Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022

California, December 2021-May 2022

Deborah E. Malden, DPhil; Vennis Hong, MS; Bruno J. Lewin, MD; Bradley K. Ackerson, MD; Marc Lipsitch, DPhil; Joseph A. Lewnard, PhD; Sara Y. Tartof, PhD


Morbidity and Mortality Weekly Report. 2022;71(25):830-833. 

In This Article

Abstract and Introduction


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.

*Persons eligible for treatment with Paxlovid include those aged ≥12 years, weighing ≥88 lbs (40 kg), with a positive SARS-CoV-2 test result, mild or moderate symptoms, not requiring hospitalization because of severe or critical COVID-19 illness at the time of treatment initiation, and the presence of at least one risk factor that can predispose them to severe disease (, without evidence of severe renal or hepatic impairment.
COVID-19 vaccine doses were categorized ≥14 days before the Paxlovid dispense date as follows: 4 doses = receipt of a fourth COVID-19 vaccine dose; 3 doses = receipt of a third COVID-19 vaccine dose ≥28 days after the second dose (and no fourth dose received); 2 doses = receipt of a second COVID-19 vaccine dose (and no third dose received); 1 dose = receipt of a single COVID-19 vaccine dose (and no second dose received); 0 = unvaccinated.
§Underlying medical conditions were defined according to the modified Charlson Comorbidity Index, which included 17 conditions of interest available in EHRs during the 12 months preceding the date of treatment. Conditions included immunosuppressive disorders, acute myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, rheumatoid disease, peptic ulcer disease, mild and moderate liver disease, severe liver disease, diabetes with severe complications, diabetes without severe complications, hemiplegia or paraplegia, renal disease, cancer, and HIV/AIDS.
Patients were considered to have received treatment with Paxlovid if they had documentation of a pharmacy dispensation of Paxlovid in their EHRs.
**Patients were considered to have a confirmed COVID-19–related hospital admission or ED encounter if their EHRs indicated that COVID-19 was either the primary reason for the encounter or if there was documentation of symptoms consistent with COVID-19 according to the latest CDC definition.
††45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.