This is one of our long reads, grab yourself a coffee! 15 min read.


*SPOILER ALERT* At the present time, there is no quick-fix solution to the COVID-19 problem. The good news is, scientists are working on it!


Antibiotics do not work!

Figure 1: Schematic to demonstrate secondary
bacterial infection following initial viral infection.

Antibiotics are not effective against viruses; they are entirely different microorganisms and therefore require different types of intervention. You may however, have heard of antibiotic use in the context of secondary infection. As the name suggests, this term describes when a patient acquires an infection secondary to the original [figure 1]. This is relatively common in patients with an infection of the lung (pneumonia), due to lowered immunity as a result of the original infection. This secondary infection may be viral or bacterial and so, may be treated with antibiotics (1,2).


A brief word on vaccinations…

Whilst there are several drug treatment options under investigation, the best way of protecting the population is through the development and deployment of a vaccination programme. Vaccines work by introducing a weakened version or fragment of the virus or bacteria to an individual’s immune system. This does not cause infection and instead elicits a mild immune response that allows the body to safely generate antibodies against the antigen. As part of this response, special memory cells that are part of the immune system, are trained to recognise and remember. Should you come across the real thing in future, your memory cells will fire into action and enable the production of antibodies to fight against it. As the immune system has already seen the antigen before, the response is more effective and much faster, making it highly efficient at eliminating the intruder and protecting your health (3,4).

Keep an eye out for our future blog post scratching beneath the surface of vaccination.


So, what are the other options?

Whilst vaccinations are in the making, there are a number of options to explore to improve patient outcome. The unprecedented global collaboration has accelerated research into these options, from drugs to vaccinations and beyond but here’s the rub… they still need to go through the clinical trials process. Here we discuss several drugs under the scrutiny of clinical trial to identify their safety and efficacy against SARS-CoV-2.


Drug treatments

The clinical trials process is of vital importance but remains extremely lengthy. It usually takes 10-15 years for a new drug to make it from start to finish, that is, from conception to approval for use. Clinical trials are essential as they serve to filter out the ineffective and unsafe. Just because a drug has made it to first-in-man (phase I) does not mean it’s a sure-fire win. In fact only 10% of medicines that enter phase I ever make it through to approval – at the cost of tens-to-hundreds of millions of pounds (5).

Figure 2: Drug development pipeline workflow. Successful drug candidates progress through pre-clinical to first-in-man and on to the various phases of clinical trial before post-market surveillance at phase IV.


At present, there is tremendous focus on the repurposing of existing medications as opposed to generating new drugs. Drug repurposing is a crucial initiative, as it may greatly reduce the cost and time spent identifying treatment options for COVID-19. There are 4 treatment options under the investigation of the clinical trial named “Solidarity”, which has been launched by the WHO in collaboration with international partners (6).


Remdesivir

What is it?

Remdesivir is a rising star in therapeutics against SARS-CoV-2. It is an investigational drug that was originally developed and trialled a treatment strategy against the Ebola virus. However, other treatment options showed greater efficacy against Ebola and remdesivir was subsequently shelved.

Why is it in trial?

Ongoing research has since demonstrated its broad antiviral activity and highlighted its promise in the fight against COVID-19. In in vitro testing, remdesivir was effective at inhibiting the replication of a range of coronaviruses including those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Remdesivir works by targeting and incorporating itself into the genetic material of the virus, so it can no longer replicate (7). Pre-clinical testing has provided strong evidence that intravenous treatment is effective at reducing viral load and preventing progression to severe pneumonia in primates (8).  

Where are we now?

Whilst remdesivir remains unlicensed and has not yet been approved for safe and effective use, it is in clinical trial to determine its utility. A Chinese study concluded that remdesivir afforded no clinically significant benefit to COVID-19 patients and demonstrated adverse events where the treatment was halted in 12% of patients. However, the authors state a key limitation of this study; the number of patients included was not great enough to detect clinical significance (9).

Recent data has shone a more promising light on remdesivir. An international study recruiting over 1000 patients has reported a 30% faster recovery time for remdesivir vs standard care, which was found to be statistically significant. The data also shows a trend towards reduced mortality rate in those receiving remdesivir however, the difference was not great enough to be significant. Although this is good news, we must still be cautious, the safety data has not yet been published and there are some concerns regarding adverse effects (10,11). Whilst it has been touted by leading scientists that remdesivir will become the new standard of care in the United States, there is still work to be done. There are many questions regarding safety, dosing regimen and patient suitability that need answering but so far so good… watch this space and we’ll keep you posted.



Hydroxychloroquine & chloroquine

What is it?

Hydroxychloroquine and its cousin chloroquine are also in the running having been publicised early on by the American Government for their effectiveness. They are similar in structure and function however hydroxychloroquine is less toxic and so much safer for a patient (12). Both drugs have already made it through to the clinical trial finish line for use in other applications, where they can be used to prevent and treat malaria. Hydroxychloroquine is also known to have anti-inflammatory action and is often prescribed for the treatment of inflammatory conditions like lupus and rheumatoid arthritis (13,14).

Why is it in trial?

Both drugs have been included in the Solidarity trial as there is a wealth of evidence demonstrating both antiviral and anti-inflammatory properties. Following the SARS epidemic in 2002, pre-clinical research demonstrated that chloroquine inhibited the replication of SARS-CoV in cells (15). More recent work has shown there may be a multitude of mechanisms through which SARS-CoV-2 infection in cells can be prevented (16). Although already approved, they must be tested for safety and efficacy in a COVID-19 setting. There are a number of reported side effects and concerns regarding potential toxicity must be carefully assessed and considered before regarding it as a viable treatment option (15).

Where are we now?

The available data from clinical trials is very mixed. A number of early trials have a small sample size and poor study design (17). One paper available on the preprint server MedRxiv found that patients critically ill with COVID-19 benefitted from administration of hydroxychloroquine. Those that received the drug had a significantly lower mortality rate and level of inflammation. However, the drug treatment group included only a small number of people and inflammation levels were reported to be twice as high as the control group at the beginning of the study (18).

In contrast, an American group found no evidence that use of hydroxychloroquine reduced the risk of need for mechanical ventilation. The authors of this study do also discuss its limitations, in that the study cohort only included men over 65 and the patients were not allocated different treatments at random (19).

It is important to remember these articles are still in preprint and have not yet been accepted for publication. Evidently the answer is not clear cut and the ongoing work is essential to better understand the treatments and outcomes.


Lopinavir/Ritonavir

What is it?

Lopinavir and ritonavir are antiretroviral drugs that have been approved and are prescribed to treat human immunodeficiency virus (HIV). They are often used in combination as ritonavir helps to boost the efficacy of lopinavir. Although HIV and coronaviruses are very different, the known mechanism of action against HIV has propelled the combination into the Solidarity trial. It is accepted that lopinavir/ritonavir work by blocking essential proteins to prevent replication of the virus (20).

Why is it in trial?

In vitro research has demonstrated that lopinavir has an antiviral effect against several coronaviruses in cells, whilst additional in vitro studies have confirmed the same effect against SARS-CoV-2 (21,22). More advanced pre-clinical study evaluating treatment of MERS in primates, revealed improved clinical outcome when lopinavir/ritonavir was combined with interferon-β1b – more on this next (23).

Where are we now?

Studies conducted early in the epidemic demonstrated no benefit to patients that received lopinavir/ritonavir, compared to those receiving the standard of care. Although less than 200 patients participated, there was no improvement in recovery time or mortality rate (24). Other studies have provided similar evidence, whereby there is no difference in ‘viral clearance’ – the time it takes for the virus to no longer be detectable in a patient (25). Alongside having no benefit, side effects involving the gastrointestinal tract and liver have also been reported in several of these trials (25,26).

At present there just isn’t enough evidence to say if this combination is effective in humans, the current clinical trials will present more data to answer this question in the future.


Interferon-β1a

What is it?

Don’t panic! Interferon-β1a is a subclass of chemical messengers that belongs to a family called type I interferons, broadly speaking they help to regulate the immune system. This β1 subclass refers to specialised signals that are produced by cells in response to infection, particularly viral. Once the signals have been released, they are intercepted and interpreted by other cells, which allows them to increase their antiviral activity. Interferons are naturally produced by the body but have also been manufactured for use in a medical setting. Some of the β1 class, like interferon- β1a, are used as a treatment for the autoimmune condition multiple sclerosis (27).

Why is it in trial?

Interferons have proved promising in in vitro and pre-clinical tests against other coronaviruses. One pre-clinical study demonstrated that administration of interferon-β1b significantly reduced viral load in the lung and severity of disease in MERS (23). There is an ongoing human trial in Saudi Arabia, assessing the utility of interferon-1 and lopinavir/ritonavir against MERS however, no clinical data has yet been published (28). The Solidarity trial is testing interferon-β1a in conjunction with the antiviral drugs lopinavir/ritonavir to see if the combination offers any advantage to patient outcome.

Where are we now?

Interferons are being used in combination with a variety of other antiviral drugs in different trials across the world. There is limited data available to say whether or not this strategy is paying off. In China interferon-B1b is being trialled in an inhaled format for direct administration to the lungs (29). One study has shown that inclusion of interferon therapy accelerated viral clearance compared to treatments that did not include interferon. However, the paper has not yet been accepted for publication and is limited by poor design, a small sample size and disproportionate male-female representation (30).  

Ongoing trials will aim to assess a much larger and more balanced sample population, so we should hope to draw more firm conclusions about this treatment option in the future.


Are there any other therapeutic options?

Convalescent plasma

What is it?

There is some exciting research into the usefulness of convalescent plasma. This may sound complicated but the basic premise centres around the plasma of a ‘convalescent’ or recovered individual. Plasma is the liquid part of blood which contains important proteins, salts and crucially, antibodies. It may be isolated through a process called plasmapheresis and for a person donating plasma, it is not dissimilar to giving blood [figure 3]. Instead of donating whole blood, a machine separates it into blood cells and plasma. This allows the plasma to be removed and so returns your blood cells and often a saline solution to replace the lost volume. For patients receiving convalescent plasma, their own will be removed and replaced with the antibody rich plasma of a recovered individual, so conferring passive immunity. This strategy works on the basis that the person donating plasma is now immune and has generated antibodies – which should be around 28 days after recovery. REF.

Why is it in trials?

The concept of convalescent plasma is not new. Use of convalescent blood has been documented as early as 1918 in the prevention and treatment of the Spanish Flu (31). More recent application in several case studies have demonstrated it may be useful against SARS, MERS and even Ebola (32). A study utilising convalescent plasma as a treatment option for SARS reported a clinically significant reduction in mortality rate in those that received it. Early treatment, less than 14 days after symptom onset, also enabled a more positive outcome (33).

Where are we now?

NHS Blood and Transplant is leading a programme to investigate convalescent plasma in clinical trial. The trial will aim to assess if its use can improve patient survival and recovery time. The programme has only just begun but previous case studies are encouraging. A number of these report convalescent plasma use only in severely ill patients but describe clinical improvement and an increase in antibodies against SARS-CoV-2. If you want to more about the convalescent plasma trials and if you could help, click here.

Figure 3: Plasmapheresis

All in all, there is no definite treatment at the moment but there are many options and trials working to gather concrete evidence to make a better judgement.


We hope you enjoyed our first long read! If you need help clarifying some of the jargon or want to know more about the concepts discussed, DM us and we’ll get back to you.

For bite-sized information on clinical trials and convalescent plasma, check out our infographics on social media.  


Citations

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