A Review of the Science
When I first heard about hydroxychloroquine (HCQ) as a treatment for COVID-19, I was excited. Wouldn’t it be great if we have a robust treatment for this disease? Unfortunately, it didn’t pan out. Hydroxychloroquine has been tested more than any other potential COVID-19 drug but has fallen short of expectations. HCQ can neither prevent nor treat COVID-19 period!
Presently there is no known cure for COVID-19. The cumulative scientific data – namely clinical trials that were randomized and controlled – all showed consistently that hydroxychloroquine is not effective as a treatment for COVID-19. In this article, I present the data that supports this conclusion.
Science Versus Politics – The dangers of promoting HCQ for treatment of COVID-19
Unfortunately, the science behind hydroxychloroquine has taking a back seat to politics. A number of influential politicians who are front-and-center to the COVID-19 pandemic continue to endorse hydroxychloroquine for treatment of COVID-19. This is disinformation and is potentially dangerous because it confuses and misleads the public. Promoting a drug that is ineffective is reckless. The average person is not a scientist. He counts on reliable information from leadership.
Politicizing of HCQ is extremely dangerous for public health reasons. Misinformation about a deadly virus is harmful for many reasons. If one person listened to the falsehood – he may subsequently take an action that causes others to catch, spread or die from the virus. Thinking that HCQ is a treatment also diverts attention away from doing the hard work needed to contain the outbreak. It diverts attention and resources from other drugs in development that might be more effective and could result in people using ineffective treatments rather than seeking care for COVID-19
Misinformation creates chaos, confusion and division in a time that requires unity in order to effectively combat this pandemic. In the setting of a public emergency we need to rely on our government to ensure that all potential therapies are tested in the most effective and objective way. It is inappropriate for our leader to short-circuit this process with “gut feelings.”
The science is unequivocal – HCQ is not effective against COVID-19.
Straight talk – in my view, HCQ is unlikely to kill you. It really is a relatively well-tolerated drug. But there are adverse effects, as all trials have shown. There simply is not good evidence that HCQ has a robust effect, and there is evidence of at least moderate harm. Ethically, the choice is clear.
The role of hydroxychloroquine against COVID-19 was first popularized by a French study published on March 20, which found the antimalarial drug, in combination with antibiotic azithromycin, was “significantly associated with viral load reduction/disappearance in COVID-19 patients.” President Trump then took to Twitter on March 21 to declare hydroxychloroquine and azithromycin as the “biggest game changers in the history of medicine.”
Once again – the data is unequivocal – hydroxychloroquine (HCQ) is not effective for treating COVID-19. Here’s why.
A search of the HCQ studies on COVID-19 reveals approximately 900. The vast majority of these are observational studies. Observational studies have utility. By way of example, much of our fundamental understanding of cardiovascular risk factors is based on multiple observations from major epidemiologic studies, such as The Seven Country Studies and the US-based Framingham Heart Study.
On the other hand, observational studies cannot be used to make definitive statements of fact about safety, efficacy or effectiveness of a drug. This is because there are always biases associated with these studies. At best, observational studies find utility in helping to formulate hypotheses to be tested in randomized controlled studies.
Contemporary clinical decision making is well supported by a wide variety of information sources, including clinical practice guidelines, position papers, and insights from randomized controlled trials (RCTs). RCTs are the benchmark and gold standard for assessing clinical efficacy and safety of a specific therapeutic approach
In an observational study, the observed effect of the exposure of interest (HCQ) on the outcome of interest is due to both its true causal effect and the characteristics of who was selected for treatment. By contrast, in a randomized trial, because the selection is random, the observed effect is due solely to the true effect of the treatment.
That’s why so much stock is placed in RCTs. Observational studies should be used to design RCTs, and RCTs should be used to guide therapy.
There are a number of RCTs that have been published recently. Here is a summary of each.
One hundred and fifty hospitalized patients in three provinces in China were randomized to receive either 1200 mg of HCQ for 3 days followed by 800 mg daily for 2-3 weeks or usual care. The groups were well balanced because this was a randomized trial. The primary outcome was absence of virus PCR on nasal swab at 28 days; 85.4% cleared the virus in the HCQ group compared with 81.3% in the usual-care group — not a statistically significant difference.
New England Journal of Medicine Study
Eight hundred twenty-one asymptomatic patients with a high-risk exposure to someone with COVID-19 were randomized to receive HCQ 800 mg once, followed by 600 mg 6-8 hours later, then 600 mg for 4 days vs placebo. The groups were well balanced because this was a randomized trial. The primary outcome was the incidence of COVID-19 at 14 days: 11.8% of those receiving HCQ vs 14.3% of those receiving placebo hit the outcome, a nonsignificant difference. The adverse event rate was 40% in the HCQ group and 17% in the placebo group.
Annals of Internal Medicine Study
Four hundred ninety-one nonhospitalized adults with COVID-19 or high-risk exposure were randomized to the same regimen from that New England Journal of Medicine trial or placebo. The groups were well balanced because this was a randomized trial. The primary outcome was change in symptom severity at 14 days.
The HCQ group improved by 2.6 points and the placebo group by 2.3 points, a nonsignificant difference with a P value of .12. There was no difference in effect among the 24% of the study population who reported zinc supplementation. The adverse event rate was 43% in the HCQ group and 22% in the placebo group.
Journal of Clinical Infectious Disease Study
Two hundred ninety-three nonhospitalized individuals with early COVID-19 were randomized to 800 mg HCQ on day 1 followed by 400 mg daily for 6 days vs usual care. There was no placebo in this study. The groups were well balanced because this was a randomized trial. The primary outcome was reduction of viral RNA load in nasal swabs at 3 and 7 days.
The viral load went down by 3.44 logs in the HCQ group and 3.37 logs in the usual-care group, a nonsignificant difference. The adverse event rate was 72% in the intervention arm and 8.7 % in the usual-care arm.
Six hundred sixty-seven patients hospitalized with COVID-19 and on 4 L of oxygen or less were randomized to receive 400 mg HCQ twice daily, 400 mg HCQ twice daily plus azithromycin, or usual care for 7 days. There was no placebo in this study. The groups were well balanced because this was a randomized trial. The primary outcome was clinical status at 15 days on an ordinal scale.
There was no significant difference in the outcome rates at day 15 for either of the treatment groups compared with usual care. The adverse event rate was 39.3% in the combined-therapy group, 33.7% in the HCQ group, and 22.6% in the usual-care group.
The COVID-19 pandemic puts a premium on finding new drugs with a therapeutic benefit. But this must be demonstrated through rigorous scientific processes so that patients can be assured both that the drugs will work. HCQ is not an effective treatment for COVID-19. Patients are already vulnerable because of the virus.
Without a properly coordinated federal response to the virus, we are become ad hoc patients, researchers, and decision-makers about our own health choices.
 Wei Tang, Zhujun Cao, et. al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomized controlled trial BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1849 (Published 14 May 2020)
 Boulware, D. et. al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 N Engl J Med 2020; 383:517-525 DOI: 10.1056/NEJMoa2016638
 Cavalcant, A, et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 N Engl J Med 2020, DOI: 10.1056/NEJMoa2019014