Another post concerning topics on Covid-19 aimed at the non-expert.
Scientists are cautious by nature, some politicians and political journalists are not. While scientists say there’s no convincing evidence antimalarial drugs such as hydroxychloroquine have any effect on Covid-19, President Trump says, “there are some very strong, powerful signs of hydroxychloroquine as a Covid-19 therapy”. Rudy Giuliani Tweeted, “hydroxychloroquine has been shown to have a 100% effective rate in treating Covid-19.” Meanwhile, in my country, the UK, Sarah Vine (Daily Mail columnist and wife of the Chancellor of the Duchy of Lancaster, Michael Gove) Tweeted, she doesn’t trust the World Health Organisation and prefers to believe 6,000 doctors who say hydroxychloroquine works on Covid-19. The claim about 6,000 doctors comes from a Daily Mail poll accompanied by an article.
Putting aside the fact Trump, Giuliani and Vine are not pharmacologists, and the Daily Mail doesn’t exactly have an impressive track record in science reporting, is there any truth in these claims? I thought I’d take a closer look. I must start however, with a disclaimer. Things are moving very fast and this blog post will probably be out of date as soon as it’s posted. There’s a range of drugs being tested to see if they have any efficacy against the SARS-CoV-2 virus and tomorrow, who knows, one maybe found to be a miracle cure. I doubt it however, and so here, I’m just focusing on hydroxychloroquine.
Scientists developed a range of antimalarial drugs in the 1930’s and 1940s to treat troops fighting wars in tropical climes. Amongst those drugs were the aminoquinolines because related quinine and quinidine had been used for hundreds of years as antimalarials. Quinine gives tonic water its bitter taste and there’s an adage gin and tonic came about as a malaria treatment in colonial India. This is unlikely because the quinine dose in tonic water is far too low to be effective. Chloroquine and hydroxychloroquine are two aminoquinoline-type drugs which were once useful but are now largely ineffective because emergence of resistant malarial parasites.
Pharmacologists don’t just pull drugs out of thin air and hope they might work. Instead they look for potential mechanisms, that is how the drug interacts with the target disease, preferably at a molecular level. The malarial parasite (Plasmodium species) enters red blood cells and hydroxychloroquine is believed to inhibit the way it interacts with haemoglobin, but the drug has other effects within the body. Chloroquine and hydroxychloroquine have anti-inflammatory properties because they decrease acidity inside certain cells altering the rate of protein degradation, and cytokine production (cytokines are protein-type molecules released by cells in the immune system that regulate inflammation).
There are several feasible mechanisms that might explain how hydroxychloroquine has antiviral properties.
For coronaviruses to enter mammalian cells, they first bind to the cell surface and then transverse the membrane, which is mediated through an enzyme called lysosomal protease. Inhibition of this enzyme by hydroxychloroquine is a potential target but a correlation between lysosomal protease activity and the entry of coronaviruses into the cell has never been established. Cytokines are protein-type molecules released by cells in the immune system that regulate inflammation and hematopoiesis (the process by which the body makes blood cells). The overall picture is further complicated, because the way coronaviruses enter mammalian cells differs from one species to another.
Some say that we have used chloroquine and hydroxychloroquine for many years, which is true, but this is not testament to their safety. The objective when developing modern drugs is to target its action as specifically as possible, so reducing side effects. This type of sophisticated drug design wasn’t a thing 80-years ago when chloroquine and hydroxychloroquine first appeared. These drugs act in many places in the body, which inevitably leads to several unwanted side effects. Although they vary from person to person and in severity depending upon dose, side effects can include anorexia, diarrhoea, nausea and skin pigmentation, as well as liver and kidney toxicity. Some side effects are hard to spot in the early stages, such as changes to the muscles of the heart, but these can later lead to arrythmia and, although rare, cardiomyopathy (where heart muscles find it harder to pump blood). Not everyone experiences these toxicities however, and many take hydroxychloroquine as an effective anti-inflammatory for rheumatoid arthritis and lupus.
Chloroquine and hydroxychloroquine have antiviral properties when tested in test tubes in the laboratory (or in vitro, which translates to in glass) and has shown activity against, Ebola, SARS, MERS and more recently SARS-CoV-2. As any drug developer will tell you however, there is a world of difference between in vitro results and clinical trials. Clinical trials with hydroxychloroquine or chloroquine with HIV, hepatitis-C, dengue, Chikungunya and influenza viruses show either no discernible or very modest efficacy.
Enthusiasm for hydroxychloroquine in treating Covid-19 appears to originate from small clinical studies in France and China. A clinical study in Marseille, France, for example, reported 100% viral clearance in nasopharyngeal swabs in 6 patients after 5 and 6 days (the trial was with a hydroxychloroquine and azithromycin combination). Although I don’t know for sure, this may be where Giuliani’s “100% effective rate” came from. Other studies in China reported some success but these are in contrast with others where no discernible effects were found. One of the principal problems is that Covid-19 exhibits a range of symptoms and severity, with some only getting a very mild disease while others are dying. It’s hard to distinguish true drug-effects from such a noisy background without carefully controlled comprehensive studies. And it’s very dangerous, and wholly unscientific, to choose those studies that give the results you want and ignore those that don’t. Other clinical trials are ongoing and results are awaited. Despite the lack of clinical evidence, the United States Food and Drug Administration (FDA) granted hydroxychloroquine “emergency use authorisation” against Covid-19. This sends entirely the wrong message in my opinion, but having dealt with the FDA in the past, it can be rather politically motivated at times. European regulators are being more cautious and are not authorising hydroxychloroquine until it’s been better tested.
So, in the words of Donald Trump, what have you got to lose? Although hydroxychloroquine is used to treat rheumatoid arthritis and lupus (its anti-inflammatory properties are useful) it is not an easy-going drug and the aforementioned side effects are something you want to avoid in a respiratory-compromised patient. There have been a few cases of people self-medicating who have died from chloroquine poisoning. Perhaps more importantly, without clinical evidence it offers false hope and might even distract from other potentially more effective interventions. Proclamations by senior politicians can also cause over-demand and thereby deprive those in genuine need of hydroxychloroquine, such as lupus patients. Overall, there is quite a lot that can be lost.
It’s my view that some politicians are struggling currently, because they so often get their opinions confused with facts. They may have such strong views on the economy or societal issues their opinions became certainty and they then search for “evidence” to support them. Such cherry-picking is the antithesis of the scientific method. And remember, viruses don’t give a flying tinker’s cuss for anyone’s opinion, they aren’t even alive to care about anything. Believe me, no one wants hydroxychloroquine to be effective against Covid-19 more than me and I’d be delighted if clinical trials confirm its efficacy. In the meantime however, the Covid-19 outbreak follows the laws of nature, not humankind but as the number of deaths increase, politicians become increasingly desperate for quick and easy answers. The trouble is there aren’t any, and that’s not an opinion it is, I’m afraid a fact.
(My thanks to Dr C. Edwin Garner, for his comments on this post in a private capacity).
Graham Lappin 