AAs he treated some of the country’s first coronavirus patients, Andre Kalil noticed something unusual about the new virus: Patients didn’t always progress linearly. They would get better, then worse. Then sometimes better again.
Initially, most researchers thought these rippling symptoms were collateral damage, since an irritated immune system continued to fire long after most of the virus was gone. However, sometimes Kalil could swab a patient’s lungs in the ICU and find that the virus continued to replicate weeks after it was admitted. Often the amount of virus rose and fell from day to day.
“I can’t tell you how many times I’ve seen patients this late in the disease with very, very high viral loads,” said Kalil, a physician and professor at the University of Nebraska Medical Center, which is home to the nation’s only federal quarantine center. “This virus is different from other viruses in the past. It has the ability to replicate for much longer.”
Kalil has been thinking about these early patients again as researchers around the world try to solve a growing mystery: the Paxlovid rebound.
Pfizer’s antiviral pill is nearly 90% effective in preventing hospitalizations due to Covid-19 and has quickly become one of the most potent additions to the pandemic arsenal since the advent of mRNA vaccines. But as its availability has increased, more and more people have found that the drug is only temporarily effective.
In these cases, a patient diagnosed with Covid-19 would typically be prescribed Paxlovid, take it, feel better, maybe even test negative, and then suddenly test positive days or even more than a week later. In some, recurrence was asymptomatic. But for others, they were just as bad or worse than the original disease.
“There were actually many symptoms associated with the rebound, almost as many as with the original infection,” said Davey Smith, an infectious disease specialist at the University of California, San Diego, who recently documented one such case. “Headache, tiredness, cough.”
Tatiana Prowell, an oncologist at the Johns Hopkins School of Medicine, documented this last week Twitter a household member’s struggle with rebound. Twenty days after the first positive test, the person is positive again and suffers from a sore throat, fatigue, runny nose, and non-stop coughing.
These stories raise important questions about how doctors should administer the most effective Covid-19 treatment yet: it could mean some patients need longer treatment cycles; Guidelines for who should take it could be refined; Exit quarantine recommendations may need to be updated.
Countering a rebound has already been discussed. Pfizer CEO Albert Bourla has suggested that patients who experience one take another course of treatment with the drug, while the Food and Drug Administration has issued guidance telling doctors otherwise. On Tuesday morning, the Centers for Disease Control and Prevention issued its first official guidance, reiterating FDA’s advice against retreatment and urging patients with rebound to isolate for at least five days and mask for at least 10 days , as the agency currently advises for new infections.
And yet, almost a month after officials at the National Institutes of Health said they “need to get to grips with the problem urgently,” researchers are still struggling to understand the phenomenon, largely because no one has any idea how common it is or how to do it follow it.
Pfizer’s clinical trials found rebound in only 1% to 2% of patients, and it occurred in both the placebo and treatment groups. Many infectious disease specialists believe it’s much higher in the real world, but that may be driven in part by the number of influential doctors and researchers Twitter who have experienced a rebound.
“We’re in a time where everyone is posting their health information on one website,” said Monica Gandhi, an infectious disease physician at UC San Francisco. “It is very difficult to distinguish perception from reality.”
Annaliesa Anderson, Pfizer’s chief scientific officer for bacterial vaccines, also noted in an interview that few people who haven’t experienced a rebound are in a hurry to report it.
“It’s very difficult to give a percentage of what’s actually happening in the general population,” she said, while noting that the company plans to analyze ongoing clinical trials for conclusive answers, including how often the rebound virus is actually contagious.
Few cases have been described in the medical literature, mostly single-case reports, allowing researchers to form hypotheses but only hint at answers. These include Smith’s preprint study and a Veterans Affairs preprint that documented a relapse in 10 patients, including two who appear to have infected others after the virus returned.
Although the NIH has presented few concrete plans for how it will study the rebound, investigations are ongoing. Gandhi said she and other doctors reported individual cases to the agency, and that Pfizer had its own system for tracking voluntary reports. (A spokesperson said the data so far have been “generally consistent” with the study.)
Michael Mina, chief science officer of testing company eMed, said the company may soon be able to launch a study that could provide an answer “in a couple of weeks” by relying on its product to allow patients to test at home and immediately Contact doctors.
So far, however, no one has announced a comprehensive study, which Kalil and others say would be necessary to understand the problem.
“All we have is anecdotal data,” said Melanie Thompson, an infectious disease physician in Atlanta, when asked about the rebound at a press briefing with the Infectious Diseases Society of America on Friday. “I wish I had a better answer.”
And in the absence of data, Kalil and others worry officials or the public may jump to conclusions. It’s possible, he points out, that the virus has been doing this all along. And more people are only noticing it now because they’re taking a pill that they expect will make them feel better.
“There’s no question that a rebound is happening – we’ve seen it since the pandemic began,” he said. “Is the rebound related to the infection itself? Is the rebound related to the administration of drugs like Paxlovid, or is a rebound related to neither? That is the question.”
Despite rebounds, doctors and researchers are emphasizing that Paxlovid remains a highly effective way to prevent deaths and hospitalizations. In a call with reporters last week, health and human services officials said they were consulting with the FDA about changing prescribing instructions, but in the meantime continue to recommend people take the drug because of its 88% potency , which it showed in clinical studies.
If anything, they say doctors should prescribe it more often, especially for patients who are most susceptible.
White House data shows that as of May 14, the US has used just 670,000 of over 2 million doses Pfizer has made available to date.
“It’s currently underused to some degree because many doctors aren’t familiar with it,” said Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina. “We have an educational thing, both for doctors and for patients.”
Rebounds don’t seem to have undermined this effectiveness. Although there is no comprehensive data, none of the cases documented to date have resulted in serious illness. But even before the CDC’s new guidance, some doctors were beginning to warn that renewed symptoms could mean renewed infectivity.
“If you get symptoms again and test yourself and come back positive on the antigen tests, you should consider yourself contagious,” said Paul Sax, an infectious disease physician at Brigham and Women’s Hospital. “Start the clock for your isolation.”
There are differing theories as to what could be driving the resurrection, assuming they are connected to Paxlovid.
Early on, clinicians ruled out the most worrying possibility: that the virus would develop resistance to the drug, a prospect that could undermine treatment before it even had time to start.
In the UC San Diego case report, researchers analyzed the genome of the virus in the patient with rebound and found no new mutations in the protease, the protein that Paxlovid acts on. They also grew the patient’s virus in a lab and found that Paxlovid still successfully neutralized it there.
That led to other possibilities. The most common is that Paxlovid in some way to Effective. It kills the virus instantly, before the pathogen has had time to set off the body’s entire array of alarms and prime B and T immune cells.
Inevitably, some patients have small pockets where the virus has survived. Once the five-day treatment with Paxlovid is complete, the surviving virions can begin recolonization, free of therapeutic or immunological predators.
However, the theory has one major flaw: Pfizer’s clinical trial data. If that was the case, why didn’t more patients in the study recover?
Researchers have pointed to many hypothetical mechanisms. The population Pfizer studied in its clinical study looked very different from the patients Paxlovid is commonly prescribed for. The former were unvaccinated, met certain high-risk criteria, and were infected with the delta variant. The latter are usually vaccinated, meet a more relaxed risk criterion, and are infected with Omicron.
Gandhi said anecdotally that doctors prescribed it to even lower-risk patients — like the vice president.
The rebounds “could simply be because we’re just not using it in the populations that it’s been studied in,” she said. “To be fair, we don’t even use them in the general public,” for which the FDA has granted emergency use authorization.
Other researchers pointed to recent work by virologist Melanie Ott’s group at UCSF, which suggests that the immune response against Omicron is fundamentally different: perhaps it simply takes longer for the body to develop the right antibody repertoire against this new variant than against previous ones.
Omicron also infects the body differently, preferring the upper respiratory tract. Paxlovid doesn’t diffuse through the body as well as many drugs, and it’s possible that the drug won’t stay in the area long enough to completely clear the virus.
For now, however, it’s mostly speculation. “Nobody knows,” said Debra Poutsiaka, an infectious disease physician at Tufts Medical Center.