As the COVID-19 pandemic rages into its third year, we continue to face the massive challenge of limited targeted therapeutics. Early on, a host of pharmaceuticals were repurposed to fight COVID despite insufficient evidence. In the face of a novel virus, this was a reasonable approach, but the majority of these agents (e.g., hydroxychloroquine, ivermectin, colchicine and azithromycin) have been found to have no benefit in subsequent high-quality research. Despite the normal setbacks in research, we have identified a handful of useful therapeutics. It’s critical that clinicians stay current on the changing landscape of COVID medications. Let’s sort through the tidal wave of publications to get to the good stuff.
Monoclonal Antibodies (mAbs)
Mechanism of action: Give patients antibodies against SARS-CoV-2 early in their disease course to help stop cellular invasion and thus the development of severe COVID.
It should be noted that mAbs have never been shown to be effective in patients who are:
- Seropositive for SARS-CoV-2 antibodies (e.g., once you have a polyclonal antibody response to infection, a monoclonal antibody isn’t going to help)
- Previously vaccinated
Millions of doses of bamlanivimab, etesevimab (and combination of the two) and the REGN-COV2 cocktail (casirivimab/imdevimab) have been administered, but the medications are currently not in use due to lack of efficacy against the Omicron variant. Currently, sotrovimab is the only mAb available for use against Omicron in the United States but is extremely limited in availability.
mAbs play a limited role in the pandemic in part due to rapid development of resistance. Efficacy research is often rendered obsolete by the rise of a new variant. Publication of the RECOVERY trial’s final casirivimab/imdevimab results is a good example; by the time all the data were available, analyzed and published, the Omicron variant was dominant, making this mAb cocktail useless.1
Additionally, mAbs are expensive, limited in availability and extremely resource-intensive, further limiting their utility. Despite these limitations, we continue to see new mAbs getting emergency use authorization, including the most recent bebtelovimab, without any clinical data.
Bottom line: Patients presenting early in their disease course (prior to mounting an antibody response) who are unvaccinated or are immunosuppressed and are unable to mount a normal response to vaccination may benefit from mAbs. Ideally, point-of-care testing would be available to determine which patients are seronegative, but this is not currently feasible.
Antiviral Agents
Mechanism of action: Although they have different specific mechanisms, all direct-acting antiviral agents seek to prevent the development of severe COVID-19. As a result, these agents only work when started (very) early in the disease course.
Remdesivir was the first targeted antiviral agent to gain widespread use based on ACTT-1, which demonstrated a four-day-shorter time to recovery versus placebo.2 Closer review of the data, however, demonstrated that the benefit was only seen in those receiving oxygen but not high-flow or non-invasive ventilation. Additionally, although recovery was more rapid, hospital length of stay was unchanged (perhaps due to the need to finish the course of remdesivir, which is only available intravenously). Subsequent data from the World Health Organization demonstrated no significant benefit in mortality, initiation of mechanical ventilation or duration of hospital stay with remdesivir treatment.3 These findings were echoed in the DisCoVeRy trial, and ultimately, we should conclude from the available high-quality evidence that remdesivir does not have a significant benefit in patients requiring hospitalization for COVID-19.4 This makes sense because patients requiring hospitalization are likely out of the early phase of infection where antivirals have benefit and have entered the inflammatory phase.
More recently, the PINETREE investigators found a 4.6 percent absolute reduction in hospitalization (NNT ~22) when remdesivir was given to outpatients with COVID-19 early in the disease course (<7 days from onset) as three once-daily infusions.5 This significant reduction is important but will require validation. Additionally, many hospital systems and communities are unable to support outpatient infusion.
The major limitation with remdesivir treatment is the resource utilization required by an intravenous medication. This limitation has seemingly been overcome with the more recent emergency use authorizations for nirmatrelvir/ritonavir (Paxlovid). Molnupiravir was shown to result in a 2.7 percent absolute decrease (30 percent relative reduction) in hospitalization when administered within five days of disease onset.6 Molnupiravir appears to have teratogenic properties limiting its use.
When compared to placebo, nirmatrelvir/ritonavir resulted in a 5.8 percent absolute reduction (89 percent relative reduction) in hospitalization or death when given within five days of symptom onset.7 Side effects were minimal. Nirmatrelvir/ritonavir use is limited by availability as well as numerous drug interactions.
The major issue with both oral antivirals is the ability to get these to patients early in the disease process. This requires that patients immediately recognize their symptoms could be due to SARS-CoV-2 infection, get rapid access to a diagnostic test, get test results quickly, get a prescription from a clinician and get that prescription filled. Overcoming these obstacles is a massive challenge for many.
Bottom line: Remdesivir does not appear to play a significant role in patients requiring hospitalization with COVID-19 but may be beneficial early in disease to prevent hospitalization; however, massive resources are required for administration. Molnupiravir and nirmatrelvir/ritonavir both offer significant benefit if early administration is possible.
Steroids
Mechanism of action: Serious outcomes (hospitalization, end-organ damage, mechanical ventilation, death) are driven by the host’s inflammatory response. Steroids act by modifying the host response.
The RECOVERY Collaborative Group found that dexamethasone (6 mg IV Q24) improved 28-day mortality in patients requiring invasive mechanical ventilation (NNT = 8.5) and in those patients requiring any supplemental oxygen (NNT = 29).8 As a result of these robust data, systemic corticosteroids have become standard care in COVID-19 patients with hypoxemia.
COVID Steroid 2 sought to determine whether a higher dose of steroids would be beneficial in those with severe hypoxemia. Though there was no statistically significant difference in days alive without life support (the primary outcome) between the 12-mg and 6-mg dexamethasone groups, 28- and 90-day mortality were numerically better in the higher-dose arm.9 A study powered for mortality may show a benefit to a higher dose in severely hypoxemic patients.
More recently, inhaled budesonide has been investigated for use in outpatients with COVID-19. Though the PRINCIPLE study demonstrated a benefit in time to symptom resolution, it suffered from a number of methodological issues (open-label, subjective outcome, co-primary endpoints) that bring the results into question.10Additionally, budesonide remains an expensive treatment, limiting patient access.
Bottom line: Dexamethasone should be given to all patients with hypoxemia due to COVID. More data are needed regarding the optimal dose in those with critical illness. Inhaled budesonide appears promising but will require higher-quality data prior to widespread use.
Inflammatory Modulators: Baricitinib
and Tocilizumab
Mechanism of action: Both agents work by suppressing the hyperactive host inflammatory response that occurs as COVID-19 progresses. Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody that inhibits interleukin-6 binding and thus suppresses the pro-inflammatory cytokine cascade. Baricitinib is a Janus kinase inhibitor that suppresses the cytokine pathway.
Initial studies on tocilizumab failed to show consistent benefits. This may have been a result of corticosteroids not being used routinely in either the control group or treatment arm. The RECOVERY Collaborative remedied that situation with its large high-quality study where the majority of patients received steroids. It found that in hypoxemic COVID patients with signs of systemic inflammation (C-reactive protein >75 mg/L), tocilizumab, when added to dexamethasone, improved 28-day mortality by 4 percent (NNT = 25).11 Additionally, the tocilizumab group performed better in terms of their secondary endpoints of mechanical ventilation and discharge home.
Studies on baricitinib have been less straightforward. Early studies showed suggestions of benefit but, as with tocilizumab, did not have widespread use of systemic steroids. Most patients in the COV-BARRIER trial did receive steroids as standard care. The trial fell short in showing a statistically significant benefit for its primary outcome of disease progression in patients with hypoxemia and signs of systemic inflammation (elevated C-reactive protein, D-dimer, lactate dehydrogenase or ferritin).12 There was a significant improvement in mortality (secondary outcome) that was more pronounced in patients with hypoxemia (9.5 percent reduction).
Bottom line: Patients who have severe COVID-19 with signs of systemic inflammation and hypoxemia should be considered for tocilizumab treatment in conjunction with systemic steroids. Baricitinib requires further research but may (or may not) be a reasonable adjunct in patients with systemic inflammation and hypoxemia.
Pharmacoequity
Regardless of the agent, pharmacoequity (“Ensuring that all individuals, regardless of race and ethnicity, socioeconomic status or availability of resources, have access to the highest-quality medications required to manage their health needs,” according to Stacie Dustezina, PhD) is a paramount consideration. There is emerging evidence of racial disparities in the administration of monoclonal antibodies, remdesivir and dexamethasone.13 Communities of color have been disproportionately affected by COVID-19 throughout the pandemic. We must ensure that all patients have access to the best available treatments. The need for antiviral medications and mAbs to be started very early in the disease course is particularly challenging because of the numerous obstacles to overcome to reach those treatments.14Streamlining the process to get tested and access medications as well as reducing or eliminating costs are critical to achieving pharmacoequity.
References
1. RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet.2022;399(10325):665-676.
2. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19 – final report. N Engl J Med. 2020;383(19):1813-1826.
3. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19 – interim WHO Solidarity Trial results. N Engl J Med. 2021;384(6):497-511.
4. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet. 2021;22(2):209-221.
5. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID-19 in outpatients. N Engl J Med. 2022;386(4):305-315.
6. Bernal AJ, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520.
7. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral mirmatrelvir for high-risk, nonhospitalized adults with COVID-19 [published online ahead of print February 16, 2022]. N Engl J Med.
8. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-704.
9. COVID Steroid 2 Trial Group, Munch MW, Myatra SN, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326(18):1807-1817.
10. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-855.
11. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645.
12. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9(12):1407-1418.
13. Wiltz JL, Feehan AK, Molinari NM, et al. Racial and ethnic disparities in receipt of medications for treatment of COVID-19 — United States, March 2020–August 2021. MMWR Morb Mortal Wkly Rep.2022;71(3):96-102.
14. Swaminathan A, Essien UR, Choo E. Molnupiravir: another COVID-19 treatment, another opportunity to recognize inequity. STAT News. 2021 Nov. https://www.statnews.com/2021/11/03/another-covid-19-treatment-another-opportunity-to-recognize-inequity/.
Dr. Swaminathan is an assistant clinical professor of Emergency Medicine at St. Joseph’s Hospital in Paterson, New Jersey.
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