EXPERT REACTION: Trial finds hydroxychloroquine doesn't stop people dying from COVID-19

Previous studies have shown that chloroquine and other quine derivatives have inhibitory properties against several viruses (including SARS-CoV-2) when tested in tissue culture but fail when transferred to animal models. The effectiveness of these drugs for clinical prophylaxis or treatment for COVID-19 patients was unknown and small trials inconclusive and associated with significant adverse effects (cardiac arrhythmias).

Data from the RECOVERY Collaborative Group published in the New England Journal of Medicine indicate that hydroxychloroquine is not an effective treatment for hospitalised patients with COVID-19. No significant difference in mortality after 28 days was observed for patients treated with hydroxychloroquine compared to those who received usual care (24.0% versus 23.5%) respectively. These results are also consistent with preliminary results from the SOLIDARITY trial being conducted by the World Health Organization (WHO).

No virologic measurements were made in the RECOVERY trial so differences in the viral load range between those treated with hydroxychloroquine and those who received usual care remain unknown. Virologic measurement is important to address possible use of hydroxychloroquine for prophylaxis or in patients with less severe SARS-CoV-2 infection that don’t require hospitalisation.

The hydroxychloroquine dose regimen for the RECOVERY trial was designed to result in rapid attainment and maintenance of plasma levels that were as high as safely possible.

Hydroxychloroquine is clearly not effective for hospitalised patients with COVID-19 however the efficacy of lower doses for prophylaxis or in patients with less severe SARS-CoV-2 infection that don’t require hospitalisation remains unclear.

This randomised trial provides robust high-quality evidence indicating that hydroxychloroquine and hydroxyquine are not effective treatments for patients with severe illness from COVID-19. This was a relatively large randomised study, thus providing some confidence in the findings. If this drug was of any significant benefit you would have expected to see some signs of this in this study, but instead the evidence suggests that hydroxychloroquine either has no effect or in fact may worsen outcomes.

The main results were that there was no statistically significant difference in the rate of death after 28 days when taking hydroxychloroquine compared to usual care. However, it is worth noting that the rate of death was actually higher for the hydroxychloroquine group at 27.0 per cent compared to 25.0 per cent for the usual care group (rate ratio 1.09) even though this difference was not statistically significant. There was, however, a statistically significant decrease in the likelihood of hydroxychloroquine patients being able to be discharged from the hospital alive within 28 days when compared with the usual care group (56.9 per cent vs 62.9 per cent; RR 0.90). In addition, those not undergoing mechanical ventilation at baseline were found to have a statistically significantly higher likelihood of requiring ventilation or of death than those in the usual care group (30.7 per cent vs 26.9 per cent; RR 1.14).

In summary, the results of this study should not be a surprise and should lay to rest for now the notion that hydroxychloroquine is a treatment for COVID-19. More concerningly, there is evidence that this drug may worsen outcomes. We should now focus our attention elsewhere on more promising treatments.

Hydroxychloroquine (HCQ) did not result in a lower incidence of death at 28 days. In fact, the statistics suggested the opposite, that there was a statistically and clinically relevant increase in death rate in the HCQ group at 28 days. In the non-ventilated patients there was also a higher risk of combined ventilation or death.

These results are expected and consistent with many other trials over the last six months. They are also consistent with the pharmacology of HCQ, which, using pharmacological principles and previous data, predicted over seven months ago that this drug would not be helpful in COVID treatment, and that it carried significant adverse event risk, including cardiac death.

Hopefully this should be the end of any more trials of HCQ in COVID. Further, in Australia we need to be investing in clinical trials in COVID that are based on sound pharmacology, clinical pharmacology and toxicology, and pathophysiological response to COVID.

There has been conflicting advice from some commentators about the use of hydroxychloroquine in people with COVID-19. These recommendations have been based on low-quality observational studies (many of which have not undergone peer review). The Recovery Trial provides rigorous evidence from a high-quality trial with a robust study design that hydroxychloroquine does not reduce the risk of death from COVID-19.

This confirms that hydroxychloroquine has no role in treating hospitalised people with COVID-19.

Hydroxychloroquine has been widely publicised as a potential treatment for COVID19 infection, which all started from a small French trial over 6 months ago. However, to date, we only have a series of evidences from a series of studies and meta-analysis on the lack of efficacy for hydroxychloroquine with or without Azithromycin and Zinc for hospitalised patients, in pre- or post-exposure prophylaxis. Importantly a large study using the golden standard randomised and controlled clinical trial was lacking to ascertain whether or not hydroxychloroquine is efficacious against standard of care for non-severe COVID-19 patients.

Finally the answer to this question came from RECOVERY trial from UK that has enrolled more than 4,600 COVID-19 patients. This was published in the prestigious journal, New England Journal of Medicine, overnight. It shows unequivocally hydroxychloroquine treatment does not have any efficacy on mortality on hospitalised patients for COVID-19. The RECOVERY trial in fact shows patients under hydroxychloroquine treatment were less likely to be discharged from the hospital at day 28 and more likely to undergo mechanical ventilation in ICU. Due to the lack of efficacy of hydroxychloroquine, the trial stopped prematurely.  

In summary, the RECOVERY trial and previous studies shows overwhelmingly that prophylaxis or curative hydroxychloroquine treatment for COVID-19 has no efficacy and it is even harmful to the patients. In my view, hydroxychloroquine should be administered to COVID-19 patients only in the context of ongoing clinical trials and not as a standard of care.

There has been a lot of hype around using the antimalaria drug hydroxychloroquine (HQ) as a treatment option for COVID-19 patients. The authors herein conducted a large randomised, controlled open-label platform trial to date, which included over 1,500 patients receiving HQ and over 3,000 patients receiving usual care. 

The primary outcome of 28-day mortality is very straight forward. 

The study was terminated early as the interim analysis showed no benefit in improving the chance of survival for patients. In fact, the patients were less likely to be discharged from hospital alive compared to the usual-care group. Patients that originally did not require mechanical ventilation were more likely to suffer severe forms of the disease such as later needing ventilation or dying, if receiving HQ treatment. 

The Australian National COVID-19 Clinical Evidence Taskforce has said for weeks that the evidence indicates HQ is potentially harmful and no more effective than standard care in treating patients with COVID-19.

Past and this new scientific data around HQ in the context of COVID-19 has been clear, strong and of high scientific quality. This study proves what we already knew. We can definitively say that HQ should not be used as a treatment for anyone with COVID-19. 

The self-evident conclusion to draw from these studies is that we move on from HQ and focus our efforts on promising drugs such as dexamethasone, remdesivir or new compounds.

This is the final publication of a randomised controlled clinical trial from the UK RECOVERY trial group, who are investigating a range of different treatments for COVID-19. We heard about the results of this study in June, when recruitment was halted after an interim analysis showed no benefit. The final analysis confirms these results, with no survival benefit in patients on HCQ compared to usual treatment. In fact, patients on HCQ were about 10 per cent more likely to die in hospital and 14 per cent more likely to require ventilation.

The side effects we worry about with HCQ include abnormal cardiac rhythms, but there was no difference in cardiac arrhythmias between patients on HCQ and usual care. All in all, this study reinforces that there is no evidence to support HCQ as a COVID-19 treatment, and it may even make outcomes worse.

The recent publication in the New England Journal of Medicine reports the results of a randomised, controlled clinical trial of hydroxychloroquine conducted by the RECOVERY Collaborative Group in the United Kingdom in patients hospitalised with COVID-19. The study concluded that those patients who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. That is, the drug was not effective in this study.

Patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group and there was a slightly higher incidence of cardiac deaths in the hydroxychloroquine group but no difference in the incidence of new major cardiac arrhythmia.

The limitations of the trial were that both patients and physicians knew what treatment was given and there was no placebo control.

A number of clinical trials have now concluded that hydroxychloroquine is ineffective when administered to patients hospitalised with COVID-19. This is consistent with independent observations showing that unbound plasma concentrations of hydroxychloroquine are unlikely to reach sufficient levels to be effective in patients hospitalised with COVID-19.

In simple biological terms, the way the virus enters cells within our nasopharyngeal tissue (and in many cells of our body) is different to what is observed within many initial drug screening efforts. In many initial drug screens that show inhibition with hydroxychloroquine and related compounds, they are using a cell line derived from a kidney of a monkey. When moving to a human cellular target (nasopharyngeal cell or equivalent), the path the virus takes is not influenced by hydroxychloroquine.

This is best highlighted at the basic science level by the laboratory of Stefan Pohlmann in Germany a few weeks prior in the journal Nature. Work by the same team highlighted a clinically available drug (Camostat/Nafamostat) does target the relevant biologically pathways the virus uses in vivo (ACE2 and TMPRSS2) and this is presently being used in clinical trials to determine if this is a viable means of treatment.

It's really a case of understanding the virus as best we can and fighting it with the right tools that target the right pathways. In our fight with other viruses like HIV, understanding this is key to designing an approach that is both specific and effective.

The findings of the Recovery Trial that hydroxychloroquine is not effective in reducing death from COVID-19 should end the interest in the use of this drug in severe COVID-19. Other randomized trials have shown that it is not effective in the treatment of milder COVID-19 or in prevention of COVID-19.

Commentators have often said that there is a lack of evidence that hydroxychloroquine is effective in COVID-19. This statement is no longer accurate. There is now strong evidence that it is not effective in COVID-19 – a very different and important conclusion.

The politicization of this drug and reliance on several flawed observational studies during a pandemic has misled patients and health professionals. Ill-advised promotion of this drug has also diverted resources away from more important research. We have to learn from this experience about the need to have a singular unwavering focus on strong science for decisions about treatments that affect the lives of millions of people.

The RECOVERY study has a history. 

• The results were released over 4 months ago, but it had not been published in a peer-reviewed journal. 
• Many believed the uniquely high dose of hydroxychloroquine rendered the trial uninterpretable.
• The dose was extremely controversial. 
• The dose in the first 24 hours was 300% to 600% of what almost all other studies had used. 
• Despite the reliance on "modelling" the dose has not been justified. 
• If we except the RECOVERY dose (300%-600% of the dose other studies used) as being correct, then it is not credible to accept any of the other RCT results. It can't be both ways. Did all the others get it wrong? 

Fundamentally, the trial also failed to study hydroxychloroquine in a way in which hydroxychloroquine has been proposed to provide benefit.  Ever mounting epidemiological evidence suggest that if given EARLY to high risk patients it has an effect to prevent progression. The average duration of symptoms in RECOVERY was already 9 days before treatment was commenced ("Number of days since symptom onset 9 [5 to 14] 9 [5 to 13]" page 21 of pre-print.), and up to 2 weeks or more! It is simply not possible to make conclusions regarding hydroxychloroquine considering this delay. 

Furthermore, the study included patients even when already on ventilators or even ECMO (out of body oxygenation). A prespecified subgroup analysis looked at patients who were not already on ventilators. However, the majority of these patients were already on oxygen support and some of them were already receiving support with breathing through non-invasive ventilation.

And at an average of 9 days (up to 2 weeks or more) post onset of symptoms, and receiving oxygen support, this was too late in the disease to make any inference regarding hydroxychloroquine; even for this group who were not already on ventilators.

From page 10 of the pre-print: " At randomization, 17% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without non-invasive ventilation), and 24% were receiving neither."

And even for that 24% who were not on oxygen, we don't know the duration of symptoms prior to randomization. The study was not designed, nor powered, to look at EARLY disease. COVID-19 is a disease of stages.

The final word: This study cannot be used to inform patients, doctors, or policy makers on whether hydroxychloroquine should be available to treat COVID-19. The claim that "the evidence" says hydroxychloroquine "doesn't work" is as misleading as saying the "evidence" says parachutes don't work.

This is explained here in a paper entitled: Hydroxychloroquine, Parachutes And How to Understand 'The Evidence': https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3676982

Due to the dose, the delay in treatment and the fact that the vast majority of patients had already progressed to a stage of the disease that was too late, this trial is not interpretable. Consider the reproducibility crisis in even benchtop biology. Now consider the RECOVERY trial.

The record of randomized controlled trials of hydroxychloroquine represents a failure of the establishment. Epidemiological data shows evidence that if taken EARLY, in HIGH RISK groups, HCQ might prevent progression of the disease. But the RCTs have predominantly looked at late disease. Those that have studied early disease have studied low risk patients who would do well without any treatment.  

This failure can be added to the failure in COVID-19 regarding: Lack of admission early on that COVID-19 has an airborne component, despite overwhelming epidemiological evidence. Failure to give healthcare workers adequate PPE despite overwhelming epidemiological evidence. The politicization of hydroxychloroquine is a sad indictment on our current society's polarized discourse.

Contemporary debates desperately need nuance. Reporting of the results of RCTs of hydroxychloroquine often lack that nuance. 

I don't have any reason to be for or against HCQ. And I can't say whether it definitely has a place or not in the treatment of COVID-19. But a sense of rationalism says that we must scrutinize the "evidence" with appropriate nuance.