Paxlovid Resistance emerges !

And viral rebound

Repeating myself, I only send multiple e-mails within a short timeframe if the situation demands it. And this surprising one does.

Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir

The SARS-CoV-2 main protease (Mpro) is a cysteine protease and a validated antiviral drug target. Paxlovid is an FDA-approved oral COVID-19 antiviral that contains the Mpro inhibitor nirmatrelvir and the metabolic booster ritonavir. The emergence of SARS-CoV2 variants mutations in the Mpro raised the alarm of potential drug resistance. In this study, we aim to discover Mpro drug resistant mutants from naturally observed polymorphisms. Through analyzing the SARS-CoV-2 sequences deposited in Global initiative on Sharing Avian influenza Data (GISAID) database, we identified 66 prevalent Mpro mutations located at the nirmatrelvir binding site. The Mpro mutant proteins were expressed and characterized for enzymatic activity and nirmatrelvir inhibition. While the majority of the Mpro mutants had reduced enzymatic activity (kcat/Km >10-fold decrease), 11 mutants including S144M/F/A/G/Y, M165T, E166Q, H172Q/F, and Q192T/S/V showed comparable enzymatic activity as the wild-type (kcat/Km <10-fold change) and resistance to nirmatrelvir (Ki > 10-fold increase). We further demonstrate that the enzymatic activity and inhibitor resistance of these single mutations can be enhanced by additional substitutions in a double mutant. X-ray crystal structures were determined for six of the single mutants with and/or without GC-376/nirmatrelvir. The structures illustrate how mutations can reduce ligand binding by impacting the conformational stability of the active site. Overall, our study identified several drug resistant hot spots that warrant close monitoring for possible clinical evidence of Paxlovid resistance.

SUMMARY

Collectively, our results have several implications. First, all 66 Mpro mutants characterized in this study are naturally occurring SARS-CoV-2 Mpro polymorphisms that could potentially affect the efficacy of Paxlovid, and continuous prescription of Paxlovid might likely increase the frequency of these pre-existing drug resistance mutants. Second, S144, M165, E166, H172, and Q192 appear to be hot spots for nirmatrelvir resistance and need to be closely monitored among circulating viruses. Mutations at these residues are most likely to maintain the enzymatic activity while cause a significant drug resistance. It remains to be further characterized whether these mutants impair the fitness of viral replication and transmission. Third, as exemplified the H172Y/Q189T mutant, double or triple mutants might emerge to compensate for the loss of enzymatic activity from the single mutant while maintaining or enhancing drug resistance. Therefore, the Mpro mutants with reduced enzymatic activity from this study should also be monitored.

I will overly simplify so it becomes easier to understand for most people. By analyzing genetic sequences uploaded to a public database, the authors tracked down mutations that already occurred, and are occurring, this is a useful tool and form for researchers to attempt to predict viral evolution and how the virus might adapt to treatments, therefore is an attempt to stay one step ahead of the virus.

Here they found several parts of the virus which are prone to mutate because of their interactions with Nirmatrelvir, one of the two main components of Paxlovid, therefore creating drug resistance. Some of these spots were pre-existent, and continuous prescription of Paxlovid will most likely create these drug-resistant mutations, making the virus harboring them harder to treat.

The following image is from this piece.

Evidence of Viral rebound following Paxlovid !

This is a image lol…

And since that piece is about Viral rebound, at the time, not a clinically recognized effect, even though on social media you could find hundreds of posts about it.

COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022

Conclusions and Relevance COVID-19 rebound occurred both after Paxlovid and Molnupiravir, especially in patients with underlying medical conditions. This indicates that COVID-19 rebound is not unique to Paxlovid and the risks were similar for Paxlovid and Molnupiravir. For both drugs the rates of COVID-19 rebound increased with time after treatments. Our results call for continuous surveillance of COVID-19 rebound after Paxlovid and Molnupiravir treatments. Studies are necessary to determine the mechanisms underlying COVID-19 rebounds and to test dosing and duration regimes that might prevent such rebounds in vulnerable patients.

Elias Said, MD, FACEP @MdFacep

@michaelzlin Rebound is NOT unique to Paxlovid. We are seeing this in inpatients treated with either Paxlovid or Molnupiravir. The rates are: Paxlovid @ 7 days=3%, at 30 days = 5% Molnupiravir 5.86% and 8.59% Data was reproduced in thousands of patients

medrxiv.orgCOVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022Abstract Importance Recent case reports document that some patients who were treated with Paxlovid experienced rebound COVID-19 infections and symptoms 2 to 8 days after completing a 5-day course of Paxlovid. The Centers for Disease Control and Prevention (CDC) has recently issued a Health Alert Net…

Molnupiravir, Merck’s drug is known for its mutagenesis aspect, and there was extensive criticism even from pro-vaccine scientists because of the possibility of the drug not acting like it was advertised and literally super-charging the mutation rate in a fairly chaotic way.

Now we also have evidence for beneficial mutations for acquiring and further enhancing the virus drug resistance. I have warned that viral rebound leads not only to mutations but after several mutations in other viruses it leads to immune evasion and can lead to pathogenicity (making you sicker).

The immune system has been compensating for the viral evolution, immune evasion, and for the outrageous, garbage tier “immunity” the vaccination causes, literally because Omicron did shift the immunity of many of the vaccinated towards a less harmful state (Fc drift is the term). But at some point, and maybe soon, the body will run out of ways to create effective antibodies to hold the virus so your body can do what it needs.

Worst case scenario, systemic inflammatory response among many, first among the vaccinated, others with co-morbidities, etc. This has an extremely low likelihood of happening as of now.

Adding the useless drugs, with useless vaccines, we have the best possible environment for evolution.

There is one other paper that I want to write about, but I will save it for later, another example of vaccine damage, with another paper demonstrating negative vaccine efficacy.

And that our hypothesis (Paradoxical Acquired Immune Dysfunction) was right…

Deep appreciation for all the supporters!