As coronavirus continues to spread persistently throughout our cities, towns and villages, the world has become a challenging, and at times frightening, place to live. The question now is, are there treatment options on the horizon to stop the propagation of this potentially deadly pathogen?
The US Food and Drug Administration (FDA) has approved the use of convalescent plasma therapy in the US – a method that has a relatively long history, having been deployed as far back as the Spanish influenza pandemic of 1918 – to treat those who become critically ill after contracting the virus. Convalescent plasma from individuals who have recovered from the disease is purported to contain anti-COVID-19 antibodies. Although this sounds ideal in theory, studies involving the use of this therapy in other respiratory infections, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and H1N1 influenza (also known as swine ‘flu), show that this approach is not necessarily that effective. Additionally, the plasma must come from recovered individuals who have been asymptomatic for 14 days and who now test negative for SARS coronavirus 2 (the virus that causes COVID-19) – this takes time and delays harvesting of plasma.
Given the current public health emergency, the FDA has granted access to this therapy for those with severe or immediately life-threatening SARS coronavirus 2 infections. Severe cases are defined as those with signs and symptoms including dyspnoea (difficulty breathing), a respiratory rate of ≥30 breaths per minute, and an oxygen saturation of ≤93%. Life-threatening cases are defined as those who are in respiratory failure, septic shock or multiorgan failure. In these cases, physicians are able to request verbal approval from the FDA, with the aim of delivering treatment within 4–8 hours of the decision being made.
The pharmaceutical company Teva Pharmaceuticals recently agreed to donate over 6 million doses of hydroxychloroquine sulfate (the less toxic metabolite of the antimalarial drug chloroquine) to the USA. Chloroquine has previously been tested on several viruses, including SARS, with promising results in vitro. Therefore, chloroquine and hydroxychloroquine sulfate have been entered into the SOLIDARITY clinical trial, which was launched by the World Health Organization to determine the effectiveness of numerous therapies against SARS coronavirus 2. Although evidence is limited, the unpublished results seem encouraging so far.
Viruses typically enter their host cells through a process known as endocytosis. The virus is internalised in a compartment called the endosome, which has an acidic environment. One way in which chloroquine and hydroxychloroquine sulfate are hypothesised to work is by neutralising this acidic environment, thereby impeding the escape of newly replicated virus particles from the endosome. Another hypothesis suggests that chloroquine and hydroxychloroquine sulfate inhibit the initial binding of the virus to the host cell, and that they have an effect on a variety of host immune cells (which explains its effectiveness in treating autoimmune conditions such as rheumatoid arthritis and lupus). However, despite these hypotheses, there is still a vital need for a randomised clinical trial to accurately assess the efficacy and safety of chloroquine and hydroxychloroquine sulfate in the treatment of COVID-19.
The SOLIDARITY clinical trial is also looking at several antiviral drugs as monotherapies or in combination, including lopinavir, ritonavir and interferon beta 1a.
Lopinavir plus ritonavir is a drug combination typically used to treat human immunodeficiency virus (HIV). This combination was recently tested in China for SARS coronavirus 2 infection in a randomised controlled trial; however, there was no enhanced benefit compared with the current standard of care. The University of Oxford has just begun a trial examining this drug combination plus the steroid dexamethasone, and it is hoped that it will yield more encouraging results.
Interferon beta 1a – a molecule that forms part of the innate immune system of the lungs to defend against viral infections – is also being trialled elsewhere in the UK. It is hypothesised that interferon production is suppressed by coronaviruses, so if it can be replaced the symptoms of COVID-19 could be reduced.
These drugs will be continually reviewed by the SOLIDARITY clinical trial team, and any new promising candidates will be included in the trial as well .
What this means for us now
For the time being, while we wait for high-quality data, as a population we must continue to be rigorous in observing social distancing measures. This will reduce the number of new cases, and so will free up NHS intensive care staff and ventilator capacity for those who do become ill and require critical care.
Ventilator capacity is also being optimised through the increased use of continuous positive airway pressure machines in appropriate cases, which are a less invasive alternative to ventilators, and do not require patient sedation, specialist nursing or intensive monitoring. Mercedes F1 has partnered with engineers at University College London and clinicians at University College Hospital, London, to rapidly produce these machines, which have now been approved by the Medicines and Healthcare products Regulatory Agency (MHRA).
It is, however, not to be forgotten that the majority of COVID-19 cases are mild or moderate. Despite this, 14% of cases are classified as severe and 5% as critical, with up to 25% of the UK population designated high risk, whether by virtue of age or comorbidity. As a result, although the search for a cure is very much on, we must all meticulously observe the isolation measures put into place by the government:
“Stay at home. Protect the NHS. Save lives.”