COVID Rebound Is Real — Is Paxlovid to Blame?

Anyone who gets COVID-19 is usually pretty eager to see the end of it. So there’s nothing more frustrating than finally testing negative only to subsequently test positive or have symptoms come back — the dreaded COVID rebound.

When COVID rebound happened to me in the summer of 2022, there wasn’t a lot of research on the phenomenon. Since then, scientists have published a small but growing number of studies. Still, many questions about COVID rebound remain.

One of the main open queries is about the role of the antiviral drug Paxlovid (nirmatrelvir and ritonavir), which aims to prevent mild or moderate COVID-19 from progressing to severe disease in high-risk patients. Some studies show that Paxlovid increases the odds of rebound; other research shows it does not.

“It’s hard to tease out the data,” says Pragna Patel, MD, chief medical officer in the Coronavirus and Other Respiratory Viruses Division of the Centers for Disease Control and Prevention (CDC). Dr. Patel explains that the criteria that make a person eligible for Paxlovid — including age, certain medical conditions, and the use of immunosuppressive drugs — also raise their risk of rebound even if they don’t take Paxlovid.

Research on this topic is also complicated by differences in how scientists define rebound. Some investigators look at the number of virus cells in nasal swabs, checking for decreases followed by increases, while others focus on symptoms.

What Is COVID Rebound and How Long Does It Last?

Rebound has been documented with other viral infections besides COVID-19, notes Jonathan Li, MD, director of the Virology Specialty Laboratory at the Brigham and Women’s Hospital and Harvard Medical School in Boston.

It has been a hallmark of COVID-19 even from the earliest days of the pandemic, long before the advent of Paxlovid, says Jill Weatherhead, MD, PhD, assistant professor of infectious diseases at Baylor College of Medicine in Houston. “However, this pattern has become more apparent with the use of Paxlovid treatments,” she says.

What Is Paxlovid?

Paxlovid is composed of two separate medications: nirmatrelvir, which blocks the coronavirus from replicating in the body, and ritonavir, which gives nirmatrelvir a boost by slowing the rate at which it is metabolized by the liver.

A typical regimen is to take two nirmatrelvir pills and one ritonavir pill in the morning and again in the evening, starting within five days after symptoms begin (the sooner, the better). The full course of treatment is five days.

However, being on these drugs doesn’t mean you can’t take Paxlovid; talk to your physician about how to space these medications.

Does Paxlovid Cause COVID Rebound?

Some studies show Paxlovid increases rates of rebound, while others don’t.

The other study that Dr. Li coauthored, published in November 2023, found that about 20 percent of those taking Paxlovid rebounded virologically (with half reporting symptom rebound) compared with only 2 percent in the no-medicine group.

Li notes that participants in his study had their noses swabbed three times a week for several weeks. Such intensive monitoring is important, because “people rebound on different days,” he says.

Li thinks less frequent monitoring may explain why the other studies, including Pfizer’s original clinical trial for Paxlovid, did not find higher rates of rebound following Paxlovid. Those studies tested people on only a few specific days post-treatment, which may lead to cases being missed, he says.

What Might Cause Paxlovid Rebound?

Scientists are still studying why Paxlovid might increase COVID rebound risk.

A leading hypothesis is based on the observation that the immune system begins to mount an immune response early in the course of a viral infection. By taking Paxlovid early too, “you are preventing the virus from replicating, so the immune-system engine does not get as revved up,” Li explains. Once Paxlovid treatment ends, the immune system is not sufficiently primed to target any lingering virus.

Li’s study supports this theory, because it found virologic rebound was more common in people starting the five-day therapy within two days of getting symptoms, compared with those who started a day or a few days later. (It must be started within five days to be effective.)

Researchers are currently exploring whether a longer course of Paxlovid might lessen rebound or whether a second round of drugs after the first is finished makes sense for people who rebound.

What to Do if You Rebound With COVID-19

Fortunately, people who rebound tend not to develop serious symptoms the second time around. Patel’s research review found no hospitalizations or deaths among those who experienced rebound, and most people’s symptoms were mild.

Who Should Take Paxlovid?

This includes everyone who is 50 or older (especially over 65) or who are younger but have a weakened immune system, heart disease, obesity, diabetes, or chronic lung disease.

“Paxlovid remains a lifesaving drug that I prescribe to my patients. If you are at high risk of progressing to severe COVID, I recommend taking it, and taking it early. Rebound is more of a nuisance than anything else,” Li says.

Is Paxlovid Still Free?

Patients with private insurance need to enroll in Pfizer’s Co-Pay Savings Program. (Your exact out of pocket cost depends on your insurer.)

Those with Medicare, Medicare, the VA’s insurance, or who are uninsured can get the drug free through the U.S. Government Patient Assistant Program.

Did I Regret Taking Paxlovid?

When I tested positive for COVID in July of 2022, I started Paxlovid on day two and had symptoms and a positive home test for another seven days. I was thrilled when I finally tested negative and thought I was in the clear. But by the afternoon of the following day, my COVID symptoms returned — as did a positive home test.

It was a bummer to spend a few more days coughing and sneezing and avoiding people in my home. But I’m glad I took Paxlovid whether or not it contributed to my rebound.