SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy

Abstract

Objective: To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound. Design: Observational cohort study. Setting: Multicenter healthcare system in Boston, Massachusetts. Participants: We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir. Exposures: Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy. Main Outcome and Measures: The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log10 copies/milliliter after a prior reduction in viral load to <4.0 log10 copies/milliliter. Results: Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene. Conclusions and Relevance: Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.

Optimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation

“…We presented evidence of a statistically significant elevated risk of VBR overall from early initiation of nirmatrelvir/ritonavir as compared to later initiation (albeit with wide confidence intervals and hence high uncertainty due to the paucity of VBR events amongst late initiators). Such findings correspond to results from a small perspective cohort study, which found a statistically insignificant association between nirmatrelvir/ritonavir initiation within 0-1 days after diagnosis and VBR, and no such association for later initiation, amongst 72 ambulatory patients with a median of 4 vaccination doses 20 . The elevated VBR risk observed amongst early initiators overall may have reflected the effects of aging on nirmatrelvir/ritonavir users, many of whom are aged 60 years or above, and whom may be susceptible to immunosenescence, weakened development of T-cell response, and poorer antiviral antibody quality 21,22 , in turn hampering the rapid development of an effective immune response to sufficiently address any leftover virus subsequent to therapy cessation.…”

A unifying model to explain high nirmatrelvir therapeutic efficacy against SARS-CoV-2, despite low post-exposure prophylaxis efficacy and frequent viral rebound

“…We hypothesize that viral rebound occurs more frequently in community settings relative to the clinical trial, because infected individuals in the community are often prescribed the drug very early after symptom development, whereas in the trial, there was a natural 1 to 2-day delay based on the enrollment and consent process. Surprisingly, this short delay may have limited rebound while not affecting the primary endpoints of the trial, a finding supported by recent clinical studies 30 , which nevertheless still suggests a clear benefit for earlier treatment in terms of preventing hospitalization in high-risk individuals 7 . Notably, antiviral therapy is not a risk factor for rebound in our model or in clinical cohorts if administered late during infection 36 .…”

“…Previous studies have defined rebound using criteria with varying virologic thresholds, timing, and sampling frequency (30) . A rebound was sometimes defined when a positive test was observed after a negative test (31) . In EPIC-HR, treatment was started within the first 5 days of symptoms (our intermediate treatment group) and rebound was defined as a 0.5 log increase on days 10 and/or 14.…”

“…Different criteria have been used to define rebound in the previous studies with varying virologic thresholds, as well as timing and frequency of sampling 28 . A rebound has sometimes been flagged when a positive test was observed after a negative test 29 . In the clinical trial, treatment in the treatment arm was started within the first 5 days of symptoms (our intermediate treatment group).…”