An editorial published in the British Medical Journal May 17th by Dr David Smith and Dr Gill tries to answer this question.  

They feel that the target is over ambitious and may risk errors.  

The UK Government has launched a COVID-19 antiviral task force with the aim of deploying drugs for home treatment by autumn this year.  

The description suggests that the Government wants direct acting, orally administered drugs that reduce replication and help eliminate SARS-CoV-2 from the body.  

They would like the drugs to be taken after a positive swab test result or prophylactically after exposure thus reducing viral transmission, morbidity and mortality.

Current COVID-19 treatments are largely limited to anti-inflammatory drugs such as dexamethasone, Tocilizumab and Sarilumab.  They save only around one in three patients who would have otherwise died.  

Remdesivir, the most commonly used antiviral for SARS-CoV-2 in the United Kingdom requires intravenous administration and does not seem to offer significantly higher survival benefit. 

The authors presented the challenge. 

Viruses encode few proteins.  They instead rely on host enzymes for replication and thus offer few viable drug targets.  

None of the currently available oral antiviral drugs are licensed for coronaviruses, and investigation into their use against SARS-CoV-2 in clinical trials has not been encouraging.  

Despite this, close to 100 licensed antivirals are available for other pathogens and collectively save millions of lives every year.  

Most are highly specific for their target virus, and activity against different viruses is the exception rather than the rule.  

The EU has shortlisted some intravenous medications for development, but these would not fit the UK Government’s brief of oral drugs to be taken at home.  

Of the available oral compounds with broad spectrum antiviral activity, only Ribavirin is licensed to treat multiple virus strains, and this is usually in combination with other drugs.  

It has toxic effects and is unlikely to be suitable for COVID-19 prophylaxis.  Favipiravir and Nitazoxanide have been shown to inhibit a large number of viruses in vitro but phase 3 trials have been completed only for influenza.  Medications against other pathogens might also have anti SARS-CoV-2 activity but several repurposing attempts have ended in disappointment including ivermectin, azithromycin and hydroxychloroquine.  

Viruses also have very short replication times and generate large numbers of copies, resulting in mutations that can confer resistance against antiviral drugs.  

More recently, the pandemic influenza strain H1N1 has developed resistance to Oseltamivir.  If SARS-CoV-2 shares the capacity to generate escape mutations, then multiple antiviral drugs may be required in combination for effective treatment or prophylaxis. 

However, the authors argue that SARS-CoV-2 does present a few potential targets for antiviral therapy.  

Strong evidence suggests that viral particles enter human cells using the angiotensin converting enzyme 2 receptor and the cell surface protease, TMPRSS2.  

Camostat is a TMPRSS2 inhibitor that seems safe in humans and phase 2 trials are currently in progress.  

The virus may exploit enzyme components of the vesicle transport system, such as a P13P5 kinase to enter the host cell membrane.  Early laboratory signs on apilimod, apikfyde inhibitor, look encouraging.

Other possible targets included RNA dependent RNA polymerase, which replicates the SARS-CoV-2 genome and is dissimilar to host enzymes.  It seems to be highly conserved between strains, suggesting low risk of resistant mutations.  

Favipiravir is thought to block RdRp and is now in phase 3 trials.  The nucleoside analogue Molnupiravir, which also targets RdRp, reduces viral transmission and disease severity in ferrets and has been well tolerated in phase 1 clinical trials.  

SARS-CoV-2 also produces 3CL protease, which is used for building viral particles from polypeptides.  Protease inhibitors could therefore prevent virus assembly.  

Nitazoxanide may work by inhibiting both cell entry and viral particle assembly and seem to improve viral clearance in patients with symptomatic COVID-19 in one small trial.  

Although the Government has specified oral treatments, mucosal topical medicines given by nasal spray may be as effective.  For example, iota-carrageenan, a complex sugar molecule derived from seaweed, is in phase 2 trials after encouraging results in vitro.

Efforts to repurpose existing drugs to SARS-CoV-2 have so far been unsuccessful and whilst promising new agents are under clinical development, proper evaluation of efficacy and safety will take time.  

Effective antivirals will be highly valuable in the fight against COVID-19, yet policy must be realistic and based on evidence, not hope or unfounded optimism.  

The UK Government’s target to deliver antiviral home treatments within the next three months does seem overly ambitious and care should be taken to ensure that this rush does not force blunders or indeed repeat previous ones.

Dr Paul Ettlinger

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