​Chloroquine, miracle drug or hype?

Author: Kerry Silva McPherson

Chloroquine has acquired infamy in the past few weeks and is currently a highly debated pharmaceutical. Chloroquine and hydroxychloroquine are antimalaria drugs and are proposed as a treatment for Covid-19. Sifting through the media’s coverage on chloroquine is frustrating. Unfortunately, many news stories report little to no scientific information about the drug, choosing instead to report it as a political issue. CNN, with a reputation for its democratic bias, reports that Trump’s optimism of the drug is dangerous rhetoric. Fox News, notorious for its right-wing ideology, argues that Democrats are spreading misinformation about chloroquine to push their anti-Trump agenda. Mistrusting the media bias, I did my own investigating using solely reliable sources to sort out the information (and misinformation) of the drug.

What are chloroquine and hydroxychloroquine?
 
Chloroquine and hydroxychloroquine are antimalaria medicines taken in the form of tablets. These drugs also act as immunosuppressants, meaning that it will lower the activity of the immune system, the part of the body that fights disease. For this reason, chloroquine also treats autoimmune diseases such as arthritis and lupus. Chloroquine and hydroxychloroquine are similar drugs; they have the same use. Hydroxychloroquine has lower toxicity.
 
Hydroxychloroquine and chloroquine's patents are expired; therefore, generic drugs are available. The patent expiration has fueled conspiracy theories that big pharma will not market chloroquine to treat Covid-19 because it will be less profitable than developing an expensive vaccine. However, multiple pharma companies, including Novartis and Sanofi, have donated their stocks of hydroxychloroquine for clinical trials and emergency use.

Is chloroquine a relatively safe drug?
 
Yes and no. Patients often experience no side effects, but side effects are possible, including headache, stomach pain, and eye disease. Overdoses can be fatal. Chloroquine can also react with other drugs and should not be used by individuals with psoriasis.
 
Evidence for chloroquine as Covid-19 treatment
 
Viruses use our cells as factories to reproduce themselves. They invade our cells, hijack our cell’s machinery (proteins) to replicate itself, and then exit the cell to do it all over again. Antivirals try to stop one of these three steps to block the propagation of the virus.
 
Hydroxychloroquine and chloroquine have antiviral activity and are currently being investigated for HIV treatment. We aren’t entirely sure why this drug is antiviral, but two theories exist: 1) the drug affects the processing of proteins that the virus needs to invade cells, 2) the drug affects inner-cellular membrane fluidity which impedes the virus’s ability to burst out of the cell. Hydroxychloroquine has anti-Covid-19 efficacy in vitro — science talk for in a test tube. But, testing anti-viral activity in a human is much more complicated.
 
Anecdotal evidence
 
Anecdotal evidence for hydroxychloroquine is quite prevalent, mostly due to social media. Doctors are claiming they are curing Covid-19 patients with chloroquine. But anecdotal evidence is dangerous; it doesn’t take into account numerous factors that affect disease progression:

1. Lies – Although obvious, it is necessary to point out social media posts are often dishonest.
2. Placebo effect – The placebo effect is a very real phenomenon in which a patient experiences an improvement due to forces other than the drug. The placebo effect can account for as high as 40% of patients experiencing an improvement in their disease when given a placebo instead of the drug.
3. Correlation vs. Causation – Lessoning of symptoms can coincide with other factors besides treatment, including timing, diet, rest, and others. For example, you get a stomach bug and are sick all night. You decide to drink ginger ale, and your stomach bug lightens up. Did your stomach bug get better because you drank the ginger ale? Or are you feeling better because your immune system started to win the fight about the same time you drank the ginger ale?
4. Susceptibility and variability – Covid-19 has a broad range of severity. Many hydroxychloroquine “success stories” might be due to the patient experiencing a mild case of the disease. 

 
So how do we account for the variables that can affect the outcome of the disease? We perform clinical trials, of course.
 
Clinical trials
 
Clinical trials are designed to discover if the outcome we observe is due to a drug or happenstance. In a nutshell, doctors and scientists assign patients to an experimental group that receives the drug and a group that gets a placebo (no drug). Clinical trials have four stages; three must be passed to earn FDA approval:

• Phase 1: Is the drug safe? Give medication to healthy individuals. Do they get sick? This stage is crucial, it tests for side effects, which often go undetected in animal and in vitro studies.
• Phase 2: Is the drug effective? Sure, it might seem effective from the initial studies, but humans are much more complicated than test tubes and lab rats. 
• Phase 3: What is the effective dose of the drug? Ok, so the drug works, what is the dose we give patients? We need a dose that hits the sweet spot, effective but not toxic.
• Phase 4: Is the drug safe for long term use across multiple populations? After FDA approval, data continues to be collected on the drug. It can be pulled off the market if serious side effects are detected, or if the drug is not as effective as initially thought.

           
Fortunately, hydroxychloroquine and chloroquine clinical trials are repurposing clinical trials. The FDA already approved the use for one disease, and they are checking if hydroxychloroquine and chloroquine will work for Covid. These trials take less time and money since we already have data collected about toxicity. If they work, they will release to market quicker than a novel medicine.
 
Chloroquine clinical trials are underway!
 
Two clinical trials yielded promising, yet inconclusive, results. A Chinese study conducted a clinical trial with 62 Covid-19 positive patients; 31 patients were given hydroxychloroquine along with the standard Covid-19 treatment, and 31 patients were given standard treatment only. 25 of 31 patients in the hydroxychloroquine treated group and 17 of 31 patients in the untreated group had improved symptoms. This data suggests the treatment may be beneficial, but statistical analysis does not confirm so. A larger test group is necessary. Furthermore, the presence of the virus after treatment was not evaluated in this study. 
 
A French study tested 36 patients, 20 treated with hydroxychloroquine, and 16 untreated. 70% of treated patients and 12% of untreated patients tested negative for Covid-19 after 6 days of treatment. Unlike the Chinese study, this study has statistically significant results, suggesting that this outcome is not by chance but due to drug efficacy. However, this study is half the size of the Chinese study. Another notable difference is the French patients received both hydroxychloroquine and azithromycin, a drug that showed promise against the Zika virus. But look at these results with a grain of salt. Six patients from the treated group were removed from the study due to complications and were not factored into the statistical analysis. 
 
Conclusion
 
The scientific community is continuing to test chloroquine as a treatment for Covid-19. In biomedical science, reproducibility is imperative. If one science does a test, another scientist should be able to perform the same experiment and get the same answer. The University of Oxford is starting a 10,000 participant study to determine if chloroquine can prevent Covid-19. The US approved emergency use of chloroquine and hydroxychloroquine to hospitalized patients, an endeavor that may save lives and help collect more data. Chinese scientists are planning a stage 3 clinical trial for hydroxychloroquine to take place in June 2020.
 
Should we expect to see an FDA approval immediately? Probably not, we still have many questions to answer about chloroquine before it’s safe for widespread use. What is the effective dose? Does it prevent the virus, or only treat viral colonization? Since chloroquine is immunosuppressive, will it increase disease spread? If treated with chloroquine, are we still carriers?
 
Even with these unanswered questions, there is advocacy to bypass FDA regulations and approve chloroquine for Covid-19 treatment and prevention. With the current data, doing so is certainly taking a chance and could set a dangerous precedence. But, perhaps, it's worth the risk.

Author

Kerry McPherson, @KerrySilvaMcph 
PhD Candidate studying biomedical sciences. Researches proteins implicated in cancer chemoresistance.
Passionate about STEM education outreach, science based policy, and inclusivity.