Discussion
nirmatrelvir resistance-associated substitutions
VIRUS
Analyses of nasopharyngeal SARS-CoV-2 RNA levels from two randomized, double-blind, placebo-controlled trials that collectively enrolled approximately 3,000 subjects did not identify a consistent association between virologic rebound and nirmatrelvir/ritonavir treatment. One analysis from EPIC-HR indicated a statistically significantly higher rate of viral RNA rebound overall in nirmatrelvir/ritonavir recipients compared with that in placebo recipients (8.3% versus 5.7%, respectively; p = 0.036), but this analysis did not account for differences in viral RNA declines while on treatment. Other analyses from EPIC-HR and EPIC-SR did not show significant differences but did show modestly (nonsignificant) higher viral RNA rebound rates in nirmatrelvir/ritonavir recipients. Collectively, these data indicate that viral RNA rebound might be more common with nirmatrelvir/ritonavir treatment. However, viral RNA rebound was not restricted to nirmatrelvir/ritonavir recipients, and rebound rates were generally similar to those in placebo recipients across all analyses. Further, regardless of virologic rebound, nirmatrelvir/ritonavir treatment did not appear to contribute to delayed viral clearance overall, as nirmatrelvir/ritonavir recipients were more likely than were placebo recipients to have viral RNA levels below the LLOQ at all study visits. Viral RNA rebound during the treatment period between day 3 and day 5 was frequently observed, indicating that viral RNA rebound after treatment cannot definitively be attributed to virologic relapse caused by drug clearance and loss of antiviral activity. Rather, at least some cases of posttreatment rebound likely reflect natural variability in virus production, periods of shedding of viral components related to host factors, or technical variability in sampling via topical swab, any of which might also explain the occurrence of rebound in placebo recipients. Although nirmatrelvir drug resistance was not typically associated with viral RNA rebound, consistent with previous studies, two nirmatrelvir/ritonavir-treated subjects in EPIC-HR had virus with nirmatrelvir resistance-associated substitutions at the time of rebound. Genomic databases should continue to be monitored for the emergence or spread of nirmatrelvir-resistant SARS-CoV-2 variants.