Hydroxychloroquine – how the principles of clinical pharmacology seem to have been ignored

Colin Garner ANTRUK announcements, Coronavirus COVID-19, Learn more

This anti-malarial drug has been making headlines since the start of the COVID-19 pandemic, yet it is not an effective treatment. So why has it received so much attention, and what can we learn from it?

As the true extent of the COVID-19 pandemic became apparent and scientists scrambled to find a treatment, one familiar name seemed to stand out from the crowd: hydroxychloroquine. In the two months that followed, the anti-malaria treatment was stockpiled. It was banned from being transported and – eventually – found to be ineffective against COVID-19. Research also showed it was but actually harmful due to cardiological side effects. Below is the timeline of events that have led to this conclusion.

Mid- February

China held a news conference that indicated that chloroquine had been shown to be effective at treating COVID-19 in what seemed to be properly-run trials. However, the data was not published. Much older research into the effects of both drugs against viral illnesses showed variable and often contradictory outcomes, such as reducing disease transmission in the lab environment, but increasing it in animal trials source).

March

These results led to a number of clinical trials being launched – nine before the first week of April was over. But, none of the detailed data was published. The focus switched from chloroquine to hydroxychloroquine. This reportedly had fewer side effects and a reduced risk of interaction with other drugs. The clinical trials used ‘in vitro’ (laboratory) methods, rather than in vivo (human trials) to show its efficacy.

At this point, we can see anecdotal evidence (i.e. the reported results of the unpublished trials) and evidence of efficacy within a lab environment. This is not enough valid data to push ahead with a decision to treat patients who are already very sick.

On 20 March 2020, stocks of hydroxychloroquine ran low in the USA . President Trump had suggested it as a possible treatment during a televised news briefing. In the following days, doctors were found to be hoarding the treatment for their relatives. A man died after consuming fish-tank cleaner that contained chloroquine phosphate, a more-toxic (and non-medical) version of the medicine.

As the panic spread, India banned the export of hydroxychloroquine in order to retain their supply. On 28 March, the US Food and Drug Administration (FDA) granted emergency use of the drug for patients with COVID-19.

There was, at this time, still no validated evidence to suggest that hydroxychloroquine would work against the virus. This is the second point at which caution could have been used to avert the use of an ineffective and harmful drug.

April

The drug is placed onto the FDA’s ‘drug shortage’ list, prompting 20 states to take measures to prevent hoarding. The Centre for Disease Control and Prevention (CDC) then removed it’s guidance that the drug. It had previously said the drug was ‘well tolerated’ and being used by US healthcare providers to treat COVID-19 patients.

At this point, doctors working on the front line began expressing their doubts about the benefits of the treatment, due to the severity of the side effects, while the British Medical Journal (BMJ) published this editorial urging caution in the use of this – and other untested – treatments. Shortly after this, a study of chloroquine was halted due to heart complications. Patients in Brazil developed irregular heart rates at a high dose.

On 21 April, pharmaceutical company Novartis launched a trial in 440 hospitalised patients, just one day before the largest study so far (by the Veterans’ Health Administration) found no benefit. These studies together could have provided the data required to make the necessary decisions.

Just a few days later, the FDA warns against the use of hydroxychloroquine outside of hospital settings. Again, they cited a risk of serious heart problems. Despite this, states and local governments have stockpiled tens of millions of doses at this point.

Finally, on 29 April, demand begins to fall due to the ongoing warnings.

Today June 16 2020

Magagnoli, et al (2020) found that hydroxychloroquine is ineffective for COVID-19. It does not reduce the risk of a patient requiring ventilator assistance with breathing, or indeed the risk of death. In fact, it was found to extend the amount of time spent in hospital.

The World Health Organisation is carrying out an international trial (called SOLIDARITY) into four possible treatments, including hydroxychloroquine – although this arm of the study was temporarily paused to re-assess the safety of the drug. Results from this study could be expected as early as the end of June.

In the largest clinical trial of hydroxychloroquine taking place here in the UK, the RECOVERY trial (RECOVERY =  Randomised Evaluation of COVid-19 thERapY) investigators concluded that hydroxychloroquine offered no clinical benefit to COVID-19 patients.

Professor Peter Horby is Professor of Emerging Infectious Diseases and Global Health in the Nuffield Department of Medicine. As the Chief Investigator for the trial, he said:

‘Hydroxychloroquine and chloroquine have received a lot of attention. They have been used very widely to treat COVID patients despite the absence of any good evidence. The RECOVERY Trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalised with COVID-19. It is disappointing that this treatment has been shown to be ineffective. Although, it does allow us to focus care and research on more promising drugs.’

Future treatments

Professor Colin Garner, Antibiotic Research UK Chief Executive writes that the basic principles of clinical pharmacology seem to have been ignored when hydroxychloroquine was proposed as an effective therapy.

Despite the devastating impact of COVID-19, the only way to know we are using a safe and effective treatment is through comprehensive clinical trials, which cost both time and money. These trials should be based on sound principles endorsed by the pharmacological and scientific societies to ensure the mistakes made early on as we all struggled to come to terms with the enormity of the situation are not repeated (https://www.bps.ac.uk/news-events/news/articles/2020/international-societies-call-on-researchers-to-app).

Just as with finding new ways to treat COVID-19, the same principles apply to finding new treatments for antibiotic resistant infections. Large sums of money are being released to fund COVID-19 treatment which are wholly justified. But, the sad fact is that just a fraction of this would make a huge difference to treating drug-resistant infections. Please SUPPORT Antibiotic Research UK in our battle to save modern medicine so that you and your loved ones can continue to gain access to the latest breakthrough medical treatments.