Emerging treatments

Introduction

No treatments have been approved or shown to be safe and effective for the treatment of COVID-19. However, there are several treatments being used off-label (use of a licensed medication for an indication that has not been approved by a national drug regulatory authority), on a compassionate-use basis, or as part of a randomised controlled trial.[198] It is important to note that there may be serious adverse effects associated with these drugs, and that these adverse effects may overlap with the clinical manifestations of COVID-19. These drugs may also increase the risk of death in an older patient or a patient with an underlying health condition. For example, chloroquine/hydroxychloroquine, azithromycin, and lopinavir/ritonavir are all potentially associated with an increased risk of cardiac death.[199] The World Health Organization and its partners have launched the Solidarity trial, a large international study to compare different treatments and ensure clear evidence of which treatments are most effective. The study will have five arms: standard of care; remdesivir; lopinavir/ritonavir; lopinavir/ritonavir plus interferon beta; and chloroquine.[200]

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine are oral drugs that have been used for the prophylaxis and treatment of malaria, and the treatment of certain autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus. Both drugs have in vitro activity against SARS-CoV-2, with hydroxychloroquine having relatively higher potency.[201][202] They are being trialled in patients for the treatment of mild to severe COVID-19.[203][204][205] They are also being trialled for prevention and post-exposure prophylaxis in the healthcare setting.[206][207] Initial data is promising, but is currently limited to one study with considerable limitations. A small randomised controlled trial found that hydroxychloroquine (with or without azithromycin) was efficient in reducing viral nasopharyngeal carriage of SARS-CoV-2 in 3 to 6 days in most patients. The addition of azithromycin was thought to be synergistic.[208] Guidelines in China and Italy recommend these drugs for the treatment of COVID-19; however, this is based on weak evidence.[209] Hydroxychloroquine has similar therapeutic effects to chloroquine, but fewer adverse effects, is considered safe in pregnancy, and is more readily available in some countries.[210] Drug regulatory agencies have stressed that these drugs are not licensed to treat COVID-19, there is no evidence that they are safe and effective for the treatment of COVID-19, and they should only be used within the context of clinical trials. Centre for Evidence-Based Medicine: chloroquine and hydroxychloroquine - current evidence for their effectiveness in treating COVID-19 external link opens in a new window

Remdesivir (GS-5734®)

A novel, investigational, intravenous nucleoside analogue with broad antiviral activity that shows in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials with remdesivir have started in patients with mild to severe COVID-19.[201][211][212][213][214][215][216] It has been used on a compassionate-use basis in areas where clinical trials are not available; however, the manufacturer has paused access to the drug via this route due to overwhelming demand while they transition to an expanded access programme. Exceptions will be made for patients with severe illness, and pregnant women and children with confirmed infection.[217] It appears to be safe to use in pregnancy.[176]

Lopinavir/ritonavir

An oral antiretroviral protease inhibitor currently approved for the treatment of HIV Infection. Lopinavir/ritonavir has been used in clinical trials for the treatment of COVID-19. Results from one small case series found that evidence of clinical benefit with lopinavir/ritonavir was equivocal.[218] A randomised controlled trial of approximately 200 patients in China found that treatment with lopinavir/ritonavir was not beneficial compared with standard care alone (primary outcome was time to improvement) in hospitalised patients with severe COVID-19.[219] It is considered safe in pregnancy.[176]

Convalescent plasma

Convalescent plasma from patients who have recovered from viral infections has been used as a treatment in previous virus outbreaks including SARS, avian influenza, and Ebola virus infection.[220] Clinical trials to determine the safety and efficacy of convalescent plasma that contains antibodies to SARS-CoV-2 in patients with COVID-19 have started.[221][222] A small case series of five critically ill patients reported clinical improvement after treatment with convalescent plasma; however, this study had many limitations.[223] In the US, the Food and Drug Administration is also facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of single patient emergency investigational new drug applications.[224]

Stem cell therapy

Stem cell therapy is being investigated to treat patients with COVID-19 in clinical trials. It is thought that mesenchymal stem cells can reduce the pathological changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[225]

Intravenous immunoglobulin

Intravenous immunoglobulin is being trialled in some patients with COVID-19; however, there are no data to support this.[21][226]

Tocilizumab

An interleukin-6 receptor inhibiting monoclonal antibody that is currently approved for rheumatological conditions (e.g., rheumatoid arthritis, juvenile idiopathic arthritis) and cytokine release syndrome. Tocilizumab is being trialled in patients with severe COVID-19 to see whether it is effective in reducing the virus-induced cytokine storm, thereby potentially reducing complications.[227][228][229][230] However, the decision to suppress the immune system of a critically unwell patient with COVID-19 is a difficult one; the beneficial anti-inflammatory effects of tocilizumab (or any other anti-inflammatory drug) must be weighed against the possibly detrimental effects of impairment of immunity.[231]

Angiotensin-II receptor antagonists

Angiotensin-II receptor antagonists such as losartan are being investigated as a potential treatment because it is thought that the angiotensin-converting enzyme-2 (ACE2) receptor is the main binding site for the virus.[232][233][234]

Other treatments

Other drugs that may show promise for the treatment of COVID-19 include teicoplanin, camostat mesylate, Janus kinase inhibitors, sarilumab, gimsilumab, and leronlimab.[235][236][237][238][239][240] Various other antiviral drugs (monotherapy and combination therapy) are being trialed in patients with COVID-19 (e.g., oseltamivir, darunavir, ganciclovir, favipiravir, baloxavir marboxil, umifenovir, ribavirin, interferon alfa, nebulised interferon beta).[241][242][243][244][245][246][247][248][249] Healthcare workers in Australia are trialling the Bacille Calmette-Guerin (BCG) vaccine.[250]

Traditional Chinese Medicine

Traditional Chinese Medicine is being trialled in some patients with COVID-19 (e.g., Xue-Bi-Jing, Shuang-Huang-Lian, Xin-Guan-2); however, there are no data to support this.[251][252][253] These medicines are commonly used in China to treat COVID-19 patients and are recommended in local guidelines.[254]

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