{"doi":"10.1101/2023.06.23.23288598","title":"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: 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.","journal":"medRxiv","year":2023,"id":392462,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9112,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":108357,"name":"Julie Boucau","orcid":"0000-0001-6731-7238","position":1,"is_corresponding":false},{"id":659569,"name":"Rockib Uddin","orcid":"0000-0001-5953-1234","position":2,"is_corresponding":false},{"id":888772,"name":"Caitlin Marino","orcid":null,"position":3,"is_corresponding":false},{"id":888770,"name":"May Y. 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Sparks","orcid":"0000-0002-5556-4618","position":14,"is_corresponding":false},{"id":1024072,"name":"Sarah P. Hammond","orcid":"0000-0002-4271-7443","position":15,"is_corresponding":false},{"id":236765,"name":"Zachary S. Wallace","orcid":"0000-0003-4708-7038","position":16,"is_corresponding":false},{"id":284649,"name":"Jatin M. Vyas","orcid":"0000-0002-9985-9565","position":17,"is_corresponding":false},{"id":646796,"name":"Amy K. Barczak","orcid":"0000-0003-3806-2381","position":18,"is_corresponding":false},{"id":226714,"name":"Jacob E. Lemieux","orcid":"0000-0002-2758-4005","position":19,"is_corresponding":false},{"id":108340,"name":"Jonathan Z. Li","orcid":"0000-0001-9914-9662","position":20,"is_corresponding":false},{"id":69650,"name":"Mark J. Siedner","orcid":"0000-0003-3506-842X","position":21,"is_corresponding":false},{"id":1024780,"name":"Gregory E. 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