Coronavirus FAQ: I took Paxlovid. I felt better. Then symptoms rebounded. What's up?

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I took the anti-COVID drug Paxlovid, my symptoms diminished — and then they returned. Is this common? Worrisome?

That's the so-called "Paxlovid rebound." And here's a first-person testimonial from NPR science correspondent Joe Palca, who's a rebounder.

"I started having COVID symptoms on Saturday, May 6. Persistent cough. On Sunday symptoms got much worse. That day I had a negative rapid test. I also dropped off a sample to the D.C. health lab so I could get PCR test as well. I learned the next day that test was positive.

"My doctor prescribed Paxlovid. She phoned in a prescription to a CVS. I started taking it Monday morning. And continued through Friday. It leaves a terrible taste in your mouth and also gives some people (me) diarrhea.

"By Thursday I was feeling much better — Friday even more so. A rapid test was negative Friday afternoon. Basically I felt fine, maybe a little tired. A rapid test Monday, May 16 was also negative. But on Tuesday I started coughing and the antigen test was positive again. In my first round of COVID-19 I had debilitating fatigue, fever, cough and congestion. Now it's just congestion and cough. Feels like a bad head cold."

So what's going on?

Well first, let's give you a refresher course on Paxlovid.

It's the go-to pill for people with a higher risk of severe disease after contracting COVID-19.

Manufactured by Pfizer, the drug came on the market in December 2021. According to Pfizer's prescribing guidelines, the 5-day treatment course of 3 pills, taken twice daily, should be started as soon as possible after a diagnosis of COVID-19 and within 5 days of symptom onset. Your doctor will also need to review with you all drugs you take since Paxlovid can interact with over a dozen medications, including most statin drugs, which lower cholesterol, and the opioid pain reliever hydrocodone. Your doctor will have to determine if you can stay off any interacting drugs for 5 days or possibly take a lower dose of certain ones while you are on Paxlovid.

Guidance from the National Institutes of Health calls for prescribing the drug to COVID patients who are older, not vaccinated or not fully vaccinated, have underlying health conditions or are immunocompromised. In the clinical trial to support its emergency use authorization, Paxlovid reduced hospitalization by close to 90% in unvaccinated people.

"Paxlovid is the preferred antiviral," says Dr. Amesh Adalja, a senior scholar at the Center for Health Security at the Johns Hopkins Bloomberg School of Public Health.

(In case you're wondering, it's not the only COVID antiviral. Merck also makes a COVID-19 antiviral pill that won emergency use authorization, but it reduced hospitalization risk by only 30% in clinical trials.)

But there is that possible rebound problem, as Joe Palca will attest. The FDA acknowledged cases on May 4, saying it "was aware of the reports of some patients developing recurrent COVID-19 symptoms after completing a treatment course of Paxlovid.

And Pfizer itself acknowledges that it can happen. In its application for emergency use authorization, Pfizer stated that in its clinical trials, 2% of 2,246 patients on the drug, and 1.5 percent of patients on a placebo, saw their COVID symptoms diminish, then rebound.

What are the theories being investigated?

At a briefing on Wednesday, Ashish Jha, coordinator of the White House's COVID-19 response said researchers are looking are the rebound issue "very carefully" and trying to determine if it happens more with the omicron variant. Says Jha: "We're talking to health systems, getting real-world experience data."

Various explanations have been floated.

"There was some suspicion that people were getting reinfected, which turns out not to be the case," says Dr. Paul Sax, clinical director of the Infectious Disease Clinic at Brigham and Women's Hospital in Boston.

Or maybe they didn't take the full course of the medicine. That also didn't prove true, says Sax.

Dr. Katelyn Jetelina, an adjunct professor of epidemiology at the University of Texas Health Sciences Center in Houston, and author of the newsletter Your Local Epidemiologist, suggests that perhaps the 5-day course it just not long enough to clear the virus in some patients. Or, she says, perhaps the decision to start the drug early in the course of the illness blunts the immune system response, which is why symptoms might return

So more investigation needs to be done – and indeed, studies are underway.

Are rebounders contagious?

Whatever the reason for the rebound, does it mean that a patient who had tested negative, then positive — as NPR's Joe Palca did – can transmit COVID to others?

"They are potentially contagious to others," Sax says. "Maybe people are incredulous that they could be contagious again. But you know, that's the unfortunate truth."

Even if it turns out that only 2% of people taking the drug see a rebound, that can add up to some biggish numbers.

With an estimated 20,000 daily prescriptions for Paxlovid, says Dr. Jha, "that would mean that about ... 400 people are having rebound every day."

Dr. Priya Nori, an associate professor of infectious disease at the Albert Einstein College of Medicine and an infectious disease specialist at Montefiore Medical Center, says that she and her colleagues at Montefiore have prescribed Paxlovid hundreds of times and are so far seeing a low incidence of COVID recurrences, but it's difficult to quantify. "We may not know about it unless the patient tells us."

"We make sure each patient is aware that rebound symptoms are possible, but it's unknown who will develop this and who will be fine after a 5-day course of Paxlovid," says Nori. "I inform patients that their symptoms are likely not dangerous to them (especially if maximally vaccinated)."

"So if your doctor determines you should take a course of Paxlovid, be sure to ask what precautions to take—such as home tests and how many days of masks—in case rebound symptoms develop.

Yet even with so many unknowns, there is one encouraging observation. Says Dr. Jha: Rebounders "are not getting particularly sick [and] are not ending up in the hospital. If the goal of this treatment, which it was, was to prevent hospitalizations and deaths, it is doing that incredibly well."

Fran Kritz is a health policy reporter based in Washington, D.C., and a regular contributor to NPR. She also reports for the Washington Post and Verywell Health. Find her on Twitter: @fkritz

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