Some SARS-CoV-2 variants are resistant to Paxlovid's main ingredient

As Paxlovid is "blunting SARS[-CoV-]2 disease pathogenesis," there are multiple transmissible coronavirus variants circulating resistant to the antiviral's main ingredient, according to a study published March 29 in Science Advances.

The clinical protease inhibitors resistant to Paxlovid's active drug, nirmatrelvir, are ∆P168, A173V, A173T, T45I and D48Y. The ∆P168 variant showed a 5.1 times increased resistance, A173V an 11.6 times resistance, A173T a 4.1 times resistance, and T45I and D48Y a twofold resistance.

"Two of the largest effects on nirmatrelvir resistance are ∆P168 and A173V," the researchers wrote. "This prompted us to test whether the combination might be additive or multiplicative in terms of drug resistance. The ∆P168/A173V double mutant shows a 51-fold increase in resistance to nirmatrelvir."

Many of these variants were documented before Paxlovid (nirmatrelvir and ritonavir) was given emergency use authorization in December 2021, according to the study.

Viral genomes containing ΔP168 "have risen multiple times independently," mostly in the delta variant but also in one omicron case — "identified in the Netherlands in November 2022" — the researchers said. The other protease inhibitor with a strong resistance to Paxlovid's main generic has "occurred multiple times independently since the emergence of Omicron, with phylogenetic clusters indicative of transmission."

All mutants displayed drug resistance characteristics when combined with P132, they wrote, "suggesting that these mutations are capable of conferring resistance to protease inhibitors in the context of currently circulating Omicron variants."


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