In a recent Morbidity and Mortality Weekly Report (MMWR) published on the United States Center for Disease Control and Prevention (US-CDC) website, researchers described cases of coronavirus disease 2019 (COVID-19)–related hospitalizations and emergency department (ED) visits in five to 15 days following Paxlovid (Nirmatrelvir/ritonavir ) treatment.

Study: Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022. Image Credit: wan wei / ShutterstockStudy: Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022. ​​​​​​​Image Credit: wan wei / Shutterstock


Nirmatrelvir/ritonavir, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) inhibitor, is marketed under the brand name Paxlovid. It received emergency use authorization (EUA) from the Food and Drug Administration (FDA) in December 2021 for mild to moderate COVID-19 cases likely at risk for developing severe disease. There are some published reports of recurrence of SARS-CoV-2 infections after completion of the Paxlovid treatment. However, there is a lack of real-world evidence to show that early intervention with Paxlovid prevents the progression of mild and moderate COVID-19 cases to severity.

About the study

In the present study, researchers used electronic health records (EHRs) from an integrated health care system of Kaiser Permanente Southern California (KPSC) in California, US, to identify recurring SARS-CoV-2 infections following Paxlovid treatment that also resulted in ED visits and admission to hospitals.

They searched all the individuals over 12 years of age who received a five-day treatment course of Paxlovid between December 31, 2021, and May 26, 2022. During the five to 15 days following Paxlovid treatment, these individuals were either hospitalized or visited EDs related to recurrent SARS-CoV-2 infection.

Study findings

The researchers identified 5,287 persons over 12 years who received a Paxlovid prescription, including four who received Paxlovid treatment twice 14 or more days apart. Of these, 4,875 individuals had received at least one COVID-19 vaccine dose, 937 had received two doses at least 14 days before receiving Paxlovid treatment, 3,836 had received three or more vaccine doses, and 412 Paxlovid recipients remained unvaccinated. In addition, over 50% of Paxlovid-treated patients also had at least one pre-existing medical condition. The median age of Paxlovid-treated patients was 61 years; 57.2% were female, and 42.5% were non-Hispanic White.

Further, the authors identified six hospitalizations and 39 ED visits during the five to 15 days following dispensing of Paxlovid treatment. These patients had symptoms consistent with COVID-19; however, they represented barely less than 1% of all the Paxlovid recipients during the study period.

Notably, EHRs only documented three hospitalized cases and 10 ED visitors. Of the 45 cases, 25 occurred in individuals over 65 years; moreover, 35/45 had at least one pre-existing medical condition. As expected, all hospitalized patients were older and had comorbidities; accordingly, they were far more susceptible to developing severe COVID-19. Of all six hospitalized patients, only four recovered from COVID-19, while all 39 COVID-19–related ED visitors recovered completely.


The study findings showed that the symptoms experienced by patients with recurrent SARS-CoV-2 infections after treatment with Paxlovid were milder than the symptoms experienced during the primary infection. Patients with reinfections following Paxlovid treatment were unlikely to get hospitalized or visit ED. Subsequently, less than 1% of patients treated with Paxlovid had to be hospitalized or visited ED due to COVID-19-related complications.

One likely explanation is that Paxlovid transiently suppresses SARS-CoV-2 replication before natural immunity completely clears the virus, thus, allowing for a short interval to observe a rebound-associated increase in loads of SARS-CoV-2. Moreover, studies have not adequately investigated the severity of the symptoms of SARS-CoV-2 reinfections. Recurrence of symptoms likely appears in some individuals regardless of treatment and vaccination status. The present study examined around 5,000 Paxlovid-treated COVID-19 patients. Thus, its findings could be reliably indicative that treatment- or immune-mediated responses, or a combination of both, could be effective in preventing hospitalization for most Paxlovid-treated patients.

It is also noteworthy that the rebound of COVID-19 symptoms after Paxlovid treatment might be related to other factors, such as treatment-resistant mutations. The researchers did not perform SARS-CoV-2 genome sequencing on samples collected from the study participants prior to and after the initiation of Paxlovid treatment. Therefore, they could not be 100% sure that the progression of the initial illness was COVID-19 reinfection. However, preliminary results from FDA research studies have indicated that SARS-CoV-2 reinfection in several individuals is unassociated with resistance mutations. To conclude, additional research could provide insights into the association between Paxlovid treatment and reduced risk for severe COVID-19, including studies with controls and precise COVID-19 severity indicators.

Journal reference:

  • Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022, Deborah E. Malden, Vennis Hong, Bruno J. Lewin, Bradley K. Ackerson, Marc Lipsitch, Joseph A. Lewnard, Sara Y. Tartof, MMWR Morb Mortal Wkly Rep. ePub: June 21 2022. DOI:,

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