On June 21, 2022, this report was posted online as an MMWR Early Release.
Deborah E. Malden, DPhil1,2; Vennis Hong, MS2; Bruno J. Lewin, MD2,3; Bradley K. Ackerson, MD2; Marc Lipsitch, DPhil4,5; Joseph A. Lewnard, PhD6; Sara Y. Tartof, PhD2,3 (View author affiliations)
What is already known about this topic?
Recurrence of COVID-19 symptoms and positive SARS-CoV-2 test results have been reported after completion of Paxlovid oral antiviral treatment for COVID-19, but real-world evidence of severe illness following Paxlovid is lacking.
What is added by this report?
COVID-19–related hospital admissions and emergency department (ED) encounters occurring 5–15 days after Paxlovid treatment were described using data from a large integrated health care system. Reports of such hospitalizations or ED encounters occurred infrequently, representing <1% of Paxlovid-treated patients over the study period.
What are the implications for public health practice?
When administered as an early-stage treatment, Paxlovid might prevent COVID-19–related hospitalization among persons with mild-to-moderate COVID-19 who are at risk for progression to severe disease.
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Nirmatrelvir/ritonavir (Paxlovid) is a combination protease inhibitor that blocks replication of SARS-CoV-2 (the virus that causes COVID-19) and has been shown to reduce the risk for hospitalization and death among patients with mild to moderate COVID-19 who are at risk for progression to severe disease* (1). In December 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for early treatment with Paxlovid among persons with mild to moderate cases of COVID-19 who are at high risk for progression to severe disease (2). FDA and a small number of published case reports have documented recurrence of COVID-19 symptoms or a positive viral test result (COVID-19 rebound) 2–8 days after recovery or a negative SARS-CoV-2 test result among patients treated with Paxlovid (3–7); however, large-scale studies investigating severe illness after Paxlovid treatment are limited. This study used electronic health record (EHR) data from a large integrated health care system in California (Kaiser Permanente Southern California [KPSC]) to describe hospital admissions and emergency department (ED) encounters related to SARS-CoV-2 infections during the 5–15 days after pharmacy dispensation of a 5-day treatment course of Paxlovid. Among 5,287 persons aged ≥12 years who received Paxlovid during December 31, 2021–May 26, 2022, 73% had received ≥3 doses of COVID-19 vaccine†, and 8% were unvaccinated. During the 5–15 days after Paxlovid treatment was dispensed, six hospitalizations and 39 ED encounters considered to be related to SARS-CoV-2 infection were identified, representing <1% of all patients to whom Paxlovid treatment was dispensed during the study period. Among these 45 persons, 21 (47%) were aged ≥65 years, and 35 (78%) had at least one underlying medical condition§ (8). This study found that hospitalization or ED encounters for COVID-19 during the 5–15 days after Paxlovid treatment was dispensed for mild to moderate COVID-19 illness were rarely identified. When administered as an early-stage treatment, Paxlovid might prevent COVID-19–related hospitalization among persons with mild to moderate cases of COVID-19 who are at risk for progression to severe disease.
Clinical and demographic characteristics from EHRs were described among patients receiving Paxlovid during December 31, 2021–May 26, 2022, within KPSC, a large integrated health care system in California. KPSC facilities include 15 large medical centers that provide care to approximately 4.6 million members across southern California. All hospital admissions and ED encounters during the 5–15 days after Paxlovid treatment was dispensed¶ were flagged for medical chart review to confirm that the hospitalization or ED encounter was related to COVID-19.** Patients identified with two Paxlovid prescriptions ≥14 days apart were followed for 5–15 days after each prescription date. For patients with both a documented hospital admission and an ED encounter during the 5–15 days after the date that Paxlovid was dispensed, the hospital admission was included in the analysis. Data analyses were performed using SAS software (version 9.4; SAS Institute). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.†† This activity was also reviewed and approved by KPSC Institutional Review Board.
During December 31, 2021–May 26, 2022, a total of 5,287 persons aged ≥12 years received a prescription for Paxlovid, including four (<0.1%) who received two Paxlovid prescriptions ≥14 days apart. Among these 5,287 persons, 3,025 (57.2%) were female, and the median age was 61 years (Table). The largest percentage of persons (2,245; 42.5%) identified as non-Hispanic White, and 30.3% (1,603) identified as Hispanic. A total of 2,999 (56.7%) Paxlovid recipients had at least one underlying medical condition. Overall, 4,875 (92.2%) persons had received at least 1 COVID-19 vaccine dose; most (3,836, 72.5%) received at least 3 doses, and 937 (17.7%) received 2 doses at least 14 days before the date of Paxlovid prescription; a total of 412 (7.8%) Paxlovid recipients were unvaccinated.
During the 5–15 days after treatment was dispensed, six (0.11%) hospitalizations and 39 (0.74%) ED encounters among persons with symptoms consistent with COVID-19 were identified, representing <1% of all patients who received Paxlovid during the study period; three hospitalizations and 10 ED encounters had a COVID-19 diagnosis code or positive SARS-CoV-2 test result documented in the associated EHR. Twenty-one (46.7%) of these 45 patients were aged ≥65 years and 35 (77.8%) had at least one documented underlying medical condition. A higher proportion of those identified with COVID-19–related hospitalizations or ED encounters were either unvaccinated or vaccinated with 1 dose of COVID-19 vaccine (eight of 45; 17.8%) compared with all treated patients (514 of 5,287; 9.7%). Among the six hospitalized patients, five had received 3 doses of COVID-19 vaccine and one had received a single vaccine dose. All hospitalized patients had comorbidities or were of advanced age (range = 61–104 years), which put them at increased risk for severe COVID-19. Two hospitalized patients died; both were at high risk for severe illness because of multiple comorbidities and age, and their deaths were attributed to underlying disease. The remaining four hospitalized patients recovered, as did the 39 patients with COVID-19–related ED encounters during the 5–15 days after Paxlovid was dispensed.
In this analysis of data from patients aged ≥12 years in a large integrated health care system who received Paxlovid treatment during December 2021–May 2022, hospitalizations or ED encounters for COVID-19–related illness during the 5–15 days after Paxlovid dispensation occurred among <1% of all patients. The rarity of these outcomes is consistent with evidence from recent case reports and large observational studies, which found that symptoms experienced by patients with COVID-19 rebound after treatment with Paxlovid are milder than those experienced during the primary infection (3–5) and are unlikely to lead to hospitalization (9,10).
The recurrence of symptoms might represent part of the natural history of SARS-CoV-2 infection in some persons, irrespective of treatment or vaccination status (6). Although little is known about the severity of COVID-19 rebound symptoms, it has been suggested that very early treatment with Paxlovid might transiently suppress viral replication before natural immunity is sufficient to complete viral clearance (3). This might allow for a short interval during which rebound-associated increases in SARS-CoV-2 viral load might be observed. However, the findings from the current study among approximately 5,000 eligible COVID-19 patients treated with Paxlovid suggest that responses (whether treatment-mediated, immune-mediated, or a combination of both) might be sufficient to prevent severe outcomes, including hospitalization, for most patients.
The recurrence of COVID-19 symptoms after Paxlovid treatment might also be related to other factors, including viral reinfection or the emergence of treatment-resistant mutations. In the current study, recovery from initial infection was not assessed and viral sequencing was not performed on specimens before and after treatment initiation; therefore, the distinction between progression of initial illness, COVID-19 rebound, or reinfection could not be made. However, in the limited studies that have obtained sequence data, similarity of viral strains between pre- and posttreatment specimens suggested that reinfection was unlikely, at least in the small number of patients studied (4). In addition, research conducted by FDA demonstrated that viral rebound in several subjects was not associated with known resistance mutations, although these analyses are ongoing (7).
The findings in this report are subject to at least five limitations. First, COVID-19–related hospital admissions and ED encounters among patients with symptoms consistent with COVID-19 illness were used as proxy indicators of COVID-19 disease severity; these instances might include admissions and encounters for persons seeking care for unrelated conditions. Although medical chart reviews were conducted to verify that COVID-19–related illness or symptoms were potentially a primary reason for these health care encounters, misclassification might have occurred because of the nonspecific nature of COVID-19–related symptoms. Second, there was no control population of persons who did not receive treatment with Paxlovid for mild to moderate COVID-19, and therefore the relative benefit of treatment with Paxlovid could not be determined, nor could it be distinguished from the overall benefit of receiving COVID-19 vaccination. However, data from randomized controlled trials and from large-scale observational studies have demonstrated a protective effect of Paxlovid on COVID-19–associated hospitalization and death (1,9,10), albeit sometimes with notably different study populations that differed by age or vaccination status. Third, data on treatment initiation and adherence were not systematically collected; therefore, persons with incomplete treatment might have been misclassified as having completed a full course of Paxlovid. Fourth, patients might have sought care within ED settings because of convenience rather than acuity of illness. However, these last two limitations would have led to an overestimation of acute COVID-19 illness after Paxlovid dispensation, which strengthens the conclusion that such events are rare. Finally, although members typically seek care at KPSC, and KPSC receives a regular data feed from the California Immunization Registry on outside vaccinations, data on Paxlovid prescriptions dispensed or vaccinations administered by non-KPSC providers might be incomplete.
This study found that <1% of patients treated with Paxlovid were identified with COVID-19–related hospitalization or ED encounters 5-15 days after treatment was dispensed. When administered as an early-stage treatment, Paxlovid might prevent COVID-19–related hospitalization among persons with mild to moderate COVID-19 cases who are at risk for progression to severe disease. Additional research is warranted to provide further understanding of the apparent association between Paxlovid and reduced risk for severe COVID-19 illness, including studies with control groups and more precise indicators of COVID-19 illness severity.
Jeniffer S. Kim, Sally Shaw, Kaiser Permanente Southern California; Manish Patel, CDC.
1Epidemic Intelligence Service, CDC; 2Kaiser Permanente Department of Research & Evaluation Southern California, Pasadena, California; 3Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California; 4CDC COVID-19 Emergency Response Team; 5Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; 6School of Public Health, University of California, Berkeley, California.
- Hammond J, Leister-Tebbe H, Gardner A, et al.; EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med 2022;386:1397–408. https://doi.org/10.1056/NEJMoa2118542 PMID:35172054
- Food and Drug Administration. FDA updates on Paxlovid for health care providers. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2022. Accessed May 27, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-updates-paxlovid-health-care-providers
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- CDC. CDC Health Advisory: COVID-19 rebound after Paxlovid treatment. Atlanta, GA: US Department of Health and Human Services, CDC; 2022. https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf
- Food and Drug Administration. Emergency Use Authorization (EUA) for Paxlovid (nirmatrelvir tablets co-packaged with ritonavir tablets) Center for Drug Evaluation and Research (CDER) review. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2021. https://www.fda.gov/media/155194/download
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- Arbel R, Sagy YW, Hoshen M, et al. Oral nirmatrelvir and severe Covid-19 outcomes during the Omicron surge. Research Square [Preprint posted June 1, 2022]. https://www.researchsquare.com/article/rs-1705061/v1
- Najjar-Debbiny R, Gronich N, Weber G, et al. Effectiveness of Paxlovid in reducing severe COVID-19 and mortality in high risk patients. Clin Infect Dis 2022;ciac443. https://doi.org/10.1093/cid/ciac443 PMID:35653428
Suggested citation for this article: Malden DE, Hong V, Lewin BJ, et al. Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022. MMWR Morb Mortal Wkly Rep 2022;71:830-833. DOI: http://dx.doi.org/10.15585/mmwr.mm7125e2.
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