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.

Source

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.

Fig 3
Data graph showing alleviation of symptoms between patients that received standard care (SOC) or SOC and hydroxychloroquine (HCQ). Source

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.

Source

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.

You may have read my recent post in regards to The Lancet article entitled “Hydroxychloroquine Poses Significant Risk of Cardiac Arrythmia in COVID-19 patients,” however due to some concerns in the reproducibility of the data, the article has been retracted.

I have since edited my original post as retracted, and with this blog post I will describe the concerns of the article and the work leading up to the retraction of the paper.

Here is a statement written by three of the authors of the original article in their retraction statement:

After publication of our Lancet Article, several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication. We launched an independent third-party peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.

Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements. As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.

Source: The Lancet

The immediate concern from this statement is that Surgisphere, the company that contains the patient data, refused to share the full data stating that it would violate client agreement and confidentiality.

It is true that it is the responsibility of the group that owns the data should not provide any information that could lead to identification of the individuals who participated in the study. However, it is extremely common to de-identify patient data, and should not be a problem for a company that routinely is sharing clinical data to scientists.

Not only is there an issue with the company not willing to share the full data set with either the co-authors or the third-party peer reviewers investigating the claims, but there also is a discrepancy in the reported numbers and their geographic locations.

Andrew Gelman, a statistician at Columbia University who reportedly started the discussion on the faulty data, wrote multiple blog posts and posted on PubPeer about the discrepancies in the data.

Gelman along with several other statisticians and medical professionals were concerned about the lack of information provided about the modification of the observational data during data analysis, and the surprisingly high mortality rate of patients who undergo hydroxychloroquine treatment. Another question arised from data collected out of Africa, where a uncommonly high percentage of COVID-19 positive patients participated in the study. The full concerns were addressed in an open letter to the authors of the original study and can be found here.

Furthermore, this is not the first article that Surgisphere has provided data for the risk of hydroxychloroquine and cardiac arrhythmia.

Surgisphere recently provided data for a New England Journal of Medicine article at the beginning of May, and is supposedly working on another article with Lee Wallace regarding COVID-19.

Wallace apparently feels confident about the dataset provided for his future article.

Wallis tells The Scientist that he has seen aggregated rather than hospital-level data, but that he is satisfied by Desai’s detailed descriptions of the dataset, and that all the necessary ethical and data-ownership requirements have been met.

Source: The Scientist

The founder of Surgisphere and a co-author on the original Lancet manuscript, Sapan Desai, reported this to The Scientist.

Desai says he can understand people’s concerns and that the burden of proof rests with Surgisphere. “We want to prove this to the world,” he tells The Scientist. “One thing that we might be able to do is get what we’ve done audited. That will be external, third party, independent of who we are, and can help validate all of this.”

Source: The Scientist

Surgisphere has also issued a response on their company website regarding their contribution to The Lancet article.

We thank the scientific community for their commitment to data integrity and for pointing out opportunities to revise and clarify our paper.

Since original publication in The Lancet, we discovered that a hospital that joined the Surgisphere registry on April 1, 2020 (in between our quarterly audit periods) self-designated as belonging to the Australasia continental designation. In reviewing the data from each of the hospitals in the registry, we noted that this hospital should have more appropriately been assigned to the Asian continental designation. This hospital was properly reclassified in our database. The findings of the paper are unaffected by this update.

We found that in the original publication, one of our data tables of propensity score matched and weighted data, was being misinterpreting as raw data, which would, if raw, make the data appear overly homogeneous. While the data were accurate, we are providing The Lancet and updated table with unadjusted data to help resolve the confusion. There was no error in analysis, and none of the results of the paper are affected.

Source: Surgisphere

I cannot find the updated table, and frankly, find it ridiculous to believe that the company will be able to solve all of the issues of this paper with one hospital incorrectly assigned and reporting unadjusted data. I have serious questions over Surgisphere and Desai as a medical proffesional and scientist. Until the dataset used for The Lancet is openly provided to the fellow authors and third party reviewers, we cannot trust the validity of the data. I would also suggest that any articles that use Surgisphere for their data analysis should also be questioned until the data can be validated for accuracy.

While it is now unclear as to the risks of hydroxychloroquine for COVID-19 positive patients, the evidence suggesting hydroxychloroquine is not effective for the prevention or treatment of COVID-19 is strengthening. I will be dedicating a blog post to this shortly, but you can read this randomized double blind placebo controlled study which will be the main focus of my next post.

As a final note, I would like to apologize to my readers for not catching this in my initial read and research of the article. I work diligently to provide scientifically accurate information, and will continue to do to the best of my ability.

One positive takeaway from this experience is that science at its core is a self-correcting process. Scientists around the world examine peer-reviewed articles every day and question articles that are not up to par. It is this fundamental drive to seek out the correct answer that drove me to a science career.

I will continue to post scientifically accurate articles, and if another post is found to be invalid, I will correct it in the same manner I have done with The Lancet post.

You might have seen her post on Facebook. Wearing a black cowboy hat and matching boots, Doctor Ivette Lozano rambled for almost 15 minutes about the “conspiracy” that is the global pandemic. She spends her time first displaying her complete ignorance regarding the current coronavirus cases in Texas, and then thorought the rest of the time rambles about her practice where she has “cured every patient” that is blessed to cross her entryway.

Let’s take a closer look at the doctor and just get a real sense for how she treats her patients.

Ivette Lozano, MD is a physician located out of Dallas, TX who appears to specialize in family medicine and general surgery. She has not spent much time in the spotlight, but recently received internet fame by attending a Texas protest rally and giving a speech. The rant was recorded, and quickly became viral.

“Texas Doctor Praises Trump’s Advice On COVID-19” and “I Want You To Know The Truth About COVID-19” are just two of the titles accompanied by her video.

Just for clarification, if someone is telling you they want to tell you “the truth” about something, you know you are about to hear a load of crap.

And of course, after her “Pro-Trump” post, Fox News took the bait and have brought her on national TV to tout her fake news.

She claims that the Texas Pharmacy Board has illegally restricted prescriptions of hydroxychloroquine or chloroquine, and requests that an evidence based diagnosis must be provided before they can fill the prescription. Lozano reports that it is a HIPAA violation and is unethical for her to release this information.

As it turns out it is not illegal, and almost every state has a similar guideline for hydroxychloroquine. A joint letter released by the American Medical Association and the American Pharmacists Association provides recommended guidelines and regulations each state currently has to obey.

Let’s take a closer look at her first video, and counteract any of her claims that are lacking scientific evidence.

Right out of the gate, she lists numbers of COVID-19 cases (in Texas). The numbers she references were accurate as of May 10th. I have added in current figures for Texas when I could find them.

She states that there are 27,000 confirmed cases (currently up to 55,348 ) with 3,000 recovered and 111 dead (now up to 1,519 deaths).

Her next sentence goes something like this: “Well if 3,000 have recovered, and 111 are dead out of a total of 27,000 then that’s some 24,000 recovered, right?”

Uhh…..no? Are you forgetting the active cases, where patients are still fighting COVID-19? I don’t practice medicine, but I can surely tell you that once you have tested positive for a viral infection, you don’t immediately get added into either the recovered column or the dead column. That’s just basic common sense.

Much of the data she reports from this point forward is personal anecdotes from her office. She discusses how all the patients she has seen have mild symptoms and are “suffering from hysteria” rather than from the disease itself.

Well, I can’t speak to her personal anecdotes because the data is not publicly available (and she actually states she does this so no one can counteract her claims), but I can speak to the overall trends of symptoms and the degrees of severity and variability we see in patients across the world.

As always, I am posting this as a source of information and not providing any sort of medical advice. If you are concerned you or someone you know may have COVID-19 please contact your nearest hospital and speak to a medical professional.

Per the CDC website, symptoms appear 2-14 days after exposure to the virus. Mild symptoms may include: Fever or chills, cough, shortness of breath, fatigue, or muscle/body aches, headaches, loss of ability to taste/smell, and in some cases nausua, vomiting or diarrhea.

More moderate to severe symptoms may include trouble breathing, pressure in the chest, confusion, and cyanotic lips/face (due to lack of oxygen). Patients that need to be hospitalized will often need to be ventilated, which is when you no longer are able to breath under your own power, and must be sedated and have a machine breathe for you. Reports of blood clotting have also been confirmed for patients with COVID-19

For more complete information on symptoms and treatments, visit the CDC website.

When you look at the percentage of patients that experience mild or severe symptoms, it varies depending on your location.

In China, rates of ICU admission ranged from 7 to 26%

In the United States, 20 percent of patients in New York required ventilation and in Washington state, ICU admission rates for COVID-19 patients were 4.9 to 11.5%.

So for Ivette Lozano, it is possible that her experience is distorted because 70 to 80% of patients may not need hospitalization. However, just because she has not yet experienced a severe COVID-19 case, that doesn’t mean they are false reports. Something else she should have learned in her years in education.

She continues her rant by saying “How did I learn to treat COVID-19 patients? I learned from the president of the United States.”

So you didn’t read the primary literature for yourself? You didn’t speak to expert physicians who have experience? You just trusted someone who is so far outside the scientific realm of knowledge because of your political beliefs? I don’t think I have to comment any further.

So she decides to prescribe them hydroxychloroquine and an antibiotic of some sort (not specified in the video, but it could be assumed to be azithromycin) and says it’s what good doctors do, they practice medicine. Without any scientific support.

I’m sorry, I don’t go to the doctor so I can be a guinea pig for their treatment combinations. I expect my physicians and the physicians for my family to use evidence-based practices. If the do want me to test a new drug combination, then I expect to be apart of a clinical trial that is properly handled and my safety is given the highest priority. Practicing medicine like this is not what good doctors do. Science-Based Medicine is a fantastic blog site where dozens of physicians talk about this very topic, and I would recommend visiting them when you get a chance.

She again continues her rant about how the pharmacist required her to provide a diagnosis that requires hydroxychloroquine.

I have already discussed this above, but I would like to mention that the job of a pharmacist is not just to count and dispense pills. Pharmacists are specifically trained to evaluate the risk of drugs for patients, and extensively study the risks involved for taking medicine. They are the true experts when it comes to drug risk factors. So they have every right to deny this doctor for what she is doing. And I am thankful that the Texas pharmacists board is taking a stand.

Since the pharmacy board requires a diagnosis, she admits to the audience that she provides a diagnosis that will allow for the prescription of hydroxychloroquine, apparently even if the patient doesn’t have the disease.

Again, I am not a medical professional, but I am about 99% sure that is illegal. At the very least it is unethical, and more than likely could be considered insurance fraud for patients with medical insurance.

But hey, she’s a doctor! She knows better than anyone else, because the president told her what to do.

Unfortunately, she is not the only doctor that as made decisions like this. The infamous Dr. Oz, who constantly posts pseudoscientific medicine, also spoke about the “wonders of hydroxychloroquine” although recently he backed off from his original statements and has listened to the current scientific body of knowledge.

The morale of the story: Doctor’s do not always follow the best medical practices and just like everyone else, are susceptible to their own biases. In the case of Ivette Lozano, it seems her political bias is influencing the decision of her medical practice, which is extremely dangerous. I can only hope that she decides to consider evidence based practices for treatment of COVID-19 cases, and listens to medical experts that understand the risks involved in such a treatment.