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

DOI record: { "DOI": "10.1101/2023.06.23.23288598", "URL": "http://dx.doi.org/10.1101/2023.06.23.23288598", "abstract": "<jats:p>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 &lt;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.</jats:p>", "accepted": { "date-parts": [ [ 2023, 6, 27 ] ] }, "author": [ { "affiliation": [], "family": "Edelstein", "given": "Gregory E.", "sequence": "first" }, { "affiliation": [], "family": "Boucau", "given": "Julie", "sequence": "additional" }, { "affiliation": [], "family": "Uddin", "given": "Rockib", "sequence": "additional" }, { "affiliation": [], "family": "Marino", "given": "Caitlin", "sequence": "additional" }, { "affiliation": [], "family": "Liew", "given": "May Y.", "sequence": "additional" }, { "affiliation": [], "family": "Barry", "given": "Mamadou", "sequence": "additional" }, { "affiliation": [], "family": "Choudhary", "given": "Manish C.", "sequence": "additional" }, { "affiliation": [], "family": "Gilbert", "given": "Rebecca F.", "sequence": "additional" }, { "affiliation": [], "family": "Reynolds", "given": "Zahra", "sequence": "additional" }, { "affiliation": [], "family": "Li", "given": "Yijia", "sequence": "additional" }, { "affiliation": [], "family": "Tien", "given": "Dessie", "sequence": "additional" }, { "affiliation": [], "family": "Sagar", "given": "Shruti", "sequence": "additional" }, { "affiliation": [], "family": "Vyas", "given": "Tammy D.", "sequence": "additional" }, { "affiliation": [], "family": "Kawano", "given": "Yumeko", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-5556-4618", "affiliation": [], "authenticated-orcid": false, "family": "Sparks", "given": "Jeffrey A.", "sequence": "additional" }, { "affiliation": [], "family": "Hammond", "given": "Sarah P.", "sequence": "additional" }, { "affiliation": [], "family": "Wallace", "given": "Zachary", "sequence": "additional" }, { "affiliation": [], "family": "Vyas", "given": "Jatin M.", "sequence": "additional" }, { "affiliation": [], "family": "Barczak", "given": "Amy K.", "sequence": "additional" }, { "affiliation": [], "family": "Lemieux", "given": "Jacob E.", "sequence": "additional" }, { "affiliation": [], "family": "Li", "given": "Jonathan Z.", "sequence": "additional" }, { "affiliation": [], "family": "Siedner", "given": "Mark J.", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2023, 6, 27 ] ], "date-time": "2023-06-27T19:30:16Z", "timestamp": 1687894216000 }, "deposited": { "date-parts": [ [ 2023, 6, 27 ] ], "date-time": "2023-06-27T19:30:17Z", "timestamp": 1687894217000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2023, 6, 28 ] ], "date-time": "2023-06-28T04:34:37Z", "timestamp": 1687926877196 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2023, 6, 27 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2023.06.23.23288598", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2023, 6, 27 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2023, 6, 27 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "http://medrxiv.org/lookup/doi/10.1101/2023.06.23.23288598" } }, "score": 1, "short-title": [], "source": "Crossref", "subtitle": [], "subtype": "preprint", "title": "SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy", "type": "posted-content" }