Until recently you probably hadn’t heard of hydroxychloroquine.
But suddenly the drug, which is used to treat malaria and inflammatory conditions such as lupus, was thrust into the spotlight when US President Donald Trump spruiked it as a treatment for coronavirus.
With a vaccine to prevent the disease at least 12 to 18 months away, and the death toll from COVID-19 mounting, scientists are scrambling to develop treatments.
Many of these drugs, like hydroxychloroquine, are already used for a range of other conditions, so they can be fast-tracked in development to go straight to large human trials.
Since the pandemic erupted, more than a 1,500 research papers have been published, and there are hundreds of trials around the world.
But there is growing concern about the quality of research and how it is being interpreted, said Steven Tong, an infectious diseases expert at the Peter Doherty Institute.
When research is unhelpful
The gold standard of clinical research is double-blind randomised controlled trials (RCT).
In these trials participants are assigned to either a control group, and given a placebo along with standard care, or a treatment group, where they are given the experimental drug along with standard care.
Neither the researcher nor the patient knows which group participants are assigned to.
Dr Tong heads up a team that will be conducting randomised controlled trials of hydroxychloroquine and some other drugs.
“Some data and the way it’s been presented can be very unhelpful in this kind of situation,” he said, referring to the hype around the original hydroxychloroquine study that purported to show some benefit when the drug was used in combination with an antibiotic.
“People shouldn’t have been making any efficacy claims about those treatments based on a really flawed study.”
Many other studies are based on retrospective data from severely ill people who’ve recovered after being given unapproved drugs on compassionate grounds as a last ditch attempt to save their lives.
“It’s where good peer review and well-designed and reported studies are what we should be aiming for,” Dr Tong said.
So let’s look at some of the treatments and what we do and don’t know at the moment.
Chloroquine and hydroxychloroquine
Chloroquine and hydroxychloroquine have been shown to stop coronavirus from entering cells under lab conditions.
Hydroxychloroquine has also been used for years to dampen the immune system in people with autoimmune conditions.
But Dr Tong said we don’t know whether it could harm someone by dampening the immune system, which they need to fight off the illness, or if it will help someone who is severely ill from coronavirus because their immune system has gone into overdrive.
Hydroxychloroquine is known to affect the heart, which is why it should only be used in carefully controlled clinical trials, where patients are monitored, he added.
The problem with developing treatments, even those that have been used in other conditions, is that we don’t know enough about the new virus or the immune response to it, said Larisa Labzin, an immunologist at the University of Queensland.
“One of the key things is that a lot of these drugs we find are going to be effective against the virus just in cells, [and] probably won’t be that effective in the disease setting,” Dr Labzin said.
“Really what we’re looking for is not just that these drugs inhibit the virus replicating in people, but also that the people who get sick with the virus actually do better.”
So far, there have been no large-scale high quality randomised controlled trials to demonstrate whether or not hydroxychloroquine is effective.
The latest study, which has not been peer-reviewed and is not a RCT, indicates it’s not.
“We don’t understand enough about what it’s doing in the context of the whole disease, but it looks like it’s not being very helpful at the moment,” Dr Labzin said.
HIV drugs, including remdesivir
Another antiviral drug capturing headlines at the moment is remdesivir.
This experimental drug, which belongs to a family of drugs used to treat HIV and hepatitis C, targets an enzyme that the viruses use to copy their genetic code, known as a polymerase.
A bit like a Trojan horse, it inserts a molecule into the virus’s RNA to stop it replicating.
Originally developed for Ebola, where it initially showed promise but eventually failed in trials, it showed some promise in the lab for treating SARS and MERS and now, the novel coronavirus.
Early compassionate use studies of remdesivir, given to patients with severe coronavirus infections, have been criticised for having no controls to see whether the results were due to the drug or if the patients would have improved anyway because of other factors.
Two randomised controlled trials were recently suspended in China, with one of those reportedly failing and having significant side effects, according to leaked documents that were posted on the World Health Organization drug trial database and then removed because the study was yet to be peer-reviewed.
The company behind the drug said the documents had “provided inappropriate characterisations of the study” and that it had been ceased due to low enrolment numbers.
“As such the study results are inconclusive,” they said in a statement today.
Scientists are now waiting for the results of large RCTs in the US and Europe.
Scientists such as Dr Tong are also looking at other drugs that treat HIV, including lopinavir-rotinavir.
Instead of targeting the virus’s genetic code, these drugs target an enzyme the virus uses to chop up proteins.
“If you stop that protease from working then those proteins aren’t chopped up the right way and it impairs the virus’s ability to make more of itself.”
This drug was shown to have a small effect in the lab and in case studies when it was used in Hong Kong for SARS, Dr Tong said, but the evidence is not strong enough at the moment to recommend widespread use.
With both approaches, there is also the possibility that the virus can identify the drugs and become resistant over time.
“We see that in HIV where we’ve learnt over the years that you have to use more than one drug to stop this resistance occurring,” Dr Tong said.
“We haven’t seen that yet [with SARS-Cov-2] but it’s early days.”
Instead of tinkering with the virus, antibody therapies aim to bolster the immune system’s ability to recognise and neutralise the virus.
One way to do this is to use antibodies in the blood plasma from someone who has recovered from the disease.
Antibodies are y-shaped molecules released by B-cells in the immune system that bind to the virus and alert other immune cells to come and kill them.
“These antibodies are generally quite long-lived and our immune system is good at pumping out loads of them,” Dr Labzin said.
Known as convalescent therapy or passive immunisation, this strategy has been used the past for Lassa fever, Ebola and swine flu, but most of the data is from case studies without controls.
If specific antibodies can be identified, they can replicated in the lab. This strategy, known as monoclonal antibody therapy, is used to treat Ebola.
But we don’t know enough yet about the antibodies: which ones work against coronavirus, how much you need or what will happen if you transfer them to other people.
“There have been a couple of preliminary trials … but we need really big randomised trials to know if patients have recovered from the convalescent serum or whether they were going to just recover on their own,” Dr Labzin said
There are a couple of large randomised controlled trials using this approach starting in the US and Canada, and it may also be an approach that is trialled in Australia by Dr Tong’s team.
Rheumatoid arthritis drugs
By the time someone becomes seriously ill with COVID-19, the problem may no longer be the virus, but the person’s immune system going into overdrive, creating what is known as a cytokine storm.
“We don’t really understand why it’s uncontrolled in some people and not others,” Dr Labzin said.
Her team plans to work on clinical trials for tocilizumab, an immunosuppressive drug that targets interleukin-6, a small protein or cytokine that has been implicated in inflammation and severe COVID-19 infections.
So far, there have been some studies of this drug, but they are based on data from patients after they’ve been given the drug and did not have any case controls.
Where do these treatments fit in with vaccines?
Vaccines are the first line of defence in preventing an infection, but ultimately, one or more of these treatments will work alongside a vaccine as a back-up.
“There is the chance we won’t have a successful vaccine,” Dr Labzin said.
“Even if we do have a successful vaccine, sometimes we have problems with vaccinating particularly elderly people or immunocompromised people because they’re no longer able to mount as good an immune response.”
In that case, she said, the antiviral could work both as a treatment if they are diagnosed with coronavirus or as a prophylactic for high risk individuals.
Dr Tong hopes some of the questions around these therapies, such as hydroxychloroquine, will be answered in the next two to three months.
For now, the challenge is to find a treatment to reduce the risk of mortality of people who are severely infected.
Ultimately, however, he thinks there will never be a perfect treatment.
“We’re not suddenly going to halve someone’s risk of mortality,” he said.
“Even a reduction of 20 per cent in your risk of dying is still a significant and important impact. And if we can find an agent that can do that, that would be a great advance.”
The only way to do that, he said, is to conduct rigorous clinical trials that provide a high level of evidence.
“At the moment it’s easy for people to throw around treatments, but you don’t learn anything from that and you don’t learn what works and what causes harm rather than being of benefit.”