A new analysis from the US Food and Drug Administration (FDA) demonstrates that, in clinical trials, the emergence of SARS-CoV-2 resistance to Paxlovid is infrequent (less than 0.3% to 1.1%).
The study was published today in Clinical Infectious Diseases, and provides the most comprehensive analysis of SARS-CoV-2 resistance to Paxlovid (nirmatrelvir/ritonavir) to date.
Researchers analyzed baseline and matching post-baseline SARS-CoV-2 next-generation sequencing data from 1,862 participants (912 who received Paxlovid, 950 placebo) to look for resistance-associated substitutions (RAS).
All participants came from EPIC-HR and EPIC-SR, phase 2/3, randomized, double-blind, placebo-controlled trials of Paxlovid in participants with mild-to-moderate COVID-19. The trials were conducted during the pre-Omicron (HR/SR) and Omicron (SR) periods of the pandemic.
By comparing amino acid tables and next-generation sequencing data, the researchers found that SARS-CoV-2 clinical resistance to Paxlovid in EPIC-HR was infrequent, occurring in 6 of 530 treated participants (1.1%).
No association with hospitalization, death
Two of those six treated participants had evidence of viral rebound by day 10 after treatment, but the authors said other studies have not linked Paxlovid rebound to resistance.
None of these substitutions were associated with clinical treatment failure, defined as COVID-19-related hospitalization or all-cause death through Day 28.
"Importantly, none of these substitutions were associated with clinical treatment failure, defined as COVID-19-related hospitalization or all-cause death through Day 28." the authors wrote.
In the EPIC-SR study, seven potential RAS were identified, but none were deemed true RAS for several reasons, including that the substitutions occurred at similar rates in the Paxlovid and placebo arms and that the substitutions were located distant from the nirmatrelvir binding site.
The clinical resistance frequency in EPIC-SR was determined to be less than 0.3% (<1/382).
"We found that the development of SARS-CoV-2 resistance to nirmatrelvir/ritonavir was infrequent, occurring in 0.7% of participants overall across the two trials," the authors wrote. "Although clinical resistance was infrequent, viral sequences should continue to be closely monitored in public sequence databases to track changes in the prevalence of nirmatrelvir/ritonavir-resistant variants."
