Treatments for Covid-19 used in UK hospitals today

On 23rd March 2022, the RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy) celebrated its second birthday. Within two years, they have enrolled over 47,000 participants across six countries, identified four effective treatments for Covid-19, debunked others rumoured to work (Hydroxychloroquine, Aspirin and Colchicine) and are continuing to explore the efficacy of potential novel treatments as they arise. Considering that before the advent of the Sars-CoV-2 Virus, most clinical trials took about ten years to generate approved medicines for use, this is truly a momentous occasion.

So, with their work ongoing, what are the effective treatments for Covid-19 used in hospitals today?

The medicines we have in our arsenal so far fall broadly into four categories:  monoclonal antibodies, antivirals, corticosteroids and re-purposed drugs (ones already approved for treating other conditions that may also work in Covid-19; not addressed in this article).  These drugs are used at different stages and/or severity of illness and give hope to people who fall ill with Covid-19, who are in the high risk group for severe illness or those who cannot have vaccines because they are allergic or do not mount a response to them.  A few of the newer generation of treatments are discussed here.

Monoclonal Antibodies (mAb)

A monoclonal antibody (mAb) is produced by mimicking our immune response in a lab setting.  White blood cells (B cell) are exposed to a target (virus, bacteria, cancer) and then produce antibodies which are used for treatment.  The advantages of this system are specificity and scale; antibodies can be generated towards one target and then grown in number to a large enough scale for widespread use.  In the case of Covid-19, the antibodies tend to be targeted toward a part of the ‘spike’ protein on the coronavirus.

Tocilizumab (RoActemra in Europe, Actemra in USA)

UK Government Patient Criteria:

• hospitalised patients

• over the age of 18

• in the early stages of critical illness

• using dexamethasone.

Tocilizumab (TCZ) is an mAb that has been used to treat Rheumatoid Arthritis safely and effectively since 2009. Because of its ability to prevent our immune systems going into overdrive (resulting in what’s known as a cytokine storm), TCZ was a logical choice to examine its potential role in treating severe Covid-19 cases involving cytokine storms. 

In two large scale studies (RECOVERY and REMAP-CAP) a single, sixty minute intravenous infusion of TCZ reduced the mortality rate and probability of patients progressing to needing ventilation.

Sotrovimab (Xevudy)

UK Government Patient Criteria:  

• most adults, and children aged 12 years or older who weigh at least 40kg.

• high risk groups

• those who have had a positive PCR test within the last 5 days

• those who have had coronavirus (COVID-19) symptoms within the last 5 days

Sotrovimab is a neutralising mAb that blocks the virus entering cells, and also appears to clear infected cells.  It binds to a part of the SARS-CoV-2 spike protein that is conserved from the original SARS virus – meaning this part of the virus is unlikely to mutate, making it more difficult for resistance to develop. It is administered by a thirty minute intravenous infusion.

Sotrovimab was approved for use in treating Covid-19 by the UK Medicines and Healthcare products Regulatory Agencey (MHRA) in December 2021.  It is demonstrated to be effective at preventing Covid-19 related hospitalisation and/or death for up to 29 days in non-hospitalised patients with mild to moderate Covid-19. Furthermore, it appears to retain its efficacy against the Omicron variant.

Tixagevimab plus Cigavimab (Evusheld)

UK Government Patient Criteria:  

• people who are unlikely to mount a response to vaccines

• those for whom vaccination is not recommended (allergic response, etc)

• recipients should not be currently infected with or had recent known exposure to a person infected with the COVID-19 virus 

Evusheld, was approved for use in treating Covid-19 by the UK MHRA in March 2022.  It is a combination of two mAbs which bind to two distinct sites on the SARS-CoV-2 spike protein, preventing the virus from attaching to and entering human cells.  Evusheld is unique because it is the first pre-exposure prophylactic (PreP) mAb to be approved for Covid-19.  Also, unlike other mAbs it is given as two separate, sequential intramuscular injections, so can be administered in General Practice surgeries or in the community, similar to vaccines.  Study data demonstrates that Evusheld reduced the risk of developing symptomatic Covid-19 by 77%. Protection continued for at least six months, with few, mild side effects.  It has also been shown to be effective against the Omicron variant.

To put this into context, the AstraZeneca vaccine reports a 76% reduction in development of symptomatic Covid-19, while Moderna and Pfizer mRNA vaccines can boast closer to 95% efficacy, but the potency of all of these begin to wane four to six months after the jab.  Evusheld appears to sit well in the company of vaccines, yielding similar levels and duration of protection against Covid-19 illness for those who cannot have vaccines.

Another mAb combination that was approved for study and used in hospital settings was a medicine call REGEN-COV (in the USA; Ronapreve in Europe).  This combination of casirivimab and imdevimab was effective in preventing symptoms, hospitalisation, severe illness, and deaths but has since been removed from treatment regimens as it has no effectiveness against the Omicron variant.

So, mAbs can be a great defence against severe illness from Covid-19 and can even act like a vaccine for people who cannot have vaccines. But, their efficacy can be wiped out by the introduction of a new variant able to dodge the antibodies.  In terms of Covid-19, that means researchers always have to be prepared to tackle new variants, whether it’s for a new vaccine or for a new antibody treatment.

Antivirals

The main goal of an antiviral is to find some way of disrupting the virus’s ability to replicate, thus preventing it from causing disease and spreading.  However, in order to do this, most of these drugs need to be administered early on in the infection.

Remdesivir (Veklury)

UK Government Patient Criteria:

• adults, or young people aged 12 years and over who weigh at least 40 kg,

• those who need supplemental oxygen for COVID-19

• those who are within 7 days of Covid-19 symptom onset

• those in the high risk group

Remdesivir, the first anti-viral used to treat Covid-19, works by blocking the activity of an enzyme the virus needs in order to multiply.  It has had very mixed results, leaving clinicians torn as to whether they should use it. The World Health Organisation takes the stance of a conditional recommendation not to use it, pending further data. 

The most recent study showed that Remdesivir, administered intravenously over 3 days to high risk, non-hospitalised patients within 7 days of Covid-19 symptom onset resulted in a relative risk reduction of 87% in hospitalisation or death at day 28.

It is clear that more research is needed to elucidate the true effect of Remdesivir on Covid-19. Furthermore, Remdesivir is a medicine delivered by intravenous infusion over days, so it is not as practical a medicine as something that comes as a quick intramuscular injection or pill.  Remdesivir currently is being overhauled to find a more practicable route of administration, like the orally administered ones below. 

Molnupiravir (Lagevrio)

UK Government Patient Criteria:

• adults aged 18 years and older

• those in the high risk group

• those who’ve had a positive PCR test within the last 5 days

• those who’ve had coronavirus (COVID-19) symptoms within the last 5 days

Approved by the UK MHRA in November 2021, in simplest terms, molnipiravir works by attaching itself to the viral mRNA inside a cell and giving it the ‘wrong’ code for replication.  This disrupts the virus’s ability to make correct mRNA strands (causing errors in its genetic code) and therefore stops it being able to reproduce and spread.

In one study, molnupiravir was found to reduce hospital admission with Covid-19 by 30%, without evident safety concerns, when initiated within 5 days after the onset of symptoms in unvaccinated, at-risk outpatients.  Furthermore, another study showed that molnupiravir accelerated the clearance of the virus from patients who had tested positive for Covid-19 when compared to a placebo.

The advantages of molnupiravir are: i) it is administered orally, so it’s more practical than mAbs that require intravenous infusion and ii) its activity is independent of spike proteins so it is effective against Omicron.

The disadvantage is that it causes mutations in the genome of the coronavirus and there is some concern that this could also do the same to human cells, which is why this is not recommended for use in children or pregnant women.  Research into this effect is ongoing and so far, no clinical evidence has been found.

Nirmatrelvir plus ritonavir (Paxlovid)

UK Government Patient Criteria:

• adults aged 18 years and older

• those in the high risk group

• those who’ve had a positive PCR test within the last 5 days

• those who’ve had coronavirus (COVID-19) symptoms within the last 5 days

Paxlovid, was UK MHRA approved in December 2021, and is a combination of a new antiviral (nirmatrelvir) developed by Pfizer and another drug (ritonavir) which has been used for many years in the treatment of HIV.  Nirmatrelvir, like Remdesivir, blocks the activity of an enzyme needed by the virus to replicate while Ritonavir slows the breakdown of nirmatrelvir, enabling nirmatrelvir to remain active in the body for longer.  Paxlovid is a tablet, so can be taken orally. 

Results of a clinical trial demonstrated that, in high-risk adults with symptomatic Covid-19 infection, Paxlovid reduced the risk of Covid-19 related hospitalisation and death by 89% when compared to placebo.  In this study, the treatment was started at three or five days from the onset of symptoms, with results similar for both start days. 

While Paxlovid and Molnupirovir are showing very promising results, one must keep in mind that in studies, they were administered at most up to 5 days after the start of symptomatic Covid-19.  This is a small window for detecting Covid-19 infection and subsequently obtaining treatment, so patients and clinicians will need to develop a system of quick diagnosis and turnaround for these drugs to be effective. 

Barictinib (Olumiant)

RECOVERY STUDY patient criteria:

• hospitalised patients

• receiving at least one other treatment (corticosteroid, monoclonal and/or antiviral)

• many patients receiving some form of respiratory support (oxygen) 

Barictinib is an antiviral pill that has been used to treat Rheumatoid Arthritis since 2018.  Like Tocilizumab, it blocks pathways to reduce inflammation caused by the cytokine storm.  It also acts as stone in the cogs of coronavirus replication, blocking the virus from making more copies of itself, thus helping to reduce its viral load.

According to the RECOVERY Trial, Barictinib, in conjunction with other anti-inflammatory treatments (corticosteroid, TCZ or remdesivir) significantly reduced the risk of death by 13% as well as the likelihood of progressing to ventilation.  The really interesting thing about this drug is that in nine clinical trials, in conjunction with other treatments, it has consistently been found to benefit patients with severe Covid-19 infection.

Vaccines Are Still First Choice

Vaccines remain the cornerstone and first line of defence against Covid-19. However, for those who cannot take advantage of the protection that vaccines offer, or who succumb to infection despite vaccination, the armoury of monoclonal antibodies and antivirals is growing.  These, alongside Corticosteroids and the repurposing of older medicines, should equip clinicians with a variety of options for treating more people, especially vulnerable groups.  More research is required to hone the activity of these and other compounds in treating Covid-19, to ensure that patients get the best treatment for their specific situation.  Given the number of studies similar to the RECOVERY trial that are currently ongoing, there appears much reason for hope on a not too distant horizon.