On Tuesday, April 14, the Arlington, Va.-based Infectious Diseases Society of America (IDSA) held a telephonic press briefing, in which infectious diseases specialists spoke about the society’s release on April 11 of treatment guidelines for COVID-19, even as the public discourse around treatment for the disease remains comingled with political developments.
Dana Wollins, DrPH, vice president, clinical affairs and practice guidelines, at IDSA, introduced Rajesh T. Gandhi, M.D., FIDSA, and Adarsh Bhimraj, M.D., FIDSA. Dr. Gandhi is a professor of medicine at Harvard Medical School and director of HIV clinical services and education at Massachusetts General Hospital in Boston; he is chair-elect of the HIV Medicine Association and an IDSA member. Dr. Bhimraj is an associate staff physician in the Department of Infectious Diseases at Cleveland Clinic, a member of IDSA, and chair of the IDSA COVID-19 Rapid Guidelines Expert Panel.
It was that panel that on April 11 released COVID-19 treatment guidelines, which included the following:
> Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine in the context of a clinical trial.
> Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine plus azithromycin only in the context of a clinical trial.
> Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial.
> Among patients who have been admitted to the hospital with COVID-19 pneumonia, the IDSA guideline panel suggests against the use of corticosteroids.
> Among patients who have been admitted to the hospital with ARDS due to COVID-19, the IDSA guideline panel recommends the use of corticosteroids in the context of a clinical trial.
> Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends tocilizumab only in the context of a clinical trial.
> Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial.
As the association describes itself on its website, IDSA is “is a community of over 12,000 physicians, scientists and public health experts who specialize in infectious diseases. Our mission is to improve the health of individuals, communities, and society by promoting excellence in patient care, education, research, public health, and prevention relating to infectious diseases.” IDSA has been outspoken on COVID-19-related issues, urging a “continued commitment to data-driven responses to the coronavirus,” supporting the opening of access to convalescent plasma use, and urging that the federal recommendation on sheltering remain in place for the time being.
All of this is very complex, the infectious diseases specialists agreed, because of the context of the panel’s recommendations. The fact that President Trump and some others have been promoting the prescribing and administering of hydroxychloroquine, in the absence of any established clinical evidence for it, has created an unprecedented situation. The panel made the decision to recommend its use only in the context of a clinical trial. Clinical trials are ongoing right now for hydroxychloroquine use, both with and without azithromycin, but it could be several months before any conclusive evidence becomes available.
Dr. Gandhi spoke first. Referring to the treatment guidelines published last week, he said, “My main message here is that clinical trials are critical now: we really need the data and the evidence” before definitive recommendations can be made around clinical practice. “We looked at two main dimensions,” he said; “one is the type of intervention, and the other is the severity of disease.” And, he said, it’s important to consider the distinction between treatments for the virus itself, and treatments to boost the immune system
“One problem,” Gandhi said, “is that the history of medicine is littered with things that looked good in animal studies and test tubes. We looked at hydroxychloroquine, with or without azithromycin, as well as HIV medications, and Remdesivir. What we concluded is that the evidence to date is insufficient to recommend any particular medication. So where do we go from here? What we really need now is clinical trials and clinical studies; this is really the call to arms now. We need to know more in a month from now than now, and in three months from now, from one month from now. We really need to be guided by the science. There are now more than 100 clinical trials taking place in the U.S., and many others around the world. And we’ll know more in two weeks.”
And, he added, “Some of us in the infectious diseases field see this as similar to the early days of the HIV crisis; we didn’t know what worked, we didn’t have data. And it was really the courage and determination of the patients and clinicians involved. Now, we have more than 30 drugs used for HIV. That’s where we’ll get with COVID-19.”
“I am a practicing infectious disease specialist; I see patients every day,” Dr. Bhimraj said. “And a couple of weeks ago, in the hospital, it was overwhelming. And taking care of the patients, and staying abreast of developments, seemed like an impossible task. And all kinds of data, some of which seemed reliable and some not, seemed insurmountable. That’s when I reached out to IDSA and asked that we get evidence-based guidelines.”
Importantly, Bhimraj said, “The IDSA put together a panel of clinical specialists and specialists with expertise in critically looking at evidence. And these recommendations, as Dr. Gandhi said, took into consideration: do these medications prevent death? Do they improve the condition of patients? These are living guidelines. So in the last couple of weeks, some patients have died and some have gotten better and gone home. Some patients got better, but some had adverse reactions.”
And, he said, “As a clinician, I think that the medications I’m prescribing are responsible for outcomes. But we lack evidence. We need trials, with some patients getting the medications and some in a control group, to determine outcomes. And patients are suffering and dying, and that makes me feel hopeless and helpless. And so in this case, prescribing a medication that could potentially be useful, makes me feel better. But based on all the evidence we’re seeing, we couldn’t actually prove efficacy. So we do need to think about clinical trials,” in order to amass a critical body of evidence on efficacy.
As the clinical trials around hydroxychloroquine move forward, Bhimraj said that clinicians can “set up a registry in your hospital to see outcomes.” Meanwhile, he said, “What we do in the COVID-19 pandemic has implications for the next pandemic and the pandemic after that. And I’m hoping in the next couple of weeks, I’m hoping that we’ll see some evidence.”
In response to the first question from the press, around why the Rapid Guidelines Expert Panel had added the qualifier “only in the context of a clinical trial,” to its recommendation on the use o hydroxychloroquine or hydrochloroquine, with or without azithromycin, Bhimraj said, “I do acknowledge that it could be a little bit confusing. We thought that hydroxychloroquine and azithromycin could cause complications. And this medication is expensive and is used for other indications, and also can produce side effects. Thus, ‘only.’ So we need clinical trials” in order to determine the true efficacy of prescribing any of these medications to COVID-19 patients.
Asked the extent to which an overactive inflammatory response might be playing in different patients’ experiences, Gandhi said, “That’s a very good question. In many infectious diseases, the immune system is part and parcel of overcoming the disease, and that’s true of COVID-19, too. But we have seen inflammation in some patients, which is a signal of an overactive immune system. Are there some medications to handle that? Sarilumab and other anti-inflammatories are being tested at Mass General and around the country right now, in this context. We need to get that balance just right. Whom should you give it to, and when? That’s what we need to answer.
Another member of the press asked this: Is there any evidence or suspicion that COVID-19 might form a reservoir that would complicate treatment in the future—find cells to hide out in?
“HIV can be controlled by medicine, but because the virus itself gets into the body’s genetic material, it forms a reservoir, which is why when medications are stopped, it pops out again, which is why treatments are lifelong,” Gandhi noted. “We don’t think that COVID-19 creates a reservoir, hides in cells. We don’t see evidence of a reservoir. Most people recover from it fully and don’t seem to be harboring the virus long-term. Exactly how long the virus lingers in a person may be weeks or longer; the infectious virus may not last as long. But I don’t think we’ll find a long reservoir like HIV.”
And what about the question of whether there will be seasonality to the presence and spread of COVID-19? “Per seasonality, many respiratory viruses do show seasonality; I think this is an area still being sorted out,” Gandhi said. “In the Southern Hemisphere, it’s their summer, and we still see COVID-19. So we don’t yet see the answer. We need to hope for the best, but prepare for the worst. And if we can practice preventive measures we know work—social distancing, handwashing, we can make progress.
Asked what practices will change in healthcare going forward, Bhimraj said, “The reality is that I think COVID-19 has changed all of our lives—not just in healthcare, but in society. Maybe handshaking will no longer be a regular practice in healthcare. And when do we start elective procedures? There are questions about screening” for patients potentially undergoing elective procedures, “and everything. We have an amazing panel of infection preventionists and infectious disease clinicians who will have answers to those questions.”
Asked about how far along the 100-plus clinical trials are right now, Gandhi said that “One drug fairly far along is Remdesivir. We may have some information from the Remdesivir studies maybe as early as later this month, or in early May. Those trials are going on here in the US but also in other parts of the world. For hydroxy, many trials have been launched. I do think we will be able to enroll those trials very quickly, because we have so many patients. So the hydroxy studies have been launched and are at different stages of progress. With some trials focused on prevention of COVID-19, you need more people, in some cases, thousands; the ones involving patients with the active infection, you just need hundreds.”
What about the fact that this country is dealing with an unprecedented situation, given that hydroxychloroquine was thrust into the highly political discourse around the pandemic before it could be clinically evaluated? The physicians were asked whether they would comment on that unusual situation. “I totally agree with you” that the political discourse has upended the clinical discussion around hydroxychloroquine, Gandhi told a reporter. “I just want to put myself into the shoes of a patient or loved one or doctor. As I said earlier, it’s frustrating not to do anything when people are suffering. And hydroxy is already available, and a lot of patients are asking for it. And given the pandemic and the fears, that concern is valid. But if you objectively look at the evidence, as we did on the panel—we said, let’s look at the data first. We asked, does the suffering of the patient improve? What about mortality? Do the medications cause harm? And we all individually concluded that at this point in time, we can’t answer the question of whether the benefits outweigh the harm. So we could not recommend routine care for this medication.”
And, Gandhi said, “We can compare this situation to that of the early days of treating HIV. There were drugs that were being tried then that we now know that turned out to be harmful, not beneficial; and it was only because of the coming together of patients and clinicians that we found out” that they were harmful. “With hydroxychloroquine, we don’t really know. So we endorse the idea of doing a careful comparison. Because COVID-19 involves the immune system, we need to do comparisons to know whether the drug works and whether it has a good risk profile and doesn’t cause side effects.”
And, said, Bhimraj, “A lot of studies will show that you can eliminate a virus, but it’s hard to tease out whether it impacts the immune systems of patients. So we need studies to look at it critically. So as guideline panelists and methodologists, we’re looking at new studies every day, and we’ll be updating the guidelines regularly.”
Asked whether some patients who have been treated with hydroxychloroquine have died, Bhimraj said, “Some of the patients who received these medications got better, some died; and some who didn’t receive the medications, got better. So we need to systemically answer the question, does hydroxychloroquine significantly improve outcomes? Right now, we just have anecdotal experience. So we need data to drive decision-making.”
How often will these guidelines be updated? “We’ll need to update the guidelines on a regular basis,” Bhimraj said. “We’re looking at studies almost every day. And on the panel, we’re asking ourselves, is there significant evidence that will change the recommendations? Whenever that happens, we’ll be doing that.” He said that, not only will the treatment guidelines be updated by the IDSA as warranted, but two other guidelines will be developed, one on diagnostic testing, and the other on infection prevention and the use of personal protective equipment.