COVID-19: Making hydroxychloroquine great again

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How a 65-year old drug became the center of partisan divide

One hour and 38 minutes into what started as a roundtable discussion with restaurant executives about the Paycheck Protection Program in mid-May, President Trump dropped the hydroxychloroquine bomb.

“I happen to be taking it,” he slid in at the end of what began as a rant about whistleblowers.

He was referring to the prescription drug hydroxychloroquine sulfate (HCQ), approved in the U.S. for the prevention and treatment of malaria, and to treat lupus and rheumatoid arthritis. At the time of Trump’s declaration, the drug had also been granted emergency use authorization by the FDA for patients hospitalized with COVID-19.

Members of the press exploded with questions. Why was Trump taking this drug? Had he been exposed to the virus? Did the White House doctor tell him to take hydroxychloroquine? Could hydroxychloroquine be used as a preventative medicine?

This was seemingly the response Trump was looking for. “I was just waiting to see your eyes light up when I said this, when I announced this,” he said.

But HCQ had already become a political hot button, far before Trump’s announcement. Results of small scale, early research coming from China and France began picking up speed on social media platforms in early March — when there were fewer than 1,000 reported cases in the U.S. — suggesting that the drug could have potential as a COVID-19 treatment.

In the weeks to come, the virus escalated quickly in the U.S. and businesses and schools around the country began closing as state after state went into lockdown, frantically trying to control the spread. Fox News political talk show host, Laura Ingraham, known for her far-right opinions, took HCQ under her wing and touted the drug to her audience. But things took a partisan turn when Ingraham’s own network hosted global pandemic expert Dr. William Haseltine, who had previously been vocal about the Trump administration’s poor COVID-19 response. Dr. Haseltine cautioned against “quack cures” that emerge during pandemics saying that it was “irresponsible to promote this drug [HCQ] at this time.”

And just like that, HCQ, a 65-year old antimalarial made by a dozen generic drugmakers and costing less than $1 a pill, found itself smack in the middle of a political divide.

Science forged its own response, as hundreds of clinical trials were launched around the world testing the potential of HCQ. But by the time Trump made his mid-May announcement that he was taking the drug, U.S. hospitals were overflowing and cases had surged to 1.4 million, with over 80,000 reported deaths. Americans wanted more than just a drug being tested for its potential. They wanted a game-changer.

At present, data from large, randomized controlled trials — considered the gold standard for ascertaining the efficacy and safety of a treatment by the FDA — does not paint HCQ as an effective COVID-19 treatment. And yet, a few non-randomized studies, anecdotal evidence from a handful of doctors claiming HCQ works and even a couple of viral conspiracy videos, have managed to kept the flames of the HCQ debate burning.

Part of the confusion can be attributed to the public’s lack of insight into how and why clinical trials are designed and how to interpret data from these trials. But even as the scientific community continues to struggle to provide clarity, it’s becoming increasingly difficult to hear the voice of science over the political screaming match.

The politicizing of HCQ — just one of many issues caught up in what has become a pandemic divided on party lines — will no doubt prove to be a cautionary tale of how quickly bias can muddy the waters of scientific progress.

The drug(s)

During WWII, the use of antimalarials by soldiers was widespread. Through this use, it was discovered that these drugs could be used to treat inflammatory arthritis and lupus. It is this combination of antiviral effects and inflammation reduction that made HCQ and chloroquine (CQ) possible candidates for COVID-19 treatment.

Antimalarials HCQ and CQ are both derived from the quinoline molecule. Both drugs have similar clinical indications and side effects. Chloroquine was developed first, however one form of the parasites that cause malaria developed widespread resistance to the drug. HCQ, developed by chemists Alexander R. Surrey and Henry F. Hammer in 1950, was demonstrated to be as effective and much less toxic than CQ, and subsequently many manufacturers shifted production to HCQ.

Chloroquine phosphate was approved by the U.S. FDA in 1949 for the treatment of extraintestinal parasites (parasites that cause liver infection) and the treatment/prevention of malaria, under the brand name Aralen. The brand is now owned by Sanofi Aventis but was discontinued in the U.S. Several generic approvals were also granted.

Hydroxychloroquine sulfate was approved by the U.S. FDA in 1955 for the prevention and treatment of malaria, as well rheumatoid arthritis and lupus, under the brand name Plaquenil. The brand name is owned by Canadian-based Concordia Pharmaceuticals. Over a dozen generics have since been approved and are available from drugmakers such as Lupin, Hikma Pharma, Mylan, Sandoz, Teva, and Amneal Pharma.

While HCQ is a less toxic metabolite of CQ, both drugs have known potential side effects such as neuromuscular reactions, including worsening of seizures; cardiomyopathy (heart muscle/rhythm problems); and retinopathy that can lead to irreversible vision problems. But in terms of the drugs’ approved uses, much clinical research has resulted in precise screening protocols and safe dosing guidelines.

The unraveling

On June 15, the FDA revoked the prior emergency use authorization (EUA) it had granted on March 28 allowing hospitals to use HCQ and CQ to treat COVID-19 in certain patients when clinical trial data was unavailable or participation was not feasible. This also meant that the Strategic National Stockpile would no longer distribute doses of HCQ and CQ to hospitalized COVID-19 patients.

But a lot had happened during those 79 days, and not all of it was related to scientific progress.

The EUA revocation was issued at the request of the Biomedical Advanced Research and Development Authority (BARDA), which had also asked the FDA to issue the EUA in March. BARDA had made the request under the leadership of leading vaccine development expert, Rick Bright. In late April, Bright was dismissed from his position at BARDA, and days later told the press that he was pressured to direct money toward HCQ, one of several of what he cited as “potentially dangerous drugs promoted by those with political connections.”

Bright went on to file a whistleblower complaint with the U.S. Office of Special Counsel.

The Department of Health and Human Services (HHS) retaliated in statements emailed to press, alleging, “Mr. Bright has not yet shown up for work, but continues to collect his $285,010 salary, while using his taxpayer-funded medical leave to work with partisan attorneys who are politicizing the response to COVID-19.” Trump, via tweet, claimed he didn’t know who Bright was.

Also within this time period, the Lancet medical journal published and then retracted a study that found HCQ and CQ not only ineffective COVID-19 treatments, but noted the chance of increased mortality from heart-related issues.

The same day the FDA announced it had revoked the EUA, the topic was broached by the media during a White House roundtable. HHS Secretary Alex Azar jumped in, justifying the poor clinical HCQ data (presumably referencing a study done at the U.S. Veterans Health Administration medical centers)  by saying the treatment was given to hospitalized patients who were “quite ill.”

“People that were, like, seriously ill. Like, they weren’t going to make it,” Trump clarified.

(The VA study was a retrospective analysis of data from 368 VA patients with SARS-CoV-2. The patients in all arms of the study were around age 70, more than half were black, and all had a BMI around 30 kg/m2, meaning they were clinically overweight.)

Azar went on to paint the FDA’s removal of the EUA as a helpful clarification to the misunderstanding that HCQ can only be used in hospital settings.

“It’s a drug. It’s approved in the United States. Has been for decades. If a doctor wishes to prescribe it, working with a patient, they may prescribe it for any purpose that they wish to do so. And this actually removes a potential barrier to that,” explained Azar.

Azar’s statement made an important point — one that clarifies some of the public misinformation swirling about HCQ use: Revoking an EUA has no impact on clinical trials, and the FDA can’t stop physicians from prescribing an approved drug for off-label uses, including COVID-19. The FDA’s action on June 15 did not ban HCQ use in our country.

But when an agency that has been protecting the public health for close to a century by ensuring the safety and efficacy of drugs states that it is “no longer reasonable to believe that oral formulations of HCQ and CQ may be effective in treating COVID-19, nor is it reasonable to believe that the known and potential benefits of these products outweigh their known and potential risks,” generally, the medical community takes that advice into consideration.

Many did, and began closely reviewing their own HCQ trial data. The National Institutes of Health halted its blinded, placebo-controlled randomized clinical trial of HCQ after its data and safety monitoring board concluded that the drug does no harm, but was very unlikely to be beneficial to hospitalized patients with COVID-19.

Novartis discontinued its own randomized, placebo-controlled phase III trial of HCQ, claiming no safety issues but also saying that it was unlikely that the trial, due to enrollment issues, would be able to collect meaningful data on the drug’s efficacy.

On a recommendation from the Solidarity Trial’s International Steering Committee, the World Health Organization (WHO) — facing its own political fire — discontinued the trial’s HCQ arm. Interim trial results showed that HCQ produced little or no reduction in the mortality of hospitalized COVID-19 patients when compared to standard of care.

But still, support for CQ and HCQ persisted. Around the same time (early July), the Henry Ford Health System published results from a large, multi-center retrospective observational study. The study concluded that, among hospitalized patients, use of HCQ alone and in combination with azithromycin was associated with a significant reduction in in-hospital mortality compared to not receiving HCQ.

To the study’s credit, the limitations were clearly stated in the results: “The study results should be interpreted with some caution, should not be applied to patients treated outside of hospital settings and require further confirmation in prospective, randomized controlled trials that rigorously evaluate the safety and efficacy of hydroxychloroquine therapy for COVID-19.”

Yet, that did not dissuade celebration of the results on social media outlets. On July 7, Trump challenged the FDA to act, tweeting, “The highly respected Henry Ford Health System just reported, based on a large sampling, that HYDROXYCHLOROQUINE cut the death rate in certain sick patients very significantly. The Dems disparaged it for political reasons (me!). Disgraceful. Act now @US_FDA.”

Researchers not involved in the study were quick to point out its science-based flaws. The study was not randomized, and thus not without bias. They also pointed out a significant factor that may have skewed results: Steroid use in patients receiving HCQ (adjunct therapy with the corticosteroids methylprednisolone and/or prednisone) was more than double the non-treated group.

Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, was among those who publicly acknowledged the study’s flaws. In his July 31 testimony before the U.S. House Select Subcommittee on the Coronavirus Crisis, Fauci stated:

“The Henry Ford Hospital study that was published was a non-controlled retrospective cohort study that was confounded by a number of issues, including the fact that many people who were receiving hydroxychloroquine were also using corticosteroids, which we know from another study gives a clear benefit in reducing deaths with advanced disease.”

Not all studies are created equal

When it comes to clinical studies, especially those evaluating controversial drugs, efforts to eliminate bias are crucial. Both the pharma industry and the larger scientific community have attempted to clarify this throughout the HCQ debate.

Novartis’ Sandoz division, which had previously donated 30 million doses of HCQ tablets to the U.S. government for use in controlled clinical studies, announced in June that it had discontinued its own sponsored HCQ clinical trial for COVID-19, due to “acute enrollment challenges.”

Immediately after this decision, Novartis CEO Vas Narasimhan, in an interview with Wired magazine, was asked what he felt the drugmaker’s responsibility was in clarifying that HCQ is not the miracle cure people had hoped it would be.

“Right now, unfortunately, the words ‘study, results, scientific evidence’ in the media are not actually reflecting what scientists know is high-quality evidence,” Narasimhan told Wired.

“There are studies that are very poor quality, or conjecture. And then we have appropriately powered randomized control blinded clinical studies, which is what regulators expect of us, and that is the only way to really know if a drug has an impact or not,” Narasimhan said.

Randomizing studies puts patients into groups by chance, eliminating the possibility, for example, that healthier patients are grouped together, skewing the results of the study. Blinding the study takes it a step further, eliminating insight into which patients are in the control group and which are in intervention group.

The HCQ studies that have become the cornerstone of the HCQ support movement, such as the Henry Ford Health System study and Dr. Didier Raoult’s Marseille study, were not randomized or blinded.

There have been issues with reliable study data on both sides of the HCQ debate, which has merely added to the confusion and skepticism surrounding HCQ. On May 22, the Lancet medical journal published a multinational, observational, real-world study (purportedly data from 96,000 patients from 671 hospitals on six continent) of patients with COVID-19 requiring hospitalization. The non-randomized study not only found that a regimen containing HCQ or CQ offered no evidence of benefit, it also noted an increase in the risk of heart arrhythmias and a greater risk of in-hospital death.

But after the study was published, several critics raised concerns about the data that had been collected and analyzed by Surgisphere, a small, little-known U.S. health care analytics company. The Lancet launched an independent third-party peer review of the company to evaluate the origination of the database elements, but Surgisphere, citing client confidentiality issues, would not transfer the full dataset to the Lancet reviewers. Unable to vouch for the veracity of the primary data sources, the Lancet retracted the paper on June 4, at the request of three out of the four study authors.

For some, this incident further hammered home the fact that controlled, randomized trials are necessary to draw reliable conclusions. Yet for others, it cast doubt over the integrity of all HCQ studies, especially those that did not reflect favorably on the drug’s potential in COVID-19 treatment.

(There may never be a) conclusion

“What do you have to lose?” This question was first asked rhetorically by President Trump during a press briefing in early April, but has since become the oft-repeated rallying cry for HCQ use in COVID-19 treatment.

But for those who already thought HCQ was great (for example, the hundreds of thousands of people diagnosed with lupus in the U.S., many of which rely on HCQ, the only drug shown to prevent progression to serious end-organ damage), there is a lot to lose. The FDA reported HCQ shortages from 11 different manufactures from late March through the end of June.

Beyond the struggle of those trying to fill routine prescriptions, there are far-reaching consequences of the HCQ political debacle when it comes to public trust for other COVID-19 related advancements — such as vaccines. If science seemingly changed its mind about HCQ, will the same scenario play out with vaccines?

While science has proven itself to be self-correcting over time, many Americans have proven themselves to be impatient when facing the restrictions of a public health emergency. Even as science does everything in its power to quicken the pace of progress, political rhetoric and chronic misinformation continue to create more barriers than solutions, and nothing illustrates this better than the never-ending saga of HCQ.

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