In April, the National Institutes of Health (NIH) announced treatment guidelines for COVID-19, developed by a panel of U.S. physicians, statisticians, and other experts to inform clinicians on how to care for patients. The guidelines are based on a combination of published and preliminary data on COVID-19, along with the panelists’ clinical expertise. Updates to the guidelines are posted as new data are published in peer-reviewed scientific literature, and as other authoritative information emerges. The guidelines can be found at covid19treatmentguidelines.nih.gov.
Many well-known HIV and hepatitis C medical providers and scientists sit on the COVID-19 Treatment Guidelines Panel. Terri Wilder spoke with panel member Arthur Kim, M.D., the director of the Viral Hepatitis Clinic within the Division of Infectious Diseases at Massachusetts General Hospital, to learn more about the treatment guidelines. (Please note that Kim is not speaking on behalf of the panel during this interview.)
Kim’s research focuses on special populations with hepatitis C, including those with HIV and hepatitis C coinfection and people who inject drugs. He recently completed a three-year term as co-chair of the AASLD/IDSA Guidance Panel for Recommendations for Testing, Managing, and Treating Hepatitis C.
Since the start of the pandemic, Kim has been leading institutional guidance for treatment of COVID-19 at Massachusetts General Hospital and is coauthor of the UpToDate chapter regarding the care of hospitalized patients with COVID-19, in addition to his duties as a member of the NIH COVID-19 panel.
Kim earned his medical degree from Harvard Medical School. After his internship and residency at Massachusetts General Hospital and fellowship in Infectious Diseases at Massachusetts General Hospital and Harvard Medical School, he joined the faculty at Harvard, where he’s currently associate professor of Medicine.
Learning on the Job: The Early Months of Treating COVID-19 in the Northeast U.S.
Terri Wilder: Dr. Kim, thanks so much for speaking with me today. Before we discuss the treatment guidelines, can you tell me about your experience taking care of people with COVID-19 in your practice?
Arthur Kim: Thank you for the opportunity to speak with you. In March and April, in Boston, we were one of the first hotspots in the country, due particularly to an outbreak related to a Biogen conference just a short distance from Mass General. We began to see primary and secondary cases from that outbreak appear in our emergency room. There was rapid deployment of our surge response teams.
As part of this, our infectious disease [ID] division rapidly put together many task forces that dealt with various issues, including infection control and testing. There are many people who invested long hours in those arenas.
I was tasked with treatment guidance and collecting experiences from Seattle, China, Italy, and other places, and trying to put together institutional guidance. Around then is when we began to receive our first consults to see if there were therapeutics for the care of patients. Thus, we collectively saw over 1,500 patients at our institution who were hospitalized with COVID-19.
While I didn’t see all of them by any means, we, together, took care of these patients and worked, not only within ID, but across disciplines to try to standardize care across the institution.
Since the surge ended, we continue to see and discuss cases on a regular basis. We’ve just learned so much about this disease, and throughout the process.
Wilder: What would you say are some important clinical best practices you’ve learned while taking care of people with COVID-19?
Kim: Well, I think the first thing that we learned, somewhat the hard way, is that sometimes it’s best to await evidence, rather than deploy certain interventions before there is good evidence, for a number of reasons. It’s very tempting to think that we should use things early on that were available and on our shelves, such as hydroxychloroquine and tocilizumab. Really, I think we learned that the best approach is probably a more careful one, where we evaluate the state of the data and, if the data aren’t good enough, question whether we should be using a lot of off-label items.
At many institutions around the world, but particularly in Boston and New York, we used a lot of hydroxychloroquine, for instance, off label. There was no way to tell whether it was working since we were not part of any trials. So, once we had those randomized trials, we very much learned that some interventions don’t work.
Perhaps the temptation to do something ruled back then. I think that we learned that probably we should be more circumspect.
Another main message from an infectious disease standpoint is that it really does help to talk with patients and get their stories. I think we pride ourselves in ID for getting the best histories, and detailed histories. I still think there’s a lot to learn, even if you know what the primary disease processes are, and to learn more about who the patients are and what their contexts and risks can be. One instance is being concerned about certain endemic infections that can reactivate—such as Strongyloides or hepatitis B—during illness, and particularly if steroids are used.
So, those are two pearls. The third pearl I would add is just that it is still useful to do physical exams. Early on, due to shortages of PPE, we were not going in rooms nearly as often as we did later in the surge where, after becoming more comfortable, we would go in and examine patients. There were definitely discoveries made from examining patients. So, the usual principle of being thorough does apply.
Inside the COVID-19 Treatment Guidelines: An HIV Clinician’s Perspective
Wilder: The NIH treatment guidelines panel had many, many recognizable HIV and hep C experts on it, including yourself. Why do you think so many HIV and hep C experts were invited to participate in the panel?
Kim: I can’t speak exactly to the process, but I do know that there’s great overlap between this panel and the antiretroviral guidelines panel. While the treatment of HIV is ultimately different in many ways, I think there’s a comfort level, from the NIH standpoint, of working with many of the same individuals, perhaps. But I can’t really speak to the exact reasons.
Wilder: The guidelines are very comprehensive. The chapters range from testing, to critical care, to antiviral therapy, to special populations. Can you talk about some of the key recommendations that are reviewed in the antiviral therapy section?
Kim: The antiviral section is, like most of the rest of the guidance, based on the principle of: What would you do with the patient in front of you now, based on the best evidence that’s available? I think overall the guidance panel seems to take that into consideration. The antiviral guidance—again, I’m not speaking for the panel per say, but just as an end user—tries to go over the medications that were deployed early on, such as hydroxychloroquine, azithromycin, and lopinavir/ritonavir.
There’s very much detailed information on remdesivir, which is one of the medications that has been most well studied and shows benefits in certain populations of patients, but not all populations of patients.
When one looks at this guidance as an end user, one can hopefully find your patient, whether you have mild, moderate, severe, or critical disease with COVID, and find information as to whether or not one should use remdesivir or dexamethasone, and then more detailed synopses of the studies. So, if you don’t have time to read the papers in detail, you can find information on the website. I think as an end user myself, I find it useful in its organization.
Wilder: Recent updates to the guidelines include new information about chloroquine and hydroxychloroquine—which were a big topic during the first few months of our response to COVID-19—and convalescent plasma, which has been in the news recently. Where are we with those approaches right now?
Kim: For the chloroquine and hydroxychloroquine question, the treatment guidance panel currently recommends against its use in hospitalized patients, and against its use in non-hospitalized patients, except in a clinical trial. I would personally agree with those recommendations. That takes into account the large body of data, but also large well-controlled randomized trials, which really are the best evidence for an intervention’s efficacy.
The convalescent plasma update also seems to be timely, given the FDA’s issuance of an emergency use authorization [on Aug. 23]. The statement appears to clarify and emphasize many elements of the FDA announcement and the current status of the data.
Wilder: What is convalescent plasma, and what does it actually help with?
Kim: Convalescent plasma is based on the principle that one can give what we call passive immunity to patients. Active immunity would be like a vaccine, where we stimulate immunity to help protect against the virus, whereas passive immunity, one can give immunity that was either generated elsewhere—in this case, in other people—or produced, like a monoclonal antibody. This approach has been tried in other pandemics, dating back to the 1918 pandemic, and also for bacterial illnesses before we had antibiotics, such as diphtheria and pneumonia.
Passive immunity has also been used for things such as rabies, hepatitis B, [and] CMV [cytomegalovirus]. Convalescent plasma will include immunity from people who have recovered from COVID-19, in hopes that applying it to patients who have active COVID-19 may [help them] recover faster, or there may be other benefits. So, convalescent plasma is also something that may be available in places where there are large numbers of people who have recovered before we have other interventions available.
Wilder: There’s a section about special populations in the guidelines. What from that section do you personally think might be important for clinicians to be aware of?
Kim: The special populations section basically goes over populations that may not be included in clinical trials, such as pregnant women. Then there are patients such as cancer patients undergoing chemotherapy and patients who have undergone solid organ transplantation or stem cell transplant, who are at high risk.
The pregnancy section does refer to and acknowledge the incredible work of other organizations, such as the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine, who also have very detailed and thoughtful recommendations for their population. I do think having this all in one place can help end users have summary recommendations, as well as links to more detailed and comprehensive guidance. Looking at it again, hopefully the end user will find these sections helpful.
Wilder: There’s also a section about intravenous immunoglobulin [IVIG] in the guidelines, and it states that there was insufficient data about immunoglobulins for treatment. Could you talk more about IVIG—what is its purpose, and with further exploring, whether it could be a possibility to help people with COVID-19?
Kim: IVIG by itself is likely to not contain anything that’s specific against the virus. Thus, the use of IVIG initially was likely for other benefits that are not specific against the virus. We know that it was deployed quite a bit in China, early on. There are some nonrandomized studies that have looked at that.
At this point, to my knowledge, there remains no definitive evidence that supports IVIG. But if there is a clinical trial, then that would be a possible approach.
Wilder: Why did researchers in China try IVIG?
Kim: Like for many of us, it was something that was available. When one looks at—not all—the papers in China, there are many series where you see that people received a variety of medications, including flu medications such as oseltamivir, known as Tamiflu here, or lopinavir/ritonavir, a well-known antiretroviral, and steroids. This was just one element that also had a theoretic rationale and thus was deployed. But, again, by the time many centers in China were able to have clinical trials in this arena, the number of cases began to decline. That phenomenon also happened in places like Boston and New York, where we were successful in enrolling some patients into trials. We definitely have more trials open now and fewer patients to enroll into them.
Wilder: Then, just to clarify, what is IVIG typically used for, and what does it do for the body?
Kim: IVIG is used in at least two fashions. One is for the modulation of certain immune diseases, such as immune-mediated thrombocytopenia. It’s also used for replenishment in patients who are deficient in their immunoglobulins.
I would note that IVIG is used for the treatment of Kawasaki disease and in COVID-19. There’s this entity called multiorgan inflammatory syndrome that is predominantly in children. IVIG has definitely been used in those patients.
PrEP for COVID-19?
Wilder: Obviously, the whole world is very focused on COVID-19. That, of course, includes HIV treatment activists. There have been lots of conversations around a PEP [post-exposure prophylaxis] or PrEP [pre-exposure prophylaxis] for COVID-19. The treatment guidelines for COVID-19 recommend against the use of any agents for pre-exposure prophylaxis, as well as recommends against the use of post-exposure prophylaxis, except in clinical trials. As we’re all in this desperate state of trying to prevent COVID-19, I’m wondering if you have any thoughts about PEP and PrEP, and whether that is something we may need to look at going forward with COVID-19?
Kim: At this time, we don’t have any agent or approach that is proven for either pre-exposure prophylaxis or post-exposure prophylaxis. I think there would be great interest in that.
One of the tensions is, if you started using something on a widespread basis and it becomes the expectation, then it can be hard to enroll into a clinical trial, where one is compared against placebo, for instance. And we need clinical trials to understand whether or not something works. Thus, while I think this reflects the current state of what’s available, we hope that in the future that section becomes populated with recommendations. I think we would love to deploy antivirals or other approaches earlier, just like we do for HIV and other infections.
What’s Ahead for COVID-19 Guidance
Wilder: A prevalent topic in the press lately is COVID-19 long-haulers, people who are not recovering after the expected recovery period. Do you think there are some key areas of research that are going to need to be explored around people who are not “recovering?” It seems like there’s a subpopulation of people that we may have to think about, instead of only focusing on the acute side of the illness.
Kim: That’s absolutely right. We know from other infectious diseases that there can be variation in how people recover, and that there are subsets of persons who, after even mild or severe infections, can have a prolonged period where they do not feel well. I do think there is a lot to be learned. There are many clinics being opened for post–COVID-19 care, both in our institution and in New York and elsewhere.
It’s still early. We may discover something that could be of benefit. But at this time, there’s not enough information to know exactly what will help the recovery of this subpopulation.
Wilder: Are there portions of the guidelines that we haven’t discussed that would be important to highlight?
Kim: I would say that it’s challenging to keep updated guidance and information and distill it for patients and for providers who are on the front lines. My hopes are that these guidelines have helped organize the literature and provided some structured advice to caregivers on the front lines.