The Centers for Disease Control and Prevention (CDC) is issuing this Health Alert Network (HAN) Health Advisory to update healthcare providers, public health departments, and the public on the potential for recurrence of COVID-19 or “COVID-19 rebound.” Paxlovid continues to be recommended for early-stage treatment of mild to moderate COVID-19 among persons at high risk for progression to 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.
Regardless of whether the patient has been treated with an antiviral agent, risk of transmission during COVID-19 rebound can be managed by following CDC’s guidance on isolation, including taking other precautions such as masking.
Staying up to date with COVID-19 vaccination lowers the risk of getting COVID-19 and helps prevent serious outcomes of COVID-19, such as severe illness, hospitalization, and death.
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:
Recent case reports document that some patients with normal immune response who have completed a 5-day course of Paxlovid for laboratory-confirmed infection and have recovered can experience recurrent 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 the initial infection.
In the Paxlovid clinical trial, a small number of participants had one or more positive SARS-CoV-2 RT-PCR test results after testing negative, or an increase in the amount of SARS-CoV-2 detected by PCR, after completing their treatment course (5). This finding was observed in persons administered Paxlovid and in persons given placebo. There was no increased occurrence of hospitalization or death, and there 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 days after rebound symptoms started. Some people continue to test positive after day 10 but are considerably less likely to shed infectious virus. Currently, there are no reports of severe disease among persons with COVID-19 rebound. Paxlovid continues to be recommended for early-stage treatment of mild to moderate COVID-19 among persons at high risk for progression to severe disease.
Recommendations for Healthcare Providers
For patients with COVID-19 rebound
For patients just diagnosed with COVID-19
Recommendations for Public Health Departments and Public Health Jurisdictions
Recommendations for the Public
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