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

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