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 is a fast-moving issue and should be read as correct at the time of publication.
- Large scale, high quality clinical trials can test if new or existing drugs are effective treatments for COVID-19. Since summer 2020 the number of trials testing COVID-19 drugs has increased from 2,300 to more than 6,000.
- The RECOVERY TRIAL is the world’s largest clinical trial of COVID-19 therapies with over 47,000 participants internationally. Led by the University of Oxford, the RECOVERY trial has so far analysed the effectiveness of a wide range of drugs. It has published evidence that supports the use of four therapies that reduce the risk of death for patients hospitalised with COVID-19.
- Seven drugs have been approved for use in the UK to treat people with COVID-19.
- Some treatments are given to patients hospitalised with severe COVID-19 to decrease the risk of death. Others are used to treat clinically vulnerable people in the community, to prevent them from becoming seriously ill and needing hospital treatment.
- One new important development is a treatment that can be given to protect people who are unable to be vaccinated or for whom vaccines are ineffective. This therapy, called Evusheld has been approved for use by the regulator; it is not yet clear if the Government will purchase it, and if so, to whom it might be offered.
- From the 1 April 2022 free universal testing for COVID-19 ended in England and Wales. Clinically vulnerable people who are eligible for COVID-19 antivirals or other therapies can still access free testing.
- Outside hospital, those at high risk can access treatments through the PANORAMIC clinical trial or through the NHS COVID-19 Medicines Delivery Units, usually within seven days of symptoms starting.
- NICE, the body providing evidence-based guidelines for the NHS, has highlighted several inequities, in the representation of some groups in drug trials, and access to some treatment. These could exacerbate existing health inequalities.
- Monitoring the emergence of resistance to drug treatments is important, and the effectiveness of antiviral drugs and antibody treatments will need ongoing review as new variants emerge.
Since POST’s July 2020 publication on this topic, hundreds of clinical trials have tested both novel (new treatments developed to treat COVID-19) and repurposed (therapies approved for use for other conditions that may work to treat COVID-19) drugs.
Effective drugs are available to treat those hospitalised with COVID-19, and in the community to prevent the people who are most at risk from becoming seriously unwell. This briefing describes the main treatments, their effectiveness and how they are used. It also discusses the latest research developments, the challenges posed by new variants and the potential for the emergence of drug resistance.
What are the most effective treatments for COVID-19?
Different approaches are needed to manage COVID-19 at different stages of the disease. In the early stages of an infection, symptoms and illness are mainly driven by the virus itself. In later stages of infection, severe COVID-19 symptoms, such as respiratory distress, are driven by the body’s immune response. Some treatments are used in hospitals while others can be used in the community. The National Institute for Health and Care Excellence (NICE) regularly reviews evidence, updating guidance for clinicians on using COVID-19 therapies as research progresses. Most of the drugs discussed here are used in people aged over 12 years, unless stated otherwise.
Drugs used in hospital
Drugs used in the community
Outside hospital, four treatments are offered to clinically vulnerable people who are at high risk of becoming seriously ill with COVID-19. All these treatments target the SARS-CoV-2 virus. Two are given orally nirmatrelvir/ritonavir (Paxlovid) and molnupiravir (Lagevrio) while remdesivir (Veklury) and the monoclonal antibody (MAb) therapy sotrovimab (Xevudy) are given intravenously in hospital outpatient settings. All of these can be used to treat vulnerable people in the community if they test positive for COVID-19. The UK Health Security Agency (UKHSA) has sent priority PCR tests to around 1.3 million people who are at highest risk of becoming seriously ill.
How can people who are not in hospital access COVID-19 drugs?
There are two ways for non-hospitalised patients to access treatments following a positive PCR test:
- through clinical trials such as the PANORAMIC or PRINCIPLE studies
- nationwide NHS COVID-19 Medicines Delivery Units (CMDUs) that dispense drugs to eligible patients. The CMDUs contact eligible patients directly after a positive COVID-19 test or are referred by a GP.
From 1 April 2022, the Government ended provision of free universal symptomatic or asymptomatic testing in England as part of the Living with COVID-19 Guidance. Those who are clinically vulnerable and therefore eligible for COVID-19 antivirals or other treatments can order lateral flow tests for self-testing. Since drug therapies that prevent the hospitalisation of clinically vulnerable people are most effective when given to patients within five to seven days of symptoms starting, scientists have expressed the importance of rapid access to tests for people eligible for treatments.
Health inequalities and drug therapies
In its summary of COVID-19 therapies, NICE describes a range of issues related to health equalities. It noted that for some drugs, people from ethnic minority backgrounds who are at higher risk of incidence and severity of COVID-19 disease than their white counterparts, are underrepresented in some of the clinical trials that have taken place. Further, they describe how some inequities may result from barriers to accessing treatment, especially in hospital outpatient settings, for people from lower socio-economic backgrounds, with disabilities or who have caring responsibilities.
Resistance to drug therapies and new variants
In common with other antiviral treatments, drugs for COVID-19 can become less effective if their target changes, as the virus mutates and new variants emerge. The risk of a virus becoming resistant to therapies depends on the drug type. There is an increased risk for the development of antiviral drug resistance in cases of prolonged infection, such as in those who are immunosuppressed, if the dosage is incorrect or if the course of treatment is not completed.
Expert scientific committees advising Government including the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) and SAGE recommend that antivirals that directly target specific regions of SARS-CoV-2 should be used cautiously. They state the importance of monitoring for drug resistance, particularly in people who take a long time to recover from COVID-19.
Using combination therapies can reduce the risk of drug resistance; by using drugs that target multiple components of a virus at the same time. This approach is very effective in treating chronic infections, such as those caused by the HIV and hepatitis C viruses.
For monoclonal antibody (MAb) treatments, drug resistance emerges if the part of the virus the drug targets changes such that it is no longer recognised by the antibody. MAb therapies require constant testing against new variants as they may become less effective at treating them. Ronapreve was the first MAb approved for use against SARS-CoV-2 in the UK in August 2021. Ronapreve is ineffective against the Omicron variant that became dominant in the UK in December 2021. Sotrovimab (Xevudy) has replaced Ronapreve, as it remains effective against the Omicron variant; however NICE recommends that more studies are required to see how effective it is against the new BA.2 variant.
How are new COVID-19 therapies tested?
Clinical trials test safety and efficacy of new treatments (or treatment combinations) compared to the current standard treatments and monitor any side-effects. Clinical trials have four phases with phases 3 and 4 having the largest number of participants. Results are used by the UK’s Medicines & Healthcare products Regulatory Agency (MHRA) to decide which therapies should be approved for clinical use. You can read more about clinical trials on the NHS website.
For those hospitalised with COVID-19, new treatments are considered beneficial if they either prevent the need for mechanical ventilation, reduce deaths (mortality) or speed up recovery compared to standard care. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, led by the University of Oxford is the world’s largest clinical trial of COVID-19 therapies with over 47,000 participants. Other large international trials include the Adaptive COVID-19 Treatment Trial (ACTT-1) sponsored by US National Institutes of Health which initially tested the antiviral drug Remdesivir. The World Health Organization (WHO) Solidarity and Solidarity PLUS trials test whether drugs already proven to be safe and effective at treating other diseases can be repurposed for treating adults hospitalised with COVID-19.
Some clinical trials have tested new treatments in the community to see if drugs can:
- prevent clinically vulnerable people with mild to moderate COVID-19 symptoms from developing more serious illness
- prevent people from requiring hospital treatment
- speed up recovery.
Drug therapies used to treat COVID-19
Direct Acting Antivirals
Antivirals suppress the virus’s ability to infect and replicate inside cells, often by inhibiting molecular interactions needed by the virus to make new copies of itself. The MHRA has approved three SARS-CoV-2 antiviral drugs. Through the UK Antivirals Taskforce, the Government has bought nearly 5m courses of Paxlovid and molnupiravir (2.75m courses and 2.23m courses respectively)
Paxlovid (Pfizer) is a combination of two drugs: a new SARS-CoV-2 specific drug (nirmatrelvir) that keeps the level of the SARS-CoV-2 in the body low and ritonavir which prevents the liver destroying nirmatrelvir and boosts overall effectiveness. Clinical trial results in high-risk adults with symptomatic COVID-19 showed that Paxlovid reduces hospitalisation and death within 28 days by 89% (0.8% Paxlovid treated patients were hospitalised or died compared to 7% in the group treated with a placebo). Paxlovid is taken orally twice a day for 5 days. Treatment must start within five days of first onset of symptoms.
Molnupiravir (brand name Lagevrio, Ridgeback Biotherapeutics and Merck Sharp & Dohme) was the first SARS-CoV-2 antiviral drug approved for use in the UK by the MHRA. It is approved for use only in those aged 18 years and over. It works by increasing the number of errors in the viral genome, preventing it from generating viable copies of itself. There is some concern that randomly introducing mutations to the SARS-CoV-2 virus may cause a new variant to emerge. Virologists suggest that this theoretical risk is low and even lower if the full course of treatment is completed.
Molnupiravir was approved for use in the UK following preliminary clinical trial results showing that molnupiravir reduced hospitalisation and death by 50% (28 of 385 participants [7.3%] vs 53 out of 377 [14.1%] with the placebo). This was reduced to 30% in the final published trial results (48 out 709 [6.8%] vs 68 out of 709 [9.7%]).
Molnupiravir remains part of the ongoing PANORAMIC trial of treatments used in the community and is also being tested by the RECOVERY trial to see if it can be used to treat those with more serious COVID-19 disease that require hospital treatment.
Remdesivir (Gilead Sciences) is an antiviral originally investigated as a treatment for hepatitis C and Ebola. It is licensed in the UK for the treatment of COVID-19. In the ACTT-1 trial, on hospitalised patients with severe disease, remdesivir shortened recovery time from 15 days with the placebo to 11 days. However more recently the results of the large international WHO Solidarity trial, showed that remdesivir had no significant effect on reducing death, recovery time or the need for ventilation compared to standard care. Further analyses of multiple clinical trial results suggest that there is little evidence that remdesivir improves survival or other outcomes in hospitalised patients. The WHO subsequently issued a conditional recommendation against the use of remdesivir to treat hospitalised COVID-19 patients in December 2020.
In January 2022 results from a randomised trial of 562 clinically vulnerable patients showed that giving remdesivir within 7 days of COVID-19 symptoms starting resulted in an 87% reduction in mortality or need for hospitalisation compared to placebo (death 0.7% vs 5.3% and hospitalisation 1.6% vs 8.6%).
For other antiviral drugs such as the influenza treatment favipiravir (now part of the PRINCIPLE trial), ensitrelvir and ensovibep, more and larger trials are needed to fully understand their effectiveness.
Monoclonal antibody (MAb) treatments use synthetic versions of the body’s own antibodies and are designed to mimic or enhance immune system functions. This is particularly useful in treating patients who are immunocompromised such as organ transplant patients. Some monoclonal antibodies are designed to bind to specific parts of the SARS-CoV-2 spike protein, preventing the virus from entering the cell. Others target parts of the body’s own immune response rather than targeting the virus. This approach is relevant to COVID-19 as respiratory difficulties and organ damage are often caused by the body’s own immune response to the virus.
Ronapreve (Regeneron Pharmaceuticals with Roche) combines two monoclonal antibodies casirivimab and imdevimab, given as a single intravenous infusion. It is an option for people who do not have any detectable antibodies. The RECOVERY trial of hospitalised patients showed Ronapreve helped patients that did not have any natural antibody response to COVID-19, and reduced death in these patients by 20% (24% vs 30% with usual care) and reduced the length of the hospital stay by an average of four days (13 vs 17 days). There was no significant benefit for people who had naturally produced antibodies in response to COVID-19. Ronapreve is ineffective against the Omicron variant.
Sotrovimab (brand name Xevudy, GSK and Vir Biotechnology) is a single monoclonal antibody. In pre-print results (not yet peer reviewed) of a clinical trial involving 1,057 high risk adults with COVID-19 symptoms sotrovimab reduced the risk of hospitalisation and death by 79% (6/528 [1%] vs placebo 30/529 [6%]). The NHS has reportedly ordered over 100,000 doses. It is given as a single 30-minute infusion, within 5 days of symptoms starting, to high-risk adults and children over 12 years old in the community with mild to moderate COVID-19. Early studies in the laboratory show promising results in sotrovimab’s effectiveness against multiple variants; however it may be less effective against the BA.2 variant.
Sotrovimab is part of the RECOVERY trial to test its effectiveness in treating more severe COVID-19 in hospitalised patients.
Evusheld (AstraZeneca), is a combination of two long-acting antibodies (tixagevimab and cilgavimab) given as separate injections. It was recently approved by the MHRA as a prophylactic, to prevent COVID-19 disease, only for those testing negative. Approval was based on the results of a trial which tested the use of Evusheld as a preventative treatment, given to unvaccinated people with no sign of previous infection. Over the course of 6 months Evusheld reduced the risk of developing symptomatic COVID-19 by 77% (between 46-90%). A second study also showed that giving Evusheld as an early treatment gave a greater reduction in risk of developing severe disease or death (50% reduction when given within 7 days of symptoms starting and 65% reduction within 5 days). This is the first drug developed to both prevent and treat COVID-19, with early preclinical data showing it remains effective against other SARS-CoV-2 variants. Evusheld offers an important option for protection for those who are unable to be vaccinated or for whom vaccines are ineffective. It is not yet clear if the Government will purchase this therapy, and if so, to whom it might be offered.
Tocilizumab and Sarilumab
Tocilizumab and sarilumab are antibodies that target and block the action of interleukin 6 (IL-6), a protein that drives the immune response to SARS-CoV-2.
In the RECOVERY trial, tocilizumab reduced the risk of death (29% vs 32%) and the risk of requiring mechanical ventilation in patients showing a strong immune reaction to COVID-19 (38% to 33%). The results were better when given together with the corticosteroid dexamethasone. NICE guidelines recommend giving tocilizumab together with corticosteroids for hospitalised patients that need supplemental oxygen and to use sarilumab if tocilizumab is unavailable. Tocilizumab and sarilumab became the second drugs recommended by the WHO following a meta-analysis of 27 clinical trials that showed that they reduced the likelihood of death for critically ill patients by 13% and reduced the risk of needing mechanical ventilation by 28% both compared to standard care. This drug can only be used in children as part of a clinical trial.
Other drugs of interest
Dexamethasone and other corticosteroids
Corticosteroids are used to treat a range of inflammatory and allergic disorders. Dexamethasone is a cheap, widely available treatment as it is off-patent and is now the standard treatment for COVID-19 patients who require oxygen support. It can be used in people of all ages, including young children on a case-by-case basis. Low doses of dexamethasone reduce the risk of death by up to one-third. It is thought that increasing the doses of dexamethasone may increase the benefits. The RECOVERY trial is comparing higher doses of dexamethasone to the current approach in hospitalised COVID-19 patients.
Baricitinib is a kinase inhibitor, with anti-inflammatory properties and is used to treat rheumatoid arthritis. It is given orally. It is thought to block the signalling molecules which overstimulate the immune system during severe COVID-19. Data from nine trials, including a pre-print (not yet peer reviewed) study from the RECOVERY trial, report that baricitinib reduces the risk of death in patients hospitalised with COVID-19 by 20%. This drug has a similar mode of action to IL-6 inhibitors so the WHO recommends that baricitinib can be used as an alternative to IL-6 inhibitors (which are given intravenously or by injection).
Empagliflozin is a treatment for type 2 diabetes which can also help chronic kidney disease and heart failure. It is thought to help stabilise the body’s metabolism and reduces inflammation caused by viral infections and increase oxygen transport in the blood. This may protect against organ damage. Empagliflozin is now part of the RECOVERY trial, however a similar drug, dapagliflozin did not significantly reduce the risk of organ failure or death in clinical trials.
Treatments that are not effective against COVID-19
As the clinical management of COVID-19 changes and improves when successful drugs are found, others of initial potential interest or those found to have only marginal benefits are no longer considered effective. The WHO’s Solidarity trial tested the treatments, Interferon-β, lopinavir, hydroxychloroquine and remdesivir and found none had a significant benefit over the standard care which changed throughout the trial.
The RECOVERY group stopped its trial of the malaria drug hydroxychloroquine early when an interim result showed no effect. Patients in the treatment group were less likely to be discharged from hospital alive within 28 days compared to those given standard care (59.6% with hydroxychloroquine vs 62.9% standard care).
Convalescent plasma is blood plasma taken from someone who has recovered from an illness and used to help others recover. In those who have recovered from COVID-19, such plasma contains SARS-CoV-2 antibodies. Convalescent plasma treatment is effective for many viral diseases but large scale clinical trials did not show a benefit in hospitalised patients with COVID-19.
Ivermectin is a widely available anti-parasitic drug that has been considered as a possible treatment for COVID-19, mainly in Latin America. Using ivermectin in this way is controversial as serious errors in multiple studies reporting a clinical benefit of this treatment were found when they were scrutinised by the academic community. High quality studies are ongoing, with the PRINCIPLE trial testing the effectiveness of ivermectin to treat mild COVID-19 in non-hospitalised adults. The WHO and NICE both state that patients should not be given ivermectin unless as part of a clinical trial.
For help in understanding technical terms used in coronavirus research you can find clear explanations in POST’s COVID-19 Glossary.
You can find more content from POST on COVID-19 here.
Explore the latest coronavirus research from teams across Parliament.
POST would like to thank Professor Penny Ward (Independent Pharmaceutical Physician, Visiting Professor in Pharmaceutical Medicine at King’s College London) and Dr Steven Griffin (Associate Professor at the Leeds Institute of Medical Research, University of Leeds) who acted as external peer reviewers in preparation of this article.
Following feedback this Rapid Response was updated on 03/05/2022 to clarify that although Evusheld has been approved for use by the regulator it is not yet clear if the Government will purchase it.
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