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

Edelstein et al., medRxiv, doi:10.1101/2023.06.23.23288598, POSITIVES
Jun 2023  
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Viral rebound -761% Improvement Relative Risk Paxlovid for COVID-19  POSITIVES  EARLY TREATMENT Is early treatment with paxlovid beneficial for COVID-19? Prospective study of 127 patients in the USA Worse viral clearance with paxlovid (p=0.038) c19early.org Edelstein et al., medRxiv, June 2023 Favorspaxlovid Favorscontrol 0 0.5 1 1.5 2+
Prospective study of 127 COVID-19 patients in the USA showing higher risk of replication-competent virologic rebound with paxlovid treatment.
Authors note that rebound substantially increases the duration of shedding of replication-competent virus.
When compared with previous studies, authors believe the higher frequency of rebound detected is due to the frequent sampling and culture analysis. When authors restrict to 3 timepoints with PCR only, as in prior studies, they detect a similar rate of rebound as in previous studies, but miss 80% of rebound events detected in this study.
viral rebound, 760.8% higher, RR 8.61, p = 0.04, treatment 15 of 72 (20.8%), control 1 of 55 (1.8%), adjusted per study, odds ratio converted to relative risk, replication-competent virological rebound, multivariable.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Edelstein et al., 27 Jun 2023, prospective, USA, preprint, 22 authors, POSITIVES trial. Contact: msiedner@mgh.harvard.edu.
This PaperPaxlovidAll
SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy
Gregory E Edelstein, Julie Boucau, Rockib Uddin, Caitlin Marino, May Y Liew, M.D Mamadou Barry, Ph.D Manish C Choudhary, Rebecca F Gilbert, Zahra Reynolds, Yijia Li, Dessie Tien, Shruti Sagar, Tammy D Vyas, M.D Yumeko Kawano, Jeffrey A Sparks, M.D Sarah P Hammond, M.D. M.Sc Zachary Wallace, M.D. Ph.D Jatin M Vyas, Amy K Barczak, Jacob E Lemieux, Jonathan Z Li, MD MPH Mark J Siedner
doi:10.1101/2023.06.23.23288598
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 nirmatrelvirritonavir 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.
References
Anderson, Caubel, Rusnak, Nirmatrelvir-ritonavir and viral load rebound in COVID-19
Boucau, Uddin, Marino, Characterization of Virologic Rebound Following Nirmatrelvir-Ritonavir Treatment for Coronavirus Disease 2019 (COVID-19), Clin Infect Dis, doi:10.1093/cid/ciac512
Charness, Gupta, Stack, Rebound of SARS-CoV-2 Infection after Nirmatrelvir-Ritonavir Treatment, N Engl J Med, doi:10.1056/NEJMc2206449
Deo, Choudhary, Moser, Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection, Ann Intern Med, doi:10.7326/M22-2381
Epling, Rocco, Boswell, Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment, Clin Infect Dis, doi:10.1093/cid/ciac663
Goyal, Reeves, Cardozo-Ojeda, Schiffer, Mayer, Viral load and contact heterogeneity predict SARS-CoV-2 transmission and super-spreading events, Walczak AM, doi:10.7554/eLife.63537
North, Barczak, Goldstein, Determining the Incidence of Asymptomatic SARS-CoV-2 Among Early Recipients of COVID-19 Vaccines (DISCOVER-COVID-19): A Prospective Cohort Study of Healthcare Workers Before, During and After Vaccination, Clin Infect Dis, doi:10.1093/cid/ciab643
Pandit, Radin, Chiang, The COVID-19 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated with Nirmatrelvir Plus Ritonavir Versus Untreated Controls, Clin Infect Dis. Published online February, doi:10.1093/cid/ciad102
Perelson, Ribeiro, Phan, National Institutes of Health. A Study to Learn About the Study Medicines (Nirmatrelvir Plus Ritonavir) in People Aged 12 Years or Older With COVID-19 and a Compromised Immune System (NCT05438602), doi:10.1101/2023.05.30.2329074713
Wong, Lau, Au, Viral burden rebound in hospitalised patients with COVID-19 receiving oral antivirals in Hong Kong: a population-wide retrospective cohort study, Lancet Infect Dis. Published online February, doi:10.1016/S1473-3099(22)00873-8
Wong, Yip, Lai, Wong, Hui et al., Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and Molnupiravir, JAMA Netw Open, doi:10.1001/jamanetworkopen.2022.45086
Wölfel, Corman, Guggemos, Virological assessment of hospitalized patients with COVID-2019, Nature, doi:10.1038/s41586-020-2196-x
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' '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). 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