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Beyond the jab: The availability of drugs for COVID-19

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CoVID virus Research is beginning to identify drugs that may prevent or treat the COVID-19 virus

When COVID-19 swept tsunami-like across a poorly prepared world, clinicians and researchers experimented with almost any treatment that seemed to have a hope of working. No-one can blame them for trying drugs that seemed like a good idea at the time. After all, they needed to save lives while working in clinically uncharted territory. A year or so later, research is beginning to identify drugs that may prevent or treat COVID-19, some of which have seemingly unlikely origins.

COVID-19 develops in two phases. Outside a cell, a virus is an inanimate particle (virion) incapable of replication.1 Viruses do not contain the metabolic machinery essential for life. So, they ‘hijack’ cells.2 Basically, they are ‘obligatory intracellular parasites’.1

Usually, the immune system responds appropriately after SARS-CoV-2 infection. This means symptoms are mild and the patient recovers.3 Nevertheless, SARS-CoV-2 may kill cells (cytotoxicity) during the first few days of the infection, such as damaging alveoli and the endothelial cells lining the lungs.4

Many signs and symptoms of viral disease arise not from the damage caused directly by the pathogen, but from the body’s attempts to eradicate the infection. Many deaths from SARS-CoV-2, for example, follow the development of acute respiratory distress syndrome. This probably results from poorly controlled immune activation, which produces the notorious ‘cytokine storm’.3,4

There are, therefore, two ways to tackle viral disease: antivirals and anti-inflammatories.5 As viruses hijack healthy cells’ metabolic machinery, developing selective drugs that block viral replication while avoiding cytotoxicity is difficult. But there have been some notable successes, including antivirals for HIV, hepatitis B and C, herpes and remdesivir for COVID-19.2,6

Coronaviruses carry their genetic code as RNA, which consists of four building blocks called nucleotides. Essentially, remdesivir is similar chemically to these building blocks. During replication, the cell’s machinery cannot tell the difference between the drug and the nucleotide and includes remdesivir in the lengthening RNA chain. This inhibits viral replication.6 This mechanism means that remdesivir shows antiviral activity against several RNA viruses including SARS-CoV-2. A meta-analysis of 1895 patients from nine studies reported that remdesivir cut mortality from COVID-19 by 30%. About half (55.3%) of patients developed side effects and 17.8% stopped remdesivir because of adverse reactions.7

Calming the storm

Anti-inflammatories limit the collateral damage from the body’s attempt to tackle the viral infection. Corticosteroids (specifically glucocorticoids), for instance, reduce mortality among people with severe COVID-19.5 Corticosteroids dampen almost every type of immune response by switching the genes that code for proteins involved in inflammation off or on (technically called changing the expression). Indeed, glucocorticoids change the expression of about 1% of the genes in the human genome.2

Recently, a meta-analysis of 57 studies that enrolled 587,280 people found that, perhaps against expectations, people with asthma are 14% less likely to acquire COVID-19 and 13% less likely to be hospitalised with the infection compared with those without asthma. The risk of death from COVID-19 was 13% lower among people with asthma, but this difference was not statistically significant.8

Most studies included in the meta-analysis were observational with a short follow-up and enrolled people with self-reported asthma. In addition, asthma and chronic obstructive pulmonary disease (COPD) are easily misdiagnosed. COPD patients would probably have more severe pre-existing lung damage and be at greater risk of poor outcomes if they develop COVID-19. This diagnostic overlap may partly explain why people with asthma are 19% more likely to need admission to intensive care and 16% more likely to need mechanical ventilation than controls. Neither difference, however, was statistically significant.8

Several factors may reduce COVID-19 risk among people with asthma. Previous studies suggest that people with a common type of asthmatic inflammation and those using inhaled corticosteroids seem to show fewer and less active angiotensin-converting-enzyme-2 (ACE-2) receptors, which bind to the spike on SARS-CoV-2. Also initial uncertainty about the impact of asthma on COVID-19 may have led patients and caregivers to be particularly careful about avoiding infection.8

Antivirals and anti-inflammatories seem to work at different phases in COVID-19’s clinical course. As is the case with influenza, patients will probably need to start taking antivirals soon after they are infected with SARS-CoV-2 to reduce viral load. This need for early treatment complicates the design of clinical studies.4 Severe COVID-19 symptoms associated with poorly controlled inflammation often develop as the SARS-CoV-2 viral load declines.5 Patients with severe and late COVID-19 may, therefore, benefit from anti-inflammatory drugs.4 Using anti-inflammatories means treading a fine line, however. Suppressing inflammation, an important part of the patient’s immune response, could allow viral replication to increase.5 As a result, combination treatment could be logical.5

Old drugs new tricks

Drug repurposing (also known as repositioning or reprofiling) involves identifying new uses for existing drugs. The safety profiles of marketed drugs are generally well characterised. This means repurposed drugs can reach the clinic more rapidly than starting from scratch. When COVID-19 emerged, researchers identified biological mechanisms that may work against COVID-19 and then looked at which drug, in theory at least, fits the bill.4 Researchers looked at, for example, existing drugs that may block the interaction between the SARS-CoV-2 spike and ACE2 or to see if anti-inflammatory or anticancer drugs could inhibit the cytokine storm.9

Most famously, perhaps, hydroxychloroquine is a ccc well-established treatment for malaria, rheumatoid arthritis and systemic lupus erythematosus.4,10 Some researchers have suggested that hydroxychloroquine could prevent SARS-CoV-2 from entering cells.4 Experimentally hydroxychloroquine seems to be effective against many viruses, including SARS-CoV-2.10

In the clinic, however, hydroxychloroquine has not shown a clinically useful effect against any viral infection.10 The World Health Organization (WHO) recently published a meta-analysis of six studies involving 6059 people. The WHO concluded that using hydroxychloroquine to prevent infection had a small or no effect on mortality and hospital admission. In addition, the WHO identified an increased risk of adverse events that meant patients needed to stop hydroxychloroquine.10

Interleukin-6 (IL-6), a chemical messenger (cytokine) produced by macrophages (a type of white blood cell), triggers inflammatory responses. COVID-19 patients often show raised IL-6 levels, which is one of a cocktail of proinflammatory messengers (which also includes tumour necrosis factor-alpha and IL-1beta) responsible for the cytokine storm.4,5

IL-6 was an especially enticing target because several drugs on the market before the pandemic blocked the cytokine or its receptor. But studies in COVID-19 report mixed results. To take two recent examples: the REMAP-CAP study found that patients who received one of two IL-6 receptor blockers (tocilizumab or sarilumab) had an in-hospital mortality of 27% compared with 36% with placebo. In contrast, the COVACTA trial reported mortality rates of 19.7% with tocilizumab and 19.4% with placebo.5

Several other studies have assessed the effect of blocking IL-6 in people with COVID-19. Most reported that IL-6 blockade reduced mortality in people with COVID-19. Several factors could contribute to the differences between the investigations including the characteristics of patients enrolled, the point at which patients received treatment and when over the last year the studies were performed. Treatment of COVID-19 evolved over the course of the pandemic, which contributed to a decline in mortality.5

In particular, almost all people with severe COVID-19, the typical patient enrolled in the studies of IL-6 inhibitors, now receive corticosteroids.5 Relatively few patients in COVACTA received glucocorticoids: 19.4% in the tocilizumab arm and 28.5% in the placebo arms. In REMAP-CAP, 93% of patients received corticosteroids.5

IL-6 blockade and corticosteroids reduce inflammation through different mechanisms. In other words, the combination may be additive or synergistic (a greater change than the effect of the two drugs added together). The increased use of corticosteroids may be a marker for other treatment changes. Of course, both factors could contribute. At the time of writing it seems that while IL-6 inhibitors appear beneficial in at least some people with COVID-19, further studies need to define their optimal clinical use.5

Anakinra, used to treat several diseases including rheumatoid arthritis, targets IL-1. A recent study, however, found that anakinra did not show reductions in the need for non-invasive or mechanical ventilation, or mortality in COVID-19 patients admitted to hospital with mild-to-moderate pneumonia compared with usual care. Ninety days after admission to hospital, for example, 27% of patients in each group had died.11

The study, however, enrolled people with mild-to-moderate COVID-19. A marked response is, therefore, perhaps not all that surprising.3,11 Other data supports a benefit, however, and IL-1 blockade may still prove to be effective in people with more severe COVID-19.11

The SAVE-MORE study assessed anakinra in COVID-19 patients with moderate to severe pneumonia. Initial results suggest that adding anakinra to the standard of care in hospitalised patients with poor prognosis reduced the risk of death or progression to severe respiratory failure. The combination also increased the number of patients who were discharged from hospital with no evidence of COVID-19 infection (see www.sobi.com/en/press-releases/sobi-and-hellenic-institute-study-sepsis-anakinra-improved-overall-clinical-outcomes).

Researchers originally isolated plitidepsin, which is being developed for multiple myeloma, from the sea squirt Aplidium albicans.9 Plitidepsin also seems to offer potential treatment for COVID-19 by targeting a structural protein in SARS-CoV-2 called the nucleocapsid. In cell culture, plitidepsin inhibited SARS-CoV-2 replication 27.5 times more effectively than remdesivir. In mice that were treated before infection with SARS-CoV-2, plitidepsin reduced viral load to a similar amount as remdesivir. Plitidepsin, however, seemed more effective against lung inflammation than remdesivir.9,12

There seems to be considerable potential in repurposing drugs. As a rule pharmacologists prefer specific drugs that act selectively on a receptor, enzyme, ion channel or transporter.2 In the case of COVID-19, however, acting at different stages of the SARS-CoV-2’s life cycle could enhance efficacy. Researchers used computer models to screen 2631 drugs approved in the US against four proteins of SARS-CoV-2 that are known targets for anti-viral drugs. The analysis identified 29 drugs that could interact with at least two target proteins. Five interacted with all four proteins.13

The vaccine is, of course, the best hope for stemming the spread of COVID-19. But treatments will be needed if, for example, the immune response to the vaccine is not sufficient to protect the patient or the virus mutates and escapes the vaccine, at least partially.14 In addition, many drugs should be effective against other viruses. It’s, obviously, a long way from a computer model to a clinic. Nevertheless, the study illustrates that effective treatments may already be available or come from some unexpected sources.

Mark Greener is a freelance medical writer and journalist

References

1. Iwasa J, Marshall W. (2018) Karp’s Cell Biology: Global Edition: Wiley.

2. Ritter J, Flower R, Henderson G, Loke YK, MacEwan D, Rang H. (2019) Rang & Dale’s Pharmacology. 9th ed: Elsevier.

3. Cavalli G, Dagna L. (2021) The right place for IL-1 inhibition in COVID-19. The Lancet Respiratory Medicine. 9(3):223-4. https://doi.org.10.1016/S2213-2600(21)00035-7

4. Asselah T, Durantel D, Pasmant E, Lau G, Schinazi RF. (2021) COVID-19: Discovery, diagnostics and drug development. Journal of Hepatology. 74(1):168-84. https://doi.org.10.1016/j.jhep.2020.09.031

5. Rubin EJ, Longo DL, Baden LR. (2021) Interleukin-6 receptor inhibition in COVID-19 — Cooling the inflammatory soup. New England Journal of Medicine. https://doi.org.10.1056/NEJMe2103108

6. Jorgensen SCJ, Kebriaei R, Dresser LD. (2020) Remdesivir: Review of pharmacology, pre-clinical data, and emerging clinical experience for COVID-19. Pharmacotherapy. 40(7):659-71. https://doi.org.https://doi.org/10.1002/phar.2429

7. Bansal V, Mahapure KS, Bhurwal A, et al. (2021) Mortality Benefit of Remdesivir in COVID-19: A Systematic Review and Meta-Analysis. Frontiers in Medicine. 7(1124). https://doi.org.10.3389/fmed.2020.606429

8. Sunjaya AP, Allida SM, Di Tanna GL, Jenkins C. (2021) Asthma and risk of infection, hospitalisation, ICU admission and mortality from COVID-19: Systematic review and meta-analysis. Journal of Asthma. https://doi.org.10.1080/02770903.2021.1888116

9. Taglialatela-Scafati O. (2021) New hopes for drugs against COVID-19 come from the sea. Marine Drugs. 19(2):104.

10. Lamontagne F, Agoritsas T, Siemieniuk R, et al. (2021) A living WHO guideline on drugs to prevent COVID-19. BMJ. 372:n526. https://doi.org.10.1136/bmj.n526

11. CORIMUNO-ANA-1 Collaborative Group. (2021) Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. The Lancet Respiratory medicine. 9(3):295-304. https://doi.org.10.1016/s2213-2600(20)30556-7

12. White KM, Rosales R, Yildiz S, et al. (2021) Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 371(6532):926-31. https://doi.org.10.1126/science.abf4058

13. Liang H, Zhao L, Gong X, Hu M, Wang H. (2021) Virtual screening FDA approved drugs against multiple targets of SARS-CoV-2. Clinical and Translational Science. https://doi.org.https://doi.org/10.1111/cts.13007

14. Mahase E. (2021) COVID-19: What new variants are emerging and how are they being investigated? BMJ. 372:n158. https://doi.org.10.1136/bmj.n158

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