Paxlovid-Resistant Covid 'Discovered' Should We Worry?

There are at least two (1) scenarios in which COVID becomes "scary" (as in 2020 scary) again. We're already witnessing one at this time; the other is theoretical and has not yet come to pass. Either alone is bad enough; both together and our reprieve from the disease will become painfully temporary. 

The first,  COVID "learning" how to evade immunity from vaccines or prior infection, has been steadily progressing with each new variant. I use the term "progressing" because it is precisely correct. As we have gone through the Greek letters, each subsequent variant of the ancestral (Wuhan) strain has become more transmissible and less susceptible to the immunological protection afforded initially by the original mRNA vaccines. (Reduction of vaccine efficacy is a related but different topic, which I will not discuss here.)

We learned this the hard way when the dangerous Delta variant, which was more virulent (making you more ill) and more infectious than its predecessors, arrived. And we learned it once again when Omicron, possibly less virulent (or possibly not), but certainly more infectious, emerged. And with Omicron, we were "treated" to previously-unknown subvariants, such as BA.5, which displayed the same virulence and additional infectivity and were even better at evading vaccine immunity. Additionally, they can avoid the natural immunity conferred by prior Omicron infection so that people who caught the BA.1 subvariant could still catch BA.5.

Fortunately, a new report in the Journal of Biological Sciences showed that nirmaltrevir, the antiviral component in Paxlovid, was similarly potent against all the variants of concern, including Omicron. This is to be expected because the drug operates by a mechanism (inhibition of viral maturation by blocking the M^pro (main protease) aka 3CL^pro (3-chymotrypsin-like protease) that is independent of mutations in the virus' spike proteins. Two other COVID drugs, remdesivir, and molnupiravir interfere with the virus' ability to synthesize new RNA. Likewise, the potency of these drugs should be unaffected by spike mutations.

There is certainly historical precedence for the use of protease inhibitors to suppress viral replication. Invirase (saquinavir), the first effective drug against HIV/AIDS, was the first of ten HIV protease inhibitors. While no longer used, these drugs formed the bases of the first "AIDS cocktails," transforming AIDS from a certain death sentence to a life-long chronic disease.

Unfortunately, neither molnupiravir nor remdesivir is as effective as nirmaltrevir (and remdesivir also has to be given by IV infusion), so at this time, we are mostly reliant on Paxlovid to keep infected, high-risk individuals out of the hospital. It works quite well for this. This makes this paper on the bioRxIV site (2) a bit disconcerting, at least until you understand what's really going on.

Source:  E. Heilmann, et. al., bioRxIV, July 4, 2022, doi: https://doi.org/10.1101/2022.07.02.495455

Heilmann and colleagues demonstrated that nirmaltrevir-resistant Covid could be generated under laboratory conditions. This is actually standard practice in proving the mechanism of action for this and other antivirals, but I would argue that it has little clinical impact. So, rather than alarming, it would be surprising if it were not possible to generate nirmaltrevir-resistant Covid strains in labs; it acts as proof of principle.

This strategy is not new; it's an example of induced selective pressure, which was used to identify mutants that became resistant to HIV protease inhibitors [emphasis mine]:

HIV drug resistance is mediated by mutations in the molecular targets of drug therapy. Drug-resistant viruses are usually first identified by in vitro passage experiments in which viral isolates are cultured in the presence of increasing concentrations of an antiviral compound. 

Clin Microbiol Rev. 2002 Apr; 15(2): 247–277, doi: 10.1128/CMR.15.2.247-277.2002

Serial passage experiments – exposing a virus to increasing concentrations of a drug to see what mutants emerge – confirm that the drug is functioning as it should. One can expect to see mutations (usually) at the binding site of the drug, confirming its mechanism of action (In fact, serial passage experiments have already been used to generate remdesivir-resistant virus strains.)

Bottom line: that scientists were able to generate "Paxlovid"-resistant viruses is not alarming; it is to be expected.

Drug-resistant virus in clinical isolates

It is one thing to force viral mutation in a laboratory; this may or may not predict whether a drug-resistant mutant virus will emerge in the general population and render that drug less useful. However, when a single antiviral drug is used, especially if used improperly, it is reasonable to expect the drug to eventually become less and less effective. (Although the mechanisms are different this also represents how bacteria become antibiotic-resistant.) Indeed, when HIV protease inhibitors were used as single agents in AIDS patients, virologic failure became increasingly common. Perhaps worse (but not unexpected) was that resistance to one HIV protease inhibitor also resulted in resistance to others in the class.

Where does that leave us?

Right now, although SARS-CoV-2 is "working hard" to find a way to generate mutants that are nirmaltrevir-resistant, there does not seem to be an immediate threat. A group from multiple universities just published a letter in the journal Cell Research reporting that nirmaltrevir retains its activity against species with mutations in the M^pro region, especially Omicron M^pro.

But the authors note this reprieve could very well be temporary:

"SARS-CoV-2 has not yet encountered M^pro antivirals. If nothing else, SARS-CoV-2 has taught us that widespread proliferation, low fidelity genome synthesis, and selective pressure might quickly produce drug-resistant phenotypes."

J. Wen, et. al., Cell Research (2022) 32:498–500; https://doi.org/10.1038/s41422-022-00640-y

Take-home message

First, the bioRxIV paper does not (at least yet) reflect what is happening in the real world; it may never. So, recent tweets from "experts" who either (for some reason) don't like the drug or don't know what they're taking about are simply alarmist since the mutations they refer to resulted from selective passage experiments, which were done under laboratory conditions that were virtually guaranteed to generate Paxlovid-resistant mutants.

On the other hand, expanded use of Paxlovid will eventually lead to the drug becoming less effective, just as we saw with the HIV-protease inhibitors, and overuse will only accelerate this process.

What to do?

• First, Paxlovid should not be used prophylactically. As I have written, it does not work in this way, nor should it.
• The more people who take it, the faster resistance will develop.
• This calls into question the use of the drug by younger, healthy people who are unlikely to become seriously ill (but not impossible).
• The CDC's revised guidelines reflect just this. "Paxlovid continues to be recommended for early-stage treatment of mild to moderate COVID-19 among persons at high risk for progression to severe disease." (Earlier guidelines included "Adults; children ages 12 years and older.") 

Bottom line

We are extremely fortunate to have Paxlovid as one of the few effective tools in our COVID treatment toolbox. For it to remain a useful tool, it must be used sparingly, only when needed. Even then, it will almost certainly lose its effectiveness. The only way to stay ahead of the virus is to continue to develop new COVID antiviral drugs, especially those that operate by a different mechanism of action (3). The rest is up to the virus.

NOTES:

(1) The third is that COVID will evolve in such a way that a new variant, undeterred by vaccines, produces different, more severe symptoms. I don't even want to think about this.

(2) BioRxIV is a site for rapidly publishing papers and communications that are not peer-reviewed.  

(3) It is much more difficult for viruses to develop drug resistance when they are "hit" with inhibitors that operate by different mechanisms. This formed the basis of the AIDS cocktails.