March 21, 2020, Trump tweet: “HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains.”

The bully pulpit of the president still carries a lot of weight, and Trump’s repeated touting of the anti-malarial drug hydroxychloroquine for the treatment of COVID-19 provided incentive for FDA officials to approve its use under the Emergency Use Authorization section of the Federal Food, Drug, and Cosmetic Act one week after the above tweet. Such authorizations allow for the use of “unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases.” The data for safety and effectiveness under an Emergency Use Authorization is decidedly not to the same standard as that applied to drugs under normal circumstances, wherein an in-depth analysis of multi-phase trials is required prior to use. In the case of hydroxychloroquine for COVID-19, there was little more than theoretical and preclinical data to suggest effectiveness. Trump’s flippant assurance that hydroxychloroquine was safe (“It can help them, but it’s not going to hurt them. What do you have to lose?”) failed to inspire confidence. If I am going to use a drug associated with rare, but potentially fatal heart rhythm disturbances, then I want more than a presidential “hunch” to go on. I want evidence. Nonetheless, with the President’s blessing and a go-ahead from the FDA, hospital systems all across the country immediately incorporated hydroxychloroquine and azithromycin into their treatment protocols.

 

 

First, a few words about COVID-19, also known as SARS-Co-2. In December 2019, a cluster of pneumonia cases from an unidentified agent was linked to a seafood market in Wuhan, China. Subsequently, a novel strain of coronavirus was implicated, isolated, and genetically sequenced. The virus, distinct from both the MERS (Middle East Respiratory Syndrome) and SARS (Severe Acute Respiratory Syndrome) coronaviruses that had resulted in prior epidemics, became the seventh member of the coronavirus family to infect humans. In nature, coronaviruses are broadly distributed across mammals, birds, and humans, causing respiratory, gastrointestinal, liver and, and neurologic diseases. Four members of the family are known to cause common cold symptoms in humans. COVID-19 is notable, however, for being far more virulent and lethal relative to its cold-causing cousins. And given today’s globe-trotting economy, it’s not surprising that the virus spread quickly, with cases now reported in 158 of the world’s 195 nations. As of April 28^th, just 5 months after the first case was detected, the number of confirmed COVID-19 cases now stands at 3,110,702, having resulted in 215,231 deaths, with nearly 2 million active cases. And the pandemic is not nearly played out.

When new, deadly viruses arise, there are three ways to handle them: 1) isolate and contain; 2) vaccinate; 3) actively treat the virus. In the case of SARS, a deadly coronavirus that first appeared in late 2002, containment measures were largely effective, and the disease burnt itself out after infecting just under 8,100 patients. MERS, an extremely lethal strain of coronavirus, erupted in 2012 resulting in fewer cases but more overall deaths. The case fatality rate (the percent of patients infected who die) for SARS was on the order of 11%, while for MERS it was 34%. In contrast, the best estimate of the case fatality rate for COVID-19 is 1.4%. The reason this outbreak is so much more lethal than the ones caused by the SARS and MERS coronaviruses is not because it’s a more deadly virus on a case-by-case basis, but rather because it is far more prevalent.

There is no vaccine.

The virus was not contained.

It spread quickly, arriving here invisible, unnoticed, and ignored. Despite comprising less than 5% of the world’s population, America is now home to more than a third of the confirmed COVID-19 cases and more than 27% of the fatalities. Per capita, we rank poorly; 10^th in mortality, a rate more than double that of Canada (172 versus 77 deaths per million), and 10^th in testing for the virus, a number less than half that of Portugal (17,200 versus 35,300 tests per million). Taken together, the data suggests that the US response has been uniquely abysmal, particularly given the 4-week lead-in time from when the World Health Organization first announced the disease on January 5^th to the first US fatality on February 6^th, and our pre-pandemic ranking as the world’s best prepared nation to deal with an emerging infectious threat (per a 2019 Johns Hopkins collaborative report). With the best technology in the world, we had the slowest, least aggressive response to the virus.

Given the absence of a vaccine and Trump’s reluctance to issue federal stay-at-home orders, that goes a long way toward explaining his enthusiasm for hydroxychloroquine. If there was an effective drug, then closing the country’s businesses would be largely unnecessary. We could ride things out over the spring and summer until a vaccine arrived. There is a certain logic to that line of thinking, but only if backed by solid evidence that hydroxychloroquine actually works. Otherwise, it’s just “magical thinking.” When Trump issued his March 21st tweet, he wasn’t completely ignorant, referencing a small French study that apparently showed benefit when hydroxychloroquine and azithromycin were given to COVID-19 patients. But, as we will see shortly, those results were little more than smoke and mirrors. Trump also placed a lot of faith in the stories circulating on FOX News at the time, including a report from a New York doctor that a cocktail of hydroxychloroquine, azithromycin, and zinc was 100% curative. It seems an odd combination—an antimalarial drug, an antibiotic, and a mineral to treat a virus?

Let’s look at the evidence. On March 20^th, a French doctor and his colleagues reported the outcomes of 36 patients infected with COVID-19 treated with various regimens. The primary outcome was clearance of the virus as determined through a negative polymerase chain reaction assay performed on nasopharyngeal swabs. Twenty patients were treated with hydroxychloroquine alone, and six with a combination of hydroxychloroquine and azithromycin, leaving sixteen untreated patients to serve as controls. After six days, the authors report that 70% the patients treated with hydroxychloroquine had cleared the virus, while just 13% of the untreated patients had.

And this is the trial Trump mentioned in his tweet. There are a lot of problems with it. Patients weren’t randomly selected. The review initially involved 42 patients, most of who were relatively healthy at the outset; only 20% had pneumonia and 17% were asymptomatic. They then excluded anyone from their final analysis who failed to complete the full six days of treatment. This group comprised six patients, one who died, three who became much sicker and required transfer to the ICU, and two who dropped out. (One patient left the hospital and the second declined treatment due to nausea.) This means they essentially excluded those who did poorly or declined treatment.  It stands to reason that when bad outcomes are excluded, good outcomes remain. Maybe it wasn’t the virus that caused the death and ICU admissions; maybe it was the treatment? From this study, it’s impossible to know.

The endpoint is also problematic. I don’t really care if an asymptomatic patient clears the virus from his/her nose in six days. That is, after all, just a surrogate marker for what counts. I want to know if people taking the drug have better patient-oriented outcomes (i.e. less pneumonia, shorter hospitalizations, less mechanical ventilation, fewer deaths). This study in no way proves that hydroxychloroquine is beneficial; 6 of 26 patients initially treated with hydroxychloroquine either died, were admitted to the ICU, or declined treatment, versus 0 of 16 untreated patients. Despite the President’s contention, if this small, non-randomized trial suggests anything, it’s that hydroxychloroquine worsens clinical outcomes in COVID-19 patients.

Shortly thereafter, the same French authors released a larger observational report on 80 adults with confirmed COVID-19 treated with hydroxychloroquine and azithromycin. The majority (92%) were considered low risk for clinical deterioration; only 15% had fever and 5% were asymptomatic. There was no control group and some of the same patients from the first trial were included in the second. Patients were monitored with regard to: 1) clinical outcomes; 2) contagiousness as defined by nasal swabs and cultures; 3) length of hospitalization. A favorable outcome (as defined by hospital discharge) occurred in 81% of the patients. One died and three required ICU transfer. By day five, 97% of the cultures were negative, and by day eight 93% of the nasal swabs were negative, but since there was no control group, this means nothing. We don’t know whether the treatment worked better than a placebo or no treatment at all. Given that 92% of the patients were considered low risk for deterioration at the trial’s beginning and yet only 81% experienced a favorable outcome by the trial’s end, it seems just as likely that the treatment caused harm as provided benefit. This trial adds nothing to our knowledge regarding the effectiveness of hydroxychloroquine and azithromycin to treat COVID-19 infections.

Then there’s the somewhat bizarre story of Dr. Zev Zelenko, an Upstate New York, primary care physician who released a video on March 21^st claiming a “100% success” rate in treating 699 patients with a cocktail of hydroxychloroquine, azithromycin, and zinc. Unfortunately, Zelenko didn’t bother testing most of his patients for the virus, so who knows what he was actually treating? His “study” wasn’t randomized and failed to include a control group, so it’s impossible to know if his cocktail worked better than doing nothing. Dismissive of scientific method, he skipped the peer-review process altogether and sent his findings straight to Rudy Giuliani who shared them with the President. They became instant believers, with Giuliani later tweeting “Hydroxychloroquine has been shown to have a 100% effective rate treating COVID-19.” This is not just bad science, but the wholesale abandonment of it. Normally, I try to keep my posts free from politics, but the hydroxychloroquine story is inextricably tied to it.

In response to the French study, Chinese researchers published the results of a similar trial looking at the rate of viral clearance with, and without, hydroxychloroquine added to a standard treatment regimen. Although it was a small trial of just thirty patients, there were no differences in the rate of clearance as determined by nasal swab testing. Nor were there any clinical differences in fever resolution or progression of chest x-ray findings. Only one patient decompensated and required ICU care, and he was in the hydroxychloroquine group. The drug didn’t work.

Next, another Chinese study, in which 62 patients infected with COVID-19 were treated with either standard therapy or standard therapy plus hydroxychloroquine. This study looked primarily at clinical markers of disease (e.g. time to fever resolution, cough reduction, and chest CT findings). Time to fever resolution was slightly shorter in the hydroxychloroquine group (2.2 versus 3.2 days), as was the time to cough resolution (2 versus 3.1 days). There were no deaths in either group. The trial was supposed to have entered 300 patients, divided into three groups of 100 patients each, testing two different hydroxychloroquine doses versus a placebo, but only 62 patients were included in the final analysis. The placebo group was eliminated, and all the treatment patients received the same hydroxychloroquine dose. Why? It’s a giant red flag when treatment protocols are altered or abandoned in the middle of a study, so it’s hard to know what to make of the results. Although this trial appears to show a modest benefit with hydroxychloroquine, the cohort wasn’t very sick, and the study fails to answer the question we really want to know: Does hydroxychloroquine prevent deaths or the need for a ventilator?

A larger Chinese trial appeared shortly thereafter, this one a multi-center, randomized trial of 150 adult patients hospitalized with COVID-19 infections, half receiving standard care and the other half receiving standard care plus hydroxychloroquine. Endpoints included time to viral clearance, fever resolution, oxygen normalization, and the clearance of clinical symptoms like cough, congestion, and shortness of breath. Chest x-rays and labs were serially monitored. The hydroxychloroquine group saw larger improvements in lab markers for inflammation (CRP protein) and infection (lymphocyte count), but this didn’t translate into more rapid symptom resolution or the prevention of serious outcomes. This is yet another study wherein hydroxychloroquine failed to provide a clinical benefit when administered to a cohort of not-very-sick COVID-19 patients (only 1% had severe illness). There was one area where hydroxychloroquine distinguished itself, and that was in the percentage of patients experiencing side-effects. More than three-times as many patients taking hydroxychloroquine (30% versus 9%) suffered side effects, mostly related to diarrhea. There were no major cardiac events observed in this study but there were in a separate study using chloroquine.

Chloroquine is primarily used to prevent and treat malaria and amoebic dysentery, while hydroxychloroquine, a less toxic metabolite, is generally employed to treat rheumatologic diseases like lupus and rheumatoid arthritis. Both are being tried as antiviral agents against COVID-19. Both have similar side effect profiles, albeit hydroxychloroquine is generally considered safer than chloroquine. Preliminary findings of an ongoing, randomized trial using chloroquine to treat ill COVID-19 patients in Brazil noted an unsafe number of cardiac rhythm events and a markedly higher death rate in patients treated with high-dose chloroquine. The trial is continuing, but only after eliminating patients form the high-dose protocol. These findings highlight the need for caution. The drugs are not benign, particularly when taken with other medications that can affect cardiac conduction (including azithromycin).

An NYU report found potentially dangerous QT prolongations (an EKG pattern predisposing patients to potentially fatal heart rhythm disturbances) in 11% of patients taking the hydroxychloroquine plus azithromycin combination for the treatment of COVID-19.  Meanwhile, Newsweek reported in early April that several hospitals in Sweden have stopped prescribing chloroquine after multiple patients suffered side-effects ranging from cramps to vision loss to heart rhythm disturbances.

Lastly, I want to report on two trials that looked at sicker patients—the ones we most need to help. The first is a French study that looked at 181 COVID-19 patients sick enough to require oxygen on admission, while excluding critically ill patients (i.e. the study looked at sick, but not-yet-dying patients). All were aggressively treated and eligible to receive other experimental drugs (including tocilizumab, lopinavir-ritonavir, and remdesivir). The primary endpoint was transfer to ICU within 7 days and/or death from any cause. The results again found no benefit with hydroxychloroquine (20.2% of the hydroxychloroquine group and 22.1% of the non-hydroxychloroquine group were transferred to the ICU or died within 7 days). The authors’ conclusion: “These results are of major importance and do not support the use of hydroxychloroquine in patients hospitalised for a documented SARS-CoV-2 (COVID-19) pneumonia.”

Finally, we come to the most recent study, the first US report, and the most damning evidence to date against the use of hydroxychloroquine. In this retrospective review of 368 COVID-19 patients admitted to VA hospitals across the country, those treated with hydroxychloroquine or hydroxychloroquine plus azithromycin had more than double the mortality of those not treated with either drug. The story is more complicated than the headline. Because this was a retrospective review and not a prospective, randomized trial, there are problems with drawing vigorous conclusions. Doctors were able to choose which patients received the drugs and which didn’t. It’s no surprise then, that the patients who received hydroxychloroquine were sicker—that’s why they were put on the drug. It’s also no surprise that this group, in turn, suffered a higher mortality. The numbers are as follows: 97 patients treated with hydroxychloroquine, 113 treated with hydroxychloroquine plus azithromycin, and 158 untreated controls, with mortality rates of 27.8%, 22.1%, 11.4%, respectively. The number requiring ICU transfer for ventilatory support was roughly the same in the hydroxychloroquine and untreated groups (13.3% and 14.1%, respectively). The authors acknowledged the differences in baseline illness severity, and computed propensity scores for the treatment groups based on them: “Nevertheless, the increased risk of overall mortality in the hydroxychloroquine-only group persisted after adjusting for the propensity of being treated with the drug” (i.e. irrespective of the severity of illness, mortality was higher in those treated with hydroxychloroquine).

The story isn’t over, and there are still multiple ongoing randomized controlled trials, but, so far, there’s a bunch of negative trials, with only one pseudo-positive result in not-very-ill patients. In those where the drug matters most, the data is all negative. Although hydroxychloroquine may yet prove beneficial when administered to specific subsets of COVID-19 patients, that doesn’t alter the basic tenant that—even in situations of dire circumstance—we still need evidence before proceeding with potentially dangerous treatments. I remain skeptical, but also more than willing to alter my stance should better data come along. I encourage you to do the same. The extraordinary and heroic efforts of so many of my colleagues during this outbreak makes me proud of my profession, but so, too, ashamed of the bullies who would push us into utilizing therapies that might jeopardize patient care in the name of political expediency. Primum non nocere.

Note: On April 24, 2020 the FDA issued the following warning: “The FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine. … We are also aware of increased use of these medicines through outpatient prescriptions. Therefore, we would like to remind health care professionals and patients of the known risks associated with both hydroxychloroquine and chloroquine. We will continue to investigate risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate publicly when we have more information. Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19 (italics added). They are being studied in clinical trials for COVID-19, and we authorized their temporary use during the COVID-19 pandemic for treatment of the virus in hospitalized patients when clinical trials are not available, or participation is not feasible, through an Emergency Use Authorization.”

 

Disclaimer: Due to the rapidly evolving circumstances surrounding the COVID-19 pandemic, much of the information contained in this post was taken from pre-publication, non-peer-reviewed reports (noted below with an asterisk).

References:

1. Na Zhu et al., “A Novel Coronavirus from Patients with Pneumonia in China, 2019,” NEJM 2020; 382: 727-33.
2. NTI/Johns Hopkins Center for Health Security, 2019 GHS Index: Global Health Security Index, https://www.ghsindex.org/wp-content/uploads/2019/10/2019-Global-Health-Security-Index.pdf.
3. *Philippe Gautret et al., “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial,” Internat J Antimicrob Agents– In Press 17 March 2020 – doi: 10.1016/j.ijantimicag.2020.10594.
4. *Philippe Gautret et al., “Clinical and Microbiological Effect of a Combination of Hydroxychloroquine and Azithromycin in 80 COVID-19 Patients with at Least a Six-Day Follow Up: An Observational Study,” https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf.
5. Kevin Roose and Matthew Rosenberg, “Touting Virus Cure, ʻSimple Country Doctorʼ Becomes a Right-Wing Star,’ NY Times, Apr 2, 2020.
6. Jeannie Lenzer and Shannon Brownlee, “Pandemic Science Out of Control,” Issues Sci and Tech; Apr 28, 2020.
7. *Jun Chen et al., “A Pilot Study of Hydroxychloroquine in Treatment of Patients with Common Coronavirus Disease-19 (COVID-19),” J Zhejiang Univ Mar 2020; doi: 10.3785/j.issn.1008-9292.2020.03.03.
8. *Zhaowei Chen et al., “Efficacy of Hydroxychloroquine in Patients with COVID-19: Results of a Randomized Clinical Trial,” MedRxiv; doi: https://doi.org/10.1101/2020.03.22.20040758.
9. *Wei Tang et al., “Hydroxychloroquine in Patients with COVID-19: An Open-Label, Randomized, Controlled Trial,” MedRxiv, doi.org/10.1101/2020.04.10.20060558.
10. *Mayla Gabriela Silva Borba et al., “Chloroquine Diphosphate in Two Different Dosages as Adjunctive Therapy of Hospitalized Patients with Severe Respiratory Syndrome in the Context of Coronavirus (SARS-CoV-2) Infection: Preliminary Safety Results of a Randomized, Double-Blinded, Phase IIb Clinical Trial (CloroCovid-19 Study),” MedRxiv, org/10.1101/2020.04.07.20056424.
11. *Ehud Chorin et al., “The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin,” MEDRxiv, doi:  https://doi.org/10.1101/2020.04.02.20047050.
12. Rosie McCall, “Some Swedish Hospitals Have Stopped Using Chloroquine to Treat COVID-19 after Reports of Severe Side Effects,” Newsweek, Apr 6, 2020.
13. *Matthieu Mahévas et al., “No Evidence of Clinical Efficacy of Hydroxychloroquine in Patients Hospitalised for COVID-19 Infection and Requiring Oxygen: Results of a Study using Routinely Collected Data to Emulate a Target Trial,” MedRxiv, doi: https”//doi.org/10.1101/2020.04.10.20060699.
14. *Joseph Magagnoli et al., “Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with Covid-19,” MedRxiv, Doi: https://doi.org/10.1101/2020.04.16.20065920.
15. Phillip Bump, “The Rise and Fall of Trump’s Obsession with Hydroxychloroquine, Wash Post, Apr 24, 2020.
16. Justin Morgenstern, “Hydroxychloroquine for COVID: No Good Evidence Yet,” First 10EM, Mar 26, 2020.