Paxlovid and Remdesivir are Creating Drug Resistant COVID Variants

For context, recall in my previous posts that paxlovid (Pronounced: fraud-lo-vid) has failed to improve clinical endpoints in three recent RCTs. Remdesivir (Pronounced: run-death-is-near) has also been found less effective than other anti-viral medicines , has not significantly reduced COVID mortality in any trial and increases the risk of acute kidney injury. New research on immunocompromised COVID19 patients might explain why remdesivir and paxlovid have been ineffective in recent RCTs and have generally failed patients hospitalized with omicron infections.

A recent whole viral genome sequencing study conducted on a handful of immunocompromised patients suffering prolonged COVID19 disease (n = 15), published in Nature Communications, found mutations in the non-structural proteins (nsp) that paxlovid and remdesivir target. Mutations of the nsp5, the target protein of paxlovid, were found in 4 out of 15 patients while mutations of nsp12, the target protein of remdesivir, were found in 9 out 15 patients. SARS sequences from 3 patients showed nsp12 mutations became the dominant variant in the population. NSP5 mutations in one patient treated with paxlovid also produced sequences at multiple time points that became major variants. One sequence with nucleotide substitutions at seven different positions on nsp12 resulted in the death of a patient treated with remdesivir after 45 days of persistent disease. A second patient treated with 2 courses of remdesivir was also found to be infected with mutant variants after the second course with two nsp12 substitutions, a nucleocapsid terminal domain mutation and even a spike mutation 18 days before the patient died. At least one patient treated with three courses of paxlovid was found to be infected with mutant variants with 7 nsp5 substitutions after the third course. These findings were replicated in cell culture and a hamster model experiments where omicron variants with non-structural protein changes had diminished sensitivity to remdesivir and paxlovid compared to the wildtype variant. While these findings are far from conclusive they may alter the consensus view of COVID19 hospital care if replicated.