EXPERT REACTION: WHO suspends hydroxychloroquine trial amid safety fears

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The World Health Organization has announced it will temporarily suspend a trial into anti-malarial drug hydroxychloroquine to treat COVID-19 due to safety concerns. The decision follows a study published in The Lancet that found people taking hydroxychloroquine were at higher risk of death and heart problems than those who were not and that there were no benefits to treating coronavirus patients with the drug. Below experts and those involved in Australian trials respond.

Organisation/s: Australian Science Media Centre, The University of Adelaide, The Australian National University, Doherty Institute for Infection and Immunity, Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne

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Media release

From: Australian Science Media Centre

Expression of Concern - Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis.

Important scientific questions have been raised about data reported in the paper by Mandeep Mehra et al—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis (1)—published in The Lancet on May 22, 2020. Although an independent audit of the provenance and validity of the data has been commissioned by the authors not affiliated with Surgisphere and is ongoing, with results expected very shortly, we are issuing an Expression of Concern to alert readers to the fact that serious scientific questions have been brought to our attention. We will update this notice as soon as we have further information.

The Lancet Editors

The Lancet, London EC2Y 5AS, UK

  1. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020; published online May 22. https://doi.org/10.1016/S0140-6736(20)31180-6

Click here to see the scimex page for the initial release.

Attachments:

  • The Lancet
    Web page
    Recent Lancet study on Hydroxychloroquine referenced by the WHO
  • Australian Science Media Centre
    Web page
    EXPERT Q&A: What is hydroxychloroquine?
  • World Health Organization
    Web page
    Section of WHO press conference on trial suspension (~ 16:30)
  • World Health Organization
    Web page
    WHO Q&A: Hydroxychloroquine and COVID-19

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor Anthony Kelleher is Director of the Kirby Institute, UNSW Sydney

The WHO decision is based on a paper published in The Lancet on May 22nd which was a multi-centre registry analysis of patients admitted to 671 hospitals on six continents with COVID-19. The paper compared  the outcomes of hospitalised patients who had received  one of the antimalarial drugs Chloroquine or Hydroxychloroquine (HCQ) or either of those drugs in combination with a macrolide antibiotic (e.g. azithromycin) to those who had not received any of those drug regimens.

The study encompassed the review of outcomes of more than 96,000 patients admitted to hospital between Dec 20, 2019 and April 14, 2020. Approximately, 14,000 of these received one of the four drug regimens: Chloroquine, 1868; Chloroquine plus a macrolide, 3783; Hydroxychloroquine, 3016; or HCQ plus a macrolide, 6221.

The in-hospital death rate in the control group was 9.3%, while approximately 18% died in the HCQ group, 23% in the HCQ plus macrolide group, 16% in the Chloroquine group and 22% in the chloroquine plus macrolide group. Prior to making the calculations of mortality
the authors made statistical adjustments for possible differences in age and other known risk factors for poor outcome such as diabetes, existing lung disease, obesity, as well as for baseline severity of COVID -19 infection across the five groups analysed.

This was not a randomised trial.  The doses of drugs were not standardised across the treatment groups, nor was the treatment received in the comparator group standardised. The results are therefore not completely conclusive as there may be unrecognised biases that are causing the differences in these outcomes. However, given the size of the effect and its consistency across the four groups it seems at least unlikely that any of these regimens are helping with the control of those with COVID-19 infection requiring hospitalisation.

The definitive data on these drug regimens would be derived from properly conducted randomised trials of these drugs. Many of these are ongoing across the globe including one run under the auspices of WHO. However, various regulatory groups which have oversight of these trials will be reviewing these data to determine if there is clinical equipoise for the continuation of these trials in light of these data.

Last updated: 17 Jun 2020 4:10pm
Declared conflicts of interest:
None declared.

The Peter Doherty Institute for Infection and Immunity, conveners of AustralaSian COVID-19 Trial (ASCOT)

Following an observational study published in The Lancet on Friday, 22 May, the AustralaSian COVID-19 Trial (ASCOT) has paused patient recruitment pending deliberations by the governance and ethics committees overseeing the trial. We expect these deliberations to occur rapidly and will provide further information as they arise.

Last updated: 28 May 2020 3:39pm
Dr Roger Lord is a lecturer (Medical Sciences) with the Faculty of Health Sciences at The Australian Catholic University and Research Fellow with The Prince Charles Hospital (Brisbane).

The use of the malarial drugs chloroquine and hydroxychloroquine as candidates to prevent COVID-19 transmission requires a very cautious approach. Chloroquine has been proposed several times in the past for treatment of acute viral disease in humans and without success.
 
In vitro studies performed several years ago suggests that chloroquine can inhibit viral replication however this in vitro antiviral activity is not observed in animal models. Both the dosage and mechanism of action of these antimalarials is known for prophylaxis (to prevent infection) but no such information existed to indicate effectiveness to prevent transmission or treat COVID-19 infection.
 
Malaria infection involves a protozoan with a complex life-cycle whereas COVID-19 is a virus. The rush to use these antimalarial drugs to treat COVID-19 infected individuals was based on two separate clinical trials which have been criticised for deficiencies in experimental design and a move towards rapid dissemination.
 
The first was a Chinese study that used elevated dosages of chloroquine and that exceeded levels to control malaria. Reported adverse events included nausea, vomiting, diarrhea and shortness of breath over the period investigated. A second French trial involved patient controls having a higher starting viral load and only surrogate outcomes measured. These antimalarials are capable of causing a plethora of serious adverse effects especially at elevated concentrations which highlighted the need for peer review and careful independent evaluation.
 
The rapid dissemination of data that is not subjected to rigorous peer review can lead to unintended consequences. Careful reflection of the risk/benefit involved in using these compounds did not prevent others caught up in the “infodemic” from self-medicating and subsequent loss of life.
 
The large clinical study published in The Lancet has shown convincingly that COVID-19 patients treated with these antimalarials are more likely to develop abnormal heart rhythms and die in hospital compared to COVID-19 patients in a comparison group. The dangers associated with these antimalarials have resulted in the WHO suspending further trials involving their use.

Last updated: 26 May 2020 5:02pm
Declared conflicts of interest:
None declared.
Dr Ian Musgrave is a Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, within the Discipline of Pharmacology at the University of Adelaide.

The suspension of the WHO clinical trials of hydroxychloroquine as a COVID-19 treatment is understandable. Every clinical trail must balance risk and benefit to its participants. Hydroxychloroquine is used to treat malaria and autoimmune disease and has known adverse effects. Its adverse effects on the heart were one of the most concerning, but potentially manageable. In the wake of substantial studies in the New England Journal of Medicine and British Medical Journal which showed no benefit, the recent large study in The Lancet that showed no benefit with significant adverse effects on the heart and a clinical trial in Brazil that was halted because of adverse effects on the heart, it makes sense to suspend the WHO clinical trials in the interests of patient safety.
 
While the results of treatment trials are negative, trials of hydroxychloroquine as a preventative treatment may still be worthwhile. The mechanism of action of hydroxychloroquine is to reduce the viruses ability to infect cells, so it may be more effective at prevention than treatment. In a prevention trial, the subjects are healthy and can be screened so participants at risk of heart problems can be excluded. People participating in these trials can be closely monitored for adverse effects and treatment stopped if issues arise.

Last updated: 26 May 2020 4:06pm
Declared conflicts of interest:
None declared.
Dr Gaetan Burgio is Group leader and head of the transgenesis facility, John Curtin School of Medical Research, at the Australian National University

Hydroxychloroquine has been widely publicised as a potential treatment for COVID-19 infection but a series of observational studies and small randomized clinical trials have raised safety concerns and lack of efficacy for Hydroxychloroquine against the virus. This culminated last week with the publication in The Lancet of a large observational study on over 90,000 COVID-19 infected patients from 6 continents and 671 hospitals showing lack of efficacy of hydroxychloroquine and an increase of over 35% of serious cardiac side effects.

Following this important report, the decision to temporally halt the Solidarity trial for Hydroxychloroquine and to review the safety data in patients that underwent this trial is expected and logical. This will enable the researchers to determine whether it is safe to continue this very large clinical trial in over 60 countries and 3,500 patients.

Last updated: 26 May 2020 4:05pm
Declared conflicts of interest:
None declared.
Professor Peter Collignon is an infectious diseases physician and microbiologist at the Canberra Hospital. He is also a Professor at the Australian National University Medical School.

The value of hydroxychloroquine for treating COVID-19 remains doubtful. 

So far there have been no large randomised trails that show a benefit. Currently in the majority of studies to date, no overall benefits in survival are seen. It may even increase death rates. Recently when large numbers of patients with COVID were looked at in a recent Lancet paper, there was a higher death rate for those taking hydroxychloroquine, compared to those not on it.

Last updated: 26 May 2020 4:03pm
Declared conflicts of interest:
None declared.
Dr Phillip Reece is a consultant to the pharmaceutical and biotechnology industry and an Honorary Senior Fellow in the Department of Pharmacology and Therapeutics at the University of Melbourne

In view of the negative results and safety concerns reported recently for hydroxychloroquine in various clinical trials, the WHO decision to recommend suspension of clinical trials of hydroxychloroquine in the treatment and prevention of COVID-19 infections is warranted in my opinion. The drug distributes widely throughout the human body after oral dosing and requires several weeks of dosing to reach plateau concentrations in blood. This is not ideal for an infection such as COVID-19 where effective concentrations are required early in the course of the disease to stop it progressing. Prophylactic use of the drug presents the risk of significant side effects in otherwise healthy subjects, the majority of whom are unlikely to be infected.

 

Last updated: 26 May 2020 4:02pm
Declared conflicts of interest:
None declared.
Professor Marc Pellegrini is an Infectious disease physician at the Walter and Eliza Hall Institute of Medical Research (WEHI)

Very careful consideration has been given to The Lancet article. We have taken the advice of the authors of that paper who emphasise their study must be cautiously interpreted and must not be generalised with regard to the treatment (or prophylaxis) of people who are not unwell. The COVID SHIELD trial is continuing and participants are being kept well informed

Last updated: 26 May 2020 4:00pm
Declared conflicts of interest:
Professor Pellegrini is lead investigator of COVID SHIELD, Australia's first clinical trial to determine whether hydoroxychloroquine can prevent COVID-19

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