Leonard Calabrese, DO, and Alfred Kim, MD, on Rebound COVID-19 Infection With Paxlovid

Drs Calabrese and Kim discuss the report of COVID-19 reinfection among patients who have been treated with the antiviral therapy, Paxlovid.
 

Leonard Calabrese, DO, is a professor of medicine and rheumatologist at Cleveland Clinic in Cleveland, Ohio.

Alfred Kim, MD, PhD, is an assistant professor in the division of rheumatology at the Washington University School of Medicine and director of the Lupus Clinic.

NOTE: When this podcast was recorded, data from a preprint indicated that Evusheld did not neutralize COVID-19 variants of concern BA.4 and BA.5. Since the recording, however, newer data has demonstrated that Evusheld CAN neutralize emerging SARS-CoV-2 variants of concern BA.4 and BA.5. 

TRANSCRIPT:

Alfred Kim, MD: Hello everyone. My name's Al Kim. I'm adult rheumatologist at Barnes-Jewish Hospital in St. Louis, Missouri, where I'm also on faculty at Washington University School of Medicine. Today we have Dr. Len Calabrese, our COVID friend, to discuss this emerging issue about rebound infection in people treated with Paxlovid. Not common, but it is an issue with some patients that have been treated with Paxlovid right after acquiring COVID-19, but there are implications in the immunosuppressed. So we're going to be discussing this entire landscape today. So Len, why don't you go ahead and tell the listeners kind of what this issue is about this rebound effect?

Leonard Calabrese, DO: Well, as everybody is probably aware, we're in a good position to treat COVID in people who are at increased risk. We still have some active monoclonals, we have some pre-exposure prophylaxis, and now over the past several months, we've had approval of 2 antiviral agents, Paxlovid combination product and molnupiravir. Paxlovid is the lead compound because its efficacy in terms of keeping people out of acute care has been quite impressive, approaching 90% in the clinical trials that led to its EUA [emergency use authorization]. This is a compound that works very rapidly. It is a 5-day course of an antiviral combined with a pharmacologic extender, ritonavir, and it has to be given within a window of 5 days of the onset of symptoms. That's how the data was generated, and that's what we knew.

So we've been using this drug kind of in fits and starts for a few months. Sometime in mid-April, I saw a tweet from Paul Sax from the Brigham that he had been getting reports that people would take Paxlovid, they would clinically improve, and then at the end of 5 days their home test — in particular, that's what people are doing — had turned negative and want to return to their business. Then within a few days, were noting return of symptoms, sometimes mild, sometimes moderate, then retesting themselves and having a very strong line. Well, this was a little bit shocking. I hadn't heard of that in the anecdotal use of it in our unit. Quickly on Twitter, many people came out and said, "Yes, we've seen this," and then that led to a more rigorous evaluation, a few case reports posted on PRE peer review platforms, and then finally, Paul Sax writing a very informative brief report of this problem and a list of questions.

Since that time, we have seen a number of patients that have fallen into that category. The questions are quite numerous right now as to what this actually indicates. This is a relapse, there is a loss of capture of antiviral suppressive activity. Is this just part of its MOA? Does this mean that there's resistance and escape? Does this mean that patients need to be retreated? Are they infectious? Those are merely some of the questions that have been posed. So I'll turn it back to you, Al, and say, "What's your upfront awareness of this, and have you guys been seeing this or talking about it?"

Dr Kim: It's so interesting because I fortunately have not seen it in our patients. Of course, our patients have been quite good about avoiding acquisition of virus by continuing to distance and mask, and also getting Evushed to be able to protect themselves as much as they can.
But I think our faculty became more aware of this when Stephen Colbert had to cancel additional shows of his late night show because he had taken Paxlovid and he stopped, and then he started having rebound symptoms. That became-

Dr Calabrese: I missed that.

Dr Kim: Much more ... Yeah, that became more public news. Then our faculty became more aware that this was a potential issue. Looking at the numbers, and these are all estimates, it does seem like it is uncommon. Again, these are estimates, but it may be about 1% to 2% of Paxlovid users have had this type of phenomenon. I'm not sure if that number's really correct, but I think it highlights that this is not to be expected. I do think Paxlovid still has an important role in the treatment, especially early on as you had mentioned, within the first 5 days of symptoms in being able to reduce the duration of symptoms, but definitely a small percentage of people, which still means it's a large number of people, are having these rebound issues.

Dr Calabrese:  I will put a parenthesis on the small number. I don't think that we know that. One of my employees' moms just had a relapse on it. Very well documented. I just get a sense that it's more than that. But having said that, one of the disappointing things to me is that ... There's a figure that has been published from the dossier that was presented to the FDA of the follow-up of cycle thresholds of patients on Paxlovid. There clearly is a post end of treatment dot on that line, showing rebound in a sizable number of patients. I say I'm disappointed because A, that figure never made into the New England Journal article, which we have all relied upon as a peer-reviewed standard bearer for the Paxlovid data. Then secondly, it is hard for me to imagine that Pfizer had not seen clinical relapses in this fairly large and robust trial. Let's just say I'm astonished that it took Twitter to put this on the map, so this is not very reassuring to me about process.

Dr Kim: I agree with you on that. Regardless of what the real percentage is, and again, at the end of the day, we'll have an idea of what the true rate of this is. The implications of this is really important, not only just for the immunocompetent, but certainly for the immunosuppressed. It looks like now that people that have rebound symptoms, they can transmit infectious virus during that rebound period. Until that person, and it seems like the kinetics looks like that these people will stop Paxlovid at day 5 and about day 6 and day 7 looks like their viral load increases and then starts to drop, which is about the kinetics of when you start making antibodies to ... Which the variant right now is going be in the US BA.2.12.1, which is a more concerning virus. It has increased transmissibility, increased infectiousness, increased prokinetics, there's immune escape in it, and I think Linfa Wang at Duke had called this, "We should be calling this SARS 3."

Dr Calabrese: Right. I heard that.

Dr Kim: Right. Right. Because it's so different. So I think as a result, even the immunocompetent people are going to have to make new antibodies, particularly if they've been vaccinated before. That gives them the best chance to be able to develop more rapid antibodies that can block the infection of BA.2.12.1. But for the immunosuppressed, and as we've chatted about before, particularly those on B cell-depleting agents and potentially those on say mycophenolate or high-dose steroids, these people are not going to be able to generate those antibody responses because of their immunosuppression potentially. So this is a huge problem.

Dr Calabrese: So I'm going to follow up on that. I agree with everything that you said. The term immunocompromised is defined by CDC as a very elusive group of people ranging from people that are just a little bit older to people that have profound primary immunodeficiencies and that they are not all the same. So let's take the group that we are most concerned about, people who are humorally deficient, whether they have a B cell malignancy, been treated with B cell-depleting agents, whether they are rituximab patients or MS patients, hypogamma patients, etc, these are special people. We know that they do exceptionally bad. I will tell you that we have adopted internally C level data for infection, whether it be breakthrough or de novo in this group. We're treating with both Paxlovid and monoclonal antibodies out of the chute for that strata of patients. Your thoughts?

Dr Kim: I 100% agree. I think there was a preprint a couple weeks ago, the only preprint that I could find neutralization data to the new omicron subvariants. At least let's take these humorally deficient, immune-suppressed people. Let's say they've gotten Evusheld ... So the interesting thing about Evusheld is that it's two antibodies, tixagevimab and cilgavimab. This binds to a protein on the outer coat of SARS-Co-V-2 virus called a spike protein. It literally looks like a spike coming out of the virus. The purpose of this protein is to bind to another protein on our own cells called ACE 2, and that mediates the infection. Most neutralizing antibodies that are made bind to that part where it interacts of the spike protein to ACE 2, which is basically on the very top kind of side of the spike protein if you kind of looked at the protein itself and where the antibody bound.

Now, what's interesting is that omicron completely makes tixgevimab and most monoclonal antibodies that bind there irrelevant. It makes it not bind at all. Now cilgavimab, which is the other antibody in Evusheld, actually binds kind of on the side, kind of away from that interaction between the spike protein and the ACE 2 protein. At first thought you may think, "Well, that's not going to help," but still actually it can neutralize probably because it's still able to block the interaction.

The preprint is a Japanese group. I'm looking at the group now. It's called Genotype to Phenotype Japan or G2P-Japan. *This consortium found that BA.2.12.1 in the US reduces the neutralization of cilgavimab by about 2-and-a-half fold, which is not that bad, so it can still bind to it. Now, what's really worrisome is the variants found in South Africa, BA.4 and BA.5. It causes a 30-fold reduction in binding, which is more way more concerning.

* PLEASE SEE NOTE ABOVE REGARDING NEW DATA.

Now, you bring up the point of monoclonal antibodies therapeutically. It looks like based off of their data, the bebtelovimab, it appears based off of their data that it can still bind both to BA.2.12.1 but also to BA.4 and .5. So I think your strategy, and again, there's a lot of confusion out there by people because even the Pfizer CEO, Albert Bourla in a interview with Bloomberg back on May 3rd said, "Just take more Paxlovid," but the FDA EUA technically does not permit that. So again, there's a lot of debate and a lot of confusion.

Dr Calabrese: Yeah, and let's just say for people who are at increased risk who are not immunocompromised, that may not be the best strategy. Maybe it's better to get your viral rebound and make your antibodies. We don't know that. I think their data is pristine in terms of it reduces your chance of landing in the hospital, but how this is all working and whether getting that kick to make antibody from the rebound is part of the enduring thing, we don't know that.

Dr Kim: Right.

Dr Calabrese: So all really good points.

Dr Kim: Yeah. I agree. So I think for people like you and me that fortunately have humoral responses, it might be okay, this rebound, because to my knowledge, and you may know more about this, I can't find any case reports of severe cases-

Dr Calabrese: No.

Dr Kim: Due to this rebound.

Dr Calabrese: I haven't-

Dr Kim: Yeah, so again-

Dr Calabrese: I haven't heard that either. I think that would've been picked up in the clinical trial, but I think that these rebounds were just kind of, I don't know, glanced over because they're obviously apparent and would've been picked up in a competent trial.

The last thing I'll mention is that to get your reaction before we close this, this Achilles heel of monoclonals is not going to go away. The virus is going to replicate, variate, and transmit no matter what we do about it. These will always be vulnerable to this, no matter what we have. So just a couple articles in Science in the past month or so of alternative strategies of monoclonals that target the ACE receptor and small proteins that can inhibit that binding. What do you think of that?

Dr Kim: I think they are interesting approaches. We obviously master the world of using autoantibodies to treat autoimmune diseases, anti-TNFs. These are our bread and butter. We know that these strategies are generally safe, and so I think it's actually a really interesting idea because there's going to be way less evolutionary pressure to target ACE 2. It is interesting. The small molecules are also interesting because you can more easily generate libraries that can be rapidly screening against new variants. Now, the question is how fast can they get through the regulatory process in order to then have it disseminated?

Dr Calabrese: Do something, create and accelerate somehow.

Dr Kim: 100% agree. 100%. Then of course there are these newer approaches to delivering vaccines, these intranasal vaccines. For the listeners' baseline knowledge, most of the antibodies we make from vaccination or IgG and Evusheld is IgG, the problem is we get infected in the airway, which is a mucosal surface. Only about 1 to 5% of our blood IgG makes it into the mucosal surface. The antibody you want for mucosal protection is IgE, and that's not consistently generated with mRNA vaccines. Some people do. Some people don't. So there have been new strategies to do intranasal delivery of vaccines. But from what I can tell, most of these are live attenuated, which may not be good for our immunosuppressed people still.

Dr Calabrese:
Yeah. So we have a ways to go.

Dr Kim: Yeah. No. So I think the future from a monoclonal preventative, a PReP approach, is that we probably have to start thinking about adding an IgE molecule into the prep along with IgG. Again, I assume someone's working on this. I have no knowledge, though. But in the meantime, I think your approach that you described earlier of giving Paxlovid and a monoclonal antibody at the same time for those people with no humoral immunity post-vaccination, that really is probably the optimal way to move forward if access is available for those type of tools.

Dr Calabrese: Sounds like a Twitter shoutout.

Dr Kim: Imagine if we didn't have Twitter, a lot of this would be kind of still talked around in just small circles.

Dr Calabrese: I totally learned about this on Twitter a month ago. It just shows you how the transmission of knowledge has changed and how careful you have to be. But that was great. Great discussion.

Dr Kim: No. Awesome discussion. So thank you very much, Len, for the discussion. Thank you everyone for listening. Take care. 

Dr Calabrese: Thank you.