What can deliberately infecting healthy people tell us about infectious diseases? How is this useful for developing treatments, and how do we manage the risks?
- This article was updated on 1 May and again on 6 July. Since its original publication on 17 April, the number of COVID-19 clinical trials has increased from 524 to 2,378.
- There is no cure for COVID-19. Researchers are testing existing drugs to see if they act against SARS-CoV-2 or alleviate the symptoms of the disease. New drugs are also in development, but this is at a very early stage.
- Results from trials on existing drugs have already been reported with some positive findings.
- Dexamethasone is a cheap steroid drug that reduces the risk of death of ventilated patients by 35% and by 20% for patients requiring oxygen therapy.
- Remdesivir is an antiviral drug; there is good evidence that it can reduce the length of time that hospitalised COVID-19 patients are ill.
- Negative findings are valuable because they allow researchers to focus on other drugs; there is good evidence that hydroxychloroquine does not offer any benefits to treat COVID-19 patients. Research to see if it might have a protective effect for at-risk groups, such as healthcare workers, is ongoing.
- There are numerous trials in progress to test a range of drugs that act on the immune system.
- This is part of our rapid response content on COVID-19. You can view all our reporting on this topic under COVID-19.
There are no specific treatments for COVID-19 disease, caused by the SARS-CoV-2 virus. The international research community is working at pace to find treatments that work and to develop vaccines, with 2,378 clinical trials currently in progress (there were 1,133 ongoing clinical trials on 1 May, up from 524 on 17 April when this article was originally published).
The approach that will give the fastest results is to repurpose existing treatments – results from this were expected within 1–2 months and there is already some evidence that existing drugs can improve clinical outcomes for people with COVID-19. Clinicians and researchers are testing whether existing drugs, or combinations of drugs, used to treat other conditions offer any benefit to COVID-patients. This information is used by health professionals to design the most effective care for patients. Other research seeks to examine whether any treatments have a useful prophylactic effect; if so, they could be used to protect those at high risk of infection, such as healthcare workers. There are numerous projects to develop completely new therapies. Like vaccines, these are likely to take much longer to develop than repurposing existing medicines.
Antibiotics are designed for bacterial infections and therefore have no benefit for viral infections like COVID-19. However, some patients hospitalised with COVID-19 may receive antibiotics because they also develop a bacterial infection.
Understanding viruses – the viral life cycle
Viruses are unable to survive and replicate independently so they must use the machinery of a host cell (an animal or person); they infect host cells and hijack them to produce copies of the virus.
While the life cycles of different viruses vary, there are key common stages:
- Attachment: the virus uses special proteins to attach to a host cell.
- Entry: processes take place to fuse the virus and host cell membranes, the virus then releases its genetic material into the host cell
- Replication: new copies of the viral genome and viral proteins are made.
- Assembly: the viral genome and proteins are combined to produce new viral particles called virions.
- Release: the virions are released from the host cell and the cycle begins again.
Features of the SARS-CoV-2 virus
This virus’s structure is very similar to other well-researched coronaviruses with the following features: a lipid (fat) envelope covered in distinctive spike shaped proteins. Inside the virus is its genetic material – a single strand of ribonucleic acid (RNA). Some viruses use RNA rather than DNA as their genetic material. Detailed examination of the viral structure highlights features that are involved in the mechanisms the virus uses to attach and infect human cells and its mode of replication; invaluable information for designing treatments to block these mechanisms. A key feature is a spike-shaped protein found on its surface that the virus uses to bind to human cells: drugs that stop this binding process from taking place could be effective treatments.
Immune response to viral infection
Infected cells produce proteins that can be recognised by specialised cells of the immune system. By signalling the presence of virus, T cells in the area are recruited to attack infected cells. T cells and natural killer cells attack infected cells through the release of chemicals. Infected cells also make a range of proteins – including a group called interferons – that try to slow the virus’s replication and to alert other parts of the immune system.
Antibodies can neutralise viruses before they enter the host’s cells. They do this by recognising proteins on the surface of the virus and sticking to them so that the virus cannot enter host cells. They also act as a danger flag to other parts of the immune system – some immune cells then engulf the flagged virus and destroy it. Cells infected with the virus will have viral proteins on their surface, antibodies can bind to these proteins and flag to other parts of the immune system that the cell is infected and should be destroyed. Therefore, treating sick people with antibodies is one research focus.
Antiviral therapies are used to control infections. All stages of the viral life cycle outlined above are therapeutic targets. For example, some HIV drugs block viral entry, while others inhibit new virus being formed. Unlike antibiotics, very few anti-viral drugs are broad spectrum – meaning that they can be used against a range of viruses; this is an area that could be a focus for future research investment. RNA viruses, like SARS-CoV-2, mutate readily and therefore any effective antiviral therapy will probably depend on the administration of a combination of drugs. Therefore, it is worthwhile testing lots of drugs, in various combinations, that have different targets.
Another approach to treating people infected with viruses is to stimulate their immune response.
All experimental drugs must be tested extensively to ensure they are safe and effective. This is done through clinical trials (see Box 1). This approach to testing also applies if an existing drug is being used in a new way. For example, an anti-viral drug used to treat influenza would need to pass new clinical trials in order to license it for use as a COVID-19 treatment. However, the existing body of evidence about its characteristics and mode of action can expedite this process. Fast-tracking research to develop treatments and vaccines has taken place before – such as during the Ebola virus outbreak in West Africa – but this raises significant ethical challenges related to all aspects of developing and testing drugs in people, especially for novel experimental therapies.
Clinical trial design and phases
Clinical trials are carefully designed and highly controlled to minimise bias and to generate statistically reliable evidence with which to measure a treatment’s efficacy and safety. This is achieved by selecting an appropriate number of patients, and by comparing the new treatment (or combination of treatments) against either a placebo or the current standard treatment.
- Phase 1 trials include the first in-human tests, so their main aim is often to test the safety of the treatment. These typically use small numbers of healthy volunteers (often fewer than 10), or patients who are ill and have few other treatment options.
- Phase 2 trials use about 20 to a few hundred volunteers or patients. Phase 2A trials test dosage levels, and phase 2B trials assess efficacy (the ability of the medicine to treat the disease or symptoms).
- Phase 3 trials may involve up to several thousand patients to assess definitively the efficacy of the treatment. Large numbers of participants are necessary to provide statistically reliable evidence, and to spot less common side-effects.
- Phase 4 occurs after the treatment is licensed for marketing. These trials are for safety surveillance to detect rare or long-term adverse effects in the wider patient population, and to compare against competitors’ products or current medical practice.
Developing treatments for COVID-19
Repurposing existing drugs
There has been research since the outbreak began into whether drugs currently used for other viral illnesses or that could treat the symptoms of COVID-19 may be effective. A common way to assess outcomes is to see whether patients get better more quickly when they receive a drug is to compare it with a placebo treatment. The definition of recovery can differ between trials. For example, it might mean being discharged from hospital, or being able to resume normal daily activities. Another measure is to see if patients are more likely to survive.
Trials to test existing drugs have produced results much more quickly than developing completely new treatments from scratch, with positive and negative results reported. Finding that a drug does not work is valuable since it means that researchers can focus on others. While interim results are being shared widely, such as through press releases, scientists are waiting for data to be properly reviewed and published in scientific journals before drawing firm conclusions.
The WHO is running a global megatrial called ‘Solidarity’, comparing four prospective treatments. The main drugs from this and other trials and the results to date are detailed here.
A steroid drug used to treat a range of inflammatory and allergic disorders. Researchers at the University of Oxford have tested this drug as part of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial. On 16 June researchers announced results from a randomised controlled study that compared outcomes for 2,104 patients receiving dexamethasone with 4,321 patients receiving standard care. The drug reduced deaths by one-third in ventilated patients and by one-fifth in other patients requiring oxygen therapy only. There was no benefit of the drug for patients who did not need respiratory support. A preprint of the data, which has not yet been peer-reviewed, was published on 22 June. A new study will examine if the drug can benefit children.
An unlicensed, experimental antiviral drug that was originally developed to treat Ebolavirus by inhibiting viral replication. It has some activity against other coronaviruses (SARS-CoV and MERS-CoV), so there is significant interest in its therapeutic value for COVID-19. The drug has to be delivered into the vein. There are 13 clinical trials in progress.
Data from trials on remdesivir are mixed. There is some good evidence that it slightly reduces the length of time that hospitalised patients are ill (by approximately 4 days). The evidence that it might improve survival rates is currently much weaker, but further work is needed to see if this a real effect.
April: Results from a randomised controlled trial of 237 patients with severe COVID-19 showed that remdesivir did not reduce the time to recover. The trial stopped early as it could not recruit more patients.
May: The international ADAPTIVE COVID-19 Treatment Trial sponsored by the US National Institutes of Health is a high quality study because neither healthcare workers nor patients know which drug they are receiving (known as double-blind). Interim data were reported in a pre-print on 29 April that was subsequently peer-reviewed and published on 22 May. Preliminary results from a trial in 1,063 hospitalised patients with COVID-19 pneumonia found that those who received the drug recovered more quickly (11 days) than those who received a placebo (15 days). There is also some data suggesting that the drug can improve survival (7.1% for remdesivir vs. 11.9% in the placebo group), but larger studies will be needed to confirm this effect.
Gilead, the drug company that makes remdesivir, is running two trials to test effects in patients hospitalised with moderate or severe COVID-19 and compared the drug with standard care. A trial compared a 5-day course of treatment to a 10-day course for patients with severe disease and found no difference in outcomes. However there was no control group, so it is impossible to conclude if the drug offered any clinical benefit and by what margin. The data could be relevant to clinical practice since shorter treatment durations mean that supplies of the drug could be used to treat more patients.
June: A study in patients with severe disease where the drug was used on compassionate grounds reports some clinical benefits for some patients. The study did not include a control group.
Gilead published some data on patients hospitalised with moderate COVID-19 who were either given a 5-day or 10-day course of treatment and outcomes were compared with patients who received standard care. Those receiving a 5-day course were more likely to show a modest improvement by day 11 than those who did not receive the drug. Gilead is reporting interim results through press releases; proper scrutiny of the quality of the research will not be possible until the results are reviewed and published in a scientific journal.
NICE published a summary to inform doctors about how and when to use the treatment for hospitalised COVID-19 patients.
Lopinavir & ritonavir (Kaletra)
An antiretroviral drug combination used to treat HIV. A randomised controlled trial in patients hospitalised with COVID-19 found that the drug offered no benefit compared with standard care. Researchers at the University of Oxford have tested this drug combination as part of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial. The trial has an adaptive design – this means that it can include and test new therapies as they become available. On 29 June, preliminary data from a RECOVERY randomised controlled study show that the drug does not offer any benefits to hospitalised patients.
Hydroxychloroquine is used to treat malaria and autoimmune conditions, such as rheumatoid arthritis and lupus. The precise antiviral activity is not fully understood but is thought to be through inhibition of viral replication. There is no evidence to support giving this drug to people with COVID-19 outside of a well-designed clinical trial, and such trials are underway. The European Medicines Agency has stated that neither drug should be used outside a clinical trial or emergency use programme. The Wellcome Trust’s COVID-19 Therapeutic Accelerator is funding clinical trials to examine the effectiveness of hydroxychloroquine and chloroquine in people who have been or are at high risk of being exposed to SARS-CoV-2. Trials are running in multiple locations, including the UK; the COPCOV study will determine if a daily dose of hydroxychloroquine or a similar compound called chloroquine can prevent COVID-19 in healthcare workers.
March: One small study in France reported some benefits but the study design was not robust.
A paper in The Lancet reviewing data from 96,032 patients reported no benefits of hydroxychloroquine or chloroquine and an increased risk of death. This led to the WHO suspending all global work on trials involving the drug. The paper was subsequently retracted because of concerns about the data. The lead scientist on this study had another COVID-19 paper about a different drug retracted for the same reason.
June: On 3 June WHO announces that trials may resume. Researchers at the University of Oxford tested this drug as part of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial. This high-quality study found that hydroxychloroquine did not lead to any clinical improvements nor did it reduce the risk of death in patients hospitalised with COVID-19. These results, a Cochrane evidence review and further negative data from a French study are considered by WHO. Subsequently the WHO stops the hydroxychloroquine part of the Solidarity trial, but trials to determine if the drug has a protective effect (prophylaxis) continue. The US Food and Drug Administration rescinds its previous approval for the use of hydroxychloroquine as a treatment.
Other drugs of interest
An antiviral drug (tradename Avigan) developed by a Japanese company, licensed and marketed only in Japan as a drug of last resort for influenza outbreaks. It acts through inhibition of RNA polymerase, and so there is interest in whether it has activity against SARS-CoV-2. There are three clinical trials in progress in China; both involve testing favipiravir alone or with another drug. Some research on COVID-19 patients’ responses to favipiravir treatment has shown no clear benefit but this was not a randomised controlled trial. Another study found that the drug was more effective than an alternative treatment, reducing the symptoms and length of illness.
There is also interest in drugs that are used to treat high blood pressure.
Angiotensin II receptor
The body contains structures called receptors – these respond to specific chemicals such as hormones or neurotransmitters. The receptor and the chemical that binds to it can be thought of as like a lock and a key. Angiotensin receptors (lock) responds to the hormone angiotensin (key), but the SARS-CoV-2 virus can also act as a key. Drugs that block this receptor would stop the virus from binding to the receptor. Drugs to block this receptor are widely used to treat high blood pressure and diabetes. Researchers are investigating whether they are useful in treating patients with COVID-19.
Angiotensin-Converting Enzyme-2 (ACE-2)
SARS-CoV-2 enters cells by attaching to the ACE-2 receptors on cell surfaces (expressed by cells in lung, intestine, kidney, and blood vessels) – blocking the virus from doing this would stop it from entering cells. Drugs that have this action are already available – they are usually used to treat high blood pressure, so they are being tested in patients with COVID-19.
There has been a debate in the scientific community about whether using these drugs increases the risk of developing severe and fatal COVID-19. This is because ACE-2 levels increase in patients with diabetes and/or high blood pressure who are treated with ACE inhibitors and Angiotensin II blockers. Other studies suggest that the medication may offer a protective effect. Several medical bodies suggest that the evidence on which this hypothesis is based are not strong and advised patients not to discontinue using these medicines. Two evidence reviews by the WHO and the European Medicines Agency reports that there is no data to suggest that taking these drugs increases the risk of becoming infected or that people with the disease who take these drugs have poorer outcomes.
Other therapeutic approaches are to modulate the body’s immune response.
Tuberculosis (BCG) vaccines
There is interest in testing whether vaccines developed to prevent other diseases can offer any protective effect. This is because some vaccines can stimulate the innate immune system, in addition to their specific effects on a virus or bacterium. The Bacillus Calmette–Guérin vaccine, used to prevent tuberculosis, stimulates the innate immune system, and there are 15 international clinical trials in progress to examine if it can offer any indirect protection against COVID-19 infections.
Interferons are proteins that stimulate the immune system to attack pathogens and other foreign cells (such as cancer cells). One class of interferons (called interferon-β) is of particular interest for treating COVID-19 since it activates cells that can engulf viruses. There are 68 trials of interferon drugs ongoing internationally. In the UK researchers at the University of Southampton are testing an inhaled interferon-β drug in COVID-19 patients. Previous research shows that the drugs can protect cells from other coronaviruses (MERS-CoV and SARS-CoV). A pre-print study from China reported that interferon nasal drops offered some protection against infection for healthcare workers. A study combining interferon-β with anti-viral therapies showed promising results but further research to examine the relative contribution of the interferon drug is needed
Antibodies are produced by the immune system to fight infection; they do this by binding to and neutralising the pathogen, and by activating other cells in the immune system to enhance the response. Therefore, researchers are developing antibodies that could be used as therapies to treat COVID-19 and as a preventative option.
Monoclonal antibodies are biological therapies synthesised in the laboratory. They mimic natural antibodies by recognising a specific target protein on a cell’s surfaces and then flagging these cells for killing or binding directly to the virus and stopping the virus from attaching to a human cell. Antibodies can be designed by using genetic sequences of interest from the virus.
There are several antibodies used for other conditions that are being tested in COVID-19 patients, and specially designed antibodies are also in development, some of which are being tested in trials:
- AstraZeneca is testing a combination of two antibodies in clinical trials.
- GSK has an antibody in a Phase 2 trial.
Other antibody therapies work to dampen down the immune response rather than attacking the virus directly. This approach is relevant to COVID-19 because the immune response caused by the virus can lead to respiratory distress syndrome.
- Antibodies acting at a receptor involved in the immune response (interleukin-6 or IL-6) are widely used to treat autoimmune disease such as rheumatoid arthritis. There are 25 clinical trials in progress to test two drugs (sarilumab and tocilizumab) that act on IL-6. Of note:
- Regeneron and Sanofi are testing Sanofi’s rheumatoid arthritis drug sarilumab in Phase 2/3 trials in patients with severe COVID-19 infections in the US and several European countries.
- Roche’s rheumatoid arthritis drug tocilizumab is already approved in China for COVID-19 patients with lung damage despite the lack of properly designed studies to test whether it is safe and effective. There are 59 trials of the drug in progress.
Another approach that uses antibodies is to take blood plasma from patients who have recovered from COVID-19 and give it to patients. This therapy is used in the UK against other viruses. The theory is that the donated antibodies in the plasma give the patient some protection while their own immune system mounts a response to the infection. This had positive results in 15 patients in 2 separate Chinese studies, but as neither were randomised controlled trials, it is unclear whether the plasma made the difference or not. The US Food and Drug Administration has issued guidance on the collection and use of donated plasma for COVID-19 therapy. NHS Blood and Transplant is running two trials to test whether convalescent plasma is effective. A Cochrane evidence review found that there are only a few low quality studies so far and so little evidence to suggest that this approach works. High quality well controlled studies in large numbers of people are needed, and this is underway as part of the Oxford-led RECOVERY trial.
Developing novel therapies for COVID-19
Researchers are examining several approaches where drugs against SARS-CoV-2 might work – these are designed around specific biological features of the virus and so fall into different categories:
RNA polymerase inhibitors
SARS-CoV-2 is a single stranded RNA virus, so there is interest in drugs that target the function of this enzyme. RNA polymerase plays a key role in viral replication so any drug that inhibits this process is of interest. This approach is a feature of some successful treatments for other viruses, including HIV and hepatitis C virus (that is more similar to SARS CoV-2).
Proteases are essential components that facilitate viral replication. A protease of SARS-CoV-2 has been characterised and a chemical that inhibits its function in mice has also been identified. Tests showed positive results when the drug was delivered directly to mouse lung and when applied to in vitro human lung cells; as COVID-2 particularly affects the lungs, this is an avenue for further drug discovery.
Drugs that modify virus binding and/or entry to host cells
Several drugs are known or are postulated to modulate viral entry into the host cell, for example chloroquine.
UK research funding for therapies
The Government announced a £20m funding allocation for COVID-19 vaccines and therapies in March. This is coordinated through the Government’s medical research funders, the National Institute for Health Research (NIHR) and UK Research and Innovation. The UKRI Medical Research Council has a new additional rolling funding stream for COVID-19 research. The NIHR has established a single national prioritisation process for COVID-19 research. There are 48 priority studies underway, of which 25 are looking at drug therapies. All the studies are designated as urgent public health research projects by the Chief Medical Officer for England. The ACCORD (Accelerating COVID-19 Research and Development platform) programme to fast track drugs that work was announced by the Government in April. The positive results from dexamethasone were announced on 16 June and authorised for use in the NHS by all the UK’s Chief Medical Officers on 17 June.
The pharmaceutical industry is also working to expedite research and clinical trials, often in collaboration with academic and other partners. The Association of the British Pharmaceutical Industry has collated information about the sector’s work on therapies, vaccines, diagnostics and NHS collaboration.
Recommending New Treatments for use in the NHS
The National Institute for Health and Care Excellence is responsible for producing evidence-based guidance and advice for health and social care services. It has produced several rapid response guidelines on care of patients with suspected or confirmed COVID-19, and for patients without COVID-19 who have specific clinical needs. It is expected that NICE will review results from drug trials and make recommendations about how healthcare professionals should use these drugs in patients with COVID-19.
You can find more content from POST on COVID-19 here.
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