Thanks for the post with a useful link that provides a good explanation of the issues with resistance.
Below are a few things that caught my eye;
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"Phylogenetic analyses indicate that nirmatrelvir-resisting variants have pre-existed the introduction of nirmatrelvir into the human population and are transmissible [56]."
"While the short (5-days) treatment course reduces selective pressure for N/R resistance, widespread deployment as a monotherapy, including to immunosuppressed patients who could fail clearing the virus after the 5-day schedule, makes the probability of resistance emergence in the near future substantial."
2.6. Relapses (rebounds)
"....Explanations proposed so far for the rebound phenomenon include the shortness of the schedule, insufficient dosing in obese patients, pharmacokinetic interactions with concurrent medications lowering plasma levels of nirmatrelvir, and/or failure of the drug to eradicate the virus from yet to be identified drug-inaccessible sanctuary tissues....."
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(My comment) These are all valid and likely IMHO. (I am simply a layman investor)
The paper makes it clear that we need a superior covid antiviral to Paxlovid.
It's directly analogous to treating with an antibiotic that may be too weak to eliminate the infection completely. There will be remaining infection post TX and that remaining infection might be more resistant.
A better treatment would be able to more fully eliminate all of the virus in the course of the treatment thus decreasing the chances of post treatment transmission to others. A more ideal treatment would be effective for prophylaxis.
Ultimately there is a need for 1) more effective treatments than Paxlovid and 2) treatments that would be more effective for the more immune compromised OR for the emerging protease inhibitor resistant strains, and 3) the idea that a weak/partial treatment could be an engine for creating resistance. It's above my pay grade, but I just hold the idea that we are currently treating with a temporary first generation drug- not the ultimate compound by any metric.
It also occurs to me that there are improved treatments on the way in trials or other treatments which could sidestep the M-pro potential resistance issues. (I'm not actually saying that M-pro isn't effective so much as a weak M-pro treatment is more of a problem)
AI
