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We are two and a half years into the COVID pandemic.  We’ve lived through lockdowns, toilet paper shortages, mask mandates, hospital surges where ICU’s overflowed, a million COVID deaths, prolonged school closures, development and roll out of novel vaccines, an explosion of social isolation and loneliness, and the invention of the “zoom meeting.” 

But what have we really learned over this seemingly endless pandemic other than how to make a quarantini?  Well, on today’s podcast we invite Monica Gandhi to sum up the evidence to date about how best to prevent getting COVID (or at least the severe outcomes of the disease) and how to treat it, including the role of Paxlovid in symptomatic disease.

Monica Gandhi is a professor of medicine and associate division chief of HIV, Infectious Diseases, and Global Medicine at UCSF & San Francisco General Hospital.  In addition to her research publications, she is a prolific writer both on social media and on media outlets like the Atlantic and the Washington Post.  Some call her an optimist or maybe a pragmatist, but I’d call her someone who inherently understands the value in harm reduction when it’s clear harm elimination just ain’t gonna happen.

So take a listen and if you want a deeper dive into some of the references we discuss on the podcast, here is a list:

Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: And Alex, this is going to be our second of our coming back to some of our old COVID guests. Who do we have with us today?

Alex: We’re delighted to welcome back, Monica Gandhi, who tweets @MonicaGandhi9 and is an infectious disease doctor and professor of medicine at UCSF. Welcome back to the GeriPal podcast, Monica.

Monica: Thank you for having me.

Eric: I want to say too, the last time I had you on Monica – my son and my wife were huge Monica Gandhi fans. My son for this one wanted to make a sign, We love Monica Gandhi. You have really done an amazing job for the last two years parsing out the science of COVID, where we are, where we’re going.

Monica: We can talk about all that.

Eric: Despite a lot of negativity on some of these social media platforms, I’ve never seen you go into a negative space or attacking people. So really very honored to have you on here.

Monica: Really excited to be here.

Eric: All right, before we start talking about COVID in older adults and those with serious illness, do you have a song request for Alex?

Monica: I always like The Beatles, and I feel like it’s really perky to think about Penny Lane. I feel like I’m tripping down something, like just flowers. So that’s my request, Penny Lane.

Alex: Great. Here’s a little Penny Lane.

Alex: (singing)

Eric: And Alex, I always thought that was a light tune, reminiscing about-

Alex: I didn’t think we were going to go there. Okay, we’re going to go there.

Alex: To our listeners. If you Google Penny Lane meaning, you will see something that you probably will regret seeing, and you can never unsee. There is sort of a hidden sexual-

Eric: A lot of sexual innuendos.

Alex: Innuendo references to this song that does seem like a cheery song about the suburbs that Paul McCartney was being very cheeky and yeah sliding some words in there and references. Yeah, the banker never wears a Mac in the pouring rain. I’ll never think about that line the same way again.

Alex: But Monica, as we were discussing a song for this podcast, we were trying to come up with something and we mentioned this one and I suggested Yesterday by The Beatles, because you’re a big Beatles fan. And you said, “No, that’s too depressing. That’s not where we are.” But Monica, I am depressed. I read this Twitter thread by Andy Slavitt, who was a former head of Medicare, Medicaid under Obama, former Biden White House senior advisor, host of In the Bubble Podcast.

Alex: And he, May 20th, he was like here’s where we are globally. In China, they have these lockdowns and they’ve tried this zero COVID policy. It’s not going to continue to work. We are going to have a massive outbreak in China. Their vaccines aren’t as effective. Who knows what’s going on in North Korea? It could be terrible there. But we have very little information, almost no information. And in South Africa, we’re continually seeing new variants emerge. And let’s think about our tools. The vaccines, they try and develop a vaccine against Omicron. Well, we’re way beyond Omicron now. And in South Africa, we saw people who are infected with the Omicron. They get reinfected with the new variants. They get reinfected with yet other variants. Those are just going to keep sweeping around the world every year, three times a year. We can’t keep up. We can’t make vaccines fast enough. Who knows what sort of viruses are going to come out of China, North Korea and South Africa. I’m concerned. I’m worried. I’m anxious. Talk me out of it.

Monica: Yeah. I totally get it. And I think Twitter is also a place where people think in their head and it’s who they are as individuals. Let’s look at this sweeping view of infectious diseases, which is how I’ve approached this pandemic throughout because unlike many others, I just happen to love infectious diseases. Went into it, wanted to be an infectious disease doctor when I was 10, read about infectious diseases, like read the history of them, think about it deeply. I’m just into it.

Alex: What got you interested in it when you were 10?

Monica: Because I learned about worms and I liked worms when I was 10, like little nematodes. I’m really just into parasites, nematodes, fungi, bacteria, virus. But actually, I’ll tell you why I’m interested in it. Because unlike something that is within your body, that is yourself, which would be like cancer or autoimmune diseases, which are very difficult. Infectious disease is always other. We can always get it in some way or the other. And if you look at the span of history of infectious diseases, we have always managed to control all infectious diseases because we have tools because it’s the other, it’s not yourself. Vaccines can be directed against that particular virus and not attack yourself. Treatments can be directed against that particular virus.

Monica: Look at HIV, very depressing for many years. But because HIV is so itself and doesn’t look like yourself, I have managed to watch, through my long history of being an HIV doctor, people rise from the dead, essentially, with HIV therapy and live totally normal lives. And that is because we can always find tools for infectious agents. So we’re in the thick of this with COVID, but we actually have way more tools than you think. And we have way more tools than we actually have for so many other RNA viruses, we’re just not paying attention to them.

Monica: So going back to what you just said about Korea, China and North Korea, China, and South Africa, Africa, no doubt we can’t eradicate COVID. And that, if we could please try to accept, will actually put in whole new veneer on this entire outlook. We can’t eradicate it. The day I knew we couldn’t eradicate it, remember the big cats in a zoo. I don’t remember which zoo, it was like Cleveland Zoo, that they had COVI.D it was April, 2020. And it was that day, because if you really look at the history of infectious diseases, you realize anything with an animal reservoir cannot be eradicated. It was that day that I was totally deflated. I actually think I cried that day because we’re never going to eradicate it. You have to keep from that unfortunate premise. 29 species of animals contain COVID-19. They killed 17 million mink and Denmark that one time. Remember that? They’ve killed hamsters in Hong Kong, dogs and cats in Shanghai. You can’t get rid of it and you can’t kill all animals. So that’s your premise.

Eric: So when you’re saying you’re optimistic, it’s not really that we’re going to get rid of COVID, right?

Monica: No. Control it.

Eric: We’re going to control it.

Monica: And we actually can’t get rid of every other virus that has inflicted human beings, except smallpox. But we have managed to control it. Do you think about measles every day? Do you think about mumps every day or rubella or other diseases, rhinovirus even? We’ve never been able to get rid of them, but we come to a state of equilibrium where we can control it, and that’s where we live. And we accept that we can eradicate, but that we have tools. And we have two tools for coronavirus that are so good, actually. I know the vaccines don’t prevent all infections. They stopped doing that with Delta. But if you really think about immunology, so simple. Antibodies will come down with time and they don’t work as well against these variants. But those T cells and B cells deep underneath that are triggered by the vaccines are still working.

Monica: And the degree of severe disease is so low worldwide, and we’ll talk about China and North Korea later, that we’re at our lowest points of death that we’ve ever had worldwide in this pandemic. That’s a huge, incredible advance. Go to Our World in Data world deaths COVID, you’ll see we’re at our lowest point. And IHME up in Seattle anticipates that July 22, we’re going to be extremely low. We’re already lower than influenza deaths worldwide. And now we’re going to go lower by July, 22nd. We’re actually lower of COVID deaths in this country than we’ve ever been since March of 2020. You won’t know it to hear about cases or hospitalizations, which can be misclassified, but we’re at our lowest point of COVID deaths in the United States.

Monica: And then yes, places who have chosen a COVID zero strategy, they are in trouble because COVID zero means there was no natural immunity in that population because they kept people away from each other for now two and a half years in counting. And they have very little natural immunity and they’re still keeping people away from each other with these lockdowns and Sinopharm and Sinovac are not as good of vaccines like you indicated. And yes, China is in trouble unless they could please work with the rest of the world. We could give them mRNA vaccines as a third shot, vaccinate and boost your elderly and then open up society there. You can’t eliminate this virus.

Eric: I loved all that. We got so much to go into right now. I’m wondering if we can start off with thinking about the prevention of COVID in older adults and those with serious illness and then potentially the management of them. When you think about prevention of these disease for higher risk individuals, just like what you were saying, what are our tools? What’s in our toolbox there? We mentioned vaccines, right?

Monica: Yes.

Eric: So Alex is saying, “Oh my God, we don’t have vaccines for Omicron. We’re doomed.” I’m hearing, you’re saying, “Hey, the vaccines still work.” Where are we with the vaccines for these newer variants?

Monica: They still work, but they don’t work to prevent all mild infections. And because mild infections can tip over older individuals, we’ll talk about the other tools. But they still work, actually. So for example, in my hospital and in your hospital too, sometimes we misclassify people with COVID in places of high vaccination, like here in San Francisco, because we swab everyone who comes into the hospital. But hospitalizations are low. In Massachusetts, they’re actually really cleanly distinguishing whether you’re sick with COVID or you have it in your nose and you’re there for something else. 30% of hospitalizations for COVID are actually there for COVID. 70% are incidental in a highly vaccinated region, which is in Massachusetts. They’re the only state that’s separating out that data. Biden said in February, he’d have all hospitals separate that data, but we haven’t had a chance. So that would be really helpful because then people would look at hospitalizations and say, actually, they’re lower than I thought because-

Eric: And it is interesting because UCSF does that.

Monica: Yeah.

Eric: So we can actually pull data from UCSF, it looks like. A little less than 50% are for COVID. Where I live in Marin County, same with Alex, they also separate it, again, less than 50% are four versus with COVID.

Monica: And South Africa did that in the early Omicron wave in BA.1 and 67% were with not for COVID. So you get more and more immunity in the population. Hospitalizations may not be the best thing unless you’re doing that separation. And I’m looking at COVID death and I keep on seeing them decrease and I’m heartened by that. So going back to the vaccine. So the vaccine is directed actually, not even towards alpha, it stretched towards what we call the OG strain. And that’s very different.

Eric: Original gangster.

Monica: Yeah. I like the gangster. I like it. It used to be called Wuhan HU. And that’s a pretty different strain than Omicron BA.1, and now BA.2.12.1 and then BA.4 and BA.5 are in South Africa. So the antibodies don’t work as well. 32 mutations across the spike protein difference, at least, with the Omicron versus the OG. So the antibodies don’t work as well. And antibodies is what protects up here in the nasal cavity because IgA mucosal antibodies, they don’t work as well. We can get mild infections. We have a lot of mild infections right now in San Francisco, because we have low rates, natural immunity. We are very closed down compared to other states. But that severe disease is still being protected. That’s your T cells and B cells. They’re adaptive and they’ll always protect you.

Monica: But who needs the antibodies the most? It’s people who are older that you treat that rhinovirus, adenovirus, very mild cold infections can make unfortunately, people who are older with multiple comorbidities, sick. We don’t have anything for rhinovirus. I couldn’t give anyone anything for rhinovirus or adenovirus. I, as an ID doctor like you as geriatricians, see older people get tipped over by mild viruses. But boy, we have two huge arms of therapy for people with mild coronavirus who can get tipped over which are monoclonal antibodies and oral antivirals we don’t have. I wish I had a paxlovid for rhinovirus for my 87 year old father, if he gets it.

Eric: We’ll talk about the management, paxlovid, too. So me, Alex, we’ve had two shots and a booster. Older adults should be getting a fourth booster, right?

Monica: They should.

Eric: Where are we with boosters?

Alex: Second booster, fourth shot.

Monica: Second booster, fourth shot. I was actually talking to the White House yesterday because we are trying to figure out, I’ve been trying to help, who needs boosters? I actually think older people need boosters every single year. So that’s going to be a population. Just like they need the higher flu vaccine dose, they’re going to need a booster every year. And that’s what the WHO says. They say vulnerable population should be boosted every year. Who’s vulnerable? I would at least take 65 year olds and above and give them a shot every year. They can get the fourth shot now, or they can get it in summer because sometimes cases will go up in the fall and winter, or they can get it now and get their fifth shot in the winter. But they’re going to need it every year. So you plan on your geriatrician, older patients, getting it every year.

Alex: And is that like the flu vaccine where we have some sense of what might be coming because of early cases on the other side of the world, and we do our best guess of let’s put together a vaccine, and we’re not even going to have time to test it and trials, whatever? We’re going to guess. That’s my understanding of the flu vaccine, we’ll give it to people and we hope we’re right, and some years we’re more right than others.

Monica: Yeah. There’s a very weird thing going on right now with the COVID vaccine, because it’s only developed against, at least the ones we have in this country, against the spike protein. And that is the particular piece, just like with influenza that mutates the most quickly. And the way that the FDA works with an EUA, you have to test it. So we don’t have the Omicron specific variant mRNA vaccine. And like you just said, Alex, at the beginning, by the time we get to fall, if we have BA.5 Here, then the BA.1 subvariant vaccine may not work as well. But two things. One is that when you give a boost, you actually boost their B cells and T cells. And B cells are adaptive and they will make variants. They will make antibodies against the variant they see.

Monica: So by boosting an older person, you’re stimulating their B cells. And there have been plenty of papers about this one recently in Cell that shows that those B cells will be stimulated to go and produce BA.4 Or BA.5 Antibodies, whatever they need to produce, because it’s not like they’re stocked full of antibodies and then they release them. They adapt and produce and evolve their antibodies based on what they see. So they should be able to get the BA.5, but you got to boost their B cells when they’re older. It’s going to probably be the same vaccine right now.

Monica: And then second, and I’ve been really pushing for this. There’s a whole virus vaccine called Covaxin, that’s in India. Sinopharm and Sinovac don’t work as well there. They don’t have a good adjuvant. Those are the Chinese made whole virus vaccines. This India one was designed with an NIH adjuvant, NIH funded adjuvant.

Monica: It’s very good. And the FDA said, if we just test it in 600 Americans, make sure it doesn’t somehow influence them differently than Indians, they’ll approve it here. So I am pushing, pushing, because I want Covaxin because I want people to see the whole virus. Who cares how many spike protein mutations you have? Seeing the whole virus really protects you. So I want that to be our booster every year.

Eric: What about nasal vaccines?

Monica: I’m going to get that when I go to India. I’m going to go get Covaxin. I’m going to India the summer. And then the third thing I want to say, and this is really important. You said these variants keep on coming. You know how they keep on saying that they’re Omicron, they’re still Omicron? They are still Omicron and they’re not that different. Delta and Omicron were really different. It’s actually we’re narrowing our variants.

Monica: And there was a stat article on May 3rd that I’d encourage people to read where it said COVID is becoming like the flu. Never was like the flu before, but now it is. May 3rd. And it said, actually it’s becoming more predictable. It’s not mutating that much. These are little offshoots. They’re like little twins of each other, but they’re not massively different human beings. So think of them as it’s actually narrowing because so much more people have immunity that hopefully, we’re not actually getting wildly, vastly different variants. They’re kind of little offshoots. Read that article, it will make you feel better. Stat May 3rd. It doesn’t say COVID is exactly like the flu. It says it’s basically starting to look like the flu. It’s being more predictable. We know what’s happening with transmissibility and we can get it.

Eric: There’s some talk about nasal vaccines too.

Monica: Yes.

Eric: Do you have hopes in those?

Monica: I do actually, because in that movie Contagion, they were giving each other nasal vaccines and everyone looked really happy.

Eric: And Contagion got everything right so far. [laughter]

Monica: So I think nasal vaccines are excellent because the idea there would be these antibodies are not working as well. How many people have you heard of that get, after a booster, a mild infection? Our department chair is always tweeting, and I think there was a fourth shot and then a mild infection in a family member. So it’s not preventing all infections, even a fourth shot. But because these antibodies up here don’t work as well, what a nasal vaccine would do would be to produce IgA up in your nose. And that would prevent you from even getting a mild infection. That would be great because mild infections at the moment with our current tools are not preventable. Sometimes people are very upset about mild infections. Many others have said, “I can live with a mild infection.” But they have to be preventable in older people, which we’ll talk about later because that can really tip them over.

Eric: Okay. Another preventative hot topic, masks. What do we know about masks to date, after two and how many months of COVID, two years and so many months? Where are we with the science of masks?

Monica: Yeah. I’ve really looked into this because I partially feel responsible for masks because I wrote this article in March of 2020, and it was being reviewed. And then the CDC suddenly recommended masks. But I wrote an article with my division chief where we said everyone should mask, universally, all the time. So I feel really responsible because I wrote that article as one of the first articles in OFID that said let’s all universally mask. And so because of that, I feel responsible to look at the mask literature and not just kind of reflexively say masks work, masks work. Like what a non nuance statement like. So I’ve really looked at the mask literature.

Monica: I’m going to put it cleanly, mask mandates, especially after vaccines, and Eric you’ve shown some of this data, did not make a difference. 37 states didn’t have mask mandates before Delta, like 37 states had dropped their mask mandates. We have a variety of states. And 13 states, including our own, kept on mask mandates and then put them back for Delta, and it didn’t matter. The cases went up, the cases went down and they looked exactly alike in places with or without mask mandates. States, cities, two counties next to each other, OC County, didn’t put back mask for Delta, LA County put back mask for Delta, exact same curve right next to each other. They had the same rate of vaccination. So go up, go down. That’s because when you get infections, you generate IgA and then you can transmit as well. So then the cases go down. So no, I don’t think mask mandates actually changed anything, at least after vaccination. I was really into them before vaccines.

Monica: So what do we know about masks, then? I just wrote a review for Infection Control Today that really went over the data. There was never any evidence in randomized control trials that any old mask prevented respiratory viruses. Surgical masks didn’t prevent colds, in a study in Japan, this is before, respiratory surgical mask didn’t prevent influenza virus in a study before the pandemic. And then a large randomized controlled data study in Bangladesh, in the context of this pandemic, didn’t show that surgical and cloth masks really influenced rates of transmission worth their salt to put on mask mandates. So what we do know is we’re back to the beginning that we knew that N95 masks prevented aerosol, helped you protect you from aerosol spread viruses. So TB, we all wear N95 masks and that does actually protect you. And then maybe KN95s, FFP2s and KF94s, if you wear them, at least in physical science studies, if you’re inside in a crowded where Warrior stadium or something, that should provide you some self protection.

Monica: But putting on blanket mask mandates on everyone, especially cloth and surgical, is not only not doing anything, it makes it seem like you’re doing something. It’s not only not doing something, people are like wearing them in different ways, and the cloth, all the leakage on the sides and same with surgical, but it actually can inhibit human communication. And to be very fair, there was a study in 2013 in family practice, this would be important, I think for those who treat older patients. But this was a family practice study where they randomized 500 healthcare providers to wear surgical masks in routine interactions, 500 to not wear masks, no difference in like anyone getting colds or anything.

Monica: And the patient said, “I don’t like my doctor wearing masks.” It reduced empathy, it reduced the ability to think that you like your doctor. People who had had long standing relationships with their doctors wanted to change doctors. This is really seen also in the school setting, like this idea that human beings need to see each other’s faces. And it is part of our being together. Part of pandemic response is pandemic recovery. Part of our recovery is mental health and seeing each other’s faces. So I’m actually quite against mask mandates, and I hope they don’t put them back in San Francisco, because our cases are rising because that won’t do anything. But anyone who wants to wear a well-fitted mask, like my 87 year old father who just went through chemo inside, I’m encouraging him to do so.

Eric: I got a question for that. So it sounds like one way masking with a high efficiency mask, N95. If you can’t tolerate N95, K95. In the beginning of the pandemic, you’d see somebody walking around with a valve on their N95 and they’d be all like murderer. Like no. I saw another article about maybe we should also rethink one way valves on K95s or N95s.

Monica: Yeah.

Eric: Thoughts on that.

Monica: I wouldn’t do that one way valve. There was actually a Journal of Infectious Diseases article that showed that it was just the best protection for yourself is fit tested N95. This was like a study where they took someone, grade them with bacteriophage. And the best way to keep it out of your nose was a fit tested N95. Now, my father, I always bring them up because he’s 87 and he just went through chemo for B-cell lymphoma. And he loves to go to Costco. Can’t get him out of Costco. Utah’s doesn’t have high cases right now. But if it did, I would please ask him to wear, I wouldn’t get him fit tested. That’s just too hard. I actually trust his vaccine. I will comment on this later, but I wrote a MedScape article that’s coming out tomorrow that shows how well the vaccines work in immunocompromised individuals on chemo. We happened to check his antibodies midstream in chemo, they were high with COVID. These are great vaccines, these mRNA vaccines. So I feel pretty comfortable. But I’ve asked him to wear this KN95 and I feel pretty good about that.

Eric: Okay. One last question about prevention for me. I’m not sure if Alex has any. What’s the role of natural immunity? That’s also been a hot topic. And how should that influence us around boosters as well?

Monica: Yeah, this is a great question. Natural immunity definitely works. It’s worked since the beginning of mankind, otherwise we’d all be dead. But with this particular virus, I think the data is extremely clean now. And there was just a New England Journal study yesterday. Today is May 26th. This was May 25, yesterday, that showed that infection protects you. But what’s the maximal protection, is hybrid immunity. And I know people are saying that’s a euphemism, but it actually is true. Hybrid immunity means either an infection plus a vaccination or a vaccination plus an infection.

Monica: And this study in the New England Journal yesterday showed that even if you’ve had natural infection, please get one dose. I’m really encouraging everyone, especially older people because it deepens that T and B cell immunity to face whatever’s in the future. This was Delta and then facing Omicron. People have said, “Omicron, fix the pandemic.” We have lower deaths worldwide. No one needs a dose. I would give every 60 year old in the globe, at least one dose of the vaccine after having natural infection because it deepens the immunity. And vice versa. If you happen to have gotten two vaccines or three vaccines or four vaccines and you get an infection, your immunity is greater. You just saw the nucleocapsid and cell membrane and hybrid immunity is stronger than either alone.

Eric: Alex, do you have any questions about prevention before we move on?

Alex: No. We got to get to treatment.

Eric: Treatments. So where are we? Let’s focus on outpatient management, nursing home management. Hot one right now, everybody’s talking about paxlovid, rebound. Does it work in vaccinated patients? Who’s it been studied on? I’m pronouncing it wrong probably too.

Monica: No, you are pronouncing it perfectly, paxlovid. Just to remind ourselves again, like an adenovirus who’s circulated at high levels, we have no monoclonal antibodies, we have no oral antivirals. So we actually have tools for people who are high risk. Usually people go through their mild reinfection after vaccination, if they’re young. But I don’t think we could afford that in older patients the types that you treat, and they need treatment.

Monica: So what was paxlovid studied in? To be fair, there was EPIC-HR, EPIC-SR and EPIC-PEP. And all three of those studies didn’t involve vaccinated patients. They were among unvaccinated patients, EPIC-HR, the HR stands for high risk, unvaccinated with multiple risk factors, like the patients you see for developing severe COVID. Unvaccinated, what did paxlovid, twice a day, five days do? Prevented hospitalizations and deaths by 89%. So what it did was it specifically, as a protease inhibitor, prevents the virus from replicating, brings down the viral load quickly and you don’t have a virus to deal with and you don’t proceed to getting very sick.

Eric: And the number needed to treat for that was around like 17. Right? It was a 87% drop. I think it was like 7%, I forget the actual numbers.

Monica: For number needed to treat?

Eric: Yeah.

Monica: Yeah. Like 17. So it’s like really very, very important intervention. Like an oral antiviral, at least in HIV is an incredible thing to get. And it’s specifically targeted against the proteinase inhibitor COVID. It’s not designed for some other virus, like molnupiravir. So it’s great. And then the EUA, if you look at it says give to vaccinated people who are at high risk, because why not? It just made sense. I’m completely for that. Just because it hasn’t been studied and vaccinated people, someone like my father, I want him to get paxlovid if he got COVID.

Eric: And symptomatic COVID right?

Monica: Yeah, you have to have symptoms. Mild to moderate symptoms and you have to be high risk. So to be fair, there’s famous people, Kamala Harris, she had four shots of the vaccine. She didn’t have any symptoms. And to our knowledge, she’s not at high risk for progressing and she got paxlovid. That would not fit the EUA because the EUA says you have to have symptoms. You have to have symptoms. You can’t be asymptomatic. And that comes up with the idea of rebound. Because say you give it to someone asymptomatic. Okay, if I get a little virus in my nose and I’m fully vaccinated and boosted, I actually have to see that virus. The reason I have to see that virus is my adaptive immunity has to kick in, to kill the virus naturally. If I bring down that little bit of viral load that I have in my nose, then my adaptive immunity doesn’t kick in. I kill the virus with paxlovid. And then five days later, the virus comes back and I’m going to have a rebound.

Monica: And I think that is what’s happening with rebound infections, that we’re not using it in populations that even the EUA specifies. We’re using it in asymptomatic people, vaccinated, symptomatic people at low risk of progression to severe disease. And they need to see a little bit of the virus. That’s what stimulate to B cells to make antibodies, IgA, bring it down, T cells come in and swoop in and kill it. So you need your adaptive immunity to work.

Alex: To clarify, so you get treated with paxlovid, kill most of the virus, but a little bit remains in your nose.

Monica: Yes. Because you can see in the phase one, two studies of paxlovid, with the viral load goes down. But it doesn’t get it all the way down to zero.

Alex: Got it.

Monica: So if I get to see a little bit of the virus. I happen to have never had COVID, but when I get COVID, which is relatively inevitable, I’m going to get my hybrid immunity. But I can only get my hybrid immunity if I see the virus. And the people who don’t create antibodies very quickly, and it takes them a while are the same ones need that fourth dose and a yearly boost, older people. I don’t think my father can afford 87 and chemo to see too much of the virus. I don’t want him to take four days to make neutralizing antibodies. I want that virus killed. So he’s going to be a paxlovid candidate if he saw COVID. And that paxlovid is excellent. But if we use it in the wrong populations, and then we tweet that we get a mild paxlovid rebound on the internet, then we are getting so confused. What’s the frequency of paxlovid rebound? I have no idea. I know among Twitter doctors, it seems to be, and relatives, it seems to be very high. 100% of COVID doctors. But I don’t know-

Eric: I saw also some articles around Hong Kong, in mixed populations, vaccinated, unvaccinated, and you’re also starting to see that number needed to treat starting to rise, to 80, 100. I forget the actual amount. So then the big question is, how well is it actually working in vaccinated patients? And all these Twitter doctors are also vaccinated.

Monica: They definitely are, and they have multiple-

Eric: Do you think that’s also contributing to the rebound?

Monica: Yes. I think it is, actually. I think it’s contributing to the rebound and it’s going to make the drug work look less than it is. Actually, I have the same complaint about the booster campaign. By forcing, not forcing, but by really stressing boosters in five year olds, as opposed to over 60 year olds, what you do is you dilute the message and you don’t make it seem like the most important thing we could have done… Hong Kong showed us this, terrible what happened in Hong Kong. They had 30% vaccination rate among their elderly when Omicron hit. And their death rate was so high during Omicron because they had distrust to the vaccine and distrust to the government. Vaccinating and boosting older people is the most important thing you can do. If we reserve paxlovid for older people, because clearly they’re the ones most at risk for going to severe disease, then that drug is going to look good even among the vaccinated. If we use paxlovid among a bunch of vaccinated, younger people who are on Twitter, who write a lot, that drug’s going to look diluted.

Eric: Last question on paxlovid. Who should get it?

Monica: So the EUA is kind of vague, so this is what I would do. The way I think of it is those at risk for severe progression, if they get COVID, whether they’re vaccinated or not. If you actually want to give a really, number to it, if you really look at the data of the booster in immunocompromised populations, it works so well that it’s really only people on B-cell depleting therapies or solid organ transplants, this is a CID paper, which I’ll post in the chat so people can see it, that really didn’t respond well to the vaccines. I really encourage people to look at this MedScape article I wrote tomorrow, because it really shows you that even people with chemo getting solid organ chemo still responds well to the vaccines.

Monica: So if you want to be purist about it, it should be people who are much older, like over 80. They were always most at risk for COVID no matter what and B-cell depleting therapy candidates and people of solid organ transplants. If I was being purist about it, I’d restrict it to those populations. No one’s going to allow me to run the world. So I would just at least think of 65 year olds and up, and then also people who have multiple comorbidities or multiple immuno compromising conditions. And if you try to restrict it to that, I think paxlovid would look pretty good.

Eric: Any other treatments besides paxlovid that’s in our pocket?

Monica: Yes. molnupiravir, I do just want to mention it’s an oral antiviral because it didn’t look great in the MOVe-OUT trial. It’s a nucleoside analog that wasn’t designed for COVID. So I think of it as AZT. It was kind of pulled off a shelf. And it looked like it prevented hospitalizations and deaths in unvaccinated people at risk for severe disease by 30%. But there was just an analysis yesterday, and I want to post this for you, that in immunocompromised patients, molnupiravir looks like it works really well. It doesn’t have the drug-drug interactions with… Just came out yesterday, I was going to post on Twitter. Doesn’t have the drug-drug interactions of paxlovid, five days. I think people should start thinking differently about molnupiravir, I like it.

Monica: Third, Evusheld. So what is Evusheld? Evusheld is a monoclonal antibody. Again, I wish I had monoclonal antibody for rhinovirus so my father never got rhinovirus as a 92 year old when he gets there. But we don’t have that, but we do have that for COVID. And it is a combination of two monoclonal antibodies. And for people who really don’t respond to the vaccines well, or are in the middle of quite severely depleting immunocompromising agents getting something, it prevents getting symptomatic COVID by 82% for a full six months, a single infusion. So this is pretty amazing. Evusheld should be used.

Eric: Is this preexposure?

Monica: Preexposure prophylaxis. Exactly. So it’s approved in December for preexposure prophylaxis. Those at high risk for COVID, we just don’t even want them to touch it. We don’t want them to get COVID, but we want them to live in the world and see their friends and families.

Eric: And that’s a different high risk, right? When we’re talking about high risk, we’re not just talking about all older adults, 65, right?

Monica: Yeah. This is for really immunocompromised populations, very immunocompromised. So someone who’s much older. And for example, going through very B-cell depleting therapy or chemo or something, I would give them Evusheld. Six months, they’re protected for six months for preexposure prophylaxis.

Alex: Do we worry about tachyphylaxis or could they get another dose in six months, if they’re in the same place?

Monica: They can get another dose in six months if they’re in the same place. So far, because it’s a combination of two monoclonal antibodies, it definitely works against Omicron. A lot of our other monoclonal antibodies have fallen by the wayside with Omicron, but this was studied even with BA.2 and BA.2.12.1 is kind of the same and it still works.

Eric: Whatever happened to remdesivir? Is that still something you’re going to recommend?

Monica: I think that remdesivir is also available for outpatient therapy, because that’s what we’re talking about. And this is 10 days of remdesivir as outpatient therapy. I’d rather give someone an oral pill because it has to be IV. So I wouldn’t actually use remdesivir in the outpatient therapy over paxlovid unless I had to. But it’s now approved down to, I believe something like seven pounds of a very young children. And so say a very profoundly immunocompromised child that gets COVID and you’re very worried, they can’t have paxlovid right now, a young child, because it’s not adopted yet for children. So I would use remdesivir.

Eric: Anything else that’s on our outpatient treatment?

Monica: Yes. There is a protease inhibitor coming, which is made by a Japanese company and it is going to have no ritonavir and it looked so good in phase one, two trials. It’s now in phase three trials. No ritonavir and it’s a protease inhibitor directly affecting COVID. That’s probably going to be with us in, I hope a year. And they’re not stopping. People are not stopping with treatments. Everyone’s looking at COVID because there’s money in COVID and because it’s going to be with us. And so there are other new treatments that I hope also will inform RSV and other RNA viruses.

Monica: And that’s why I feel so not depressed because I keep on thinking so much money, as it should be, was put into the pandemic. So much development, development that’s actually going to improve the care of other RNA viruses that we just let people die of, like RSV or influenza. Oseltamivir isn’t that great. And instead, I just see progress on the horizon. And all these tools I’m mentioning to you are medical. They’re not keeping people away from each other. I know I’ve been different in the City of San Francisco than others about that. But boy, I think for mental health, human beings need to not only see each other, but see each other’s faces.

Alex: So you’re giving me hope.

Monica: I want to give you hope.

Alex: Before we get back to Penny Lane though, long COVID. New York Times headline last week that 75% of those who with long COVID were not hospitalized. They didn’t have severe infections. I feel like there are several wild cards with COVID.

Eric: CDC just published something. One out of five, they’re using the word COVID survivors, which is an interesting terminology, have long COVID symptoms or new medical problems.

Monica: That was a very misleading article on behalf, from our major public health agency. So let me just put it cleanly. CDC, just two days ago, like you said, said one in five, quote, survivors, and these were people who had had mild infections often, had a serious medical problem. Let’s just remember how many people have seen COVID in this country. There was a seroprevalence study put out in a very same journal by the CDC, MMWR, on April 26, that said 75% of children zero to 18, have seen COVID. And that’s probably even more because that was by nucleocapsid antibodies and those go downward time. So if you saw it in March, 2020, you may have T-cells but we’re not measuring those. So probably more than 75% of children. And in that study, 60% of adults had seen COVID by nucleocapsid antibodies. IHME, the Seattle modeling company, company or group, estimates that 75% of the world’s population have seen COVID by this time.

Eric: And that was by February.

Monica: Yes. Yes, good point. If one in five people, if 75% of the world’s planet has seen COVID, it’s probably been more. And one in five people had a serious COVID complication. We in the medical community would know it because our hospitals would be full of cardiovascular disease, of pulmonary disease, of other things.

Eric: Yeah. PEs and DVTs was number two in that. We would be seeing PEs and DVTs.

Monica: We’d be having tents with PE management. So it’s simply not right. It was a terribly done study, the CDC study. And for the New York Times to report on it, I was disappointed by that because I felt like they also have fact checkers in house. On the other hand, you assume the CDCs going to put out good data. And it was confusing, but I think we’ve seen a political angle to the CDC through the first administration of COVID, through now this administration through COVID. And they frankly, admitted the MMWR isn’t peer reviewed. So at this point I’m now really confused and I take anything from the MMWR with the grain assault. They once said every child, not every child but many children got diabetes from COVID. Wow, 75% of our children have had COVID, we’d be seeing a lot of children with diabetes. Pediatricians don’t tell me that.

Monica: So I’m very disappointed in the CDC and unfortunately, so is the planet. And what I mean by that is right now, Americans have a 31% trust of the CDC, as of May, 2021. It may even be lower now, and that’s very risky. You don’t want Americans to distrust their major public health agency. I’d really work on an external audit of the CDC at this point. So going back to what’s the incidence of long COVID, two studies come to mind that I think were better done. One is in the Annals of Internal Medicine. We know this, good journal, and it was performed by NIH. I’m going to give them credit. This is our major research agency. This was published the day before that disastrous CDC study. It looked at people who had COVID and not had COVID. You always have to compare people who have not had COVID. Because for people right now to be depressed, mental illness, anxious-

Eric: Anxiety. Like who doesn’t have all of those things?

Monica: Who doesn’t have it? Alex, before this, was looking very sad. We all feel awful.

Eric: Yeah. Everybody on Twitter has depression and anxiety, just because of Twitter.

Monica: MDs on Twitter. Twitter, man, that is an echo chamber of an abyss of misery. So really, I think about this NIH study and because I respect the NIH, NIH funded, and really respect their work. And they have put out these big grants. And so what they did is they looked at people who had COVID and didn’t have COVID, and looked at a number of health conditions, and importantly, all these biomarkers. Because people are saying, “Could you have autoimmune antibodies? Could you have inflammatory biomarkers?” And they showed zero difference if you hadn’t had COVID and had COVID, in any of these long COVID markers. I thought it was a well done study. It was very rigorous.

Monica: The risk factor for having long COVID symptoms, in that study at least, was having a history of anxiety. That was a major risk factor, and also being female gender. So I do think that us looking at anxiety and us looking at mental illness, because that is also a treatable condition, we have the duty, as physicians, to think about mental illness right now in our patients. And then also, other studies have shown that vaccinated people don’t seem to get long COVID, if they get a breakthrough, it’s a big Israeli study. Send you all these studies to post on your podcast.

Eric: If you want to prevent long COVID-

Monica: Get vaccinated. Vaccination is the best thing anyone could do. We got vaccines within nine months.

Eric: What about paxlovid? Because this is also coming up, like, “But I don’t want long COVID.” So maybe that decreases my chance of getting long COVID.

Monica: There were three people whose long COVID symptoms got better with paxlovid. I don’t know if that’s placebo or not. Unless we get a randomized trial, I think we can’t assume that’s going to happen, that paxlovid would take away long COVID symptoms. But fluvoxamine, as one of the treatments, probably works on the depression, anxiety pathway, and it’s terribly important for us to treat people for what they’re having. One in five people with COVID, with mild COVID, do not go on to get a serious medical condition.

Eric: It’s really hard too, because the definitions. We definitely see people who are post ICU from COVID with incredibly bad lung disease from COVID.

Monica: Severe COVID can lead to long COVID symptoms. Absolutely. And that’s why I’m so grateful we have the vaccines because get vaccinated to prevent severe COVID, get vaccinated to prevent long COVID.

Eric: Monica, my last question. You got a magic wand, running out battery. You can do one thing around COVID with this magic wand, what would it be, influencing policy, treatment, prevention?

Monica: Approve two new vaccines in the United States, Novavax, which is being reviewed on June 7th, which is a traditional vaccine with a protein and an adjuvant. Because I think that we cannot underestimate, in the medical community, the deep distrust of the mRNA vaccines because of misinformation. I want people to have that option. And the second is getting Covaxin, a whole virus vaccine. Give that once a year to everyone and we have a great vaccine, way better than influenza, which are just spike proteins. And we can keep this under control. Those two things.

Eric: All right. Thank you Monica.

Monica: And let people see each other and stop scaring people. I’m going to say this, I’m going to say it because only this podcast allows me to say it. Stop scaring people. Don’t put your stories of a mild COVID infection on Twitter.

Eric: Has fear-based messaging worked for any public health intervention?

Monica: Never, never. Monkeypox, you can see the same Twitter doctors who used to say stay away from COVID and never let your children go to school say, “Let’s let… People should have sex.” Of course, people should have sex. Of course, people should see each other. Of course, people should go to Tears for Fears, which is a concert coming next week I’m going to. It’s June 2nd.

Eric: We should have played Tears for Fears.

Monica: Human beings should see each other. And this fear-based messaging was so severe in California and San Francisco, and it just took our already an anxious place and it made it so much higher. And I thought it was really strange. Please stop scaring people. We have so many tools. I am just so, so optimistic about COVID.

Eric: Man, we could have played. Everybody Wants to Rule the World. Mad World would’ve been a great one. Mad World.

Alex: Not only did I learn a tremendous amount, but Monica managed to work Tears for Fears and the Warriors into the podcast.

Monica: And go to Warrior games if that’s your thing. Go.

Alex: Yes, it’s definitely my thing.

Monica: Okay.

Alex: Go Warriors.

Monica: Excellent.

Eric: Since we talked about sex, let’s hear about this song that’s all about sex. [laughter]

Monica: We just found out.

Alex: (singing)

Eric: Monica, a very big thank you for joining us on this GeriPal Podcast.

Monica: Thank you so much for having me.

Eric: And keep up the amazing work. And to Archstone Foundation, thank you for continued support and to all of our listeners.

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