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Over the past few weeks, we’ve heard a lot about the drugs hydroxychloroquine and chloroquine which are primarily used to treat malaria and autoimmune diseases. US President Donald Trump, for example, has been pushing for its use and recently called it a ‘game-changer’ in the fight against Covid-19.
We spoke to Associate Professor Sean Wasserman, Infectious Diseases Specialist at Groote Schuur Hospital, University of Cape Town and Professor Wolfgang Preiser, Head of the Division of Medical Virology at the University of Stellenbosch on what the evidence suggests.
'Game changer' or not worth the risk?
Misleading claims that there is good evidence to suggest that hydroxychloroquine and chloroquine can treat Covid-19 have been doing the rounds for some time. But evidence suggests otherwise.
Hydroxychloroquine, which is closely related to chloroquine, was first approved by the US Food and Drug Administration (FDA) in 1955 as a treatment for malaria, and has also been widely used for long-term use in autoimmune diseases, such as lupus and rheumatoid arthritis. There’s plenty of safety data and experience on its use for these indications, explains Professor Wasserman.
However, studies looking at these prescription drugs as a potential treatment for Covid-19 have been in the works for a short period. Conversation around these drugs as potential treatments for Covid-19 started in China in January this year, reports the Washington Post. Wasserman explains that for a long time, it’s been known chloroquine has antiviral effects, in vitro – which means in the lab, and not on humans.
“Scientists infect these cells (from different sources – often monkey cell lines) with the virus and add known concentrations of hydroxychloroquine or chloroquine to the infected cells, and have ways of testing if the virus and the cells are alive or dead,” explains Wasserman.
“And in those systems, hydroxychloroquine and chloroquine have an effect against several viruses, including the virus that causes Covid-19. Hydroxychloroquine appears to be more potent than chloroquine, but they both have antiviral effects in these systems.”
While this appears promising, Wasserman cautions that it’s only known to a certain extent how these drugs work against SARS-CoV-2, the virus that causes Covid-19, the disease.
“And the postulated way in which they work is by causing changes within the cell, in the respiratory tract, which leads to the blocking of viral attachment to the cells by changing the structure of ACE2 receptors. Simply put, the direct antiviral effect may result from blocking viral entry into cells in the respiratory tract of the host.”
There is another potential mechanism wherein the drugs can play a role, in that they have immuno-modulatory effects, says Wasserman.
“They modify the immune system to dampen it down, that’s why they’re used for certain autoimmune diseases. Part of the reason why Covid-19 is so dangerous is because there’s an exaggerated immune response in some people with severe disease.
“And so, there may be dual mechanisms of action: one is in a direct, antiviral effect, and the other is modifying an aberrant immune response. Now, we don’t actually know whether these drugs work or not – in people. And that’s the most important point to make here. They’re experimental therapies and we have no good clinical evidence that they are safe and effective in treating people with Covid-19.”
Medical experts refer to this situation as ‘equipoise’: “This means that we don’t know whether they cause harm, or whether they cause benefit, compared to other treatments. We can only answer those questions with randomised controlled trials,” adds Wasserman.
Current evidence is flawed
So far, there have been a few small-scale studies done, among them a Chinese study, this report by French doctors, and a more recent Chinese clinical trial.
Scientists and medical professionals have pointed out that these studies are flawed in one way or another: either they weren’t randomised clinical trials (RCTs) (these are reliable scientific experiments that reduce bias when testing the effectiveness of new medications); the studies were too small; or they weren’t peer-reviewed, meaning we cannot make any definitive statements about them just yet, says Wasserman.
In a March report titled 'Clinical management of suspected or confirmed Covid-19 disease' by the South African Department of Health and the National Institute for Communicable Disease (NICD), researchers support the point that there is no credible evidence from RCTs to recommend any specific treatment for patients that present with suspected or confirmed Covid-19 infection.
“This is an area of active study. Candidate drugs undergoing investigation include remdesivir, lopinavir/ritonavir, chloroquine, interferon, and toculizumab. To date, published clinical data on most of these agents consists largely of in vitro studies, with little or no human data. Hence we do not know whether these medicines benefit or cause harm to patients with COVID-19….
“Chloroquine has received considerable interest, given its relatively low cost, (limited) local availability, known side-effect profile (at registered doses), and some promising in vitro data. Published data from human trials is currently lacking,” the report reads.
Professor Wolfgang Preiser, who is one of the contributing authors, iterated this stance to Health24:
“There is some, but very limited, evidence that chloroquine may have beneficial effects on Covid-19. There are small and poorly done (which is not necessarily a criticism – researchers did what they could under a lot of stress) studies of which some show some benefit and others not. Only proper clinical trials of the randomised controlled kind will show whether there is any value or not.
“South Africa is, with several other countries, about to embark on the Solidarity trial which will do exactly that. When done we will know whether the drug holds benefit or not. We are not expecting a massive benefit in any case but even some degree of benefit might be worth it,” said Preiser, adding that outright claims that the drug can treat Covid-19 is sparking panic-buying and is worryingly leading to those who actually need it for lupus and rheumatoid arthritis, not being able to get them.
Hydroxychloroquine and chloroquine: Side effects
As is the case with any drug, there are also potential side effects, including nausea, skin rashes, diarrhoea, and mood swings. The most dangerous side effect that medical professionals worry about is cardiac heart toxicity, says Wasserman.
“It can interfere with the repolarisation of the electricity in the heart, the QT interval, and that is a risk factor for fatal arrhythmias,” he explains.
A more recent Brazilian trial of chloroquine to treat Covid-19 had to be stopped early due to some patients developing serious heart complications. It was found that a quarter of the patients had severe ECG abnormalities (QT prolongation) and two patients, who received the higher dose of chloroquine, had died from arrhythmia.
“This trial illustrates that we don’t know which dosage to use,” says Wasserman. “So it’s not just about using the drug – it’s about understanding how to optimally use it. And we don’t currently know this for chloroquine or hydroxychloroquine. If you give an experimental drug to patients in an uncontrolled way, and some of those patients die, you don’t actually know if they died because of the drug, or the disease you are trying to treat.”
However, new trials are ongoing, and the World Health Organization (WHO) are conducting larger clinical trials of these drugs in treating Covid-19. One began earlier this month in the US and is said to enroll 510 patients at 44 medical centres.
