For well over two months, scientists all over the world have been working towards treating or preventing COVID-19.
An unprecedented global effort to developing a cure has been initiated, and at breakneck speed over 100 FDA approved drugs have been or currently are being tested.
One such drug, hydroxychloroquine (or hydroxychloroquine with azithromycin), has become infamous due to President Trump’s decision to place his penny down after an article was published in late March (Gautret et al) that showed “remarkable results”.
Spoiler alert: the results were not as extraordinary as the appeared.
This study was hoping to expand on previous work. In 2004 an in vitro study was published suggesting choroquine or hydroxychloroquine was a good preventative measure for preventing infection of the previous SARS virus (first documented in 2001). More recent evidence late last year and early 2020 suggested it may also be beneficial for SARS-CoV-2 (see this published commentary for more history on the antiviral properties of hydroxychloroquine). So it is plausible based off of the in vitro evidience that hydroxycholoroquine could be an effective treatment. However, not only did the Gautret et al paper mispresent their data, it also sparked huge controversy and prematurely raised hydroxychloroquine as a frontrunner for COVID-19 treatment
David Gorski MD PhD provided a detailed analysis of the issues within the study and I will not dive too deep into it with this post. Here is a quote from the article, as well as the response by Dr. Gorski. For his full report, click on this link.
We enrolled 36 out of 42 patients meeting the inclusion criteria in this study that had at least six days of follow-up at the time of the present analysis. A total of 26 patients received hydroxychloroquine and 16 were control patients. Six hydroxychloroquine-treated patients were lost in follow-up during the survey because of early cessation of treatment. Reasons are as follows: three patients were transferred to intensive care unit, including one transferred on day2 post-inclusion who was PCR-positive on day1, one transferred on day3 post-inclusion who was PCR-positive on days1-2 and one transferred on day4 post-inclusion who was PCR- positive on day1 and day3; one patient died on day3 post inclusion and was PCR-negative on day2; one patient decided to leave the hospital on day3 post-inclusion and was PCR-negative on days1-2; finally, one patient stopped the treatment on day3 post-inclusion because of nausea and was PCR-positive on days1-2-3. The results presented here are therefore those of 36 patients (20 hydroxychloroquine-treated patients and 16 control patients). None of the control patients was lost in follow-up.
So basically, an intent-to-treat analysis was not done, and patients who dropped out in the treatment group because they got sicker were excluded from the analysis. This is not how things are done. These patients were obviously sicker and could easily have had higher viral loads. Leaving them out of the final analysis was not justifiable.
Sources: Gautret et al, Science-Based Medicine
Furthermore, a separate French lab attempted to replicate the data of Gautret et al, and were unable to do so. Here is a quote from their report.
In summary, despite a reported antiviral activity of chloroquine against COVID-19 in vitro, we found no evidence of a strong antiviral activity or clinical benefit of the combination of hydroxychloroquine and azithromycin for the treatment of our hospitalised patients with severe COVID-19. Ongoing randomised clinical trials with hydroxychloroquine should provide a definitive answer regarding the alleged efficacy of this combination and will assess its safety.
Source: Molina et al
While the majority of the medical and scientific community were initially skeptical of hydroxychloroquine, it did not prevent an enormous spike in prescriptions. Dr Fauci, director of the National Institute of Allergy and Infectious Diseases, and a group of experts recommended the drug should only be taken as part of a controlled clinical trial. Meanwhile President Trump elected to double down on his bet to support hydroxychloroquine, promoting it to the public, and even taking it himself for a period of 14 days.
As time passed, and more studies have been released, the evidence for hydroxychloroquine has been trending towards the negative. But should we give up on hydroxychloroquine and spend our energy and time on another compound? Let’s look at the current data available.
A Review of Previous Studies Examining Hydroxychloroquine
In May and June, five articles have been released sequentially that address hydroxychloroquine treatment through observational studies, as well as open source clinical trials, and the final study published just a few days ago being the first randomized, placebo-controlled clinical trial. I will spend time discussing each of them below.
The first study, published in the New England Journal of Medicine (NEJM) was an observational study based out of New York City. Patients were selected based off of COVID-19 positive test and with moderate to severe respiratory symptoms (oxygen saturation below 94%). Out of a total of 1376 patients, 811 received hydroxychloroquine. 46% of those patients were treated after 24hrs after visiting the ER, while 86% were treated after 48hrs. Azithromycin treatment was initially considered, but during the study was removed from treatment regimen, and the data was not included in the study (however you can see the amount of patients that received azithromycin or not in Table 1 of the paper).
From the total population of patients, 346 died (either with or without intubation). This study reported no significant difference between patients treated with or without hydroxychloroquine.
There are most definitely issues with this study. To begin with, this is an observational study, meaning that scientists did not make any decisions towards patient treatment, and it was not controlled, double-blind, and did not include a placebo control. While observational studies can provide beneficial evidence for or against a medical treatment, they are by no means the most rigorous of studies.
To further confound issues, patients within this study also included patients who were currently enrolled in other research treatments for either sarilumab or remdesiver. The authors also note that hydroxychloroquine treated patients were more severely ill at the beginning of the study, which may have confounded the results of the data.
With all things considered, the study is not conclusive, but does report no significant treatment with hydroxychloroquine. However as I have mentioned multiple times, one study does not make or break a conclusion, and larger more thorough trials are needed to further examine the effects of hydroxychloroquine.
Another study, also based out of New York, also conducted an observational analysis of COVID-19 patients, but included groups as azithromycin alone and both hydroxychloroquine+azithromycin. This study also showed no significant difference among any of the treatment groups. However, this was the first study that noted an increase in cardiac arrest for patients receiving both hydroxychloroquine and azithromycin, but again patients in these treatment groups initially presented with more severe symptoms, and had a higher proportion of preexisting conditions such as obesity, and diabetes, and possessed a higher proportion of male candidates.
The list of limitations of the study continues, and is listed in detail in the article, but the main takeaway is similar to the original NEJM study.
Two additional studies were simultaneously published in the British Medical Journal (BMJ) in regards to hydroxycholorquine treatment for COVID-19.
One of them was a third observational study that was much smaller in patient size (181 patients) and reported no difference between patients who received hydroxychloroquine and those who did not. This study also reported patients with cardiac symptoms (10% ) after 4 days of treatment.
This study has similar limitations as the previous studies, with added problems associated with the small sample size and larger variations with care across hospitals (some hospitals treated all COVID-19 patients with hydroxychloroquine, while others did not) that further counfounds the data, and does not include azithromycin.
The second article published in BMJ is the first reported controlled trial where patients were separated into groups and assigned either hydroxychloroquine or no hydroxychloroquine. Patients were based out of China, and the study was conducted from February 11 to Februrary 29. It is worth noting early that this study is a randomized clinical trial, however it was not double blinded, and did not include a placebo control.
150 patients were included in the study, with 148 reported as mild to moderate disease, and 2 reported with severe disease. Designations are outlined in the quote below.
Mild disease includes patients with mild symptoms but no manifestation of pneumonia on imaging. Moderate disease includes patients with fever, cough, sputum production, and other respiratory tract or non-specific symptoms along with manifestation of pneumonia on imaging but no signs of severe pneumonia defined as the presence of SaO2/SpO2 below 94% on room air or a PaO2 to FiO2 ratio of 300 or lower.
Source: BMJ 2020; 369
At the end of the study, 56 patients in the control group and 53 patients in the hydroxychloroquine group recovered from COVID-19 (negative test) and the probability of alleviated symptoms was also similar, which concludes to no significant difference between the two groups.
Of course while this study is more rigorous in design than what we have already discussed, it still has limitations.
First, the study was limited in patient size due to a decline in eligible new COVID-19 cases in China, the study was shortened, due to the relatively quick recovery time of the patients included in the study. Also, mentioned above, the study has a vast majority of their patient population presenting with mild or moderate symptoms, and therefore conclusions cannot be established for severe patients.
One other limitation to ALL of the studies I have discussed thus far is that they include patients who have been admitted to the hospital for their treatment of COVID-19. None of the studies above evaluate the prophylactic capabilities of hydroxychloroquine.
The most recent article I would like to discuss is the first article that is randomized, double blinded, placebo controlled clinical trial for hydroxychloroquine as a preventative measure against COVID-19 infection.
Published on June 3rd in NEJM, this article consisted of patients that exposure to someone with confirmed COVID-19 either with a face mask or shield (dubbed moderate-risk exposure) or without a face mask or shield (high-risk exposure). Hydroxychloroquine was given was given within 4 days after the initial exposure, and patients were randomly assigned to hydroxychloroquine or placebo.
The patient size was 821 patients, with 719 reported for high-risk exposure to a confirmed COVID-19 contact. Over a period of 14 days, patients were remotely given hydroxychloroquine or placebo, and were asked to submit surveys on days 1, 5, 10, and 14.
Over the survey, the percent of new COVID-19 cases was examined and, as you can see with the above figure, there was very little difference between hydroxychloroquine or placebo. This study is short, only two weeks in length, and does not include azithromycin as a combination for treatment. It also is a study based off of survey participation from patients, which has it’s own problems. Patients often do not appropriately describe their symptoms, or do not respond to surveys that may result in an improper collection of the data. That being said, it is the most rigorous study performed to date, and shows no benefit to hydroxychloroquine in prevention of COVID-19.
Conclusion
At this time, it is really difficult to say whether we should drop hydroxychloroquine and focus on other treatments. While we have evidence suggesting it is not effective for either a treatment or as a prevention, we are still in the early stages, and more studies are needed to more thoroughly examine the effects of hydroxychloroquine for COVID-19 patients. There has also been some preliminary evidence for remdesivir, that initially has shown some promise, but we are far from confirming any sort of treatment for COVID-19.
The morale of the story here is that until we have a sufficient stock of evidence, medical doctors, scientists, and politicians should not openly prescribe or recommend treatments that have not been extensively researched. Not only will it prevent the overuse of prescriptions potentially needed for severe illnesses, but it also may save lives.
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