What coronavirus treatments are around the corner?

TheBHF

Updated 21 May 2020

We explain some of the medications being tested as potential treatments for Covid-19 coronavirus, and what this could mean for people with heart and circulatory disease.

Potential vaccines against Covid-19 are being tested – but this isn’t the only way researchers are working to tackle coronavirus.  No vaccine will be able to prevent all cases of the disease. That’s why researchers worldwide are also working to develop the best possible treatments for Covid-19. Developing completely new treatments can take years, but research is happening to find out if existing medications could be used in new ways to help people recover from the disease. This is sometimes referred to as ‘repurposing’ drugs.

From tests in the lab, to looking for clues in healthcare records, to hundreds of Covid-19 clinical trials – these are some of the potential treatments.

Anti-viral medications

One potential approach is to use medications which may be able to directly block the ability of the coronavirus to infect and reproduce itself within the body. The main candidates are:

Hydroxychloroquine – an antimalarial drug

Hydroxychloroquine is a drug which has been used for decades to treat malaria and certain auto-immune conditions, such as rheumatoid arthritis and lupus. It’s become well-known since the President of the United States announced that he was taking it – although this is not recommended. 

A synthetic form of quinine (the bitter flavouring found in tonic water), there is some evidence from laboratory studies that hydroxychloroquine and the related drug chloroquine could help to limit the ability of coronavirus to get into our cells. It’s also thought that many of the severe complications of Covid-19 could be linked to the body’s immune response to the infection – so a drug like hydroxychloroquine, which can dampen down parts of the immune response, also has the potential to help to limit this.  

However, although hydroxychloroquine has recently received a lot of media attention as a potential ‘game-changer’ against Covid-19, there is not currently enough good quality clinical trial evidence to support this. Importantly, it’s also well known that this type of drug can have side effects on the heart, including serious arrhythmias (such as Long QT syndrome). So even if any of the current trials of hydroxychloroquine in Covid-19 do show a benefit, it’s clear that the drug may not be safe for everyone – particularly those with certain pre-existing heart conditions.

Remdesivir – a “broad-spectrum” anti-viral

Remdesivir is antiviral drug originally developed to treat hepatitis C, which was also tested in recent outbreaks of Ebola virus disease. It works by mimicking one of the building blocks that coronaviruses and other similar viruses use to reproduce themselves. “Broad-spectrum” means that it works against a range of viruses.

Having shown promise against the Covid-19 coronavirus in lab experiments, interest in this drug was fuelled by a report showing that a small number of patients in hospital with severe Covid-19, who were taking remdesivir, showed improvement in their symptoms. But it’s impossible to know from this small study – which involved 53 patients from all over the world and at different stages of the disease, and didn’t have a comparison with a similar group of patients not taking the drug – if the improvement was due to receiving remdesivir.

But evidence about remdesivir is now starting to emerge from randomised controlled trials (the gold standard way of testing a treatment). In a trial conducted in Hubei, China, 273 patients hospitalised with severe Covid-19 were randomly allocated to remdesivir or inactive placebo. Overall, remdesivir did not seem to improve clinical outcomes in this group, but the result may have been affected by not being able to enrol enough people (due to the outbreak in Wuhan being controlled). Experts have also suggested that people in this study may have received remdesivir too late in the course of the disease for it to have an effect.

Early findings have now also been announced from a US-led trial of remdesivir, suggesting that a five or ten day course of the drug may help people hospitalised with Covid-19 recover quicker. This trial was stopped earlier than planned as – having shown this benefit – the team behind the study felt it was no longer ethical that people in the control group (the comparison group) would not receive the drug. Remdesivir is now being tested in combination with the anti-inflammatory drug baricitinib (see section below).

While this is encouraging, how useful it is can’t be properly assessed until the final, published results are available – including information on possible side effects. There are also concerns about whether remdesivir could be made widely available. For example, the team behind the UK-led RECOVERY trial (which is testing a range of possible treatments for in people hospitalised with Covid-19) intended to include remdesivir, but were unable to get supplies of the drug.

Lopinavir–ritonavir – a combination used to treat HIV

Lopinavir works by blocking the function of a molecule required for the generation of new infectious virus particles. It’s been tested in combination with ritonavir, which helps to prolong the activity of lopinavir. This combination has been previously shown to be effective against the coronaviruses which caused the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks. 

The first randomised clinical trial results for lopinavir–ritonavir in Covid-19 – from a study of 199 people in hospitals in Wuhan, China – were recently published, but did not show a conclusive benefit for those receiving the medication. However, some experts feel that people in this study may have received lopinavir-ritonavir too late in the course of their disease for it to have an effect. 

Lopinavir–ritonavir is now being tested in the RECOVERY trial and the World Health Organisation-led SOLIDARITY trial. But it can be dangerous when combined with some other medications, including some types of statins. While it may be appropriate to stop regularly taken medications for a short time during immediate treatment for coronavirus, there’s some evidence that statins themselves could be beneficial in Covid-19. More research is needed in this area and some studies are now getting under way.

Famotidine – used to treat heartburn and stomach ulcers

Famotidine is a heartburn medication which is available over the counter in many parts of the world. The first signs that it could help to treat coronavirus came from preliminary studies in China and a single hospital in New York suggesting that people in hospital with Covid-19 were less likely to die if they took famotidine. 

Famotidine helps to reduce stomach acid production by blocking histamine receptors in the stomach. Researchers believe it can also block an enzyme needed for the replication of Covid-19 coronavirus. (They did this by using computers to study the proteins that the genes in the Covid-19 produce, compared them with other types of coronaviruses, predicted their structures and then cross-reference these against “libraries” of existing drugs to see which ones are likely to work on the genes in the Covid-19 coronavirus.)

A research trial testing famotidine in people with Covid-19 is now under way in the US. But it’s using famotidine in combination with hydroxychloroquine, because at the time this trial was being developed, hydroxychloroquine was commonly being given to people in hospital in the US with coronavirus (which is not the case in the UK and in many other countries). So it won’t be able to tell us about how well famotidine works to treat Covid-19 on its own.

Anti-inflammatory medications

Many of the severe complications of Covid-19 are thought to be linked to the body’s immune response to coronavirus infection. When the immune response goes into overdrive it can itself become damaging. So several drugs are being tested to see if they can safely dampen down this response and improve symptoms.

Corticosteroids – commonly used anti-inflammatory drugs

Corticosteroids, or steroids, are a type of drug used to help reduce inflammation in a wide range of conditions – such as arthritis and asthma. Steroids were used to try to help manage respiratory symptoms and the damaging immune response in people with SARS and MERS, but evidence about whether or not they were beneficial for people with these conditions is mixed. Some small observational studies in people with Covid-19 have suggested that receiving a low dose of a steroid medication may help to reduce death in people with severe forms of the disease – but good quality clinical trial evidence is needed. Low dose dexamethasone is one of the treatments being tested in RECOVERY.

Whether the immunosuppressive effects of steroids could make people more or less susceptible to catching Covid-19 coronavirus is also controversial. But it’s important to note that the current, evidence-based advice is that people who regularly take this type of medication for other conditions should keep taking them as advised by their doctor. NICE has also issued guidance highlighting that people who are prescribed corticosteroids to help manage flare-ups of a chronic condition, such as COPD, should seek advice from their doctor rather than ‘self-start’ the medication if they develop Covid-19 symptoms.

Tocilizumab – an arthritis treatment

Tocilizumab is an immunosuppressant drug originally developed for rheumatoid arthritis (which is caused by inflammation). While it might seem strange to try to block the body’s immune response during an infection, several preliminary reports have shown that having high levels of a specific inflammatory molecule called interleukin 6 (IL-6) in the blood is be linked to developing severe complications of Covid-19.  Previous work led by BHF Professor John Danesh has also shown that having high levels of IL-6 in the longer term is linked to a higher risk of developing coronary heart disease.

There is now some early evidence that tocilizumab, which blocks the effects of IL-6, may help recovery from Covid-19. For example, a small study of 63 people hospitalised with Covid-19 in Italy suggested that receiving tocilizumab earlier in their hospital stay is linked to increased likelihood of survival. Several randomised clinical trials testing this drug are now ongoing, including RECOVERY.

Azithromycin – an antibiotic

The antibiotic azithromycin is widely used to treat bacterial infections, such as chest, sinus or ear infections. It is also used in some people with inflammatory lung conditions, such as COPD, because it may help to dampen down damaging immune responses. Interest in azithromycin as a potential treatment for Covid-19 grew following reports suggesting that – when combined with hydroxychloroquine – it could help improve recovery from the disease. 

However (as described in our hydroxychloroquine behind the headlines) these reports have come under intense scrutiny due to concerns about the way in which the studies were carried out. And like hydroxychloroquine, azithromycin can have dangerous side effects on the heart’s rhythm. Azithromycin is now being tested in large randomised controlled trials of patients with Covid-19, including the UK’s RECOVERY trial. This drug may not be suitable for people with Long QT syndrome, or those already receiving hydroxychloroquine.

Baricitinib – an arthritis treatment

Like tocilizumab, baracitinib is an immunosuppressant drug used in people with rheumatoid arthritis. It works by blocking two molecules called JAK1 and JAK2 – which play an important role in activating inflammatory signalling pathways within our cells. As well as potentially helping to dampen down the damaging immune response in Covid-19, there is some evidence that baracitinib could help to block the virus from getting into cells. 

Baracitinib is now being tested in several Covid-19 clinical trials, including a trial in the US looking at its effects in combination with remdesivir. In the UK, baracitinib is being tested in the TACTIC trial, led by researchers from King’s College London and Cambridge. However, there are some concerns that using baracitinib could limit the body’s own mechanisms of trying to fight off viral infection. For example, taking baracitinib for rheumatoid arthritis has been linked to an increased risk of herpes zoster and simplex infections (viruses that cause shingles and cold sores) – so more evidence is essential before it can be safely used outside research studies.

Medications to manage Covid-19 complications

Finally, treatments are also being tested which could help manage severe complications that can develop in people with Covid-19 – such as clotting in the lungs, or heart and circulatory symptoms.

Drugs affecting blood clotting

As we continue to learn more about the effects that coronavirus infection can have, we’re getting more evidence that it may cause dangerous blood clots. Clotting in the blood vessels in the lungs has been shown in people with severe Covid-19, and there are anecdotal reports suggesting that the inflammation caused by the virus, which makes the blood more ‘sticky’ and therefore more likely to clot, could increase the risk of a heart attack or stroke. A study in a US hospital also showed that people hospitalised with Covid-19 who received anticoagulant, or blood thinning, medication during their hospitalisation seemed to have better outcomes than those who didn’t.

Many different types of medications are used to help limit blood clotting. These include

antiplatelet drugs, such as aspirin, which are usually prescribed after a heart attack
anticoagulant drugs, which may be used to help prevent strokes
thrombolytic (‘clot-busting’) drugs used to quickly break up clots causing a heart attack or stroke

Research will help to reveal how best these different medications could be applied to help prevent severe complications of Covid-19. For example, a trial in the US is testing whether giving alteplase – a clot-busting drug used in the UK as an emergency treatment for stroke – can help reduce respiratory failure in people hospitalised with Covid-19.

ACE inhibitors and angiotensin receptor blockers (ARBs)

You may have seen news stories warning about a link between taking common heart and blood pressure medications such as ACE inhibitors or angiotensin receptor blockers (ARBs) (medications ending in -pril or -artan that are used to treat heart failure and high blood pressure) and the risk of coronavirus infection. As we previously covered in our Behind the Headlines story, these claims didn’t have evidence behind them. Since then, expert groups have concluded there is no evidence to support stopping taking these common heart and blood pressure medications if you have been prescribed them for a heart or circulatory condition.

The initial stories came about because of concerns that taking ACE inhibitors and ARBs could increase the levels of a molecule called ACE2 in the body – which the Covid-19 coronavirus binds to in order to get into cells. But there’s no clear evidence that ACE inhibitors or ARBs can have this effect in humans. In fact these medications could even help to reduce some of the damaging effects on the heart that Covid-19 can cause.

A recent study looking at 1200 patients in hospital with Covid-19 in London suggested that those on ACE inhibitors or ARBs were less likely to die or need to be transferred to a critical care unit – although these early results have yet to be formally reviewed by the scientific community. Another larger study, looking at 8910 patients hospitalised with Covid-19  across the US, UK and Asia (including 706 people from the UK), showed that taking ACE inhibitors or ARBs was not linked to a higher risk of dying, and that taking ACE inhibitors or statins seemed to be linked to better survival. However, the authors caution that no firm conclusions about this observation can be made until we have good clinical trial evidence.

Several trials of ACE inhibitors and ARBs in people who are being treated in hospital for Covid-19 are now under way. Most of these trials are focusing on people who were already taking these medications before they caught coronavirus, and measuring whether stopping or continuing their medication makes a difference. 

A trial in the US is due to test whether taking ramipril – an ACE inhibitor commonly used to treat high blood pressure, heart failure and after a heart attack– can help people who have Covid-19. This study will look at people who were not already taking an ACE inhibitor or ARB.

Driving research forward 

What is clear from the range of treatments being tested against coronavirus is that a vaccine is not our only hope. But given that many of these treatments have potential side effects on the heart and circulatory system, and there are still many unanswered questions about the link between Covid-19 and heart health, we know that more research is needed.

We recently announced that the BHF has joined forces with the National Institute of Health Research (NIHR) to launch a UK-wide initiative to help prioritise and support Covid-19 research, with a focus on research relevant to the heart and circulatory system. By helping to bring together the research community, it’s hoped that this initiative will help to fast-track advances in our understanding of why people with heart and circulatory diseases are more at risk of getting seriously ill from Covid-19, how the disease can affect your heart and circulatory system – and ultimately, help to find the best possible ways to treat it. 

The UK is in a unique position to capitalise on its healthcare structure and research expertise to make world class contributions to the global effort to tackle Covid-19, and through this partnership the BHF is helping to make it happen.


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