Paxlovid Escape Mutations?

President Biden's two and a half-week Covid-19 marathon

President Biden continues to harbor the COVID-19 virus (SARS-CoV-2) in his body. He first contracted COVID-19 on July 21, two and a half weeks before the present. Is this because of immunosuppression - due to his heavily boosted status, or for some other reason? That being said, the single antiviral drug regime of Paxlovid may also be causing the virus to stay in his body for a long time, an effect otherwise referred to as “the rebound” effect:

“The hypothesis is that the immune system didn’t have a chance to see the full extent of the virus, since Paxlovid suppressed replication early in disease,” Dr. Roberts says. Scientists are studying the effects of longer treatment durations, longer periods of isolation, and other ways of managing the problem, he adds. (Scott Roberts, MD, a Yale Medicine infectious diseases specialist.)

I believe that the word “rebound” is a misnomer in this context. The virus has never left President Biden’s body. It is still circulating, it was just at a fairly undetectable level for a while. What could possibly go wrong? Oh, I know! Viruses resistant to Paxlovid are spawned, the virus population explodes and then the “rebound” effect is observed -only this time with Paxlovid resistant strains.

Paxlovid manufacturer Pfizer and the Food and Drug Administration have both acknowledged reports of rebound COVID-19 cases associated with the drug.

This is truly the worst case scenario for a single mechanism of action drug used as a therapy against COVID-19, as described in more detail below.

But it isn’t just that Paxlovid causes the virus to stick around for weeks on end, it doesn’t work very well either: “Warning! Biden’s Pushing Paxlovid, the Pfizer Flop Drug”

Upon launch, Pfizer said their new anti-viral drug Paxlovid cut hospitalization and death by 90%. An updated, more recent analysis from 1,153 patients (out of a possible 2,246 patients) showed a lackluster, non-significant 51% relative risk reduction.

A sub-group analysis of 721 vaccinated adults with at least one risk factor for progression to severe COVID-19 showed a non-significant relative risk reduction in hospitalization or death (treatment arm: 3/361; placebo: 7/360).

How can we control SARS-CoV-2’s evolution of resistance to drugs?

SARS-CoV-2 (the cause of COVID-19) is an RNA virus, just like HIV is an RNA virus. RNA viruses evolve very rapidly and have a lot of genetic mutations. And just like HIV, the COVID-19 virus evolves so quickly that it evolves right out from under single “mechanism of action” (single agent) drug therapy. When a patient begins taking Paxlovid, it appears that the drug keeps many of the viruses from reproducing. Because some of the new mutations happen to have a certain level of resistance to the drug, some viruses do survive. Because of COVID-19’s speedy evolution, the virus responds to selection pressures quickly. So, viruses that happen to survive the drug are favored and then resistant virus strains evolve within the patient. When a patient is immunosuppressed and doesn’t clear the virus (as seems to be happening with Paxlovid), then this evolution has a longer runway to evolve before the virus is cleared by the body. These new strains are then spread through out the population. So, other people can contract the escape mutant resistant lineage. A new variant is born.

When HIV single dose therapies failed, physicians soon realized that basic evolutionary theory leads to a solution from this dilemma. That is evolution of resistant viral strains can be delayed by prescribing a multi-drug therapy. That is why so many early, multi-drug treatment COVID-19 docs use drug cocktails.

So why is it, that the FDA, knowing this - did not chose to exclude immunocompromised individuals from using the drug?

Severely immunocompromised patients can experience prolonged periods of SARS-CoV-2 replication, which may lead to rapid viral evolution. There are theoretical concerns that using a single antiviral agent in these patients may produce antiviral-resistant viruses. Additional studies are needed to assess this risk. The role of combination antiviral therapy or a longer treatment duration in treating severely immunocompromised patients is not yet known. 

Right now, patients consuming the Pfizer drug as a single agent therapeutic are increasing the risk of spawning resistant escape mutant variants. If you want a case example of how this works - just look to President Biden and his current treatment plan. That is, round three of the current treatment plan. That is two and a half weeks of having circulating virus in his body. That virus is busy evolving to escape the drug and/or his vaccine.

Now, what we learned also from HIV is that the virus mutates so rapidly, that it evolves so quickly, that it evolves right out from under vaccines - particularly in immunosuppressed patients, who do not rapidly clear the virus. Then vaccine escape mutants are generated with are resistant to the vaccine. So, the fact that Paxlovid is prolonging the virus in the body can only lead to more vaccine escape mutants.

One might think that Pfizer and Moderna wanted to prolong this outbreak…

Naw, that would be too cynical, even for them, right?

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“I think some clinicians have unfortunately written off Paxlovid as not a good option for patients who would very much benefit from it based on what is a misperception that it doesn’t work or doesn’t do a good job,” said Jennifer Nuzzo, an epidemiologist and director of the Pandemic Center at Brown University School of Public Health. “I just worry that we are robbing people of an important tool.”

I just worry that public health officials won’t bother to actually read the scientific literature, understand what an effective drug does and learn some basic principles about virology.

When will they ever learn?

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“Lies My Gov’t Told Me” will be published soon.