COVID-19 Monthly Update: Focusing on Anti-inflammatory, Antiviral, and Immunologic Agents

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COVID-19 Monthly Update: Focusing on Anti-inflammatory, Antiviral, and Immunologic Agents

INTRODUCTION

The United States continues to lead the world in cases and deaths from coronavirus 2019 disease (COVID-19). With fall upon us and schools opening in many places, the situation looks bleak as well as bizarre. Despite availability of several nonmedical and effective actions that people can use to protect themselves and those around them — including behavioral, environmental, social, and systems interventions1 — many Americans continue living as if nothing is happening. Polls show that large numbers of people — as high as 40% — would not take a COVID-19 vaccine if one is approved. That makes achieving the herd immunity necessary to interrupt the pandemic difficult; even with adequate herd immunity, localized and sporadic transmission of the virus would continue.2,3

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of COVID-19, remains a poorly understood, unpredictable, and serious pathogen. It is easily transmitted by both asymptomatic and presymptomatic individuals, and COVID-19 has thus far produced mortality rates higher than those of seasonal influenza. In fact, during the devastating spread of COVID-19 in the New York City area this spring, the incident rate ratio for all-cause mortality was only 30% lower than the peak mortality rate seen during the 1918 H1N1 pandemic in that city. In addition, since today’s baseline mortality rate is much lower than it was a century ago, the increase in COVID-19 is much more striking.4

With or without an effective vaccine, the tools that could prove most useful in the current pandemic are drugs and biologic agents useful for preventing or treating COVID-19. As with human immunodeficiency virus (HIV) and other viral diseases, SARS-CoV-2 is requiring combinations of agents to achieve optimal management. In this month’s COVID-19 update, let’s look at the potential agents for use in COVID-19 cocktails; these generally fall into the anti-inflammatory, antiviral, and immunologic categories.

Anti-inflammatory Agents

The National Institutes of Health (NIH) treatment guidelines available online are one of the most useful tools for practicing pharmacists looking for specific advice on direct care of patients with COVID-19. These are updated frequently to reflect study results as those become available. Advice is divided into several sections and presented in this order: Critical care, antiviral therapy, immune-based therapy, adjunctive therapy, concomitant medications, and special populations.5

This arrangement of available agents is logical. After stabilization of patients requiring critical care for viral infections, the clinician’s mind generally turns to ways of combatting the pathogen, either through agents that directly target highly conserved viral functions or proteins (ones that do not change much as a result of mutation) or host proteins and structures involved in viral entry, translation, replication, transcription, and/or virion assembly and release.6 If antiviral therapy and immune-based therapies need reinforcement, adjunctive therapies and other medications are then explored to help the patient directly or interrupt viral transmission among people in close contact with one another.

Consistent with this treatment progression, dexamethasone and other steroids are presented later in the document, under “concomitant medications.” This belies their current importance in therapy in management of COVID-19. The antiviral agent remdesivir and convalescent plasma have provided some encouraging decreases in some indicators of severity of COVID-19, but dexamethasone is the only agent with consistent mortality-reducing effects documented in randomized controlled trials.

Based on findings in the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial (discussed below),7 dexamethasone 6 mg/d for up to 10 days is recommended by the NIH panel for patients with COVID-19 who are mechanically ventilated and patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated. The NIH panel recommends against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen and provides advice for use of dexamethasone in two important subgroups of people with COVID-19 — pregnant women (recommended) and pediatric patients (individualized considerations).5

The number of pregnant women — particularly Blacks and Hispanics — with COVID-19 hospitalized is higher than would be predicted based on their representation in the population. Whether hospitalizations are needed for increased levels of symptoms, labor and delivery, or merely a precaution is not yet clear. In the hospital, pregnant women are more likely to be placed in intensive care and to receive mechanical ventilation than other patients, but mortality rates are similar.8 In the United Kingdom, COVID-19 among pregnant women most often occurs during are the second and third trimesters, emphasizing the need for physical distancing by pregnant women. Little viral transmission to newborns has been documented.9

The evidence supporting use of dexamethasone comes from the controlled, open-label RECOVERY trial, which randomized 2,104 patients with COVID-19 to oral or intravenous dexamethasone 6 mg/d for 10 days and 4,321 patients to usual care. A primary outcome of 28-day mortality showed that those in the dexamethasone group were 17% less likely to die than patients on usual care (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75–0.93; P <0.001). Level of respiratory support at the time of randomization was important in the outcomes. Significant differences in mortality were evident among patients on mechanical ventilation or noninvasive oxygen at the time of randomization, compared with those on usual care. For participants not requiring oxygen, mortality rates were not significantly different between the two groups.7

When dexamethasone is in short supply, other glucocorticoids can be substituted. Based on emerging evidence and pharmacology of the drug class, agents such as hydrocortisone, methylprednisolone, and prednisolone should have very similar clinical effects.10,11

A potentially unfamiliar complication of dexamethasone therapy is Strongyloides hyperinfection or dissemination syndrome. Similar to protocols for patients undergoing organ transplant, a test-and-treat strategy can help identify patients who could be at risk for this sometimes severe complication should steroid therapy becomes necessary. For patients starting oxygen treatment, presumptive treatment with ivermectin is reasonable in moderate- to high-risk patients who were not previously treated or tested. When testing is unavailable or results are delayed, presumptive ivermectin therapy should be started, advises authors of a JAMA Viewpoint.12 This advice was not adopted by the NIH COVID-19 Treatment Guidelines Panel, which advises in its August 27 update against use of ivermectin for the treatment of COVID-19 except in a clinical trial.

Antiviral Agents

Even with safe, effective SARS-CoV-2 vaccines, antiviral agents could remain critically important for both treating overt infections of this virus and for prophylaxis in unvaccinated people exposed to the virus. This knowledge makes the lack of progress in finding antiviral agents for COVID-19 even more disappointing.

Remdesivir

Remdesivir is a novel antiviral agent originally developed by Gilead for treating Ebola virus. It is a nucleotide analogue that acts through chain termination during RNA replication. When a single molecule is incorporated into the growing strand, replication is stopped and the resulting virion is not infective. At low in vitro concentrations, remdesivir reduces viral titers by several logs.6

The clinical use of remdesivir for COVID-19 was investigated initially in the first stage of the Adaptive Covid-19 Treatment Trial (ACTT-1), a double-blind, randomized, placebo-controlled trial in adults hospitalized with COVID-19 who had evidence of lower respiratory tract involvement. Patients received intravenous remdesivir 200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days, or placebo for up to 10 days. The study was unblinded early after an interim analysis showed that remdesivir had significantly shortened the time to recovery, the primary outcome of the study. In 1,059 patients randomized to remdesivir (N = 538) or placebo (n = 521) at that time, those who had received remdesivir had a median recovery time of 11 days (95% CI, 9–12), compared with 15 days (95% CI, 13–19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P <0.001). While these results achieved significance, they also showed that remdesivir was producing incremental improvements rather than clinical cures.13

Based on these early clinical trial results and lacking any alternatives for COVID-19, FDA issued an emergency use authorization (EUA) on May 1, 2020, for use of remdesivir for treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. This EUA was expanded on August 28 to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19, regardless of disease severity.

The NIH panel guidelines issued on August 27 continue to make the following recommendations for use of remdesivir based on the limited benefits of remdesivir in COVID-19 and considering the limited supplies of the drug7:

  • Remdesivir should be prioritized for use in hospitalized patients with COVID-19 who require supplemental oxygen but who are not on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (moderately strong recommendation based on high-quality evidence). Use in patients with mild or moderate COVID-19 is not recommended because of lack of evidence.
  • Remdesivir should be used for 5 days or until hospital discharge, whichever is earlier. The regimen should be completed even if oxygen is no longer needed. If patients have not improved at day 5, some experts recommend continuing the drug through day 10 (low-quality evidence based on expert opinion).

A recently published study of remdesivir was conducted during the same general time period as ACTT-1, and it also produced mixed, difficult-to-interpret results. From March 15 through April 18 at 105 hospitals in the United States, Europe, and Asia, hospitalized patients with confirmed SARS-CoV-2 infection and moderate COVID-19 pneumonia (pulmonary infiltrates and oxygen saturation >94% on room air) were randomized to intravenous remdesivir 200 mg on day 1 and 100 mg daily thereafter for 5 or 10 days or to standard care. The study was open label because of a lack of placebo-containing vials. The primary study end point was clinical status on day 11 on a 7-point ordinal scale ranging from death to discharged.14

Interpretation of these results is complicated by a high early discharge rate in treatment groups, particularly for those randomized to the 10-day remdesivir course; 76% and 38% of participants in the 5- and 10-day groups completed their respective courses of treatment. Among those stopping treatment, hospital discharge was cited as the reason for discontinuation in 35 of 46 patients in the 5-day group and 98 of 120 participants in the 10-day group. The odds of a better clinical status on day 11 was significantly higher among participants in 5-day group, compared with standard care (odds ratio, 1.65; 95% CI, 1.09–2.48; P =  .02). The difference between the 10-day group and standard care was not significant (P = .18 by Wilcoxon rank sum test). Nausea, hypokalemia, and headache were more common in participants on remdesivir than standard care. Exploratory analysis of the data using time to improvement, recovery, modified recovery, and discontinuation of oxygen support showed no significant differences among the groups.14

These studies and ongoing trials illustrate the difficulties of determining whether remdesivir is effective in patients with COVID-19. Measures based on clinical status through day 28 miss the adverse outcomes in patients who develop multi-organ disease and/or later die of COVID-19. Studies relying on time to a specific endpoint generally use ordinal 7- or 8-point scales for which a 1-unit change can represent very different events (such as a patient dying versus just requiring initiation of noninvasive oxygen therapy). Because of the demonstrated improvements in some measures in those receiving remdesivir, future trials are unlikely to compare the drug with placebo, which could make finding significant differences less likely.15

In a July 7–9, 2020, survey of pharmacy practice leaders, the American Society of Health-System Pharmacists found that two-thirds of 112 respondents who received supplies of remdesivir had enough of the drug to treat all eligible patients under the FDA’s EUA criteria. The survey showed concerns over employee stress, with 77% of respondents reporting that their department or health system is taking action to minimize stress and reduce the risk of burnout during the pandemic. Availability of most cleanroom supplies has improved from previous surveys, with standard gowns intermittently available according to 57% of respondents (up from 37%) and gowns for hazardous drug preparation intermittently available to 49% of respondents (up from 30%).

Other Antiviral Agents

The SARS-CoV-2 RNA codes for a pair of protease enzymes that are essential to production of viable virions upon release. Protease inhibitors have been highly effective for treating patients with infections of human immunodeficiency virus (HIV) or hepatitis C virus, and that activity led Chinese physicians to begin use of available agents early in the pandemic. However, thus far, lopinavir–ritonavir has produced limited evidence of efficacy in patients with COVID-19. Outside clinical trials, the NIH Treatment Guidelines Panel recommends against use of protease inhibitors in patients at risk for or with COVID-19.7

In the most recently published update of a living systematic review and network meta-analysis, lopinavir–ritonavir showed a significant difference in only 1 of 5 outcomes for which sufficient numbers of participants (100) were available. The overall mean reduction in time to symptom resolution was 1.22 days (95% CI, –2.00 to –0.37) in the meta-analysis, a significant reduction. All other outcomes— mortality, viral clearance, duration of hospital stay, and time to viral clearance — were not significantly different from standard care.11

Certain antiviral agents are unlikely to be useful. Use of neuraminidase inhibitors (e.g., oseltamivir, peramivir, zanamivir) is not logical, since coronaviruses do not have a gene for neuraminidase. Nucleoside analogues (e.g., acyclovir, ganciclovir, ribavirin) would be expected to exert effects only at high levels since the coronavirus has an exonuclease that would recognize and remove the analogues when incorporated into the viral genome.16,17

Hydroxychloroquine exhibits antiviral effects in vitro, but like remdesivir, those have not translated into robust clinical advantages. The NIH panel recommends against use of chloroquine or hydroxychloroquine for treatment of all hospitalized patients with COVID-19, and against use of these drugs in nonhospitalized patients with COVID-19, except in a clinical trial. The panel also recommends that clinicians not use high-dose chloroquine (600 mg twice daily for 10 days) for treatment of COVID-19.5

Coadministration of azithromycin with hydroxychloroquine increases the risk of QT prolongation, an adverse effect of both drugs. This can be monitored in the hospital but not generally in ambulatory settings. With the lack of both rationale and evidence for adding azithromycin to a chloroquine-based regimen, its use is not recommended by the NIH panel.5

Other agents are in development for use in preventing or treating COVID-19. A Merck drug, MK-4482, has been the object of attention by the financial community, but the company has released little information at this time. The product is administered orally, which would make it very important both from clinical and manufacturing perspectives if it is effective for prophylaxis or treatment of disease in the ambulatory setting. At the end of July, Merck said the drug was in phase 2 trials, and media reports indicate phase 3 trials could begin in September.

Oleandrin is an extract of the common landscaping shrub oleander, known to be highly toxic when any part of the plant is ingested because of the presence of a pharmacologically active digoxin-like chemical. It has been promoted in the past without supporting clinical evidence for treatment of cancers, congestive heart failure, hepatitis C, and acquired immunodeficiency syndrome. While oleandrin has shown activity in Vero cell cultures against SARS-CoV-2,18 clinical evidence of its efficacy and safety are lacking. Oleandrin has been promoted in White House presentations as “the miracle of all time” by an executive with a financial interest in a company that markets the extract.

Immunologic Agents

FDA’s August 23 EUA for COVID-19 convalescent plasma (CCP) was controversial but important. Limited vaccine supply and effectiveness combined with rising vaccine hesitancy and possible waning of immunity mean that millions of people will be without protection against SARS-CoV-2 indefinitely. With no for-sure antiviral agents known thus far, antibodies could be a critical element in resolving the COVID-19 pandemic.

The White House announced issuance of the FDA’s EUA on the Sunday evening leading into the Republican National Convention. Data cited in the presentations were inaccurate and misleading, and critics speculated that politics was behind the decision. FDA released a clinical memorandum supporting its decision, and it shows randomized controlled trials have not reported significant advantages to use of CPP in patients with COVID-19. CPP “meets the ‘may be effective’ criterion for issuance of an EUA,” the FDA reviewer wrote, but added that “adequate and well-controlled randomized trials remain necessary for a definitive demonstration of CCP efficacy and to determine the optimal product attributes and appropriate patient populations for its use.”

In its EUA memorandum, FDA made these key points:

  • Current evidence suggests clinical benefit of CPP is most likely in hospitalized patients treated early in the course of the disease (e.g., prior to intubation) and with the use of CCP with higher antibody levels or neutralization activity.
  • Based on the available evidence, CCP with lower activity against SARS-CoV-2 (low titers) may be effective in treating COVID-19, and the known and potential benefits of products with low activity outweigh their known and potential risks. Health care providers can decide whether to use these “COVID-19 Convalescent Plasma of Low Titer” based on an individualized determination of potential benefit and risk.

The sponsor of the EUA, the Assistant Secretary for Preparedness and Response of the U.S. Department of Health and Human Services, cited 4 types of evidence in support of CPP, including past use of convalescent plasma for other respiratory coronaviruses, preclinical safety and efficacy in animal models, and the limited clinical trial data. The strongest evidence came from a Mayo Clinic expanded access treatment protocol (EAP) for CCP. The purpose of this program was to provide access to CCP, with a secondary objective of demonstrating safety of the intervention. Evidence of efficacy was generated in post hoc exploratory analyses. Overall, 70,000 patients have received CCP infusions through this program, FDA said in a news release.

Adverse effects of CCP in an initial population of 20,000 participants receiving CPP infusions included transfusion reactions (<1%), thromboembolic or thrombotic events (<1%), and cardiac events (3%). The overall mortality rate was 8.6%, with higher rates in those in critical care units (10.5%, compared with 6.0% among those in noncritical care settings), on mechanical ventilation (12.1% versus 6.2% in nonventilated patients), and those with septic shock or multiorgan dysfunction or failure (14.0% versus 7.6% in patients with these complications).

In its August 27 revision, the NIH COVID-19 Treatment Guidelines Panel continued its prior recommendation neither for nor against the clinical use of CPP in patients with COVID-19, citing a lack of evidence. The panel did add a recommendation against use of anti-interleukin (IL)-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) or the anti-IL-6 monoclonal antibody siltuximab for the treatment of COVID-19 except in a clinical trial.5

Monoclonal antibodies under development for use in patients with COVID-19 could be beneficial for prevention and/or treatment of this condition. Several such agents were entering clinical trials over the summer, according to authors of a JAMA Viewpoint, who concluded that such agents “would be a major advance in the control of the COVID-19 pandemic.”19

Conclusion

As the influenza season begins in the highly populated Northern Hemisphere and no known “magic bullet” on the horizon for SARS-CoV-2 in sight, stopping the transmission of this virus using nonpharmacologic means continues to be important. Without that, the slow building of herd immunity through active infections will translate into levels of morbidity and mortality — large numbers of additional cases and deaths — that most people consider unacceptable.

As noted in a BMJ editorial that discussed therapies in development, “by the time [vaccines or other agents] are widely available the pandemic’s human and economic cost will have been enormous. Therefore, immunological tools will at best complement public health vigilance, preparedness, and early control measures, which will remain vital for combating future potential pandemics.”20

REFERENCES

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  2. Posey LM. COVID-19 monthly update: focus on the vaccine endgame. Power-Pak. Available at: https://www.powerpak.com/course/preamble/120074. Accessed August 14, 2020.
  3. NPR/PBS NewsHour/Marist Poll National Tables August 3rd through August 11th, 2020. Available at: http://maristpoll.marist.edu/wp-content/uploads/2020/08/NPR_PBS-NewsHour_Marist-Poll_USA-NOS-and-TABLES_202008121039.pdf#page=3. Accessed August 31, 2020.
  4. Faust JS, Lin Z, del Rio C. Comparison of estimated excess deaths in New York City during the COVID-19 and 1918 influenza pandemics. JAMA Netw Open. 2020;3(8):e2917527.
  5. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at: https://www.covid19treatmentguidelines.nih.gov/. Accessed on: August 31, 2020.
  6. Denison M (Vanderbilt University). Presentation to the National Vaccine Advisory Committee, February 13, 2020, Washington, DC. Agenda available at: https://www.hhs.gov/vaccines/nvac/meetings/2020/02-13/index.html. Accessed on: August 31, 2020.
  7. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. 2020 July 17. doi: 10.1056/NEJMoa2021436. [Epub ahead of print]
  8. Ellington S, Strid P, Tong VT, et al. Characteristics of women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status — United States, January 22–June 7, 2020. Morb Mortal Wkly Rep. 2020;69(25):769–775.
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  10. Corral L, Bahamonde A, delas Revillas FA, et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv. 2020 June 18. Available at: https://www.medrxiv.org/content/10.1101/2020.06.17.20133579v1. Accessed on: August 31, 2020.
  11. Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. 2020;370:m2980.
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  14. Spinner CE, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. 2020 August 21. doi: 10.1001/jama.2020.16349. [Epub ahead of print]
  15. Lin D-Y, Zeng D, Eron JJ. Evaluating the efficacy of therapies in COVID-19 patients. Clin Infect Dis. 2020 Aug 21: ciaa1231. [Accepted manuscript]
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  17. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811–818.
  18. Plante KS, Plante JA, Fernandez D, et al. Prophylactic and therapeutic inhibition of in vitro SARS-CoV-2 replication by oleandrin. BioRxiv [preprint server]. 2020 Jul 14. Available at: https://europepmc.org/article/med/32699848. Accessed August 31, 2020.
  19. Marovich M, Mascola JR, Cohen MS. Monoclonal antibodies for prevention and treatment of COVID-19. 2020;324(2):131–132.
  20. Sewell HF, Agius RM, Kendrick D. Vaccines, convalescent plasma, and monoclonal antibodies for covid-19. 2020;370:m2722. [Editorial]

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