Dear Editor,
I DO wish to lend my voice to the debate on the use of hydroxychloroquine, an anti-malarial medication and azithromycin, an antibiotic, in the treatment of COVID-19. Before I venture into this medically directed missive, it behoves me to emphatically state that presently a curative treatment for COVID-19 is outside of our medical knowledge, hence there is some justification in using the aforementioned medications at the time of this paralysing pandemic. Having said that, both hydroxychloroquine and azithromycin do come with contraindications, that is circumstances and conditions that they should be avoided in. These contraindications need to be carefully considered when one is undertaking a risk-benefit analysis.

Most, if not all readers would be understandably confusticated by the proposition of doctors using an anti-malarial and antibiotic to treat a viral condition. Surely, the only comparable “preposterous” act that can closely compete with this medical irregularity is someone using their car to mow the lawn. The fact is, the associated potential curative treatment of COVID-19 with hydroxychloroquine and azithromycin occurred by chance, even as we are still in the process of understanding the mechanisms of actions. I must hasten to add that this chance occurrence, or coincidence for want of a better word, is not unusual with a notable example being minoxidil(Rogaine) which is an anti-hypertensive, that was later found to be effective in testosterone- driven hair loss.

At this time of great uncertainty- driven questioning, I would not be overly surprised if readers at this stage would wish to rightfully probe the medical rationale underpinning the use of hydrocychloroquine and azithromycin for the curative treatment of COVID-19, when there are many unanswered questions. I shall address these uncertainties utilising a two- part answering schema. Firstly, it is without doubt that both hydroxychloroquine and azithromycin were both extensively studied in malarial and bacterial infections respectively, with good safety profiles. Secondly, with these good safety profiles and limited evidence of benefit in COVID-19, it could be argued that in a potentially fatal condition where there is no curative treatment, there is justification for using hydroxychloroquine and azithromycin, provided the benefits far outweigh the risks. This argument somewhat loses substance due to the absence of quality studies for the aforementioned drugs in COVID-19.

Notwithstanding these limitations, the fact that hydroxychloroquine and azithromycin both have good safety profiles in the curative treatment of malarial and bacterial infections respectively, along with limited promise and absence of curative treatment in COVID-19, then it was not a complete surprise that the FDA provided emergency approval in the treatment of COVID-19. In my humble opinion, if these two medications were completely new with no pharmacological history, then it is unlikely that the FDA would have taken this position.,

Further, it is my professional view that the limitations of both hydroxychloroquine and azithromycin in treating COVID-19, are multifactoral. For the reader to have a better appreciation of these limitations, it is imperative that they first have a basic understanding of the processes involved in testing drugs efficacy for any medical condition. Firstly, the efficacy of any drug in treating any given condition is assessed by a process known as a, Randomised Control Trials(RCT). A RCT, which is the gold standard research process for assessing the efficacy of a medical intervention generally involves two cohorts of patients.

One cohort of patients would have the condition in question and are known as the cases, while the other cohort without the condition are known as the controls. The drug to be tested is compared to an unidentifiable placebo. The placebo is a completely impotent drug-mimic, since it has no drugs inside and sometimes could simply be a sweet that has the shape of a capsule. For simplicity I will denote the real drug as A and the placebo as B. Following on, the drugs A or B are then randomly administered to each case and control.

This simply means that the cases or controls will randomly receive either A or B, but not both. The cases and controls are completely unaware of what they are given. Using researchers language, the cases and controls are blinded to A or B. They don’t know what was administered, hence they cannot fake benefits. On some occasions the researcher may also be blinded to the drugs administered to any given case or control. Since cases, controls and researchers are all blinded,- then the research is considered to be double- blinded. To have a wider cross-section of patients and improve credibility of the results, the research may be undertaken in many hospitals. As a result, the research may now have another label of being multi-centred. This would result in research of this nature to be called a “Double- blinded, Multi-centred RCT.” This is the gold standard in medical research and takes years from start to completion.This is the type of rigorous testing that any drug would undergo before it is given approval by the relevant authorities. Once completed the data is analysed by researchers and statisticians and the findings are ultimately published in medical journals and presented at medical conferences.

Now armed with this knowledge, I will expound on the limitations of hydroxychloroquine and azithromycin. The fact is that approximately 80% of patients with COVID-19 will recover on their own, without medical intervention. Approximately 17% may require some form of medical intervention and will recover without any drug administration.

Approximately 3% would unfortunately die despite medical intervention. From examining those numbers, it can be concluded that 97% of patients with COVID-19 will make a complete recovery without drug treatment. Therefore, if a patient is given Hydroxychloroquine and/or azithromycin and recovers, it is difficult to determine what contributed to this recovery. Was this recovery down to the fact that the patient would have recovered anyway, or was this recovery down to the intervention of administering hydroxychloroquine and/or azithromycin? It is these questions that any future RCT would hope to answer before we can confidently state that hydroxychloroquine and azithromycin are both curative treatments for COVID-19. This in a nutshell outlines the limitations of both hydroxychloroquine and azithromycin in the present- day treatment of COVID-19. There is no RCT to support its use, hence they have no research legs to stand on.

On the other hand, many would swear by hydroxychloroquine and azithromycin because Donald Trump has endorsed them. The reality is that medicine is not a political race of endorsements. The danger, for want of a better word, is that Donald Trump is a businessman and not a medical doctor, therefore he is completely oblivious to the medical information and drug- testing protocol. For all we know, Donald Trump may be advancing his own business interest. More concerningly, all President Trump has to support his weak case is anecdotal or hearsay evidence, which is frowned upon in the scientific world, since It is the lowest level in the hierarchy of scientific evidence. In summary, both hydroxychloroquine and azithromycin can be used in COVID-19, but it is critical that one carefully considers their limitations and contraindications. Finally, I do wish to extend condolences to those who have lost loved ones from COVID-19. I would also like to wish those afflicted with COVID-19 a quick recovery. And for the rest of the citizenry, I would like to stress the importance of following the guidelines outlined by the government to reduce COVID-19 transmission.

Regards
Dr. Mark Devonish MBBS MSc Med. Ed FRCP(Edin) FRCP(UK)
Consultant Acute Medicine
Nottingham University Hospital, UK