Could drugs be a solution to the virus?

Covid-19 would be less of a worry if there was a very effective treatment

It is an obvious fact that the world might not worry about the dangers of catching Covid-19 if there was an effective and safe (and hopefully cheap) drug to stop the disease ‘in its tracks’. The idea is that it could be taken when people  had the very first minor symptoms of being unwell or even when testing positive.  As a  historical parallel, in the pre-antibiotic era, infections that we now consider minor such as ear infections and sore throats could have led to life threatening complications.  The population now, though, no longer worries about such disorders because antibiotics are so effective (although the major concern of antibiotic resistance is real).  This post thus addresses how likely is it that we could get such antiviral drugs that could be similarly effective and appropriate for widespread use in Covid-19.

Comparison with antibiotics The comparison with antibiotics and bacterial infections is interesting.  In most countries those who visit their general practitioner with a  sore throat or a chest infection these days would be denied antibiotics:  the advice being that (without testing)  the illness (a) is due to ‘a virus’ and hence  does not respond to antibiotics and (b) will settle down on its own.  Thus, we have developed an acceptance  that common viral infections do not  need specific treatment and are not likely to become serious.  Covid-19 has proved the latter to be untrue, so where are we on the path to addressing the former? 

When might drugs be used in Covid-19? Drugs might be used at 3 stages

• To stop people becoming infected after being exposed to the virus 
• To stop the virus actively producing many copies of itself in the body and prevent severe clinical problems
• To treat the ongoing clinical problems, and especially the complications, caused by the virus

Vaccines cover the first stage. Drugs for the third stage cover the range of drugs from simple agents that control symptoms such as paracetamol, to those used to treat and control the serious consequences and the complications of infections.  (Drugs in this class include dexamethasone that received much publicity recently as it reduced the number of deaths in Covid-19 patients admitted to intensive care units.)  

What is lacking are drugs that stop the virus, once it has established itself, from causing further harm.  Viruses work by entering our cells and then taking them over and using them to produce millions of copies of themselves.    If that process can be stopped, then if someone became infected the virus would be unable to cause much harm.  Such drugs are known as antiviral agents.

Are antiviral agents effective in other viral infections? Although many viral infections lack an effective drug to stop the virus multiplying, there are  also a large number of infections where antiviral drugs are useful.  These  drug names often end in ‘vir’.  Most widely known is acicolovir/acyclovir (trade name Zovirax), which can even be bought ‘over the counter’ for the treatment of cold sores and shingles. There are also a number of antiviral drugs that work in influenza.  These include drugs such as oseltamivir (known as Tamiflu) and zanamivir (known as Relenza).  Indeed, in the previous epidemics of bird flu and swine flu, governments spent millions stockpiling these drugs.  They were of variable benefit and in fact were never widely used. There are also now at least 20 antiviral agents that have been used to stop viral multiplication in HIV/AIDS.

Does each virus need its own antiviral drug? Antibiotics, such as  penicillin, are typically active against many different bacteria.  The range of bacteria covered by one antibiotic can vary. Some antibiotics are ‘narrow spectrum’ and active against a few bacteria , whereas some are ‘broad spectrum’ and active against a larger range.  By contrast there are very few antiviral drugs that are considered broad spectrum (apart from remdesivir, see below) and most are very specific.  Indeed, the large number of drugs used to treat the AIDS virus attack very different aspects of the virus’s activity (and indeed are used in combination).

Where to start looking for antiviral drug against Covid-19? One major hope was that there might be no need to develop a new antiviral drug, as that would take too long, but that drugs of known benefit in other viral illnesses could be also used for Covid-19.  Covid-19 is one of a family of so called RNA viruses which include those that caused the epidemics with SARS in 2002 and the MERS (Middle Eastern Respiratory Syndrome) in 2012.  It is also related to the Ebola virus which caused such concerns in Western Africa in 2014-16. 

Remdesivir is one of the few broad spectrum antiviral agents and has the potential to block the pathway by which RNA viruses multiply.  It was originally hoped it would be useful to combat the Ebola and MERS pandemics.  In practice, in clinical trials, remdesivir did not prove useful in treating Ebola but the drug was still a strong candidate to try in Covid-19. 

There have been at least 10 trials and there are now a number of studies suggesting that this drug can be useful in severe Covid-19.  The most widely published study showed that in patients who developed severe lung complications, remdesivir reduced the length of time  a patient was in hospital from an average of 15 to an average of 11 days.  Around 20% had serious side effects.  Thus, whilst useful it is not a miracle cure and the safety profile means that it is not suitable for widespread use in  people with mild disease.

Are there any new antiviral drugs on the horizon that can treat people with early Covid-19 to prevent serious complications?

As implied above most of the work has been done on reusing (or ‘repurposing’ in the jargon) existing drugs, and there is no obvious candidate.  To develop a drug from scratch that is directed towards Covid-19 will take some time.  The approach is first to study how the  virus divides and attacks human cells.  This information is then used to design drugs to block such actions.  This can be very complex work but in June research from California has achieved in 3 months what in normal times can take two years.  The research has identified the key mechanism that the virus uses to multiply in human cells and is now starting to design drugs to address this.  They will have to be tested carefully of course for safety and benefit.  Even with success at every stage, having a new drug available for widespread use must be a couple of years away.

Does resistance occur with antiviral drugs?

Like everything else the answer is ‘it varies’!  It depends on whether the virus mutates in such a way that is still causes illness but escapes the process by which the drug works.  The cold sore virus has not become resistant to acicolovir as far as I am aware, despite the drug being so widely available.  By contrast the problem for patients with HIV/AIDS is that the development of new antiviral agents barely keeps up with the development of resistance to existing agents. It is too early to know for sure whether Covid-19 virus will develop resistance to remdesivir but a study at the end of June, from India and Japan, suggests that the virus could mutate to become resistant to remdesivir.

One problem with Covid-19 is the long incubation period

The incubation period for seasonal flu is probably about two days.  Indeed, the studies with Tamiflu showed that one needed to take it within a day of symptoms appearing to have the desired effect.  Covid-19 has a longer incubation period of maybe 5-7 days and by the time that symptoms are present, the virus has already multiplied and it is perhaps too late for any antiviral drug to work.  However, recent research from Belgium using computer simulations has shown that with a robust ‘track and trace’ system which can identify individuals and their contacts with the virus, the use of antiviral drugs even before any symptoms appear can make a big difference in helping control local outbreaks

Conclusions:

• There are no existing drugs that are useful in treating people with Covid-19 to prevent the infection becoming serious.
• It should be possible to develop new drugs to stop the virus multiplying  in the body’s cells and prevent the serious complications
• This will take time to develop and especially to prove the drugs are safe and do not cause more health problems than they prevent
• Being optimistic, strategies that combine successful contact tracing and testing with early use of any such treatments could be an alternative to a vaccine if the latter proves too difficult to achieve