Clinical Evidence Summaries

This page provides rapid evidence reviews related to COVID-19. As the situation is evolving rapidly, the information may be revised as new evidence emerges.

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Should Baricitinib be Used for COVID-19?

Baricitinib is a Janus-associated kinase inhibitor (JAK inhibitor) acting against JAK1 and JAK2. It is currently approved by regulatory agencies (including US FDA, EMA and HSA) to treat rheumatoid arthritis.

Artificial intelligence has identified a group of drugs (including baricitinib) that could inhibit receptormediated endocytosis, which is the mechanism that most viruses use to enter cells. A known regulator of endocytosis is the adaptor-associated protein kinase-1 (AAK1) and disruption of this regulator may interrupt the passage of the virus into cells and the intracellular assembly of virus particles. Baricitinib has shown particularly high affinity for AAK1 and also binds cyclin G-associated kinase (GAK) another regulator of endocytosis. Further, there is growing interest in using baricitinib in combination with direct-acting antivirals, including lopinavir, ritonavir and remdesivir, since it has minimal interaction with the relevant cytochrome P450 drug-metabolising enzyme. However, there are also concerns with its use as baricitinib can inhibit a variety of inflammatory cytokines including interferon-α, which plays an important role in curbing virus activity.

While other JAK inhibitors such as ruxolitinib and fedratinib may also have activity against COVID-19, the predicted unbound plasma exposure required to inhibit receptor mediated endocytosis with these treatments greatly exceeds their tolerated doses. Therefore, they are unlikely to be suitable for patients with COVID-19 to reduce viral infectivity.

Recently, online news articles have listed JAK inhibitors, such as baricitinib, as potential COVID-19 treatment options.

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Should Favipiravir be Used for COVID-19?

A news article titled “Japanese flu drug 'clearly effective' in treating coronavirus, say China” was published in the Guardian on 18 Mar 2020. Favipiravir (brand name Avigan), an antiviral drug, is a new type of RNA-dependent RNA polymerase (RdRp) inhibitor which can block the replication of RNA viruses and may have antiviral action against SARS-CoV-2.

It was approved in Japan in 2014 for the treatment of novel or re-emerging pandemic influenza virus infections. Use is limited to cases in which other influenza antiviral drugs are not sufficiently effective because favipiravir was only investigated in non-clinical studies in avian influenza A (H5N1 and H7N9), and efficacy against seasonal influenza A or B has not been sufficiently demonstrated.

Favipiravir was also trialed for treating Ebola; however, there was no evidence that favipiravir monotherapy was effective.

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(Updated as of 02 Apr 2020) Should Protease Inhibitors be Used for COVID-19?

Protease inhibitors developed to treat HIV infection, have previously been trialed as a treatment for patients with Severe Acute Respiratory Syndrome (SARS-CoV); however their clinical efficacy was inconclusive. As SARS-CoV and COVID-19 both belong to the Coronavirus family, protease inhibitors are currently being studied as a potential antiviral treatment for COVID-19 infection. Most ongoing trials are focusing on lopinavir/ritonavir (brand names: Kaletra, Aluvia), following reports of its efficacy in a patient with COVID-19 in South Korea.

Click here for full review. (Updated as of 02 Apr 2020)

Should Remdesivir be Used for COVID-19?

Remdesivir is a novel nucleotide analog prodrug (broad spectrum antiviral). It was developed by Gilead Sciences as a treatment for Ebola and Marburg virus infections, though it has subsequently shown reasonable antiviral activity against more distantly related viruses including MERS-coronavirus. Possible activity against other coronaviruses including COVID-19 infection is predicted.1,2 Remdesivir is not currently approved to treat any condition by any regulatory agencies, including the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

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(Updated as of 27 Mar 2020) Should Interleukin-6 Inhibitors be Used for COVID-19?

The 7th edition of the Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment published by China National Health Commission on 4 March 20201 included tocilizumab (IL-6 receptor inhibitor) as an option for patients with severe COVID-19, extensive lung lesions and elevated IL-6 levels. This was following reports of positive outcomes from the use of tocilizumab to control dangerous lung inflammation in 21 patients with severe COVID-19 in China.

Clinical experts have observed that many patients with severe COVID-19 appear to have features of cytokine storm syndrome. Some have hypothesised that tocilizumab, which is licensed in the US and Europe for chimeric antigen receptor T-cell-induced severe or life-threatening cytokine release syndrome, may be effective in a subgroup of patients who have cytokine storm syndrome associated with severe COVID-19.

Subsequently, tocilizumab, sarilumab and siltuximab, which are commercially available anti-IL-6 drugs, have been cited in media articles as potential treatment options for COVID-19. Twelve other anti-IL6 drugs are in clinical or preclinical development

Click here for full review. (Updated as of 27 Mar 2020)

(Updated as of 02 Apr 2020) Should Convalescent Plasma be Used for COVID-19?

Convalescent plasma is blood plasma from a person who has recovered from an infection. It contains antibodies against the infection such as COVID-19. Recovered patients with high titres of neutralising antibody can donate plasma for administration to those at-risk to prevent infection (prophylaxis) or to those with confirmed disease to reduce symptoms and mortality. This is known as passive antibody therapy or passive immunotherapy.

Related to convalescent plasma is immunoglobulin for intravenous use (IVIG), which contains concentrated globulin from pooled human plasma with the benefit that it can be given in a smaller volume and is a more uniform product compared with plasma. Hyperimmune immunoglobulin (H-IVIG) is IVIG chosen for its high titre of specific antibodies.

Published articles have raised convalescent plasma as a potential treatment option for COVID-19 citing its use and perceived efficacy in SARS, Ebola virus, H1N1, and MERS outbreaks. International news coverage has reported that convalescent plasma has been applied in China against COVID-19.

Click here for full review. (Updated as of 02 Apr 2020)

(Updated as of 02 Apr 2020) Can Antimalarials be Used to Treat COVID-19?

An article by Gao et al. titled “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies” announced preliminary findings of 15 clinical trials from 10 hospitals in China on 19 February 2020. The authors report that results from more than 100 patients have shown chloroquine, an antimalarial treatment, is efficacious in preventing exacerbation of pneumonia, improving lung imaging findings, promoting virus free conversion, and shortening the disease course. This led them to recommend chloroquine as a treatment option for COVID-19 in the Chinese National Health Commission Guidelines for Prevention, Diagnosis, and Treatment of Pneumonia caused by COVID-19. Preliminary results of a clinical study by Gautret et al. published on 17 March 2020 also reported that hydroxychloroquine (an analog of chloroquine) is effective in treating COVID-19.

Following these early positive findings, news of chloroquine poisoning from inappropriate use, including a report of a fatality, have surfaced in the U.S. and Nigeria.

Click here for full review. (Updated as of 02 Apr 2020)

Should Ibuprofen be Used for COVID-19?

A news article titled “COVID-19: Ibuprofen should not be used for managing symptoms, say doctors and scientists” was published in BMJ on 17 Mar 2020. It claims that anti-inflammatory drugs (eg. ibuprofen, cortisone) could aggravate infection in patients with suspected COVID-19 and paracetamol should be used in these patients; however different views were expressed.

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Should ACE Inhibitors and Angiotensin II Receptor Blockers be Stopped for COVID-19?

Two recent articles by Madeddu in the British Medical Journal (BMJ) and Fang et the Lancet Respiratory Medicine have raised concerns about angiotensin-converting enzyme inhibitors (ACE-i) and angiotensin II receptor blockers (ARB) potentially increasing the risk of COVID-19 and related respiratory distress syndrome. The authors hypothesise that angiotensin-converting enzyme 2 (ACE2) is upregulated in patients treated with ACE-i or ARB, which would facilitate COVID-19 infection as ACE2 is a functional receptor of the virus. Madeddu maintains that ACE-i and ARB should not be suspended due to the lack of epidemiological data, and Fang et al. suggest that patients with cardiac disease, hypertension, or diabetes currently under treatment with ACE-i or ARB should be monitored for these medications.

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