CI: from 1 fewer to 0 fewer). COVID-19-related hospitalizations and the composite of all-cause hospitalization or death likely results in little to no difference among patients receiving molnupiravir rather than no molnupiravir (RR: 1.03; 95% CI: 0.78, 1.35; moderate CoE and RR: 0.92; 95% CI: 0.74, 1. 14; moderate CoE, respectively).

Harms

Patients treated with molnupiravir may not experience greater serious adverse events or adverse events than those receiving placebo (RR: 0.57; 95% CI: 0.22, 1.52; moderate CoE and RR: 0.81; 95% CI: 0.47, 1.40; moderate CoE, respectively).

Based on findings from animal reproduction studies, molnupiravir may cause fetal harm when administered to pregnant individuals [250]. Other concerns with molnupiravir include the possibility of  viral mutagenesis in persons with compromised immune systems who are unable to clear the virus. Females of childbearing potential should be counseled to use a reliable method of contraception during treatment and for four days after the last dose. Breastfeeding is not recommended during treatment with molnupiravir. Lactating individuals may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treat-ment and for four days after last dose of molnupiravir [251]. Men of reproductive potential who are sexually active with females of childbearing potential should be counseled to use a reliable method of contraception during treatment and for at least three months after the last dose of molnupiravir. It is also not recommended in children <18 years of age for the concern of bone growth.

Molnupiravir does not require renal or hepatic dose adjustment.

Other Considerations

The panel agreed that the overall certainty of evidence for treatment of ambulatory patients was low, given concerns with imprecision, driven by few reported events and a relatively small effect.

The use of molnupiravir presents additional considerations and potential concerns regarding viral mutagenesis in immunocompromised persons and safety in persons of reproductive age, for which more data are needed to quantify such effects. The panel recognized that alternative treatment options exist with the possibility of greater benefit with a smaller known safety profile. The FDA required the manufacturers to conduct additional animal studies on the impact of the drug on spermatogenesis and to establish a pregnancy registry if the drug was inadvertently administered during pregnancy.

The evidence confirms that using molnupiravir early in the disease process when viral loads are high confers maximum benefit. It is critical to make a rapid diagnosis and treat ambulatory patients with COVID-19 early in the disease course.

More recent studies in mild-to-moderate COVID-19 have shown lower rates of progression to hospitalizations or death, which could likely be due to changes in population immunity and lower virulence of recent circulating variants.   Given this observation, the panel discussed about the role of patient centered outcomes (e.g., meaningful decrease in severity or duration of symptoms) other than mortality and hospitalizations in trials evaluating treatment of mild to moderate COVID-19. The panel agreed that such outcomes should be evaluated in double-blind placebo-controlled trials to reduce the risk of bias. Such outcomes also should be measured using validated instruments and should be coupled with measures of disability or quality of life. The studies evaluating molnupiravir which reported such outcomes had a high risk of bias so were not considered for making the recommendation.

Conclusions

The guideline panel suggests the use of molnupiravir for ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease who are within five days of symptom onset and have no other treatment options. More data are needed on the potential adverse effects of this medication. The evidence supporting this recommendation will be reassessed with the release of updated published information from newer trials.

Supplementary Information

Study characteristics:

• Table s32. Should ambulatory patients with mild to moderate COVID-19 at high risk for progression to sever disease receive molnupiravir vs. no molnupiravir?

Forest plots:

• Figure s11a.  Forest plot for the outcome of mortality for molnupiravir vs. no molnupiravir
• Figure s11b.  Forest plot for the outcome of hospitalization for molnupiravir vs. no molnupiravir
• Figure s11c.  Forest plot for the outcome of hospitalization or death for molnupiravir vs. no molnupiravir
• Figure s11d.  Forest plot for the outcome of serious adverse events for molnupiravir vs. no molnupiravir
• Figure s11e.  Forest plot for the outcome of adverse events for molnupiravir vs. no molnupiravir

Risk of bias:

• Table s33. Risk of bias for randomized controlled studies (molnupiravir vs. no molnupiravir)

Recommendation: Remdesivir

Section last reviewed and updated 2/7/2022

Last literature search conducted 1/31/2022

Recommendation 16: Among patients (ambulatory or hospitalized) with mild-to-moderate COVID-19 at high risk for progression to severe disease, the IDSA guideline panel suggests remdesivir initiated within seven days of symptom onset rather than no remdesivir. (Conditional recommendation†, Low certainty of evidence)

Remarks:

• Dosing for remdesivir in mild-to-moderate COVID-19 is 200 mg on day one followed by 100 mg on days two and three. Pediatric dosing is 5 mg/kg on day 1 and 2.5 mg/kg on subsequent days.
• Options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, three-day treatment with remdesivir, molnupiravir, and neutralizing monoclonal antibodies. Patient-specific factors (e.g., patient age, symptom duration, renal function, drug interactions), product availability, and institutional capacity and infrastructure should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.

Recommendation 17: In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation†, Low certainty of evidence)

Recommendation 18a: In hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation†, Moderate certainty of evidence)

*Severe illness is defined as patients with SpO₂ ≤94% on room air.

Recommendation 18b: In patients with COVID-19 on invasive ventilation and/or ECMO, the IDSA panel suggests against the routine initiation of remdesivir (Conditional recommendation††, Very low certainty of evidence)

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Why is Remdesivir Considered for Treatment?

Remdesivir (GS-5734) is an antiviral drug with potent in vitro activity against a range of RNA viruses including MERS-CoV, SARS-CoV 1 & 2 [154-156]. Remdesivir acts by causing prem-ature termination of viral RNA transcription [156]. Its use improved disease outcomes and re-duced viral loads in SARS-CoV-1 infected mice [155]. In rhesus macaques, therapeutic treat-ment with remdesivir showed reduction in SARS-CoV-2 loads, pathologic changes, and progres-sion of clinical disease [157]. In this same animal model, remdesivir treatment initiated 12 hours post-inoculation reduced clinical signs, virus replication in the lungs, and decreased the presence and severity of lung lesions.

Summary of the Evidence

Patients with mild-to-moderate disease who are at high risk for progression to severe COVID-19

One RCT compared treatment with three days of intravenous (IV) remdesivir (200 mg on day one followed by 100 mg on days two and three) initiated within 7 days of symptom onset or no remdesivir in unvaccinated patients [158]. The study enrolled patients at high risk for progression (e.g., obesity, diabetes mellitus, hypertension, immune compromise etc.) or age 60 years or older who were symptomatic seven days or less without prior treatment (e.g., mono-clonal antibodies), but were not expected to receive oxygen at time of enrollment (>94% on room air). The outcomes assessed were mortality, hospitalizations for any cause, and COVID-19-related medically as well as serious adverse events. 

Hospitalized patients with SpO2 ≤94% on room air

Three RCTs comparing treatment with remdesivir (200 mg day one, 100 mg daily days 2-10) against no remdesivir treatment [32, 159, 160], and one RCT comparing five days of treatment (200 mg day one, 100 mg daily days 2-5) against 10 days (200 mg day one, 100 mg daily days 2-10) of treatment [161] served as the best available evidence among hospitalized persons with severe COVID-19 (Table 17-18). The outcomes assessed were mortality, time to clinical improvement, need for mechanical ventilation, serious adverse events, and adverse events leading to treatment discontinuation.

All trials used different definitions of severe disease for participants. ACTT-1 partici-pants were considered to have severe disease if they required mechanical ventilation, supple-mental oxygen, if SpO2 was 94% or lower while breathing ambient air, or if they had tachypnea (respiratory rate >24 breaths per minute) [159]. Within the SOLIDARITY trial (available only as a pre-print at this time), participants with severe disease were receiving mechanical ventilation [32]. In Wang 2020, severe participants had a SpO2 <94% while breathing room air or a ratio of arterial oxygen partial pressure to fractional inspired O2 of <300 mm Hg and radiologically con-firmed pneumonia.

Updated analyses include the final analysis from the ACTT-1 and the interim analysis of the SOLIDARITY trial [32, 159]. SOLIDARITY reported mortality among persons remaining in hospital up to the duration of the study; however, among patients discharged before the end of the study, mortality may not have been collected completely. The study by Wang et al (2020) was stopped early due to lack of recruitment into the trial due to decreased incidence in China.

Randomization performed in Goldman 2020 failed to establish prognostic balance be-tween baseline clinical status among the 397 patients randomized into the treatment arms, with patients in the 10-day arm more severely ill at study entry. Even with the adjusted analysis, residual confounding is possible. In addition, participants, healthcare workers, and outcome as-sessors were not blinded to the treatment arms.

Hospitalized patients on invasive ventilation and/or ECMO

Subgroups from SOLIDARITY and ACTT-1 reported on the outcomes of mortality, time to recovery and serious adverse events among patients on invasive ventilation or ECMO [32, 159] (Table 18b). The duration of ventilation at time of treatment with remdesivir was not reported in ACTT-1. This may introduce uncertainty when assessing outcomes of mortality or time to re-covery.

In ACTT-1 [159], randomization was stratified by study site and disease severity at en-rollment. Disease severity groups were mild-to-moderate COVID-19 (SpO2 >94%) and severe COVID-19 (SpO2 ≤94%). The severe COVID-19 stratum included patients who were hypoxemic with various degrees of severity including those requiring low flow oxygen by nasal cannula, those needing high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation and ECMO. In addition to analyses on established strata, authors performed post hoc analyses for subgroups within the strata (e.g., receiving oxygen, receiving high-flow oxygen or noninvasive mechanical ventilation, or receiving mechanical ventilation or ECMO), which may introduce concerns with risk of bias and imprecision when making inferences on efficacy of remdesivir among these subgroups including mechanically ventilated patients.

Benefits

Patients with mild-to-moderate disease who are at high risk for progression to severe COVID-19 

Treatment with remdesivir for three days in ambulatory patients reduced hospitalizations and COVID-19-related medically attended visits throughout day 28 (HR: 0.28; 95% CI: 0.1, 0.75, low CoE; and HR: 0.19; 95% CI: 0.07, 0.56, low CoE, respectively). No deaths were observed. 

Hospitalized patients with SpO₂ ≤94% on room air

The pooled analysis failed to show a mortality benefit at 28 days (RR: 0.92; 95% CI: 0.77, 1.10; low CoE) [32, 159, 160]. Patients receiving treatment with remdesivir trend toward greater clinical improvement at 28 days than patients not receiving remdesivir (RR: 1.13; 95% CI: 0.91, 1.41; low CoE) [160]. In addition, based on a post hoc analysis of patients with severe COVID-19, receiving treatment with remdesivir had a shorter median time to recovery (median 11 vs. 18 days; rate ratio: 1.31; 95% CI: 1.12, 1.52; low CoE) and decreased need for mechanical ventilation (RR: 0.57; 95% CI: 0.42, 0.79; moderate CoE) [159]. 

In the study by Goldman et al that compared five and ten days of treatment, the shorter course of remdesivir showed a trend toward decreased mortality (RR: 0.75; 95% CI: 0.51, 1.12; low CoE) and increased clinical improvement at 14 days (RR: 1.19; 95% CI: 1.01, 1.40; low CoE); however, the evidence is uncertain because the persons in the 10-day group had more severe disease at baseline and there is the possibility of residual confounding despite the adjusted analysis [161].

Hospitalized patients on invasive ventilation and/or ECMO

Treatment with remdesivir failed to show a reduction in mortality (RR: 1.23; 95% CI: 0.99, 1.53; low CoE). Similarly, remdesivir failed to show or exclude a reduction in time to recovery among patients on invasive ventilation and/or ECMO (HR: 0.98; 95% CI: 0.70, 1.36; very low CoE).

Harms

Patients with mild-to-moderate disease who are at high risk for progression to severe COVID-19 

As with other remdesivir studies published so far, three days of remdesivir infusions did not appear to be associated with a greater risk of serious adverse events compared to no remdesivir (RR: 0.27; 95% CI: 0.1, 0.7; moderate CoE).

Hospitalized patients with SpO₂ ≤94% on room air

Patients treated with remdesivir do not appear to experience greater serious adverse events (grade 3/4) than those not receiving remdesivir (RR: 0.87; 95% CI: 0.59, 1.28; moderate CoE) [159, 160]. 

Patients receiving five days of remdesivir may experience fewer serious adverse events and adverse events leading to treatment discontinuation than patients receiving 10 days of remdesivir (RR: 0.61; 0.44, 0.85; low CoE and RR: 0.44; 95% CI: 0.21, 0.95; low CoE, respectively); however, this evidence is uncertain because of the increased severity of disease among patients in the 10-day arm [161].

Hospitalized patients on invasive ventilation and/or ECMO

Patients on invasive ventilation and/or ECMO treated with remdesivir do not appear to experience greater serious adverse events than those not receiving remdesivir (RR: 0.79; 95% CI: 0.54, 1.16; moderate CoE).

Other Considerations

Patients with mild-to-moderate disease who are at high risk for progression to severe COVID-19 

The panel agreed that the overall certainty of evidence for the treatment of patients with mild-to-moderate COVID-19 was low due to concerns about imprecision, as less than half of the original projected sample size was enrolled leading to few events and fragility of the effect estimate. However, compared to prior trials, giving remdesivir early in the course of the viral infection appears to have a robust effect within the limitation of a limited sample size. The panel agreed that benefits are likely to outweigh any potential harms in patients with COVID-19 who are at high risk for severe disease. The evidence confirms that using remdesivir early in the disease process when viral loads are high confers maximum benefit. It is critical to make a rapid diagnosis and treat ambulatory patients with COVID-19 early in the disease course.

Hospitalized patients with SpO₂ ≤94% on room air

The panel agreed that the overall certainty of the evidence for treatment of persons with severe disease with remdesivir compared to no remdesivir treatment was moderate due to concerns with imprecision. Given the inconsistent definition used in the evidence to describe baseline severity, the panel recognized a knowledge gap when assessing whether greater benefit could be attained for patients with oxygen saturation >94% and no supplemental oxygen; however, they agreed that the reported data supported the prioritization of remdesivir among persons with severe but not critical COVID-19.

The panel agreed on the overall certainty of the evidence for treatment with a five-day course compared to a 10-day course of treatment as low due to concerns with risk of bias and imprecision. The panel recognized the benefit of a shorter course of treatment, if providing similar or greater efficacy, on the availability of remdesivir. However, in a subgroup analysis of mechanically ventilated patients, the duration of treatment was 10 days in ACCT-1 trial; therefore, the panel recognized that a longer course of treatment could be desirable in this population.

Hospitalized patients on invasive ventilation and/or ECMO

The panel agreed on the overall certainty of the evidence for treatment of patients on invasive ventilation and/or ECMO with remdesivir as very low due to concerns with risk of bias and imprecision. The panel recognized that the estimates of effect for mortality and time to recovery exclude almost any benefit.

Pediatric use

The evidence for the use of remdesivir in children is limited. For ambulatory children at risk for severe disease, the RCT included 8 children aged 12 to 18 years, limiting our confidence in the available direct evidence for ambulatory care.

There are no randomized controlled data assessing efficacy of remdesivir for treatment of hospitalized pediatric patients with COVID-19. A report of 77 children who received remdesivir through compassionate use early in the pandemic found good tolerability in this population with a low rate of serious adverse events [162].

An ongoing study of remdesivir in children [163] is using 5 mg/kg on day one (maximum dose 200 mg) followed by 2.5 mg/kg daily in patients over 14 days of age, gestational age more than 37 weeks, and weight greater than or equal to 2.5 kg. The FDA EUA applies to patients weighing over 3.5 kg and applies to the lyophilized powder formulation only.

Conclusions and Research Needs for this Recommendation

The guideline panel suggests remdesivir for patients with mild-to-moderate disease who are at high risk for severe COVID-19.

The guideline panel suggests remdesivir rather than no remdesivir for treatment of severe COVID-19 in hospitalized patients with SpO₂ <94% on room air. However, the guideline panel suggests against the routine initiation of remdesivir among patients on invasive ventilation and/or ECMO. Additional clinical trials are needed to provide increased certainty about the potential for both benefit and harms of treatment with remdesivir, as well as to understand the benefit of treatment based on disease severity.

Prescribing information in the United States recommends against use of remdesivir in patients with estimated glomerular filtration rate less than 30 mL per minute. This recommendation arises from concern about accumulation of the excipient (betadex sulfobutyl ether sodium) in such patients with potential for hepatic and renal toxicity due to that substance. Additional research into safety of remdesivir in patients with reduced renal function is needed to ascertain whether this concern is substantiated.

Immunocompromised patients who are unable to control viral replication may still benefit from remdesivir despite SpO₂ that exceeds 94% on room air or a requirement for mechanical ventilation. Management of immunocompromised patients with uncontrolled viral replication is a knowledge gap and additional research into such populations is needed.

In addition, research is needed to address gaps in the evidence of effectiveness of remdesivir based on viral load.

Supplementary Information

Study characteristics:

• Table s17.  Remdesivir vs. no remdesivir (hospitalized patients)
• Table s18.  Remdesivir vs. no remdesivir (ambulatory patients)

Forest plots:

• Figure s8a.  Outcome of mortality for remdesivir vs. no remdesivir in hospitalized patients with severe disease
• Figure s8b.  Outcome of severe adverse events (grade 3/4) for remdesivir vs. no remdesivir in hospitalized patients with severe disease
• Figure s8c.  Outcome of mortality for remdesivir vs. no remdesivir in hospitalized patients on invasive ventilation and/or ECMO
• Figure s8d.  Outcome of serious adverse events (grade 3/4) for remdesivir vs. no remdesivir in hospitalized patients on invasive ventilation and/or ECMO

Risk of bias:

• Table s19.  Randomized controlled studies (remdesivir vs. no remdesivir)

Recommendation: Convalescent Plasma

Supplementary Information

Study characteristics:

• Table s15.  Should patients (hospitalized or ambulatory) with COVID-19 receive treatment with convalescent plasma vs. no convalescent plasma?

Forest plots:

• Figure s7a.  Forest plot for the outcome of mortality for convalescent plasma vs. no convalescent plasma in hospitalized patients
• Figure s7b.  Forest plot for the outcome of mechanical ventilation for convalescent plasma vs. no convalescent plasma in hospitalized patients
• Figure s7c.  Forest plot for the outcome of adverse events (mild to severe) for convalescent plasma vs. no convalescent plasma in hospitalized patients
• Figure s7d.  Forest plot for the outcome of mortality for convalescent plasma vs. no convalescent plasma in ambulatory patients
• Figure s7e.  Forest plot for the outcome of COVID-19-related hospitalizations for convalescent plasma vs. no convalescent plasma in ambulatory patients
• Figure s7f.  Forest plot for the outcome of all-cause hospitalizations for convalescent plasma vs. no convalescent plasma in ambulatory patients
• Figure s7g.  Forest plot for the outcome of serious adverse events for convalescent plasma vs. no convalescent plasma in ambulatory patients
• Figure s7h.  Forest plot for the outcome of adverse events for convalescent plasma vs. no convalescent plasma in ambulatory patients
• Figure s7i.  Forest plot for the outcome of mortality for convalescent plasma vs. no convalescent plasma in hospitalized immunocompromised patients
• Figure s7j.  Forest plot for the outcome of SAEs for convalescent plasma vs. no convalescent plasma in hospitalized immunocompromised patients

Risk of bias:

• Table s16a.  Risk of bias for randomized controlled studies (convalescent plasma vs. no convalescent plasma)
• Table s16b.  Risk of bias for non-randomized studies (convalescent plasma vs. no convalescent plasma)

Recommendation: Glucocorticoids

Section last reviewed and updated 9/25/2020

Last literature search conducted 9/4/2020

Recommendation 7: Among hospitalized critically ill patients* with COVID-19, the IDSA guideline panel recommends dexamethasone rather than no dexamethasone. (Strong recommendation, Moderate certainty of evidence)

Remark:

• If dexamethasone is unavailable, equivalent total daily doses of alternative glucocorticoids may be used. Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent glucocorticoid dose may be substituted if dexamethasone unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.

Recommendation 8: Among hospitalized patients with severe**, but non-critical, COVID-19, the IDSA guideline panel suggests dexamethasone rather than no dexamethasone. (Conditional recommendation†, Moderate certainty of evidence)

Remark:

• Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent glucocorticoid dose may be substituted if dexamethasone unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.

Recommendation 9: Among hospitalized patients with mild-to-moderate*** COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation††, Low certainty of evidence)

Severity definitions:

• *Critical illness is defined as patients on mechanical ventilation and ECMO. Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is ARDS
• **Severe illness is defined as patients with SpO₂ ≤94% on room air, including patients on supplemental oxygen.
• ***Mild-to-moderate illness is defined as patient with a SpO₂ >94% not requiring supplemental oxygen.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

††The guideline panel concluded that the undesirable effects outweigh the desirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

The last literature search was conducted on September 4, 2020, and we identified eight RCTs and seven comparative non-randomized studies.

Why are Corticosteroids Considered for Treatment?

In the early days of the SARS-CoV-2 pandemic, based on experience in both SARS and MERS, recommendations [73] cautioned against the use of systemic corticosteroids due to risk of worsening clinical status, delayed viral clearance, and adverse events [74-76]. Given the hyper-inflammatory state in COVID-19, immunomodulatory approaches, including steroids, continue to be evaluated to address both ARDS and systemic inflammation. ARDS stemming from dysregulated systemic inflammation may translate into prolonged ventilatory requirements and in-hospital mortality. In non-viral ARDS settings, there is increasing support for the role of steroids in the management of ARD [77]. A recent multicenter RCT in patients with moderate to severe ARDS demonstrated a reduced number of ventilatory days and reduction in mortality with use of a 10-day regimen of dexamethasone [78].

Summary of the Evidence

Critical illness

Our search identified one systematic review that analyzed eight RCTs reporting on treatment with glucocorticoids among 1,844 critically ill patients with COVID-19 [79]. Three RCTs reported on patients treated with low- and high-dose dexamethasone [78, 80, 81]; three RCTs reported on patients treated with low-dose hydrocortisone [82-84]; and two RCTs reported on patients treated with high-dose methylprednisolone [79, 85]. The definition of critically ill varied across trials; however, the majority of patients had ARDS.

Severe and mild-to-moderate illness

Our search identified one RCT, one “partially” randomized trial, one prospective cohort, and five retrospective cohort studies [80, 86-92]. The RCT provided the best available evidence on treatment with corticosteroids for persons with COVID-19 [80]  (Tables 7-9). Corral-Gudino et al. reported on a study that randomized patients to receive methylprednisolone or standard of care; however, patients expressing a preference for methylprednisolone were assigned to the same treatment arm [86]. Corral-Gudino et al. did not report the disaggregated results from the randomized trial; therefore, succumbing to the same potential for bias as reported subsequently for the non-randomized studies. The non-randomized studies had significant limitations with controlling for multiple co-interventions and disease severity at baseline [87-92]. All non-randomized studies had concerns with risk of bias due to lack of adjustment for critical confounders or potential for residual confounding. Timing of receipt, dose and duration of corticosteroids varied across studies.

The RECOVERY trial is a randomized trial among hospitalized patients in the United Kingdom [80]. In that study, 2,104 participants were randomized to receive dexamethasone (6 mg daily for up to 10 days) and 4,321 were randomized to usual care. The RECOVERY trial reported on the outcomes of mortality and hospital discharge. Participants and study staff were not blinded to the treatment arms.

Benefits

Critical illness

Among hospitalized, critically ill patients, the odds of mortality at 28 days was 34% less among patients treated with glucocorticoids than among patients not treated with glucocorticoids (OR: 0.66; 95% CI: 0.54; 0.82; high CoE). In addition, at 28 days, patients receiving dexamethasone were more likely to be discharged from the hospital (RR: 1.11; 95% CI: 1.04, 1.19; moderate CoE).

Severe illness

Among hospitalized patients, 28-day mortality was 17% lower in the group that received dexamethasone than in the group that did not receive dexamethasone (RR 0.83; 0.74-0.92; moderate CoE). In addition, at 28 days, patients receiving dexamethasone were more likely to be discharged from the hospital (RR: 1.11; 95% CI: 1.04, 1.19; moderate CoE).

Mild-to-moderate illness

In a sub-group analyses of patients without hypoxia not receiving supplemental oxygen, there was no evidence for benefit and a trend toward harm with dexamethasone in participants who were not on supplemental oxygen (RR 1.22; 0.86, 1.75; low CoE).

Harms

A systematic review of six studies did not report a difference in the events of serious adverse events experienced by patients randomized to receive treatment with glucocorticoids or no treatment with glucocorticoids (64/354 among those receiving glucocorticoids versus 80/342 among those not receiving glucocorticoids).

Patients receiving a short course of steroids may experience hyperglycemia, neurological side effects (e.g., agitation/confusion), adrenal suppression, and risk of bacterial and fungal infection [87, 93, 94].

Other Considerations

Critical illness

The panel agreed that the overall certainty of the evidence for treatment with glucocorticoids for patients with critical COVID-19 was moderate due to concerns with indirectness and imprecision.

Severe illness

The panel agreed the overall certainty of evidence for treatment with glucocorticoids for patients with severe COVID-19 as moderate due to concerns with indirectness since the evidence was from dexamethasone.

Mild-to-moderate illness

The panel agreed that the overall certainty of evidence for patients without hypoxemia requiring supplemental oxygen as low due to concerns with risk of bias (post hoc analysis) and imprecision.

The panel agreed the overall certainty of evidence for treatment with glucocorticoids for patients with severe COVID-19 as moderate due to concerns with indirectness since the evidence was from dexamethasone. The panel agreed that the overall certainty of evidence for patients without hypoxemia requiring supplemental oxygen as low due to concerns with risk of bias (post hoc analysis) and imprecision.

Conclusions and Research Needs for these Recommendations

The guideline panel recommends dexamethasone for patients with critical COVID-19. The guideline panel suggests dexamethasone for patients with severe COVID-19. If dexamethasone is not available, then alternative glucocorticoids may be used (see details above). The guideline panel suggests against glucocorticoids for patients with COVID-19 without hypoxemia requiring supplemental oxygen.

Additional research is needed to inform the generalizability of treatment with different glucocorticoids for patients with COVID-19 (Supplementary Table s2).

Supplementary Information

Study characteristics:

• Table s9.  Corticosteroids vs. no corticosteroids

Risk of bias:

• Table s10.  Randomized controlled studies (glucocorticoids vs. no glucocorticoids)

Recommendation: Janus Kinase Inhibitors (Baricitinib and Tofacitinib)

Baricitinib

Section last reviewed and updated 4/29/2022

Last literature search conducted 3/31/2022

Recommendation 21: Among hospitalized adults with severe* COVID-19, the IDSA panel suggests baricitinib with corticosteroids rather than no baricitinib. (Conditional recommendation†, Moderate certainty of evidence)

Remarks:

• Baricitinib 4 mg per day (or appropriate renal dosing) up to 14 days or until discharge from hospital.
• Baricitinib appears to demonstrate the most benefit in those with severe COVID-19 on high-flow oxygen/non-invasive ventilation at baseline.
• Limited additional data suggest a mortality reduction even among patients requiring mechanical ventilation.

Recommendation 22: Among hospitalized patients with severe* COVID-19 who cannot receive a corticosteroid (which is standard of care) because of a contraindication, the IDSA guideline panel suggests use of baricitinib with remdesivir rather than remdesivir alone. (Conditional recommendation†, Low certainty of evidence)

Remark:

• Baricitinib 4 mg daily dose for 14 days or until hospital discharge. The benefits of baricitinib plus remdesivir for persons on mechanical ventilation are uncertain.

*Severe illness is defined as patients with SpO₂ ≤94% on room air, including patients on supplemental oxygen, oxygen through a high-flow device, or non-invasive ventilation.

†The guideline panel concluded that the desirable effects outweigh the undesirable effects, though uncertainty still exists, and most informed people would choose the suggested course of action, while a substantial number would not.

Why is Baricitinib Considered for Treatment?

Baricitinib, a selective Janus kinase 1 and 2 (JAK1 and JAK2, respectively) inhibitor currently FDA-approved for the treatment of RA, is being investigated in multiple studies for treatment of COVID-19. The proposed benefits of baricitinib in the management of COVID-19 may be two-fold as it has both anti-inflammatory and potential antiviral activity [168]. Janus kinase (JAK) mediates cytokine signaling, which contributes to inflammation; JAK inhibitors, therefore, may decrease cytokine-mediated inflammation. Baricitinib inhibits host intracellular membrane proteins AP2-associated protein kinase 1 (AAK1) and also binds cyclin G-associated kinase (GAK), both thought to play a role in receptor mediated endocytosis of many viruses including Ebola, dengue, hepatitis C, and SARS-CoV-2 [169-171]. Baricitinib has been evaluated in people with COVID-19 in both randomized and non-randomized studies