Viral Load Rebound in Placebo and Nirmatrelvir-Ritonavir Treated COVID-19 Patients is not Associated with Recurrence of Severe Disease or Mutations

Abstract

Nirmatrelvir-ritonavir was developed for the treatment of COVID-19 and has shown efficacy in a Phase 2/3 study of high risk patients (EPIC-HR1). Monitoring for the emergence of viral resistance and recurrence of symptoms is a critical component of any antiviral drug development. As part of the study of viral resistance, a sub-analysis was conducted to examine viral load rebound (VLR) following nirmatrelvir-ritonavir treatment in the EPIC-HR study. Nasopharyngeal or nasal swabs were collected from all study participants at Day 1, Day 3, Day 5, Day 10, and Day 14, and analyzed for viral RNA load and next generation viral sequencing. Two categories of viral load rebound were considered including present/persistent and transient. In EPIC-HR, the proportion of present/persistent VLR was low, occurring at 1.73% (17/980) vs 2.32% (23/990) and for transient VLR 2.35% (23/980) vs 4.65% (46/990) in placebo vs nirmatrelvir-ritonavir participants, respectively. VLR occurred in both treatment arms and was not associated with low nirmatrelvir exposure, hospitalization or death, severe symptom relapse, serological status, or Mpro gene/cleavage treatment emergent mutations. In summary, viral load rebounds are likely a phenomena COVID-19 disease course and nirmatrelvir-ritonavir continue to be an important treatment option for high risk COVID-19 patients.

An explanation for SARS-CoV-2 rebound after Paxlovid treatment

“…Some individuals with viral rebound are reported to have culturable virus up to 16 days after the initial diagnosis (7) and it is possible that transmission to close contacts may occur during the rebound period (8). Furthermore, viral rebound does not appear to be caused by the emergence of drug resistant mutants (8)(9)(10).…”

Nirmatrelvir plus ritonavir in COVID-19: a profile of its use

“…In a longitudinal cohort study (POSITIVES), virological rebound after treatment with nirmatrelvir plus ritonavir was associated with high viral load and, in some patients, culturable virus [ 21 ]. In the EPIC-HR trial, viral load rebound occurred in 2.3% of nirmatrelvir plus ritonavir recipients and 1.7% of placebo recipients, but was not associated with recurrence of severe COVID-19 symptoms [ 24 ]. The occurrence of viral load rebound in the placebo group suggests that some patients with COVID-19 may experience the phenomenon as part of the disease’s natural progression [ 24 ].…”

“…In the EPIC-HR trial, viral load rebound occurred in 2.3% of nirmatrelvir plus ritonavir recipients and 1.7% of placebo recipients, but was not associated with recurrence of severe COVID-19 symptoms [ 24 ]. The occurrence of viral load rebound in the placebo group suggests that some patients with COVID-19 may experience the phenomenon as part of the disease’s natural progression [ 24 ]. Virological rebound has also been reported after other COVID-19 treatments such as molnupiravir, indicating that the phenomenon is not unique to nirmatrelvir plus ritonavir [ 25 ].…”

Nirmatrelvir treatment blunts the development of antiviral adaptive immune responses in SARS-CoV-2 infected mice

“…Despite its effectiveness at reducing viral titers and the risk of progressing to severe COVID-19 (5,6), the impact of nirmatrelvir treatment on the development of adaptive immunity to SARS-CoV-2 is unknown. It is also unclear why some patients experience a surprising rebound of viral load and a rapid relapse of COVID-19 symptoms shortly after the completion of an early and effective nirmatrelvir treatment (7)(8)(9)(10)(11)(12)(13)(14)(15). Viral sequencing indicates that the relapse is not associated with the selection of treatment-resistant mutations, nor due to infection with different SARS-CoV-2 variants (7,8).…”