This is an official

CDC HEALTH ADVISORY

Distributed via the CDC Health Alert Network

May 24, 2022, 9:00 AM ET

CDCHAN-0467

COVID-19 Rebound After Paxlovid Treatment

severe disease. Paxlovid treatment helps prevent hospitalization and death due to COVID-19. COVID-19

rebound has been reported to occur between 2 and 8 days after initial recovery and is characterized by a

recurrence of COVID-19 symptoms or a new positive viral test after having tested negative. A brief

return of symptoms may be part of the natural history of SARS-CoV-2 (the virus that causes

COVID-19) infection in some persons, independent of treatment with Paxlovid and regardless of

vaccination status. Limited information currently available from case reports suggests that persons

treated with Paxlovid who experience COVID-19 rebound have had mild illness; there are no reports of

severe disease. There is currently no evidence that additional treatment is needed with Paxlovid or other

anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected.

Background

Paxlovid (nirmatrelvir tablets; ritonavir tablets) is a prescription oral antiviral drug that reduces the risk of

hospitalization and death for patients with mild-to-moderate COVID-19 who are at risk of disease

progression and severe illness (1). It is available under Emergency Use Authorization (EUA) by the U.S.

Food and Drug Administration (FDA) for adults and pediatric patients (12 years of age and older weighing

at least 40 kilograms or 88 pounds). Treatment should be initiated as soon as possible and within 5 days

of symptom onset among persons eligible to receive the treatment under the EUA who:

• Test positive for SARS-CoV-2 infection;

• Have mild to moderate illness;

illness 2 to 8 days later, including patients who have been vaccinated and/or boosted (were up to date

with COVID-19 vaccination) (2-4). These cases of COVID-19 rebound had negative test results after

Paxlovid treatment and had subsequent positive viral antigen and/or reverse transcriptase polymerase

chain reaction (RT-PCR) testing. Both the recurrence of illness and positive test results improved or

resolved (median of 3 days) without additional anti-COVID-19 treatment. Based on information from the

case reports, COVID-19 rebound did not represent reinfection with SARS-CoV-2 or the development of

resistance to Paxlovid; also, no other respiratory pathogens were identified among known cases. Possible

transmission of infection during COVID-19 rebound has been described (3); however, it remains unknown

whether the likelihood of transmission during rebound differs from the likelihood of transmission during

was no evidence that the rebound in detectable viral RNA was the result of SARS-CoV-2 resistance to

Paxlovid (5).

COVID-19 rebound is characterized by a recurrence of symptoms or a new positive viral test after having

tested negative. People with COVID-19 rebound should follow CDC recommendations regarding isolation

of infected patients regardless of treatment with an antiviral agent and/or previous isolation after the initial

infection. People with recurrence of COVID-19 symptoms or a new positive viral test after having tested

negative should restart isolation and isolate again for at least 5 days. Per CDC guidance, they can end

their re-isolation period after 5 full days if fever has resolved for 24 hours (without the use of fever-

reducing medication) and symptoms are improving. The individual should wear a mask for a total of 10

For patients with COVID-19 rebound

• There is currently no evidence that additional treatment for COVID-19 is needed for COVID-19

rebound. Based on data available at this time, patient monitoring continues to be the most

appropriate management for patients with recurrence of symptoms after completion of a

treatment course of Paxlovid.

• Advise people with COVID-19 rebound to follow CDC’s guidance on isolation and take

precautions to prevent further transmission. Patients should re-isolate for at least 5 days. Per

CDC guidance, they can end their re-isolation period after 5 full days if fever has resolved for 24

hours (without the use of fever-reducing medication) and symptoms are improving. The patient

should wear a mask for a total of 10 days after rebound symptoms started.

For patients just diagnosed with COVID-19

• Healthcare providers should counsel patients on available COVID-19 treatment options,

particularly for those patients at increased risk of developing severe COVID-19.

• Paxlovid should be considered for any patient who meets the eligibility criteria. For information on

Paxlovid eligibility, refer to FDA’s Fact Sheet for Healthcare Providers.

• Due to the potential for severe drug-drug interactions with the ritonavir component of Paxlovid, it

is strongly suggested that healthcare providers not experienced in prescribing this drug refer to

the Fact Sheet for Healthcare Providers, the Paxlovid Patient Eligibility Screening Checklist Tool

for Prescribers, and the NIH Statement on Paxlovid Drug-Drug Interactions | COVID-19

Treatment Guidelines. Healthcare providers can also contact a local clinical pharmacist or

infectious disease specialist for advice.

Recommendations for Public Health Departments and Public Health Jurisdictions

• State and local health departments should be aware of COVID-19 rebound and disseminate the

recommendations for healthcare providers and the public.

• Health departments should communicate to individuals about measures to prevent further

transmission. The phenomenon of COVID-19 rebound reiterates the importance of following

CDC’s isolation guidance. Isolation should be restarted after the onset of rebound symptoms or a

positive test result. Per CDC guidance, people can end re-isolation after 5 full days with resolution

of their fever for 24 hours (without the use of fever-reducing medication) and if their symptoms

are improving. The individual should wear a mask for a total of 10 days after rebound symptoms

started.

• If you experience COVID-19 rebound, you should follow CDC’s isolation guidance. Isolate again

and restart the recommended 5-day isolation period at the time of recurrence of symptoms or a

new positive COVID-19 test result. You can end re-isolation after 5 days if you are fever-free for

24 hours without the use of fever-reducing medication and your symptoms are improving. You

should also wear a mask for 10 days after rebound.

• Contact a healthcare provider if your COVID-19 rebound symptoms persist or worsen.

• Consult with your healthcare provider if you have additional questions about your treatment.

• You are encouraged to report a possible case of COVID-19 rebound after Paxlovid treatment to

Pfizer using the following online tool: Pfizer Safety Reporting.

For More Information

• FDA Updates on Paxlovid for Health Care Providers | FDA

• NIH Statement on Paxlovid Drug-Drug Interactions | COVID-19 Treatment Guidelines

• Pfizer Safety Reporting

References

1. Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. Oral

Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19. New Engl J Med 2022;

386(15): 1397-1408.

2. Gupta K, Strymish J, Stack G, Charness M. Rapid relapse of symptomatic omicron SARS CoV-2

infection following early suppression with nirmatrelvir/ritonavir. 26 April 2022, PREPRINT (Version

1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1588371/v1].

nirmatrelvir/ritonavir. 13 May 2022, PREPRINT (Version 2) available at Research Square

[https://doi.org/10.21203/rs.3.rs-1588371/v2].

4. Carlin AF, Clark AE, Chaillon A, Garretson AF, Bray W, Porrachi M, et al. Virologic and