TWiV 897 COVID-19 Clinical Update #113

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 7 May 2022

Pdf of this transcript available (link)

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick.

[music]

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 897, recorded on May 5th, 2022. I’m Vincent Racaniello and you’re listening to the podcast, all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: This is update Number 113. Are cases going up, Daniel?

DG: Recorded on Cinco de Mayo.

VR: Oh, that’s right. You know what yesterday was, don’t you?

DG: May the Fourth be with you.

VR: Oh, you’re with it. You’re good.

[laughter]

DG: I try to keep up. All right, so let’s go. Let’s start with the quotation. We have a lot to cover today. “It’s a recession when your neighbor loses his job. It’s a depression when you lose yours,” and that’s Harry Truman. Actually, my dad is a great Harry Truman fan. I was just reading an article about him recently. That got me thinking about Harry Truman. I think that’s one of the tough things about so much in life here is that, for a lot of people, it’s been somewhat abstract, people that have been able to keep themselves safe.

For a lot of people, this has been really personal and tragic. I was speaking to a social worker today that does a lot of counseling for elders who have lost a lot of people close to them. Hardest hit parts of our population, the vulnerable, the elderly, socioeconomic, different race, so been a tough time for a lot of people. Where are we headed? We have a schedule of FDA meetings for June, so there’s a lot of exciting things that are going to be happening in June.

June 7th, the FDA intends to convene to discuss an EUA request. It’s going to be the VRBPAC to discuss an EUA request for a COVID-19 vaccine manufactured by Novavax to prevent COVID-19 in individuals 18 years of age and older. I know we’ve had a lot of individuals– Actually, a lot of our listeners have been asking, “When is this going to happen?” If there’s folks out there still waiting for this, June 7th, June 8, 21, and 22, the FDA held dates for the VRBPAC to meet to discuss updates to Moderna and Pfizer-BioNTech EUAs for their COVID-19 vaccines to include younger populations.

This is going to be exciting there. June 28th, for the rest of us, those of us over 5, over 18, the FDA plans to convene to discuss the SARS-CoV-2– They say “strain composition.” All right, composition of COVID-19 vaccines, whether they should be modified. What exactly are we going to do as far as booster doses, as far as the composition of those COVID-19 vaccines going forward? Really, we’re talking about the fall of 2022.

All right, this was something that just came across as a preprint. I don’t know if I’m flogging a dead horse or if I’m ever going to gain any traction here because you say something five times, it suddenly becomes true. That’s not actually reality. “SARS-CoV-2 Omicron Variant is as Deadly as Previous Waves After Adjusting for Vaccinations, Demographics, and Comorbidities” was posted as a preprint.

These investigators linked state-level vaccination data with quality-controlled electronic health records from a large healthcare system, including 13 hospitals in Massachusetts here in the USA. They then performed a weighted case-control study to compare risks of hospital admission and mortality, so death across the SARS‑CoV‑2 waves in over 130,000 COVID patients. They found that after adjusting for confounders, including various demographics, the Charlson Comorbidity Index scores, and vaccination status, they found that the risks of hospitalization and mortality were nearly identical between the various periods.

Their analysis suggested that the intrinsic severity of the Omicron variant may be as severe as previous variants. As I like to say, what makes Omicron mild is vaccination and perhaps early treatment. All right, children, COVID, other vulnerable populations. Children are at risk for COVID according to the CDC and the American Academy of Pediatrics as of, basically, the end of April, so the 28th of April. Over 1,000, so 1,010 children have died here in the US from COVID. That’s a hard number, a hard outcome. There were another 19 deaths just that week.

Now, we’re down at a large scale. We’re down to about 1,750 COVID deaths a week here in the U.S. That is about the lowest since the pandemic started, well below the 25,000 deaths per week at the height of the pandemic. Remember, this is in the context of lots and lots of cases out there. Anyone who doesn’t quite get it, vaccines work. Now, I want to make sure I keep this in sort of our, “What do we do at different times?”

We’ve always talked about the pre-exposure period, right? This is theoretically before you’ve been exposed. What can you do? Testing, we always talk about here. One of the things that we were talking about and an overlap with children is we are starting to see not only COVID, but we’re seeing flu, we’re seeing overlaps of COVID and flu. We were actually discussing one of the pediatric flu deaths that we recently had in our area.

Just to point out, we just talked about over 1,000 deaths in children from COVID. As per the CDC, we’ve had about 23 pediatric flu deaths so far this year, 3,200 total deaths from influenza. Again, the perspective, we have more deaths every two days from COVID even at this lowest level of the pandemic, so just remember. I want people to be thinking, getting ready for the next fall when not only are they going to hopefully get a COVID shot, but they’re also going to get that flu shot.

VR: Just to emphasize, the vast majority of the deaths are in unvaccinated people, is that correct?

DG: Actually, that’s great. We’re going to be getting into that here in a little bit. Yes, the majority of the deaths are still– Well, I’m going to say for flu. 90% of the flu deaths are in unvaccinated. Maybe we’re going to start realizing that it’s not just about the flu preventing flu-like illness visits. It’s about the flu vaccines preventing deaths. Really, this paradigm, hopefully, we’ve taught a lot of people with the COVID vaccines.

All right, and excellent points, and I think that’s something we’re going to be drilling a little bit coming up. Also, in this pre-exposure period, how do you keep yourself safe? We have testing before we go to these events. We also have masks and we’ve talked a bit about the one-way masking. If you’re in a situation where you are concerned, you want to protect yourself, you may be opting for the higher quality, the KN95, the N95. Even the 94 is there.

Again, outside is safer. Better ventilation. I still want people to keep washing their hands, but this is a virus you get by breathing, not necessarily by touching things, but that is different. We’ll talk about, hopefully, other viruses where touching might be more of an issue. Maybe that’ll be the arena of our new Puscast, active vaccination, never miss an opportunity to vaccinate.

Finally, and I do say “finally,” the article, the publication, ”Comparative Effectiveness Over Time of the mRNA-1273 (Moderna) Vaccine and the BNT162b2 (Pfizer-BioNTech) Vaccine,” was published in Nature Communications by my friends and colleagues. A little shout-out to Nazmul Islam, Natalie Sheils, Megan Jarvis, and Ken Cohen from OptumLabs in Minnetonka, Minnesota.

This took a long time to see the light of day. It almost didn’t get published before our next paper that, hopefully, we’re submitting in the next few days will get published. These are the results of a retrospective cohort study using de-identified administration claims for 3.5 million fully-vaccinated individuals in a research database with a follow-up period of between 14 and 151 days after their second dose.

The primary outcome was the rate of COVID-19 infection occurring at 30, 60, and 90 days, at least 14 days after the second dose of either the mRNA-1273, the Moderna vaccine, or the BNT162b2, the Pfizer-BioNTech vaccine. Also, some sub-analyses included incidents of hospitalization, ICU admission, and death hospice transfer. A separate analysis was conducted for individuals above and below age 65 and those without a prior diagnosis of COVID-19.

What did they find? This is the betting on the dogs or the horses. I’m not sure if any of that’s politically correct anymore, but people might still do it. Which wins? Which are we thinking? In this cohort, immunization with the Moderna vaccine compared to the Pfizer-BioNTech vaccine provided slightly more protection against SARS-CoV-2 infection. Well, this reached statistical significance at 90 days, but how many was the number needed to treat? Greater than or equal to 290.

Really pretty similar. No differences in terms of what I really care about, vaccine efficacy for hospitalization, ICU admission, death. A few limitations. This is where our next paper will come in. This is pre-Delta, pre-Omicron. As one might realize, there might be differences with different variants. Be particularly interested in looking at the outcomes during the period of Delta predominance than Omicron, and then the next variant, so more data to come as we see variants with more immune evasion.

All right, I hope nobody has buyer remorse after that. I think it was sort of reassuring. The mRNA vaccines are continuing to work incredibly well and it’s subtle, any sort of differences here. Vincent brought up, and I think this is really important, who is still dying from COVID-19? I bring this up and I put this in my section of passive vaccination, right? No-brainer, straight ahead. Everyone, get fully vaccinated. Get up-to-date with those vaccines.

Apparently, that’s a new language. Fully-vaccinated and up-to-date with your vaccines includes getting that shot at six months, but I want to reinforce that the majority of people that are dying are still the unvaccinated. We’re still seeing over 200 a day, but who’s still dying? This is some interesting data I will go through. Back in September, about 77% of the people dying were unvaccinated. 77% of a much larger number. We’re down to a smaller number. We’re still at 60%, where still the majority of people dying are unvaccinated.

As you can see, we’ve gone from 23% up to about 40%. Who are those people who are vaccinated that are still dying? Predominantly, those that are older, above age 75. As we’ve heard before, predominantly, those people with comorbidities, with immunosuppression. Realize, these individuals are that perfect candidate or the perfect candidates for receiving Evusheld, which can give us another 80% reduction in hospitalization or severe disease. As we talked about those data, it was actually nobody in the Evusheld died. All the deaths were in the people that did not get Evusheld.

All right, post-exposure period. This is changed over time. It’s a little bit of a gap. Now, you’ve gone out. You’ve gotten exposed. You said, “Why did I go to that big indoor dinner party and take off my mask to find out that that person I was sitting at the table with had COVID?” Maybe you had a great time. Now, you’re saying, “Well, what can I do now?” Things have changed over time.

There was a time when we were giving post-exposure monoclonals. Actually, that was pre-bebtelovimab. That was earlier variants. If we remember the data, that was about an 80% reduction in people going on and even getting symptomatic COVID. What about Paxlovid? We’re now in the days of oral antivirals. I got this question and, actually, it was right hot off the press when this information became available.

It was my buddy, David Wertheim. He’s the head of our allergy immunology division, so he apologizes for calling me. When it gets up to about three a day, I start giving him a hard time. I love talking to practicing immunologists about their complicated patients and COVID risk factors, but his question was this compromised individual living in the home with their son who has acute COVID.

As he said to me, “Dan, it’s just a question of when that PCR turns positive in this high-risk person. Should I just start the Paxlovid now?” I said, “David, let me talk about the hot-off-the-press Phase 2/3 EPIC-PEP results.” This was a study evaluating Paxlovid for post-exposure prophylactic use. This trial involved 2,957 adults. Enrolled adults had a negative rapid antigen test, were asymptomatic.

It was within 96 hours of that exposure and then they were put into three groups, so 1:1:1 randomization. Either they were going to get Paxlovid for five days, either they were going to get Paxlovid for 10 days, or they were going to get placebo for 10 days. In this trial, compared to placebo, Pfizer observed reductions of 32% and 37% in adults who received Paxlovid for 5 and 10 days respectively, but, and I maybe should just stay this right up front, the results were not statistically significant.

Remember, this is a big study. It’s 1,000 people in each group. They did not reach their primary endpoint. They did not demonstrate that Paxlovid reduced the risk of confirmed and symptomatic COVID-19 infection in adults. The EUA was not extended. We’ll go into this just a little bit more because we still don’t have all the data. That was the primary outcome, was a decrease in resulting symptomatic infection.

At a fairly large, robust trial, we did not see that. There are a number of secondary outcome measures, which actually might be more important to me. I’m just sort of going to jump to them. What about the outcomes of hospitalization or death from any cause? In getting there early, is that going to be better? We’re, of course, going to have to compare this to, “What if you just wait till they’re positive?” and then start in those select people.

What about duration of COVID-19-related signs and symptoms? Are these people going to get better quicker? Are those symptoms going to be milder? What about severity? As I mentioned, are these going to be milder? What about all-cause mortality? Is there a mortality benefit? Remember, starting it in the first three to five days, there were no deaths in the treatment arm.

There may not be a problem with waiting until someone tests positive. What about if they do end up in the hospital, the number of days in the hospital or the ICU? Then also just the impact on our healthcare system. Is just getting them going right away going to reduce the number of medical visits? Because the paradigm, as you can imagine in this situation, was to do daily testing.

Then when this woman turns positive, then you would start it. Then I don’t want to leave out, what about Long COVID? If you get the people treated right away, is that going to have an impact on Long COVID? Then as we get into stuff later, is starting it early for those five days going to be a problem? Because maybe you’re going to be finishing therapy right about the time when you should be starting therapy.

VR: Daniel, I have a couple of questions here.

DG: Excellent.

VR: This high-risk individual, he asked you, “Should I just start the Paxlovid?” Why not give them Evusheld and get six, eight months pre-exposure protection?

DG: This is actually a great thing. Poor David was able to get some doses, right? He’s been sending his patients to different places, but through one of the local health systems, he got 10 doses of Evusheld. I called him up. I was like, “Hey, David, I hear you got 10 doses of be Evusheld for your patients.” He was like, “That’s supposed to be a secret.”

I was like, “David, it’s all public knowledge. It’s on the website. Not only do I know you have it, but I knew exactly the number of doses.” Yes, this individual has already been vaccinated. They’ve already gotten Evusheld, so really trying. That’s a nice thing. This is an individual who’s getting all that protection. Unfortunately, they have pretty significant immune issues. Living in this high-risk situation, they may still end up infected.

VR: I don’t know. I don’t want to be on Paxlovid and ritonavir for extended periods of time. I think Evusheld is a better choice. The other question is the name of this study is “Paxlovid for Post-Exposure Prophylaxis,” but then they’re talking about pre-exposure. Why the two? I don’t get it.

DG: Yes, pre-exposure is actually, as you bring up, are you going to really just sit on it for the season like, “Oh, now that it’s December, I’m high risk. I’ll take Paxlovid every–” Yes, that’s going to be a harder lift.

VR: Because in your notes, you say they reserve risk reductions of 32% and 37% in adults to prevent infection, but they weren’t statistically significant. I didn’t think that was the goal of this study because it says post-exposure prophylaxis.

DG: Yes, so their idea here is you have an adult, who’s had a high-risk exposure. They’re still negative, but it’s after that exposure, so you’re within 72 hours after that high-risk exposure. No, there are other trials looking at just being on these things. Some of the monoclonals were looked at in those contexts. That’s what Evusheld really is, saying, “Let’s get this in there before the exposure, and let’s get that six months of protection,” with what has turned out to be a very safe therapy.

All right, so what about Paxlovid? As we went through, now, it’s post-exposure and you’ve gone onto the next level. You’ve now tested positive. We’re now in the period of detectable viral replication. For some, it’s the viral symptom phase. Some people are asymptomatic and we’re going to talk about that in a second. What is the number one thing that we recommend right now per the guidelines? It’s Paxlovid with 89% to 88% reduction in progression if given in the first three to five days. Now available at greater than 30,000 locations across the U.S.

When I was writing that, I was thinking like, “It sounds like an ad.” [chuckles] One of the things that has been coming up here, well, I’ll do write off, is you don’t need symptoms, right? This is a high-risk individual. They’ve tested positive. You’re concerned that they’re going to progress. You don’t wait around. This comes up, “Well, why don’t we wait and see how they do?” You’re losing time.

You do not wait to see how they do, but there is this concern lately. It’s been all over social media and mainstream media. I’m going to discuss a preprint that addresses this concept of recrudescence. The preprint, “Rapid Relapse of Symptomatic SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir.” That’s Paxlovid. This is a description of a single case. This is a case report. It’s an interesting case report.

This case report described a 71-year-old, fully-vaccinated, and boosted male, so up-to-date with his vaccinations, with intermittent asthma, had a high-risk exposure on day negative two, right? We’re going to go back here. Nasal quantitative PCR was negative on the morning of day minus one, but he started to have symptoms, so mild rhinorrhea, runny nose developed that evening, and antigen testing was positive the morning of day zero. Wow, the antigen tests actually work.

[laughter]

DG: The timing was fine. He developed symptoms. The next morning, got a test. The symptoms progressed rapidly [laughs] on day zero to sore throat, increasing runny nose, coryza, asthma, cough, fatigue, malaise chills, and fever of 38.4. Paxlovid was started at 3:00 PM on day zero right in there, continued every 12 hours through the morning of day five, so got his five days.

Symptoms improved rapidly after the start of the Paxlovid with only mild runny nose, a little bit of asthma on day one, and complete resolution of symptoms by day two. It’s actually fairly in keeping with the experience we’re seeing people. I think this is why Paxlovid may end up doing well is we’re not just telling them that it’s going to keep them out of the hospital. They feel better within a day or two.

Then they tell their friends, “Wow, I felt better within a day or two,” and their friend who didn’t take Paxlovid is still feeling crummy. On day nine, while still isolating, I like the fact that they mentioned that, this individual developed typical cold symptoms with runny nose, sore throat, coryza, and asthma. These peaked on day 10 and resolved by day 12, right? For a couple of days there, he had a little bit of a return of the symptoms.

The viral genome sequencing demonstrated the Omicron subvariant BA.1. We do have a nice figure. They call it Figure 1, but there’s no other figure, so it’s figure. A few interesting points I will raise. People should go ahead and take a look at this, but I’ll walk people through the figure and talk. It’s in reverse, so they’ve got cycle threshold going up while the person is on the Paxlovid.

Going up means the amount of viral RNA is going down, the individual stops the Paxlovid, and then we actually start to see the cycle threshold going down. The RNA copy number is going up. It peaks at about day nine and then, actually, the CT value goes up, so the RNA copy number is now just going down, down, down. I’d give you a couple of numbers here. By about day 16, day 18, you’re getting to those RNA copy numbers in the 30s.

VR: I like this that when the cycle threshold is the highest, that’s when the antigen is negative, right?

DG: [laughs] I like this figure because not only do you have the RNA CT, cycle threshold, but all across the bottom, you have the antigen test, photos of the antigen test. You actually see this correlation between how dark that line is relative to control going across. It starts off. It’s positive. It starts to get lighter and then it gets really dark again at day nine when you have the CT value down around 18 and the RNA copy numbers up in the millions.

Then, again, you see it phase out and you see that antigen test turned negative by about day 15. A couple of things I want to make a comment about. I think people are sloppy here. As I like to say, this is RNA copy number. This is not viral load. Who knows, at day 12, 15, 16, whether or not this is viable infectious virus? That’s important. I think this is really critical because, boy, a lot of people have a lot of opinions and advice on this.

1% to 2% of the patients in the Pfizer clinical trial tested positive for COVID-19 after having initially tested negative at the end of their round of antivirals, but I want to point this out. That happened for the people that got Paxlovid and that also happened for the people that got placebo. Those of us that have taken care of– because at this point, hundreds, thousands of people with COVID-19, for a lot of individuals, that could be a biphasic nature.

You feel crummy, you feel better, then you feel crummy again, and then you feel better. The interesting thing is that 1% to 2% of the people who got placebo had the similar pattern and the RNA copy number as did the 1% to 2% on the Paxlovid. This 1% to 2% seems consistent with what we’re seeing. You got to be careful, right? Confirmation bias when you hear about it, you remember it. When your patient takes Paxlovid, does great, doesn’t call you back, you don’t hear about it.

One of the things I want to say, too, I’m going to quote John Farley, the director of the FDA Office of Infection Diseases. They released an update this week basically pointing out, “There is currently no evidence of benefit at this time for a longer course of treatment,” because I know there’s been some influencers out there saying, “Well, you know what I would do,” and then recommending retreatment, recommending longer courses. It is notable that most of those “influencers” actually don’t have MD degrees or not actively seeing patients. This is an EUA drug. There’s rules. There’s science. Don’t just make it up as you go.

VR: Any cardiologists in there?

DG: [laughs] There’s actually some epidemiologist who works for some drug testing company, but we won’t mention him. All right, [laughs] remember, for Paxlovid, we have the locator. It’s actually getting better and better and we’re privileged here. New York City has a program where people, you prescribe– Actually, it gets delivered to their home within 24 hours. Just another reason to live in the New York tri-state area.

All right, number two, and I will point out. Now, acute viral replication, symptoms are not– You’re high risk. You’ve tested positive. For some reason, maybe you can’t get Paxlovid because of drug-drug interactions or some issues with renal function. Number two is now remdesivir. Now, I’m completely familiar with the fact that in a lot of areas, this is logistically not an opportunity for people.

For those of you that don’t live within 15 minutes of St. Francis Hospital and Stefan Muehlbauer, even though the data is really strong for that three-day early IV data with 87% reduction in progression, even though this is the only option for those high-risk children, operationally, a lot of folks have not made this happen, but that is number two based upon that outcome data.

I am going to jump in right here and talk about a nice article that was just published in CID, “Pre-Hospital Administration of Remdesivir During a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Outbreak in a Skilled Nursing Facility.” Here, the authors are reporting on the experience at the Idaho State Veterans Home Boise, a state-owned, 124-bed skilled nursing facility.

Beginning on the 31st of October 2020, all patients with a SARS-CoV-2 diagnosis within the preceding 10 days were offered, in this case, a five-day course of remdesivir. They reported that completion of a five-day course of remdesivir was associated with approximately 17-fold increased odds of survival among a sample of 54 nursing home residents with acute SARS-CoV-2 infection during the course of an outbreak.

Remdesivir was well-tolerated. Administration was logistically feasible right there. In the nursing home, someone can come there. They can put in the IV. They can get the remdesivir. In this case, they were using five days. We now know three days is a reasonable approach. I have to say, this article, even though it’s fully published, it didn’t really see what was the control group. I just struggled with trying to understand 17-fold increased odds of survival compared to what other groups, so just by the way.

All right, number three, and why is it number three? Monoclonals have fallen a little bit. We’re now down to just bebtelovimab in adults and pediatric patients, 12 years of age and older. It’s because we’ve lost all the other monoclonals where we actually have real-world efficacy data. Here, we’re just saying we have neutralizing data. We think this will probably work. Also, by the way, we’re running out of bebtelovimab. We’re having shortages in a lot of parts of the country.

That’s also one of the reasons why remdesivir, which is much more available as far as the drug, not necessarily operationally being able to get it, has moved up to number two. Don’t forget number four. Thor’s hammer sitting there at the bottom of the barrel. A last option with only about a 30% reduction in progression. Less impressive, but an easy lift. No renal issues, no drug-drug interactions. Remember that negative pregnancy test, not authorized for those under 18. A little bit different there in our target audience.

All right, the early inflammatory phase we’ve gone through. Hopefully, we’ve vaccinated the person. Hopefully, we’ve given passive vaccination. Maybe we’ve tried to jump in early, but sometimes none of those things happen. Sometimes all those things happen and the person still progresses. Now, they end up in the early inflammatory phase. This is where a lot of those folks might end up in the hospital.

Remember, number one, steroids at the right time in the right patient at the right dose. Generally, this is dexamethasone. That’s 6 milligrams for 10 days in those individuals who have oxygen room-air saturations less than 94%. We’re not running them up and down the stairs. There is some flexibility there, but the 6 milligrams tend to be the best overall general dosing.

Number two, anticoagulation and we have a new article for anticoagulation, “The American Society of Hematology Living Guidelines on the Use of Anticoagulation for Thromboprophylaxis in Patients with COVID-19: January 2022 Update on the Use of Therapeutic-Intensity Anticoagulation in Acutely-Ill Patients.” This just became available in advance online, in Blood Advances on May 3rd, 2022. I’m one of the authors for full disclosure.

OK, let’s go through the recommendations. Really, I think that this is important just to think about this because, a lot of times, infectious disease doctors might feel like, “Well, what am I doing making anticoagulation recommendations?” Somebody has to keep up in the literature, so it might as well be you. You’ve got a lot more free time now that there’s less folks in the hospital, so you can be reading these recommendations.

Number one, what about those folks who are in the hospital, those ICU patients, those with critical illness? The ASH guideline panel suggests using prophylactic-intensity anticoagulation, so that’s that lower dose. Now, what about number two? These people are less sick. In the hospital, they have acute illness. They’re hospitalized, but not at ICU levels. This is not geographic. This is based on severity. In those individuals, the panel is suggesting using therapeutic-intensity anticoagulation.

Number three, what about, “It’s time to go”? The guideline panel suggests not using anticoagulation when the patients leave the hospital unless they’re at high risk or have some other reason to be on anticoagulation. Of course, an individual assessment of the patient’s risk of thrombosis and bleeding is important when deciding on anticoagulation. This is guidance. These are not check-the-box rules.

Look at that person if they’re being admitted, but they’re walking around. You’re wondering why they’re in the hospital. Think about whether or not they want to be on full-dose or not. If you’ve got an obese person who’s laying there, not moving, having a lot of trouble breathing, you might make a different decision. Remember, we need a physician, not just a guideline algorithm.

All right, number three, pulmonary support. We’re not going to talk too much about that today, but that’s a lot of what brings folks into the hospital. Actually, where they are in that spectrum is going to guide some of our management. Number four, remdesivir. Maybe if we’re giving it early. The final results of the solidarity trial are now published. I know Vincent was just waiting for those, right?

[laughter]

DG: “Remdesivir and Three Other Drugs for Hospitalized Patients with COVID-19: Final Results of the WHO Solidarity Randomized Trial and Updated Meta-Analyses,” was published in The Lancet. Again, the issue of timing of those started on therapy prior to intubation and mechanical ventilation but requiring oxygen, 14.6% assigned to remdesivir died versus 16.3% assigned to control. That was a relative risk reduction. Relative risk, 0.87, P-value of 0.03. Relative risk of 0.87, that’s a reduction of about 13%.

That’s a mortality outcome. Of those who started on remdesivir after being put on a ventilator, so they waited, it was not helpful. Just pointing again, timing. If you’re going to use the remdesivir in those hospitalized patients, you really want to be using it early. If you wait, give it to someone on a ventilator. You’re not doing anything helpful. Again, the remdesivir in that early first three to five days, that may actually be keeping them out of the hospital.

All right, number five, tocilizumab. They seem to have been progressing. Tocilizumab. In some cases, baricitinib. Well, more news about tocilizumab. That does actually have a T. This is a paper I talked about before it was published, but it was just published this month, May, in the journal Respiratory Care. This is the article, “Impact of Timing of Tocilizumab Use in Hospitalized Patients with SARS-CoV-2 Infection.” It is behind a paywall, which is a little bit painful. Since I have access to this article, let me share the results.

This was a retrospective chart review of 11,512 patients, in fact, with SARS-CoV-2 who are admitted to a New York health system, Northwell, by the way, from March to May of 2020. The New York health system. The first author is my colleague, Anup Singh, who was kind enough to share some of these results many months ago and they then shared with you, but what were the results? They found that the overall hospital mortality was significantly reduced in the tocilizumab group when tocilizumab was given at the nasal cannula level.

They did not see mortality benefit when they waited after the person had progressed to mechanical ventilation. Given early, toci had a mortality benefit. It also decreased the progression to mechanical ventilation. Again, no improvement in mortality when tocilizumab was given at the time of requiring non-rebreather, high-flow nasal cannula, non-invasive ventilator, or being ventilated. If you wait, you’re going to miss your window. You’re not going to provide benefits, so think about that if you’re putting any guidelines out there.

All right, so two years later, I feel like I keep repeating myself, but OK. All right, also, the meta-analysis, “Interleukin-6 Inhibitors Reduce Mortality in Coronavirus Disease-2019: An Individual Patient Data Meta-Analysis From Randomized Controlled Trials,” published in the Journal of European Internal Medicine. With all the limitations of a meta-analysis piling lots of studies and hoping they then turn into gold, ultimately, the authors here included 11 studies incorporating 7,467 patients.

IL-6 inhibitors were associated with decreased risk for death compared to standard of care. In their one-stage meta-analysis, we had a hazard ratio of 0.75, so about a 25% reduction. When they did a second-stage meta-analysis, has a ratio of 0.85, so about a 15% reduction. Leave that out there for those of you thinking about adding something. Hopefully, we’re going to have better treatment.

What about baricitinib? The article, “Unravelling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2,” was published in Open Forum Infectious Diseases. In this study, the authors characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support and enrollment.

They estimated the effect of baricitinib on cumulative incidence of clinical improvement and deterioration. They found that baricitinib resulted in more improvement and lower incidence of clinical deterioration compared with just giving remdesivir. Hazard ratio of 0.74, so in that same range as adding tocilizumab. About a 26% reduction. Again, timing. They found that baricitinib did not benefit patients who were mechanically ventilated at enrollment.

All right, the tail-phase Long COVID, post-COVID. I’m beginning to think I may have selection bias because I always talk about articles where we find out that having had COVID shrinks your brain. The article, “Cortical Grey Matter Volume Loss Links to Neurological Sequelae in Post-COVID-19  Long Haulers,” was actually posted as a preprint by Ted Rothstein. I’m most curious when there’s a single-author paper, but Ted Rothstein is down at George Washington University Department of Neurology, down in Washington, D.C.

This study involved 19 consecutive post-COVID-19 surviving long haulers, who experienced neurological symptoms, right? There’s a selection here. We’re looking at those with neurological symptoms. Each patient had a brain MRI with three-dimensional, voxel-based morphometry. I went right down the rabbit hole and spent hours looking at this technology, which is pretty cool.

Anyway, all the patients had relatively mild respiratory symptoms, which did not require oxygen supplementation, hospital, or assisted ventilation. These were “mild” non-hospitalized, non-severe, non-critically ill. The three-dimensional, voxel-based morphometry was obtained for the whole brain, forebrain, parenchyma, cortical grey matter, hippocampus, and thalamus. They found that there was a statistically significant loss of cortical grey matter volume in the long-haulers.

VR: Well, may I make a comment?

DG: Please do.

VR: Not my area, but for controls, they didn’t actually have patients that didn’t have COVID. They just pulled data out of a database and compared it, so I’m not sure that’s kosher.

DG: Remember, this is very small. This is a small group. It’s a select group, so yes, and it is. This is a preprint. This is preprint by one individual down at GW, so all these points are very–

VR: The problem is that it’s a preprint. The press gets a hold of it and then people freak out, right?

DG: [laughs] My brain is shrinking, yes.

[laughter]

DG: I think it’s good. If it’s out there and they’re talking about it, it’s probably good for us to give it that context. Remember, this is a preprint. It’ll be interesting to see. By the time it comes out published, people have lost interest and moved on-

VR: Of course.

DG: -Which is a bit of a challenge with preprints. All right, the rest of the world, no one is safe until everyone is safe. Well, I always tell everyone, “Pause right here. Pull off to the side of the road. Don’t crash.” Go to parasiteswithoutborders.com and click on the Donate button. We are now starting our fundraiser, Foundation for International Medical Relief of Children, FIMRC. During the months of May, June, and July, donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000.

This, I have to say, is a particular close-to-home challenge. What we’re trying to do is help support the clinic in the Bududa District of Eastern Uganda. They have been struggling. They actually were ready to shutter this clinic, which takes care of over 100 children per day. These are children, a lot of them, with acute malaria who will die without treatment. If we can get enough funds, it looks like they may be able to, after a short hiatus, reopen the clinic and move forward. It’s going to take your generous support, so please go to parasiteswithoutborders.com and help us support FIMRC.

VR: All right, it’s time for some of your questions for Daniel. You can send them to [email protected]. Kimona writes, “I feel like monoclonals used to be right up there with Paxlovid on the list for prescription of mild-to-moderate early diagnosis and disease and remdesivir was third and molnupiravir last, but perhaps that was when sotrovimab was still relevant. Now, monoclonals have fallen to the sea, or weak recommendation. I realize there is only in vitro data, indicating effectiveness against BA.2 and no Phase 3 trials, but many of my colleagues are still scheduling patients for bebtelovimab infusions as long as we have it in stock, even in patients who could perhaps take Paxlovid. Giving remdesivir IV for three days is simply a pain in the arse.”

DG: [chuckles]

VR: “Should they not be? We even give bebtelovimab right in the ED when time permits. It’s like a one-and-done for those mild-to-moderate patients with risk factors for progression, yet in the first five to seven days. I apologize if I’ve misinterpreted the guidelines or missed one of your clinical updates; possible.”

DG: Now, Kimona, you are right on target here with everything you say. As you say, the guidance has changed. That changed just a couple of weeks ago as far as moving remdesivir up and the monoclonals down. Paxlovid is number one. Actually, I have to say, some of the ERs actually have Paxlovid in stock, which I really applaud. What they do is they look through. If the person meets the criteria, they give them the first dose. They send them home with the packet. This is paid for by the government, so there’s no cost to the ERs to be doing this.

Actually, there’s a saving because we’re 90% reduction and those people then bouncing back and requiring admission. Paxlovid is number one with that 89%, 88% reduction in progression if given in the first three to five days. Number two, yes, you are right. Not everywhere are they offering access to remdesivir. I would love to see a one-dose study. Maybe 200 milligrams. Maybe that’s better than the option. Yes, bebtelovimab, it’s a decent third option.

You bring up all the issues. We don’t have efficacy data for bebtelovimab. We’re extrapolating, but it’s an easy lift, right? It sits in the refrigerator. There isn’t that thawing time that we used to have, that one-hour thawing time we had with some of the other monoclonals. It is a 30-second infusion, so you can put in a butterfly, push it in, and then you just watch the person for an hour. It’s not a terrible option. It’s actually a pretty decent option. It’s much better than not treating them or dropping down to number four, which is molnupiravir.

VR: Tara writes, “Our local pharmacist doesn’t know how recently kidney function needs to be checked before prescribing Paxlovid. Any ideas? 30 days, 90 days if no history of kidney disease? Thanks.”

DG: Yes, that’s a great question. There’s no direction, right? If you look at the e-way, go into subsection 8.6, see, I’m doing too much of this, they actually talk about renal function. If you’re not sure, if you have concerns, you can always start the medicine. Send off the blood work. Check it the next day. Adjust doses as needed. No, they don’t give you any guidance.

This is just the way we do with so many other medicines. There’ll be a little bit of a clinical judgment. It’s going to be a little bit of a challenge for pharmacists, right? We could use some guidance there where a pharmacist is told. If it’s within 30 days, it would be reasonable. If not, then some sort of system where that can get checked. Yes, there’s no formal guidance at this point.

VR: James sends the information from Dr. Farley that you mentioned above that in the trial of Paxlovid, they didn’t see the rebound in 1% to 2% of the patients. He writes, “I have to wonder if the immunocompromised patients, part of the high-risk group, are unable to fully clear the virus due to their impaired immunity. This is just speculation, of course.”

DG: Thanks for bringing this up because this will allow me to reinforce that. Remember, when the study was done looking at the impact of Paxlovid, it was not that, “Hey, we need to clear the virus out of here.” This is not some public health measure to get rid of the virus and prevent its spread. This is basically a way of keeping people from dying, keeping people from ending up in the hospital. They saw this 89%, 88% reduction in progression.

These people who have this “recrudescence,” feeling crummy for a couple of days. I was reading an article. It comes raging back. It does not come raging back. It does not come roaring back for a couple of days. They feel bad and then they’re fine. We are now giving out thousands and thousands of doses. We’re not seeing anything to contradict that, so we will learn more. For 1%, 2% of the people, whether they got Paxlovid or not, they had this similar clinical progression.

VR: Finally, Kai writes, “A question I haven’t heard you address yet. If one is in a university or company that does regular surveillance testing and one tests positive without symptoms, should one try to get Paxlovid? I help run the surveillance testing lab at Caltech and was wondering about your opinion. We have a lot of faculty and staff who are over 60. Would your advice to them, depend on age and comorbidities? If so, what would be the cutoff age at which one should try to get Paxlovid as soon as one tests positive without waiting to develop symptoms?”

DG: OK, so this is great and it isn’t subtle to get. I know it is hard to keep up with all this. Paxlovid does not require symptoms, so this is an individual that is judged to be at high risk. There’s a number of these factors. 65 or over, it might be 55 and up but have hypertension or heart issues. There’s a list of medical problems, diabetes, obesity, BMI maybe greater than 30.

Some people are now pushing it down to 25. Asthma, lung disease, et cetera. For Paxlovid, that high-risk person tests positive. You don’t wait for them to get symptoms. Remember, and I think this is the confusion, the monoclonals required symptomatic. You had to fish. Does your head hurt? Are you feeling a little crummy? Are you sure you’re at 100%? There’s no fishing with Paxlovid and the recommendation is to treat those high-risk individuals.

VR: That’s COVID-19 clinical update Number 113 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you and, everyone, be safe.

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