April 2020

A Summary of Potential Pharmacotherapy for COVID-19: A Review of the Available Literature.

By Robert G. Smith, DPM, MSc, RPh

[Editor’s Note: In early March of this year, the World Health Organization characterized infection by COVID-19, caused by the severe acute respiratory syndrome coronavirus (SARS-COV-2), as a pandemic. The human physiologic response to the novel coronavirus that causes COVID-19 has been wide-ranging—from fatal micro-blood clots and Kawasaki disease-like inflammatory syndrome in children to minor sniffles and the annoying anosmia to asymptomatic carriers—making the search for a treatment frustratingly difficult. LER is providing this online update as part of our efforts to keep you informed and able to answer patient questions accurately.]

<<regular text>>At the time of this writing, we as lower extremity providers are in the midst of a COVID-19 pandemic.  Per the World Health Organization (WHO), there is no current evidence to recommend any specific anti-COVID-19 supportive or antiviral treatment for patients with confirmed COVID-19.1 The global agency reported there are many ongoing clinical trials, and data is emerging frequently. The WHO advised that the use of additional investigational anti-COVID-19 therapeutics should be done under approved, randomized, controlled trials, whenever feasible.

The following is a current review of many of the medicines being tested for efficacy against this potentially deadly virus. See Figure 1 for factors that influence the pathogenesis of SARS-CoV-2.

Fraud Alert

The U.S. Food and Drug Administration (FDA) has provided data over the last few months centered on its efforts to combat the sale of fraudulent products during the coronCOVID-19 pandemic. The Operation, known as Quack Hack, has uncovered several scams related to fraudulent drugs, testing kits, and personal protective equipment (PPE). The FDA has identified and written 42 letters issued to companies for selling fraudulent products with claims to prevent, treat, mitigate, diagnose, or cure COVID-19.  Warning letters issued by the FDA and the Federal Trade Commission (FTC) have been sent to several companies selling fraudulent products claiming to treat or prevent COVID-19. The products sold by these companies include teas, essential oils, tinctures, and colloidal silver, all of which carry claims related to the cure, treatment, or prevention of serious illness related to COVID-19. The FDA has put its efforts into preventing the import of unproven products into the country and encourages lower extremity providers to report any suspected fraudulent products for COVID-19 to the FDA.

Monotherapy

A. Aminoquinolone (Antimalarial)

Chloroquine’s potential mechanism of action (MOA) is that it increases endosomal pH required for virus-cell fusion as well as interferes with glycosylation of cellular receptors for SARS-CoV-2. Further, in vitro studies have demonstrated chloroquine functioned at entry and post entry stages of SARSCoV-2.2 Chloroquine has immune-modulating activity that may synergistically enhance antiviral effect in vivo. According to guidelines published by the Society of Critical Care Medicine: “There is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine.”3

Figure 1. Viral and host factors that influence the pathogenesis of SARS-CoV-2. Bats are the reservoir of a wide variety of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) -like viruses. SARS-CoV-2 may originate from bats or unknown intermediate hosts and cross the species barrier into humans. Virus-host interactions affect viral entry and replication. Upper panel: Viral factor. SARS-CoV-2 is an enveloped positive single-stranded RNA (ssRNA) coronavirus. Two-thirds of viral RNA, mainly located in the first open reading frame (ORF 1a/b), encodes 16 non-structure proteins (NSPs). The rest part of the virus genome encodes four essential structural proteins, including spike (S) glycoprotein, small envelope (E) protein, matrix (M) protein, and nucleocapsid (N) protein, and also several accessory proteins. S glycoprotein of SARS-CoV-2 binds to host cell receptors, angiotensin-converting enzyme 2 (ACE2), that is a critical step for virus entry. The possible molecules facilitated membrane invagination for SARS-CoV-2 endocytosis are still unclear. Other virus proteins may contribute to pathogenesis. Host factors (Lower panel) can also influence susceptibility to infection and disease progression. The elderly and people with underlying disease are susceptible to SARS-CoV-2 and tend to develop into critical conditions. RBD, receptor-binding domain; HR1, heptad repeats 1; HR2, heptad repeats 2. Use is per the Creative Commons Attribution 4.0 International License.

Hydroxychloroquine’s potential MOA is that it increases endosomal pH required for virus-cell fusion and it interferes with glycosylation of cellular receptors for SARS-CoV-2. Although it shares the same MOA as chloroquine, hydroxychloroquine is noted to be a less toxic derivative of chloroquine. In vitro studies reveal hydroxychloroquine has more potent antiviral activity based on consistently smaller half-maximal effective concentration when compared with chloroquine.3 Results from physiologically based pharmacokinetic models suggest the recommended dose is a loading dose of 400 mg by mouth twice daily followed by a maintenance dose of 200 mg by mouth twice daily for four days.4 The Italian guidelines specifically state that they are “against the possible use of chloroquine/hydroxychloroquine in prophylaxis for COVID-19. At the time of writing this article, there is no evidence of efficacy of this drug in the prevention of disease COVID-19; therefore, this strategy is not recommended.”3,5,6,7 Both chloroquine and hydroxychloroquine can prolong the QTc interval, a risk increased in patients with pre-existing cardiovascular disease. A longer QTc interval is associated with cardiac arrhythmias and sudden cardiac death. The potential adverse effect on the heart is especially troubling if COVID-19 patients suffer heart damage from the disease.

B.  Antivirals (Protease Inhibitors)

Lopinavir/ritonavir (LPV/RTV) potentially targets SARSCoV-2 protease activity. It must be considered that HIV protease belongs to the aspartic protease family, whereas the two coronavirus proteases are from the cysteine protease family. HIV protease inhibitors are specifically optimized to fit the C2 symmetry in the catalytic site of the HIV protease dimer, but the C2 symmetric pocket is absent in coronavirus proteases. The Society of Critical Care Medicine suggests against routine use of LPV/RTV because of weak low quality of evidence.3

LPV/RTV can be used with darunavir in HIV therapy protocols. However, in an online statement, the drug’s manufacturer, Johnson & Johnson,  suggests that darunavir’s (an antiretroviral medication) structural analyses show very few interactions with the active site of the SARS-CoV-2 protease.8 Further, early unpublished results suggest that it is unlikely that darunavir will have significant activity against SARS-CoV-2 when administered at the approved dose for HIV-1 infection.8

C. Antiviral (Nucleoside Analogs)

Ribavirin’s potential MOA is that it inhibits the replication of RNA and DNA of viruses. Based on sequencing analysis, modeling, and molecular docking, ribavirin can tightly bind to SARSCoV-2 RNA-dependent RNA polymerase, a crucial enzyme in the life cycle of coronavirus. Ribavirin has been recommended in combination with interferon or LPV/RTV at a dose of 500 mg intravenous given twice or three times daily, not to exceed 10 days.9

D. Antiviral (Neuraminidase Inhibitors)

Oseltamivir acts at the stage of viral replication by inhibiting the function of viral neuraminidases. This prevents its reproduction by budding from Coronaviruses which do not utilize neuraminidase for the budding stage of reproduction. Due to the limitations of the study design and use of multiple medications, the effectiveness of oseltamivir for treatment of COVID-19 infection is unknown.

E. Antiviral (Miscellaneous)

Ganciclovir inhibits binding of deoxyguanosine triphophate to DNA polymerase resulting in inhibition of viral DNA synthesis. Ganciclovir should be avoided for SARS-CoV-2.10

Remdesivir is a broad-spectrum antiviral medication that inhibits RNA synthesis developed by the American biopharmaceutical company Gilead Sciences.11 Remdesivir was originally developed to treat Ebola virus disease and Marburg virus disease but was ineffective for these viral infections. The proposed dosing regimen for remdesivir in clinical trials is 200 mg as a single IV dose on day 1, followed by 100 mg once daily for a total duration of 5 to 10 days. Data and results reported from a large, worldwide clinical investigation comparing remdesivir and placebo indicate it may be the first clear signal that a drug can effectively be used to treat Covid-19.11 These early results from a large clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) appear to position remdesivir as the standard therapy for hospitalized COVID-19 patients going forward.11

In the trial, patients who received remdesivir recovered 31% faster than those who received a placebo, a finding of superiority that could not be attributed to chance, researchers reported.  Specifically, half of the patients who were randomly selected to be treated with remdesivir were considered completely recovered within 11 days, and half of those patients took longer. By comparison, it took 15 days or less for half of those who received the placebo to recover.11

Further, the results suggested that patients who were given remdesivir were more likely to survive COVID-19 than were those who got the placebo. But the difference in rates of fatalities were found to be 8% for the group that received the drug versus 11.6% for those  who received the placebo.11 On May 1, 2020, remdesivir won the FDA’s authorization for wider use in COVID-19 treatment. In the midst of these encouraging results, it’s important to remember that the drug is far from a “cure all.” Antivirals do not immediately knock out the viruses they target. Instead, they inhibit their ability to replicate, so response takes a while. The expected course of treatment will likely be 5 to 10 days.

F. Biological Response Modulators

Interferon α2b, interferon α1B, and interferon β all inhibit the replication of SARS-CoV-2 in cell culture. The relative effectiveness of different IFNs against SARS-CoV-2 is unknown.3

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. It plays a key role in driving the inflammatory immune response that causes acute respiratory distress syndrome (ARDS) in patients with COVID-19. Tocilizumab is a biologic approved by the FDA for use in rheumatoid arthritis and several other conditions. It reportedly binds to soluble and membrane-bound IL-6 receptors and inhibits IL-6 mediated signaling through these receptors. The effectiveness of tocilizumab use the treatment of COVID-19 is currently under investigation in a controlled clinical trial.12 Being a prophylactic rather than therapeutic agent, IFNs may have their highest utility in the prophylaxis or early post-exposure management of SARS.13 There is insufficient evidence to issue a recommendation on the use of tocilizumab in critically ill adults with COVID-19.3

Combination Therapies

A. Azithromycin and hydroxychloroquine

Azithromycin’s MOA is unknown, theorized as possibly anti-inflammatory. Concerns regarding drug-drug interactions, particularly QT prolongation with combination use of hydroxychloroquine and azithromycin have been raised.14 It must be emphasized to the lower extremity specialists that combining aminoquinolone drugs with azithromycin could increase their danger, as the FDA has warned that the antibiotic may increase the risk of fatal heart rhythms, particularly in patients with QT-interval prolongation.

B. Remdesivir and Baricitinib

A treatment regimen that includes the investigational antiviral remdesivir plus the Janus kinase inhibitor baricitinib is being evaluated in hospitalized adults with COVID-19 in a clinical trial sponsored by the NIAID.15,16 Baricitinib is currently marketed under the brand name Olumiant® for the treatment of rheumatoid arthritis. There has been evidence suggesting that regulating overactive signaling through the Janus Associated Kinase- Signal Trandsucer and Activator of Transciption (JAK-STAT) pathway during a cytokine storm could be a potential treatment approach for COVID-19 patients. This study, which is expected to enroll over 1000 patients from both US and international hospitals, is assessing the combination therapy vs remdesivir monotherapy in patients with confirmed SARS-CoV-2 infection who have either a need for supplemental oxygen, abnormal chest X-ray, or illness requiring mechanical ventilation.

Patients will be randomized to receive oral baricitinib (for up to 14 days of treatment) plus  IV remdesivir (for up to 10 days of treatment) or placebo plus IV remdesivir; if necessary, baricitinib will be crushed and given through a nasogastric tube. The primary end point of the study is time to recovery, defined as a patient no longer requiring supplemental oxygen or ongoing medical care in the hospital; patient outcomes at day 15 will also be evaluated as a key secondary outcome measure using an ordinal 8-point scale ranging from fully recovered to death.

C. Ruxolitinib and Standard of Care

Another investigation in a phase 3 trial is evaluating ruxolitinib for the treatment of COVID-19-associated cytokine storm is being initiated in patients 12 years of age and older.17,18 Ruxolitinib is an inhibitor of  JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors. Some evidence has suggested that regulating overactive signaling through the JAK-STAT pathway during a cytokine storm could be a potential treatment approach for COVID-19 patients.

This RUXCOVID study will be sponsored in the United States and Novartis Worldwide will enroll approximately 400 patients globally. This study will evaluate the safety and efficacy of ruxolitinib versus placebo in patients with COVID-19 associated cytokine storm receiving standard of care therapy. Patients will be randomized to receive oral ruxolitinib 5mg twice daily or placebo for a total of 14 days; an additional 14 days of study therapy may be administered to those whose symptoms do not improve or worsen after 14 days of treatment. The primary outcome measure of the study is the proportion of patients who die, develop respiratory failure requiring mechanical ventilation, or those who require intensive care unit (ICU) care by day 29.

B. Interferon- α2b (IFN- α2b) and ribavirin

IFN α2b and ribavirin concentrations required for viral inhibition must be achievable in humans in order to be relevant for clinical use.  At present, there are no data on the serum concentrations required for treatment of COVID-19 patients.19

C. Oseltamivir, Ganciclovir, and Lopinavir/Ritonavir

A combination regiment of oseltamivir, ganciclovir, and lopinavir/ritonavir was used in January 2020 in China to treat 99 patients with COVID-19 pneumonia that included 4 patients being mechanically ventilated and 13 patients who were described as having noninvasive ventilation.20 Medication regimens were described as ranging between 3 and 14 days. Drug treatment dosages were described as oseltamivir 75 mg by mouth twice daily, ganciclovir 250 mg intravenously every 12 hours and lopinavir/ritonavir 500 mg by mouth twice daily. On January 25, 2020, 31 patients were discharged, 11 patient deaths were reported, and the rest remained hospitalized. Without a comparator group, an intervention impact on outcomes cannot be assessed and it is recommended that further investigations are needed to validate a positive outcome from this 3-drug combination for treating COVID-19.

Corticosteroids

The WHO does not recommend the routine use of systemic corticosteroids for treatment of viral pneumonia outside of clinical trials due to prior studies in patients with closely related viruses (SARSCoV and MERS-CoV) showing a lack of effectiveness and possible harm. Clinicians considering corticosteroids for a patient with COVID-19 and with sepsis must balance the potential small reduction in mortality with the potential for prolonged shedding of coronavirus.7 Given the current literature, caution should be exercised until further evidence emerges surrounding the use of corticosteroids in COVID-19 patients.

ACE Inhibitors/Angiotensin Receptor Blockers

There is interest in the potential role of ACE-inhibitors and angiotensin receptor blockers (ARBs) in the pathophysiology of this disease since the SARS-CoV-2 virus binds to the ACE2 receptor for cellular entry. Researchers have observed that a high proportion of patients with COVID-19 take renin-angiotensin-aldosterone system (RAAS) blockers, including ACE inhibitors or ARBs. As these drugs increase expression of ACE2, which the SARS-CoV-2 coronavirus uses to infiltrate cells, some have speculated that the drugs may increase susceptibility to the virus. A study published May 1 in the New England Journal of Medicine provides powerful points for discussion about risks versus benefits of ACE inhibitors and ARBs in light of COVID-19.21 The  researchers conducted a case-control investigation of the association between the RAAS blockers and the risk of infection with SARS-CoV-2. They matched the 6,272 individuals with confirmed novel coronavirus infection between February 21 and March 11 in Lombardy, Italy, to 30,759 beneficiaries of the Regional Health Service by age, sex, and municipality.21 They concluded there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.21 Current guidance from cardiology organizations (i.e., American College of Cardiology/American Heart Association/Heart Failure Society of America) state that there is not enough evidence to recommend for or against these medications in the setting of the COVID-19 pandemic.7

A Word About NSAIDs

The FDA is aware of news reports stating that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) could worsen COVID-19. However, there is no scientific evidence to support these claims to date. There had been some speculation that NSAIDs, such as ibuprofen, might make things worse for some COVID-19 patients, but the researchers did not find evidence to support this statement. The agency is investigating this issue and currently does not have any specific recommendations to withhold NSAID therapy in these patients. The European Medicines Agency has also issued guidance that there is not enough data to recommend avoiding NSAIDs in COVID patients.7 A recent study has found that there is no evidence for or against the use of NSAIDs for patients with COVID-19.17 Given the current  literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs in COVID-19 patients.22

Respiratory Treatments

Inhaled medications can be delivered either by metered dose inhalers (MDIs) or by nebulization; when delivered by nebulization, these can be aerosol generating. For COVID-positive patients or those suspected of having COVID, the use of MDIs is preferred when/if available.7

Conclusion

The aim of this review was to collate the evolving available information from the published literature to identify the evidence base behind therapeutic claims with the aim of advising clinicians on how best to treat patients. SARS-COV-2 appears to spread easily and sustainably between people, with data from numerous countries suggesting that this virus spreads more efficiently than influenza, although not as efficiently as measles, which is highly contagious. As COVID-19 continues to infect more people, researchers around the world will continue to investigate how the virus interacts with commonly used medications and make further treatment recommendations. Other drugs will certainly be required to effectively treat COVID-19.

REFERENCES
  1. World Health Organization. Coronavirus: Overview. Available at https://www.who.int/health-topics/coronavirus#tab=tab_1 Accessed May 14, 2020.  
  2. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
  3. Alhazzani W, Moller MH, Arabi YM, et al. Surviving sepsis campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020 Mar 27:10.1097/CCM.0000000000004363.
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  6. Handbook for the Care of People With Disease-COVID19. 2nd Lombardia, Italy:Italian Society of Infectious and Tropical Diseases. Updated March 13, 2020.
  7. COVID-19 Pharmacotherapy Treatment Guidance March 23, 2020. Livonia, Michigan:Trinity health Available at https://www.trinity-health.org/workfiles/covid-19/covid-treatment-guide.pdf. Accessed May 15, 2020.
  8. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2. Johnson & Johnson web site. Published March 17, 2020. Accessed May 15, 2020.
  9. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19 [online ahead of print February 28, 2020]. Life Sci. 248:117477. doi: 10.1016/j.lfs.2020.117477.
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  11. Healy M. Coronavirus treatment: Remdesivir clinical trial success may be a turning point. Los Angeles Times for The Associated Press. Apr 30, 2020. Available at https://www.syracuse.com/coronavirus/2020/04/coronavirus-treatment-remdesivir-clinical-trial-success-may-be-a-turning-point.html. Accessed May 15, 2020.
  12. Novel coronavirus pneumonia diagnosis and treatment plan (Provisional 7th edition). China Law Translate web site. Available at https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/. Accessed May 15, 2020.
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  14. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949.
  15. Magro G. SARS-CoV-2 and COVID-19: What are our options? Where should we focus our attention on to find new drugs and strategies? Travel Med Infect Dis. 2020; Apr 22:101685.
  16. NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins [news release].Bethesda, MD: National Institutes of Allergy and Infectious Diseases Office of Communications. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib-covid-19-begins. May 8, 2020. Accessed May 15, 2020.
  17. Ernst D. Pipeline: Investigational therapies for COVID-19. MPR. April 13, 2020. Updated April 29, 2020. Available at https://www.empr.com/home/news/drugs-in-the-pipeline/pipeline-investigational-therapies-for-covid-19/. Accessed May 15, 2020.
  18. Cennimo DJ, et al. Coronavirus Disease 2019 (COVID-19) Treatment & Management. Bronze MS (ed). Medscape: Drugs & Diseases. May 13, 2020. Available at https://emedicine.medscape.com/article/2500114-treatment. Accessed May 15, 2020.
  19. Falzarano D, DeWit E, Martellaro C, et al. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Nature Sci Rep. 2013;3:1686.
  20. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223): 507-513.
  21. Mancia G, Rea F, Ludergnani M, et al. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med. 2020; May 1. doi: 10.1056/NEJMoa2006923.
  22. Russell B, Moss C, Rigg A, Van Hemelrijck M. COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting? 2020;Mar 30;14;1023.

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