A recent analysis by the US Food and Drug Administration (FDA) reveals that SARS-CoV-2 resistance to Paxlovid (nirmatrelvir/ritonavir) is uncommon, occurring in less than 0.3% to 1.1% of cases in clinical trials. This comprehensive study, published in Clinical Infectious Diseases, offers an in-depth look at resistance patterns to the antiviral medication.
Researchers examined baseline and post-baseline SARS-CoV-2 next-generation sequencing data from 1,862 participants enrolled in the EPIC-HR and EPIC-SR trials. These phase 2/3, randomized, double-blind, placebo-controlled trials evaluated Paxlovid in individuals with mild-to-moderate COVID-19 during both pre-Omicron and Omicron periods.
Resistance Analysis
By comparing amino acid tables and next-generation sequencing data, the researchers found that clinical resistance to Paxlovid in EPIC-HR was infrequent, observed in 6 of 530 treated participants (1.1%). In the EPIC-SR study, the clinical resistance frequency was even lower, 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.
Clinical Implications
Notably, none of the identified resistance-associated substitutions were linked to clinical treatment failure, defined as COVID-19-related hospitalization or all-cause death through Day 28. While two participants showed evidence of viral rebound by day 10 after treatment, prior studies have not consistently associated Paxlovid rebound with resistance.
"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 emphasized.
Monitoring Recommendations
Despite the low frequency of clinical resistance, the researchers advocate for ongoing surveillance of viral sequences in public databases. This monitoring is crucial for tracking potential shifts in the prevalence of nirmatrelvir/ritonavir-resistant variants and informing future treatment strategies.
