EXPERT REACTION: WHO suspends hydroxychloroquine trial amid safety fears

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.

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.

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.

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.

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.

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.

 

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

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.