Paxlovid rebound happens, though why and to whom are still a mystery

As an emergency department physician in New York, I often field calls about medical issues from family members, friends, and even friends of friends. Since the Covid-19 pandemic began, the number of these calls has dramatically increased.

The latest slew of these, about Paxlovid and rebound Covid-19 — which President Biden now apparently has — has revealed the confusion surrounding this phenomenon for me, my physician colleagues, and at least one Nobel laureate.

I recently got a call from my friend Joachim Frank, who shared the Nobel Prize in Chemistry in 2017, about his rebound Covid after doing what he was supposed to do: taking Paxlovid as his doctor had prescribed.

Then I heard from my brother-in-law, Gary, that he had experienced Paxlovid rebound as well, then my friend Dave, then friends of friends of friends. I began to wonder how rare this really was: At least a subset of my contacts was beginning to wonder if taking the medication had really helped them, or just prolonged their illness and all the logistics that come with a diagnosis of Covid-19.

The Centers for Disease Control and Prevention sounded the alert about rebound Covid in May. It described patients with Covid who, after being treated with the antiviral Paxlovid, initially became symptom-free and in many cases had negative tests for SARS-CoV-2, the virus that causes Covid-19, but then got sick again. The same phenomenon occurs with another antiviral oral medication to treat Covid, Lagevrio (molnupiravir) and at the same rates, but Lagevrio may not be as effective as Paxlovid and therefore has not yet become as much of a household name.

Since the CDC alert, there have been a number of rebound studies, including a recent investigation of 92 million people nationwide showing rebound rates of less than 6% for Covid infection — and less than 1% for hospitalizations after Paxlovid treatment — most occurring in unvaccinated people and in those with underlying medical conditions.

To offer my patients, family members, and friends the best advice possible, I reached out to David Ho, a virologist at Columbia University in New York who first figured out how HIV replicates and the go-to genius on many current virus issues. By chance, he and a family member had recently experienced Covid rebound and, in fact, feature prominently in research findings of his that will soon be published in the New England Journal of Medicine. “I am Patient #2 and my family member is Patient #3,” he told me.

In an email exchange, Ho characterized the frequency of rebound Covid as “common enough,” and that with more and more people taking Paxlovid, the number of rebound Covid cases will likewise increase.

My emergency medicine physician colleagues are seeing tons of it.

Joachim Frank had been in Germany for the 71st Lindau Nobel Laureate Meeting — a gathering of 30 or so Nobel laureates and select young scientists. His days in Lindau were the culmination of five weeks he and his wife, Carol Saginaw, spent in Europe, packed with lectures, dinners, and scientific seminars. On July 3, he told me he felt like a “rush going through my head, comparable to fever fantasies I had when I was a child,” and had developed a cough and highly sensitive skin all over his body — it hurt so much he could barely touch it. After a rapid test was positive for SARS-CoV-2, he began a five-day course of the three-pill Paxlovid regimen: two pink nirmatrelvir tablets and one white ritonavir tablet twice a day.

With full understanding of the research showing Paxlovid helps reduce hospitalization and death in his and other age groups and among people with preexisting conditions, starting Paxlovid was a no-brainer for him. With the exception of the “awful metallic taste” — likened by my brother-in-law to the taste of a can of Coca-Cola that has been sitting open for a month — and some stomach upset, he had no complaints with the Paxlovid. And it worked. After a day and a half, the cough had disappeared and his skin was no longer especially sensitive.

On the fifth day of the Paxlovid regimen, Frank, who was then testing negative, and his wife, who had been testing negative daily since her husband became ill, flew back to New York. The next day, she felt fatigued and had a cough, and then tested positive; she started Paxlovid too. Frank felt fine and went back to work, though fully masked.

But six days after taking his last dose of Paxlovid, Frank was sick again. That’s when he called me. He was queasy and tired, his skin again too painful to touch, and his Covid test turned positive so quickly he was fearful the control line would not have time to appear.

He had lots of questions for me: Is this rebound Covid? If it is, what does it mean for me? If he was positive again and his wife was now negative after her own illness, did he need to mask around her? Does she need to wait two to eight days after finishing her course of Paxlovid before she can go food-shopping? Do they eat in separate rooms? Is Paxlovid rebound as contagious as the first go-around?

There are no clear and easy answers to these questions, just as there is no solid explanation for how or why Paxlovid rebound occurs. One theory is the virus mutates and develops resistance to nirmatrelvir and ritonavir, the two drugs that are combined to produce Paxlovid.

Ho has his own ideas. He doesn’t think drug resistance is at work and, after he and his team had done viral sequencing, found no viral mutation. He theorizes that Paxlovid is successfully blocking viral replication and disease while the drug is in the body. But what Ho calls an “intermediary form of the virus” starts replicating again once the drugs are no longer circulating.

Ho’s team has also conducted viral sequencing among contacts of rebound cases — information the average person does not get with the yes/no red bar on a rapid test. Family members of people with rebound Covid who then get Covid-19 themselves share the same viral subvariant with their familial contact — which suggests that people with rebound Covid are contagious.

Based on Ho’s theory, it’s possible that people may need to take Paxlovid for longer than five days. Ho tells me that some clinicians are already prescribing for longer treatment periods, but there are no official recommendations — yet.

People with rebound Covid do not seem to be getting terribly sick. Frank had additional days of fatigue and painful skin; my brother-in-law lost his taste and couldn’t smell basil; my friend Dave had three days of a cough. But the rebound prolongs the logistical complications of Covid that can wreak havoc on peoples’ lives, including return to work, caring for children or other family members, travel, and participation in social events.

For me, rebound begs the question: Is Paxlovid worth it? The CDC advisory states in black, bold, and no uncertain terms that, despite the risk of rebound Covid, “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.” But the definition of “high risk” in this situation has been a moving target since the first days of Covid-19.

Someone who is 80 years old with multiple risk factors for severe disease, like asthma, cancer, or heart disease, certainly qualifies as high risk. But whether “high risk” applies to someone who is 65 years old, in great shape, and vaccinated is less clear, even though age has been one of the most-used determinants in Covid-19 treatment. And what about the 35-year-old with asthma? Are they, or even those younger with asthma, at high risk?

Many people opt out of taking Paxlovid, or take a wait-and-see approach. Those who consider the risk of rebound Covid one they don’t care to take may, says my colleague Rebecca Press, an outpatient internist with New York Physicians, be eligible for monoclonal antibodies. Formerly a logistical nightmare to obtain, Press says monoclonal antibodies are now easily available and effective and that infusion teams will now bring the intravenous medication to one’s home and administer it.

Does Joachim Frank regret taking Paxlovid, which led to rebound Covid, which prolonged his isolation, which caused him to miss work and kept him from seeing his grandchildren for at least five additional days? He doesn’t.

But the jury is clearly still out. Although people tend to think of medical care as something that is certain, it is actually a real-time experiment. Paxlovid, like a lot of Covid-19 care, is a reminder of this.

Joan Bregstein is an emergency medicine physician in New York City, a professor of pediatrics (in emergency medicine) at the Columbia University Vagelos College of Medicine, and a medical writer.