Trial comparing two potential antiviral treatments for early intervention in patients with COVID-19
- Chelsea and Westminster Hospital NHS Foundation Trust
- Royal Brompton Hospital
- Imperial College
A randomised controlled trial comparing antiviral drug favipiravir and a combination of hydroxychloroquine(HCQ) /azithromycin/zinc as interventional treatment for COVID-19 patients with mild to moderate disease
Chelsea and Westminster Hospital NHS Foundation Trust (Chelsea and Westminster Hospital and West Middlesex University Hospital) has launched a randomised controlled trial to compare two potential treatments for COVID-19 as it first presents in hospital. The two potential treatments were originally the antiviral drug favipiravir and the combination treatment of HCQ/azithromycin/zinc. These treatments have the potential to be used for early intervention through inhibiting the virus’s ability to replicate and prevent the diseases progression to the later, more serious phase. However, acting on guidance from the MHRA, the combination treatment arm of HCQ/azithromycin has now been dropped while safety issues around HCQ are being investigated.
- Professor Pallav L Shah, Imperial College, London; Chelsea and Westminster Hospital NHS Foundation Trust
- Dr Luke Moore, Chelsea and Westminster Hospital NHS Foundation Trust
- Professor Anton Pozniak, Chelsea and Westminster Hospital NHS Foundation Trust
- Professor Mark Johnson, Chelsea and Westminster Hospital NHS Foundation Trust
- Dr Michael Pelly, Chelsea and Westminster Hospital NHS Foundation Trust
- Professor Gavin Donaldson, Imperial College, London
- Dr Christopher Orton, Royal Brompton Hospital
- Dr Pankaj K Bhavsar, Imperial College, London
Potential of repurposed therapeutic for COVID-19 pandemic
COVID-19 is thought to be a disease which in its early phase when first symptoms present, sees the virus replicate significantly. This is followed by an inflammatory phase which can cause severe damage to the lungs and potentially other organs, which is commonly, the deadly symptom of COVID-19. Although the drugs suggested have been trialled in these later stages of disease, earlier treatment may inhibit virus replication before severe symptoms can manifest.
Favipravir (FPV) is a nucleoside analog which via phosphorylation converts to its active form FPV-RTP. The active form is then able to inhibit a component of COVID-19 replication machinery, preventing further virus replication. Inhibiting viral replication reduces the likelihood of the disease developing into the later more serious phase.
Each component of the combination treatment HCQ/azithromycin/zinc has different modes of action that effect the virus’s impact on patients. HCQ has multiple modes of action which affect the virus’s activity. This includes its ability to target viral replication and the host immune response through multiple mechanisms. One of these mechanisms is its ability to impact the host receptor ACE2. The viruses utilise this receptor to gain access to the host cells. Without the viruses ability to enter the host cells the virus is unable to replicate and cause further damage.
Researchers propose using HCQ in combination with azithromycin/zinc. Azithromyic (AZ) has been shown to have antiviral properties. It is a weak base which can accumulate in endosomal vesicles, blocking viral shedding into the cytoplasm and in turn limiting viral replication. Zinc also has the ability to impact viral replication by inhibiting RNA-dependent RNA polymerase, an essential mechanism for viral replication.
FPV is an approved antiviral treatment for influenza. HCQ is an approved anti-malaria drug readily used as an anti-inflammatory treatment and AZ acts as an antibacterial widely used to treat chest infections like pneumonia. By LifeArc focusing its funding on repurposed drugs such as these, if successful, the treatment can be available to patients in a much shorter period than any newly developed drug.
As mentioned above, the MHRA has now asked for HCQ to be dropped in trials while safety issues are investigated. Therefore, the PIONEER study now only comprises one arm – that of favipiravir – vs standard of care.