The research on hydroxychloroquine as a treatment for COVID19. And other therapeutics

Hydroxychloroquine and COVID-19

Emerging evidence about this medicine | Updated 5 June 2020
In response to international interest in the use of hydroxychloroquine for the prevention and treatment of COVID-19, the disease caused by the virus SARS-CoV-2, we look at emerging evidence, current guidelines and whether hydroxychloroquine is actually a ‘miracle drug’ that will save lives during this pandemic.

Australian hydroxychloroquine COVID-19 treatment trial

On 21 April 2020, the Australasian COVID-19 trial (ASCOT) was launched. The trial aims to generate clinical evidence about treatments that can be applied during the pandemic to reduce mortality or the need for mechanical ventilation in hospitalised but not yet critically ill patients with COVID-19. A key feature of the trial is that it will be applying an 'adaptive' methodology that will allow evidence about treatments to be continually updated with new information as it becomes available, while at the same time maintaining trial integrity.

The first treatments to be trialled are lopinavir/ritonavir and hydroxychloroquine. Both medicines are already in use for the treatment of other conditions.

What is the COVID-SHIELD Trial?

The COVID-SHIELD Trial is looking to see if hydroxychloroquine (the medication under investigation) can help prevent COVID-19. The medication under investigation for this trial is already prescribed in Australia for conditions such as lupus and rheumatoid arthritis.
We are looking for health care workers in Australia who are at significant risk of illness by the new coronavirus to take part in the trial. COVID-19 is a condition caused by the new coronavirus (SARS-CoV-2), presenting as fever, cough and shortness of breath. More serious cases require hospital admission and the need for assisted ventilation, with a risk of death.
In this trial, participants will be randomly assigned to receive hydroxychloroquine or matching placebo daily. This will allow us to see if hydroxychloroquine is better than placebo in preventing COVID-19 and if hydroxychloroquine reduces the severity and duration of COVID-19 symptoms.
About 2,250 health care workers in Australia will take part in the trial.

Hydroxychloroquine and COVID-19

Why was the use of hydroxychloroquine stopped in the Solidarity Trial?

On 17 June 2020, WHO announced that the hydroxychloroquine (HCQ) arm of the Solidarity Trial to find an effective COVID-19 treatment was being stopped.
The trial's Executive Group and principal investigators made the decision based on evidence from the Solidarity trial, UK's Recovery trial and a Cochrane review of other evidence on hydroxychloroquine.
Data from Solidarity (including the French Discovery trial data) and the recently announced results from the UK's Recovery trial both showed that hydroxychloroquine does not result in the reduction of mortality of hospitalised COVID-19 patients, when compared with standard of care.

From Australia's TGA - Therapeutic Goods Administration:

New restrictions on prescribing hydroxychloroquine for COVID-19

24 March 2020

In recent days there has been considerable focus on the potential for hydroxychloroquine and the similar compound chloroquine (which is not marketed in Australia) to help in treating COVID-19.
Hydroxychloroquine is used for treatment of malaria and certain autoimmune diseases.
Recent reports of increased off-label prescribing of medicines containing hydroxychloroquine have raised concerns that this will create a potential shortage of this product in Australia.
Clinical trials are underway around the world examining their potential to treat COVID-19. However, these medicines pose well-known serious risks to patients including cardiac toxicity (potentially leading to sudden heart attacks), irreversible eye damage and severe depletion of blood sugar (potentially leading to coma).
Given the limited evidence for effect against COVID-19, as well as the risk of significant adverse effects, the TGA strongly discourages the use of hydroxychloroquine outside of its current indications at this time other than in a clinical trial setting or in a controlled environment in the treatment of severely ill patients in hospital.
To limit use of hydroxychloroquine to currently approved indications, there have been new restrictions placed on who can initiate therapy using it. Only certain types of specialists will be able to prescribe hydroxychloroquine to new patients (see information for health professionals below). General practitioners and other medical practitioners (e.g. hospital Resident Medical Officers (RMOS) and doctors in training) can continue to prescribe repeats for hydroxychloroquine to patients in line with the registered indications for patients in whom the medication was prescribed prior to 24 March 2020. From 24 March 2020, general practitioners and doctors in training can only prescribe these medicines for continued treatment of patients where initial treatment has been authorised by one of the specialists.

 

Three big studies dim hopes that hydroxychloroquine can treat or prevent COVID-19

Praised by presidents as a potential miracle cure and dismissed by others as a deadly distraction, hydroxychloroquine was spared a seeming death blow last week. On 4 June, after critics challenged the data, The Lancet suddenly retracted a paper that had suggested the drug increased the death rate in COVID-19 patients, a finding that had stopped many clinical trials in their tracks. But now three large studies, two in people exposed to the virus and at risk of infection and the other in severely ill patients, show no benefit from the drug.

“We’d be better off shifting our attention to drugs that might actually work.” 

On 5 June, researchers in the United Kingdom announced the results from the largest trial yet, Recovery, in a press release. In a group of 1542 hospitalized patients treated with hydroxychloroquine, 25.7% had died after 28 days, compared with 23.5% in a group of 3132 patients who had only received standard care. “These data convincingly rule out any meaningful mortality benefit,” wrote the investigators.

Hydroxychloroquine for the Prevention of Covid-19 — Searching for Evidence

Some researchers have promoted chloroquine and hydroxychloroquine for the treatment and prevention of illness from a variety of microorganisms, including SARS-CoV.  Hydroxychloroquine can inhibit replication of SARS-CoV-2 in vitro. Some observational studies have suggested benefits of hydroxychloroquine for the treatment of Covid-19, whereas other treatment reports have described mixed results...

The advocacy and widespread use of hydroxychloroquine seem to reflect a reasonable fear of SARS-CoV-2 infection. However, it would appear that to some extent the media and social forces — rather than medical evidence — are driving clinical decisions and the global Covid-19 research agenda...

The results reported by Boulware et al. are more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined...

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care.

NIH COVID19 Treatment Guidelines

Overall Recommendations

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19, except in a clinical trial (AII).
• The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI).

FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems

Does not affect FDA-approved uses for malaria, lupus, and rheumatoid arthritis 

July 1, 2020 Update: A summary of the FDA review of safety issues with the use of hydroxychloroquine and chloroquine to treat hospitalized patients with COVID-19 is now available. This includes reports of serious heart rhythm problems and other safety issues, including blood and lymph system disorders, kidney injuries, and liver problems and failure.

Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19

Annotation by Ian Breakspear, Naturopath and Senior Lecturer at Endeavour College of Natural Health:

This study by Arshad et al, is a retrospective observational study which is interesting. The study does indicate those treated with HCQ had a lower mortality rate. It gives no indication as to whether the patients had reduced or zero viral loads after administration (however this is not a major limitation - regardless of viral loads, a reduction in mortality rate is a good thing! It just means we need to then also understand whether it reduces the pathophysiological consequences of the disease, or kills the infection or both - which we don't know yet). In addition to the HCQ or HCQ + azithromycin, both corticosteroids and tocilizumab were used for most patients (which they controlled for in their statistical analysis, but I find it interesting people are not talking about these medications as part of treatment, and just focusing on the HCQ). 

Some limitations I see are: 

1) Only first admission for each patient was included in the data, and subsequent admissions were not included. It would be valuable to know what the numbers of subsequent admissions were, if they were COVID-19 related, and outcomes. To me this is really important. If they had severe disease in their initial admission, were discharged (i.e. not a fatality) and then subsequently readmitted (even if they survived the second readmission) then that says to be that the value of the treatment is quite limited. 

 2) The authors themselves point out a limitation in that it wasn't randomised or blinded. I don't think that this is a big issue, it just points out that ideally we need to also conduct randomised and blinded studies, to have a better understanding of whether these results are just correlation, or if there is an actual causative link between HCQ usage and reduced mortality. However what I find interesting is that some outlets (like the Christian Broadcasting Network) are reporting this study as a randomised double blind study, which it is not. 

 3) The authors also point out their results need to be interpreted with caution (good scientific practice) and "should not be applied to patients treated outside of hospital settings" which was the opposite of what the "America's Frontline Doctors" press conference was saying.

Global HC Q studies. PrEP, PEP, and early treatment studies show high effectiveness, while late treatment shows mixed results.

This  link it is an interesting clustering of available HCQ studies. It is pointing in the direction that perhaps prophylactic usage or early stage usage may result in improved outcomes. The limitation here is it is mixing together different outcome measures (mortality rates, severity of symptoms, infection rates, etc). However it is great to see as an early attempt at weighing the evidence.

Everything you need to know about the COVID-19 therapy trials

There are thousands of clinical trials investigating treatments and preventative measures for COVID-19.

 

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A major ivermectin study has been withdrawn, so what now for the controversial drug?

 

Huge study supporting ivermectin as Covid treatment withdrawn over ethical concerns

The preprint endorsing ivermectin as a coronavirus therapy has been widely cited, but independent researchers find glaring discrepancies in the data.

The study found that patients with Covid-19 treated in hospital who “received ivermectin early reported substantial recovery” and that there was “a substantial improvement and reduction in mortality rate in ivermectin treated groups” by 90%.

But the drug’s promise as a treatment for the virus is in serious doubt after the Elgazzar study was pulled from the Research Square website on Thursday “due to ethical concerns”. Research Square did not outline what those concerns were.

 

Wait for the Principle Trial ...

What now for ivermectin?

Professor Andrew McLachlan reviews the medication and its potential against COVID-19 in the wake of a major study being withdrawn.

What now for ivermectin?

Professor Andrew McLachlan reviews the medication and its potential against COVID-19 in the wake of a major study being withdrawn.