What is going on with Paxlovid rebound?

Testing and Contact Tracing Treatments

A: Some people who use Paxlovid to treat COVID-19 experience a “rebound”, which is like a bad sequel that debuts 2-14 days after recovery. Once again, you’re testing positive with rapid antigen tests and /or feeling crummy. You’re also potentially contagious. While a COVID-19 rebound can be really frustrating, Paxlovid is still highly effective at preventing hospitalization and severe COVID-19 disease in high-risk individuals.

TL;DR: There are a lot of stories circulating about Paxlovid rebound – when the same COVID-19 infection comes back after you thought you were done with it. We’ve learned a lot about this phenomenon in the last few months, but there’s a lot we still don’t fully understand. For now, the most important things to know are that Paxlovid is still recommended if you are eligible, and that people should be aware of the potential for rebound.

According to the CDC’s recent Health Advisory announcement, Paxlovid rebound is “characterized by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative”. Thus, either symptoms, a positive COVID-19 antigen test, or both, qualifies as rebound.As a reminder, Paxlovid is an antiviral combination drug treatment (nirmatrelivir and ritonavir) that reduces the risk of hospitalization and death from COVID-19 in high-risk populations. It has been used by millions of Americans, including prominent figures like President Joe Biden, Dr. Anthony Fauci, and Dr. Peter Hotez.

As we tackle your Paxlovid FAQs, bear in mind we are working with very limited data, and that some of these answers may evolve as we learn more. That’s how science works!


❓When does rebound occur? Rebound typically begins around 9 days after recovery, but could be as early as 2 days, or as long as 14 days later.

❓Do I need to self-isolate again? Am I contagious? Current evidence suggests that caution is warranted, as several case reports have documented transmission during rebound, including one case of pre-symptomatic spread to a baby grandchild 😔. Current guidelines from the US Centers for Disease Control and Prevention (CDC) advise following the same isolation and masking protocols as new infections (isolate 5 days, mask for another 5 days).

❓Do I need a second course of Paxlovid? Probably not. According to the CDC: “Limited information 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.” Dr. Anthony Fauci opted for a second round when his rebound symptoms were worse than his initial symptoms, but this is not the standard recommendation.

❓How common is rebound? The current best guess is that roughly 5-6% of Paxlovid treated cases will recur. This estimate is from a June 2022 study that has not yet been peer-reviewed. The study population looked at COVID-19 positive in January to June 2022, who were treated with Paxlovid (n =11,270) or with Molnupiravir (n =2,374) within 5 days of their COVID-19 infection. Notably, rebound rates did not differ between the two drugs. It seems that that the more we look for rebound, the more we find it. Earlier estimates were closer to 1-2%. The chances of a rebound may be impacted by many factors, including the variant, vaccination status, health status, and more.

🤔Some experts say that rebound may be part of the natural history of the disease, and occur with or without Paxlovid. Indeed, COVID-19 rebound was observed before Paxlovid was around, and was just as common in the control group of one of Pfizer’s Paxlovid trials.

❓What causes rebound? It seems that the initial viral infection is not truly cleared, and the virus won a tug-of-war with the immune system. We don’t really know why this is happening. Some say that giving Paxlovoid so early may not allow the immune system to fully rev up; others wonder if we should be giving longer courses.

⚠️Rebound is NOT typically caused by viral mutations that cause drug resistance, according to a handful of studies that sequenced the viral genetic blueprint following rebound. This doesn’t mean that drug-resistant mutations don’t happen (they do happen!), but they are not a major cause of rebound at this time.

❓Who is most likely to rebound? Data on this question are really sparse, so it’s hard to generalize. One of the larger studies found 4 rebound cases among 483 Paxlovid-treated patients. All four rebound cases had multiple serious health conditions and had been vaccinated more than 90 days before their COVID-19 infections.


👉 If you are eligible for Paxlovid treatment, don’t let a potential rebound deter you. Paxlovid treatment is well established to reduce hospitalizations and deaths in high-risk individuals. Talk to your doctor or pharmacist about eligibility based on your risk factors and medications.

👉 If you take Paxlovid, be on the lookout for a rebound. For the first two weeks after recovery, keep tabs on your symptoms, and use rapid antigen tests to boost your chances of an early warning sign (daily, or every 2-3 days if asymptomatic, depending on test availability). Test immediately if you develop symptoms, and consider testing (and masking) before exposure to vulnerable people.

👉 If you experience Paxlovid rebound, assume that you could be contagious, and follow the same isolation and mask protocols as with new infections. Assume that you do NOT need a second course of Paxlovid, as this is the current CDC guidance. That said, it remains possible that a second course of Paxlovid may be recommended for some people by their health care clinician based on a risk/benefit assessment.

🧪Rapid antigen tests are your best bet for detecting and monitoring rebound. PCR tests are typically positive for a few weeks even in the absence of rebound, because PCR detects tiny bits of old, dead virus. Antigen tests, by contrast, only light up if you are carrying a LOT of intact viral protein.

Thanks to Nerdy Girl Dr. Chana Davis @fueledbyscience for this post.

Additional Links

Dear Pandemic: What you need to know about Paxlovid

Dear Pandemic: Why is my PCR still positive?

Paxlovid Rebound (May, 2022, by Your Local Epidemiologist)

CDC Health Alert Network Health Advisory

COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022

From Positive to Negative to Positive Again—The Mystery of Why COVID-19 Rebounds in Some Patients Who Take Paxlovid

Rebound Phenomenon after Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease-2019 in High-Risk Persons

Virologic and Immunologic Characterization of COVID-19 Recrudescence after Nirmatrelvir/Ritonavir Treatment

Link to Original Dear Pandemic Facebook Post