White House COVID Chief on Why Paxlovid Is Underused

; Ashish K. Jha, MD, MPH


January 31, 2023

This transcript has been edited for clarity. This interview was conducted on January 24, 2023.

Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief of Medscape. I'm really privileged today to be joined by Dr Ashish Jha, the White House COVID-19 Response Coordinator, who has weathered a tough pandemic era since he joined the administration. Welcome. It's great to have a chance to speak with you.

Ashish K. Jha, MD, MPH: Thanks for having me here. I'm really excited to spend some time with you.

Topol: Several weeks ago, you called attention to the Paxlovid issue, whereby a lot of people of advanced age (65 or older) were not the people who were most frequently getting Paxlovid. You called it out. Could you review where we stand on that?

Jha: You've written and talked about this. Paxlovid is extraordinarily effective at keeping people out of the hospital, preventing death and serious illness. With SARS-CoV-2, older people are at highest risk.

That's always been true in this pandemic. Right now, when we look at the 400-500 people who are dying every day, almost all of them are over 75. What is interesting to me — and not in a great way — is that when you look at Paxlovid use, it certainly goes up with age. But once you get to about age 75 or so, it actually starts declining very rapidly.

Many of the people who are dying today did not receive Paxlovid. It's a major problem. We can talk about what the issues might be, but people in their 70s and 80s should not be denied treatments. Too many of them are not being treated when they become infected with SARS-CoV-2.

Topol: As you underscored, the studies — not just the randomized trial, but also subsequent effectiveness studies — have shown a 90% reduction in hospitalizations and deaths in high-risk groups treated with Paxlovid.

After you pointed this out, Medscape conducted a survey to try to find out from clinicians, including physicians, pharmacists, and nurses, why people of advanced age aren't getting Paxlovid.

They had over 1500 respondents. Number one on the list was fear of drug interactions. There's a lot of data to suggest that for the vast majority of drugs, there are no interactions of concern because you can just stop the statin or other medication for 5 days.

What do you think about that reason for not prescribing Paxlovid? People of advanced age are frequently taking other medications. Do you think that's a reason to withhold Paxlovid?

Jha: It's a really interesting question. When Paxlovid first came out about a year ago, there was a lot of confusion about how serious these drug-drug interactions were. As you know, Eric, over the past year, a whole bunch of clinical societies — organizations such as the Infectious Diseases Society of America (IDSA) and others — have put out guidance for physicians on how to think about drug-drug interactions with Paxlovid.

The truth is that almost everyone can take Paxlovid no matter what medicines they're already taking. In fact, the IDSA identifies only two drugs that could lead to serious drug interactions: rivaroxaban and salmeterol.

For other medications the patient is taking, you might just have to make modifications, such as lowering the dose or stopping the medication for the 5 days of Paxlovid treatment. We do that all the time clinically. For example, for a patient scheduled for a dental procedure, we often stop their blood thinner temporarily. If a patient becomes dehydrated for some reason, we will often stop their blood pressure medicine for a short period of time.

These are not unusual situations for clinicians to manage. It's another way of saying there is no good reason for patients to be denied treatment. For patients taking rivaroxaban or salmeterol, we have other options for COVID-19 treatment, such as Lagevrio (molnupiravir) and intravenous remdesivir.

In my mind, there is no good reason not to treat older and higher-risk patients who have COVID-19. Most of the time, you can use Paxlovid.

Topol: The second most common concern in the Paxlovid survey was rebound. Physicians were saying they don't prescribe Paxlovid because the patient will rebound. And some high-profile people have experienced COVID rebound.

We did a systematic study with Michael Mina and the group at Scripps, doing PCR and rapid testing of hundreds of people over the course of several weeks. Compared with people who didn't take Paxlovid, we saw rebound (defined as a positive COVID test or symptoms) in only about 10% of those who took Paxlovid.

Although some people in the Twitterverse and other places believe that Paxlovid rebound is really common, when you look at it carefully, the rates of rebound aren't that high. And we also see rebound in people who were not treated with Paxlovid.

What do you think about rebound as a reason for not giving treatment?

Jha: Unfortunately, it has become a bit of lore. It didn't help when very high-profile folks like Dr Fauci and the President of the United States got rebound. But I always say, anecdote aside, you have to go to the evidence. And in that study, you pointed out some of the best evidence we have in a contemporary population.

I want to reemphasize for clinicians what you saw among people who did not get Paxlovid: About 9% of those people also got rebound. Among people who took Paxlovid, that number was higher, at 14%. It's a very small difference and not statistically significant, so there was no statistical difference in rebound between those two groups.

So it's not even clear that there is more rebound with Paxlovid than with no treatment at all. But when rebound occurs after Paxlovid, which is infrequent, it doesn't lead to people getting super-sick and being hospitalized. You have to ask yourself, why aren't you giving Paxlovid?

If your number-one goal is to make sure that high-risk patients don't end up getting sick or admitted to the hospital, you tolerate a tiny bit more rebound for the massive benefit of preventing serious illness. It is the biggest clinical no-brainer. Rebound has gotten a little bit overemphasized, and social media is not helpful.

Every time somebody has rebound, they report it. The millions of people who have not had rebound are not on Twitter saying, "I didn't get rebound." That is classic bias in information ascertainment. And as clinicians, we ought to look beyond that and go to the evidence.

Topol: I certainly thought that, when we did the study, the rebound rate was going to be at least 30%-40%, based on the bias of reporting, as you rightly highlighted. The other thing that's interesting about Paxlovid, which we didn't expect, is that because of the inactivation of the virus, basically stopping replication soon after the drug is taken, there might be a reduction of long COVID.

And the study from Veterans Affairs suggested that Paxlovid treatment could reduce long COVID by at least 25%-26%. That seems like a bonus factor, but it doesn't get adequate attention. Do you buy into that possibility?

Jha: It's an observational study, so we're always going to be thoughtful about not overinterpreting it. But it's an observational study in the context of logic and reason about what causes long COVID. Now, we think there are multiple factors that contribute to long COVID.

It stands to reason that if you shut down viral replication, you're going to get a different kind of immune response. You may get less immune dysfunction. One thing we think may be causing some long COVID is persistence of the virus. If you shut down viral replication with a really powerful antiviral, you're going to get less persistence of virus.

There are a lot of mechanisms by which it makes sense to me that Paxlovid would reduce long COVID. We're going to get more data on this. But it's one more reason to use it. At the end of the day, when you have a powerful antiviral like Paxlovid, you should begin with the question, why am I not giving it to the patient, as opposed to, why should I give it to the patient?

I'm 52 and, thankfully, relatively healthy. I would take it. I'm eligible. And I have encouraged my family and friends to take it. I've been saying to my clinician friends, with every patient over age 50 with chronic conditions, you have to ask yourself why you are not treating this patient's COVID-19 infection.

And if there's a very good reason to not treat them, fine. But other than that, your default — the standard of care — should be to treat people with infections. You've got a viral infection, you've got a very good antiviral — you should treat that person.

Topol: When you took over leading the coronavirus response, you had limited tools. You weren't getting billions of dollars of support from the government, so you did something with your colleagues that was actually pretty much unprecedented. You gave pharmacists the power to prescribe Paxlovid to avoid the hangup of getting hold of a physician. What was surprising in the Medscape survey is that pharmacists are reluctant to prescribe Paxlovid. Comments about that?

Jha: This was a decision made by the FDA. First of all, I'll take a step back and say I think pharmacists are among the most underutilized healthcare providers in our healthcare system. They have a lot of capability. When you think about a drug like Paxlovid, where the main concern may be around drug-drug interactions, well, guess who understands drug-drug interactions really well? It's pharmacists.

That said, for some pharmacists, because they're not used to prescribing, often to complicated patients, there may still be a learning curve. I was also surprised to see the low rates of prescribing among pharmacists. My hope is that over time, with more comfort and experience, we will see more pharmacists prescribing Paxlovid.

It's a really important access point for a lot of Americans, particularly poor Americans who often don't have a regular source of care. But they go to the pharmacist twice a week or a couple of times every month to pick up medicines. They know their pharmacist. The pharmacist knows them. It's an important access point that we have to figure out how to bolster and support.

Topol: As the pandemic has gone along, we've lost the ability to use monoclonal antibodies that were initially quite potent. We had different choices, but eventually, the more recent variants have outrun our ability to have effective antibody treatments. We're left with a pill rather than an infusion of an antibody or Evusheld, which is a preventive tactic for people who are immunocompromised.

We are left with a drug that eventually could develop resistance — mutations in the enzyme responsible for replication in some strains of the virus. What are your thoughts about the fact that we have little else to offer people at high risk?

Jha: This is one of the really unfortunate side effects of congressional inaction and lack of funding. We want to have an expanding toolbox, with more treatment options, but what we actually have is a shrinking toolbox.

Two years ago, we had monoclonals. When one monoclonal stopped working, we had two more in our toolbox and one of them could get pulled out. That existed because we had funding and we could work with companies and say, "If you build it, we'll buy it." And that created the incentive for companies to build it. We had a nice number of monoclonals. And if we lost one or two, we could manage.

Once the funding ran out, the companies stopped investing in new monoclonals. No new monoclonals have come onto the market or have been made by a company in almost the past year. And so now when we lose it, we've got nothing to replace it. We're finding ourselves in a worse place in terms of therapeutic options.

It's fantastic that Paxlovid is working as well as it is. We do have Lagevrio, which the clinical data suggest is not as good, but it has some benefit. And then, obviously, we have remdesivir. But the truth is that the mainstay now is Paxlovid. We don't want to be so reliant on one medicine, especially when in the laboratory we've seen the emergence of resistance.

We worry about what happens if that becomes clinically widespread. We will find ourselves in real trouble. We're trying to figure out what we can do in the administration to try to encourage development of more therapeutic options. It's not where we should be as we start our fourth year of this virus. We should have more tools in our toolbox, not fewer, over time.

Topol: That gets us to what you have touched on, which is the lack of support, the recognition that we're not done with this virus. We need other treatments and ways to prevent infection. You've been a champion. You have tried everything you can, as far as I know, to get backing for nasal vaccines and vaccines that would achieve mucosal immunity, whether that is oral vaccines or next-generation vaccines that would be more durable and variant proof, with fewer side effects.

But you've hit obstacles — a lack of support. What is the basis for this?

Jha: In some ways, we've been the victim of our own success. The mRNA vaccines that we have right now are extraordinarily good at preventing serious illness and death. We have had a 10-month period where death numbers have been relatively low. They are still too high, but relative to the earlier part of the pandemic, they are much lower.

This changes the discourse on making the case for more support. It becomes harder because people say, "Well, our hospitals are not overwhelmed. We're not seeing 2000-3000 people dying every day." Well, thank goodness. We don't want to be seeing that.

But the numbers of people dying each day (400-500) are still too high. I think we can dramatically lower that. We can do much better, but we're going to need more tools in our toolbox. We have made that case pretty aggressively to Congress.

We're not done. We're going to look in every place we can within the federal government and go back to Congress as we need to. We've got to keep fighting this fight because a lot of people are dying unnecessarily of this virus. The virus is going to be with us for a very long time, probably for the rest of our lives.

We need a long-term strategy for managing it that doesn't lead to 150,000-200,000 Americans dying every year. That is an unacceptable toll. We have the ability to do something about it. And certainly in the administration, we're not giving up.

Topol: What's sad here is that the science is pretty extraordinary. For example, you mentioned the monoclonals. So many potent, variant-proof monoclonals have been identified, most of them naturally occurring in certain treasure-chest people who have developed these antibodies. But they're not being pursued because of funding not being available.

It extends to nasal vaccines, which are being developed in India using licensed intellectual property from Washington University. We're seeing them developed in Mexico with licensing from Mount Sinai in New York, and, obviously, in China and other countries.

Where the science is solid but there's unwillingness to take on risk and put up the funding, does this fall under the complacency umbrella? Or is it just that people don't believe these reports? What's going on here?

Jha: I think it's complex. First of all, you're absolutely right. The science here is beautiful and has been moving in the right direction. A lot of that science is being done here in the United States. I remind our friends up on Capitol Hill that while these nasal vaccines and mucosal vaccines are good for COVID, that technology is going to help us with the next coronavirus outbreak. Because the truth is, three deadly coronaviruses have popped up in the past 15 years. Anyone who thinks that we're done with coronaviruses is kidding themselves. We may very well get a pandemic flu at some point. Knowing how to build intranasal vaccines can be incredibly powerful for any respiratory pathogen.

So there are some very important long-term investments here. I don't think it's anti-science. I just think people feel that we've made so many investments for COVID and we're in a better place. So we have been making the case that this goes well beyond COVID. This is really important for the long-term security of our nation. I'm finding more and more people beginning to understand and get motivated by that.

Topol: One thing that strikes me is that people tend to think of SARS-CoV-2 the same way they think of the flu. For example, the nasal vaccine FluMist is just not that potent. It's only useful in certain patient populations. Tamiflu is not a very strong pill. The flu vaccines don't work that well.

Now here we have a virus for which vaccines were — before Omicron set in — 95% effective against every outcome, including infections and transmission. We have Paxlovid, which makes Tamiflu look like a weak hitter. We have a completely different virus that is potentially much more susceptible to a nasal vaccine, and we've seen some success.

Do you think this idea that flu as a precursor is part of the reason why people have a defeatist attitude about coming up with better treatments, such as nasal vaccines?

Jha: It's a really interesting question, Eric. I hadn't thought of it that way. But you're absolutely right. First of all, flu becomes our kind of default comparison. People have done this from the beginning: Oh, it's just like the flu or it's not like the flu. When people say, "Oh, it's not any worse than getting the flu," I say, "If you've ever had the flu, it's pretty miserable."

A bad flu season kills 30,000-40,000 Americans. It is a bad virus. That isn't something we should be trying to achieve. But you're absolutely right that our tools against the flu have never been terrific. They're just not that great.

And our vaccines — some years are good, some years are a miss. Tamiflu is very weak. It doesn't have a large impact on hospitalizations or deaths, the outcomes that we really care about. We have the ability, with these investments, to make COVID far more manageable. We can tame this virus. But we're going to have to make those investments. But let's not use flu as some golden ideal. We should be able to do much better than that.

Topol: The FDA is meeting this week, basically to come up with a plan for boosters that was used this past year — picking a bivalent in June, rolling it out in September. That had a mixed response but particularly poor uptake among Americans.

Even among those who were at high risk and would benefit particularly from Paxlovid, less than 40% have had a booster. How are we going to just keep along with this booster plan when there's progressively less interest in getting these shots? There's obviously the reactogenicity and side effects that people don't want to sign up for, especially with boosters that don't block infection.

People want boosters that block the infection like they used to. Are we listening? Or are we going to basically continue to have a problem getting reception for more booster campaigns?

Jha: There are several really important questions embedded in that. Let me take them all on. First, there is no question that people want a vaccine that prevents infection and blocks transmission. And that's where we've got to invest in mucosal vaccines because that's our best bet there.

This is one of the reasons we've made this a priority in the administration. We've gone to Congress multiple times. We're actually doing a lot with the resources we have, and our hope is to do more. The American people want it. It's clearly scientifically important for public health. We've got to do that.

In terms of the booster campaign, it's been a long 3 years and people have had a lot of shots. People often say to me, "Well, this is my fifth shot or six shot; how many shots do I need?" And I always say, "I think I've probably gotten 28 shots of the flu vaccine." Sometime in my early 20s, I started getting the flu vaccine, and I get it every year. I don't go in the fall and say, "I think this is my 29th shot"; it's just my annual flu shot. I get it because it prevents me from getting seriously sick over the flu season. We need to move toward something like that, where it just becomes a routine part of how you keep yourself healthy. We'll see what FDA comes out with, but for a majority of Americans, you get it once a year.

If you're a 35-year-old, relatively healthy person, you get your COVID shot in the fall. And yes, you've got waning. You may not have as much protection against infection in the spring. But you're relatively healthy. And you're going to do fine. Maybe for higher-risk people it's a bit of a faster cadence. We'll have to see.

But the bottom line is that we have to routinize it and build the vaccine tools that allow us to get out of the cycle that we're in right now. In the short to medium run, if we can get people vaccinated once a year, maybe high-risk people a bit more often than that, it will drive deaths way down. And that's what we need to stay focused on.

Topol: We'll be cheering for you and hope that there will be a break in this relative impasse. We all acknowledge that this virus is here for many years ahead. And we don't know whether there'll be a new family, like an Omicron that we've had for over a year, which is even more formidable as a challenge. And that's why being prepared would be a whole lot better than where we stand now.

Thanks so much for joining me. I really enjoyed this conversation. I think it's been illuminating about better uses of Paxlovid that override some of the concerns seen in the Medscape survey. And hopefully, over time we'll have a better armamentarium to deal with this virus and someday even get ahead of it rather than always chasing its tail. Thanks so much.

Jha: Thank you for having me. It was really a pleasure.

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