COVID Transmissions for 11-8-2021

Another oral antiviral is coming!

Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.

It has been 722 days since the first documented human case of COVID-19. In 722, the Battle of Covadonga marked the beginning of the Reconquista, the retaking of the Iberian peninsula by Christians from Muslim forces. The process of the Reconquista was a bloody, brutal, sectarian conflict that lasted another 7-and-a-half centuries. And the end of it led right into the Spanish Inquisition, also not a great moment in history.

Preferably, the end of COVID-19 won’t take nearly so long, nor be as violent and divisive.

Today we’ll talk about the new Pfizer antiviral, ritonavir, which along with monupiravir is poised to change how we deal with COVID-19 as a society. There’s very good news there, and it’s a great way to start the week.

Bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.


Pfizer oral antiviral reduces hospitalizations or death by 89% in trial

There is a new oral antiviral option on its way: A combination therapy consisting of the compound PF-07321332 and ritonavir, brand name PAXLOVID (for the combination), from Pfizer. This is because in the interim analysis of the EPIC-HR trial of PAXLOVID1 in patients with high risk for severe COVID-19, the data were so good that they passed the bar for obvious trial success. These results just recently became available: https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate

The headline on this one says the key finding: that the rate of hospitalization or death, as a joint event outcome, was reduced by 89% relative to placebo. Something else that jumped out at me is that while there were 10 deaths in the placebo arm, there were no deaths in the PAXLOVID arm. These rates are out of 612 patients in the placebo arm and 389 in the PAXLOVID arm.

The PF-07321332 component of PAXLOVID is a 3CL protease inhibitor, and the ritonavir component is a metabolic booster of protease inhibitors.2 3CL protease is a product of the SARS-CoV-2 genome, so PAXLOVID is not likely to be a very broad spectrum antiviral that could target a wide range of other viral illnesses—in this way, it is different from molnupiravir, which may have wider applications.

The 3CL protease is a key part of the SARS-CoV-2 lifecycle. In the course of replicating, SARS-CoV-2 produces large protein products known as “polyproteins,” each of which is made from a single gene. These polyproteins need to be broken down into smaller functional protein units by a specific protease—protein-processing enzymes—so that these smaller units can do their work in the viral life cycle. This strategy of polyproteins being processed to produce smaller functional units is shared with some other viruses, and they are evolutionarily advantageous for a variety of reasons. One of them is that it helps the virus have a more efficient genome; every gene needs control elements, and by making multiple proteins off of a single gene, the need for additional gene control elements in the genome is reduced. With limited room inside the virus particle, this saves valuable space in the genome.

By inhibiting the 3CL protease, which processes a SARS-CoV-2 polyproteins, the virus is unable to complete its life cycle. That leads to the overwhelmingly positive results that we see in this clinical trial.

In the wider COVID-19 context, this story feels similar to the news with molnupiravir, where an oral antiviral has yielded eye-popping results that will get the product on the market and treating people with early COVID-19 as soon as possible.

What’s really interesting here in a wider sense is that we are about to enter a world where COVID-19 can be treated in high-risk patients with a pill that is administered orally. That’s the model that we’re always hoping to get into with infectious disease treatment; people expect to be able to go to their doctor to get a pill, take that pill, and get better. That is an outpatient approach that reduces burdens on the system and reduces deaths in the patients we’re trying to treat.

These two new options—which I’m sure will eventually be tested in combination—start to move us into that world. However, these options both need to be started early in the disease course. That leaves us with a problem in countries where the testing paradigm still relies on time-intensive PCR-based tests. In the administration of these oral antivirals, a couple of days can make a huge difference. To make sure that the right patients are being identified, we need testing to turn around faster than that.

Rapid antigen tests, which give results in minutes, and are cheap enough to be administered every day, offer a solution that might work here. It’s worth picking up a few to have in your home—it’s about $15/test in the US currently, and much much cheaper in other countries. If you start to feel sick at all, take one each day until symptoms subside. There are no downsides to this, because a negative result gives you peace of mind and a positive result tells you information that you need in order to be able to treat your infection properly—and also to keep others safe.

If we want to live in a future where wearing masks can go away, rapid antigen tests and oral antivirals are going to be a big part of that future. This recent news is a step in that direction.


What am I doing to cope with the pandemic? This:

Re-reading: Swordspoint, by Ellen Kushner

Ellen reads this newsletter, and is one of its best supporters. So, I’ll be upfront about the fact that I’m reading her debut work yet another time because her enthusiasm about what I’m doing with this newsletter made me nostalgic for when I first heard her read her work (from a Swordspoint sequel) live at the New York Review of Science Fiction reading series.

In other words, this plug is both highly conflicted and highly biased—both of those in the positive direction, because Swordspoint is awesome.

It’s a “fantasy of manners,” focusing on swordplay, social intrigue, and all kinds of romances in quite a gender-agnostic fashion. Nostalgia and having made a new friend brought me back to it, but the escape to a world driven on very subtle human interactions is really welcome after these years so isolated from others in the midst of this pandemic.


You might have some questions or comments! Join the conversation, and what you say will impact what I talk about in the next issue. You can also email me if you have a comment that you don’t want to share with the whole group.

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JS

1

Normally I try to avoid using brand names, but because the therapy is a combination, it is easier to use the brand name in this instance.

2

In detail, ritonavir is an inhibitor of CYP3A4, an enzyme that processes protease inhibitors in the liver, degrading them so that they can be eliminated from the body. By adding ritonavir to the cocktail, CYP3A4 is inhibited, and the other compound in PAXLOVID is stabilized in the bloodstream so that it can reach the cells it needs to reach in order to fight COVID-19.