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If you watch the news on television during the age of Covid-19, you’ll see a kind of story often featured on the legacy networks and cable stations. Heartwarming and filling you with hope, these stories are about a survivor—someone who was in an intensive care unit, on a ventilator, and not expected to live for much longer. Then, a plucky spouse fights to get his or her partner access to an experimental treatment, and, once it is administered, the near-dead rises up like Lazarus. Except most of these stirring tales are tall ones, not true in the causal sense. That is, while our valiant couple may vanquish their SARS-CoV2 infection together, their stories do not provide evidence that the new drug was behind these stunning clinical reversals of fortune. With many diseases, people often just get better—with or without an experimental treatment. That is why we do randomized clinical trials: to keep from fooling ourselves.
Over the past few months, we’ve seen this cycle of hope and disappointment play out with several drugs. The most famous couple was hydroxychloroquine and chloroquine, which were touted by President Donald Trump and even led his China trade adviser Peter Navarro to scold our nation’s leading infectious disease researcher, Dr. Anthony Fauci, for not being sufficiently credulous about the “evidence” that was out there. I’ve seen these boom-and-bust cycles before—in the 1980s and early 1990s during the age of HIV/AIDS, when, for over a decade, we grasped in desperation for the latest cure. In the mid-1990s, we developed drugs that finally brought that virus under control, making AIDS a chronic, manageable illness for those who had access to these medications.
There are four classes of treatments currently under study for use against SARS-CoV2 and Covid-19: antiviral medicines, which are meant to attack SARS-CoV2 itself; the two quinolines, hydroxychloroquine and chloroquine, which, although used for malaria and lupus, have been tested for indirect antiviral activity as well; immunomodulatory therapies, often antibodies targeted at disease-fighting molecules in our own body (these can end up doing more harm than good in what are known as “cytokine storms,” where our immune systems in overdrive starts devouring us); and convalescent plasma, blood products from survivors of Covid-19, which are thought to be enriched in antibodies that can target the virus through passive transfer to another patient with the same blood type. All of these have been in the news.
I talked to a few of my colleagues who worked with HIV/AIDS about the landscape of treatments for Covid-19: Dr. Rochelle Walensky, chief of infectious diseases at Massachusetts General Hospital; Dr. Robert “Chip” Schooley, a professor of infectious diseases and global health at University of California at San Diego; Dr. Carlos Del Rio, a professor of infectious diseases and global health at Emory; and James Krellenstein, an AIDS activist with the group PreP4All in New York City. Each of them is now working on Covid-19 and following the research closely. Some are treating Covid-19 patients themselves. All of them agree: None of these therapies have yet been shown to be effective as treatments for SARS-CoV2 or the disease it causes. We have to wait to see what happens in the clinical trials. Data from those should be forthcoming in the next few weeks or months.
Meanwhile, many of these therapies are being used around the country off-label or as part of expanded access programs, in which drug companies offer their experimental treatments to patients with no other options. However, the impact of these agents on individual patients doesn’t signal a breakthrough on Covid-19; nor do the results from small, poorly designed studies or preliminary results from clinical studies underway.
Just this week though, the prospects for the quinolines took a hit. Without evidence for benefit from clinical trials, a panel at the National Institutes of Health issued recommendations against the use of hydroxychloroquine in combination with the antibiotic azithromycin because of toxicities associated with this two-drug cocktail. In particular, these two drugs in combination can cause a type of irregular heartbeat that can lead to cardiac arrest. This same panel also warned against the use of a class of immunomodulatory molecules, called interferons, outside of the context of clinical trials as well, as they have their own toxicities and haven’t been shown to be effective against SARS-COV2’s cousins, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
So where does that leave us? First, we have to wait. Acting without evidence has consequences. Untested medicines are not uniformly helpful and can, in fact, present dangers to those who try them even as a last resort. We’ve seen this throughout the history of medical research, where a new drug can shorten life, or make a disease worse. In what is known as the therapeutic misconception, we wrongly assume if it’s being studied in a clinical trial, it must be beneficial to us.
If you have Covid-19, what do you have to lose? Without evidence of clinical benefit from well-designed randomized clinical trials, the life you lose could be your own. We’ve also got to beware of policy vultures, who never let a crisis go to waste. These are groups, like the Goldwater Institute and others, who see this moment as just another reason to suggest that the FDA is standing in the way of access to new treatments and demand rollback of more regulations that protect us from unsafe and ineffective drugs. Lastly, we have to keep an eye on the state of medical research and drug development.
We’ve seen a crisis in leadership throughout the SARS-CoV2 pandemic. It’s absolutely crucial to advocate a coordinated, fast-tracked effort bringing together all our nation’s research agencies, academic centers, and drug companies to move us more expeditiously to the goal of an effective treatment for Covid-19. James Krellenstein, from PreP4All, which is issuing a report shortly on the state of anti–SARS-CoV2 research, warned me this week that what they’re seeing is a lack of leadership of this critical national project.
The problems that PreP4All are documenting run from basic tasks like coordinating high-throughput screening of candidate molecules active against SARS-CoV2 among all the compound libraries in the United States, in private hands or run by the US government, to the management of clinical trials to ensure we have adequately powered, well-designed studies targeting treatments based on the best scientific evidence and preliminary data. Susan Ellenberg, a professor of biostatistics at the University of Pennsylvania underscored this last point to me in a recent email: “Many sites, especially those with large numbers of patients, are doing their own trials. But we will get answers faster if people collaborate…. As some treatments show evidence of benefit we will be moving to studies of drug combinations and these trials will require larger sample sizes, meaning in most cases multicenter trials.”
That’s what’s needed. Instead. as this article goes to press there are over 100 studies of hydroxychloroquine underway, listed in the federal clinical trials registry, based on hype, hope, and desperation.