When Berkeley resident Myriam Misrach tested positive for the coronavirus last month, she started taking the COVID antiviral pill Paxlovid the same day. Over the five-day course of treatment, her cough and shortness of breath mostly faded, but a couple days after taking the final pill, her symptoms came roaring back.
For 48 hours thereafter, she also had a fever, headache, nausea, runny nose and lost her sense of taste, she said. And she once again tested positive for the virus — despite having tested negative and feeling much better just a few days prior.
“I had everything in the book,” said Misrach, 66, who is vaccinated and boosted. “It was not at all a mild case.”
Misrach continued testing positive for two weeks after that and today is still coughing, though the other symptoms have subsided. What was even more puzzling, she said, was that her husband had also just taken Paxlovid and for him, it “worked beautifully” — he started feeling better almost immediately and stayed that way, though he too tested positive after initially testing negative.
“I’m not blaming Paxlovid but I think they need to study it more,” she said.
As the number of Americans taking the Pfizer drug skyrockets, many people are reporting similar “rebound” after taking the drug — including some vaccine scientists and doctors who’ve documented their experiences on Twitter. In addition to a recurrence of symptoms, rebound also means that someone who thought they’d recovered might still be infectious and should isolate for additional days.
All known cases of Paxlovid viral rebound appear to have been resolved without patients needing hospitalization, say doctors who prescribe the drug and researchers who are studying the issue. They overwhelmingly agree that this does not give them pause about prescribing the antiviral medication, which in clinical trials reduced the risk of COVID hospitalization and death by nearly 90%. They say if someone is eligible for Paxlovid, the patient should still get it, despite the potential of experiencing rebound symptoms, because it’s living up to its promise by indeed keeping people out of the hospital.
Rebound, also known as relapse, isn’t uncommon in infectious diseases. Doctors often see it in patients who took antibiotics or antivirals, where the infection returns after the treatment is completed because the virus or pathogen wasn’t cmpletely cleared, said Dr. Prasanna Jagannathan, a Stanford immunologist and infectious disease physician.
The Paxlovid rebound phenomenon is an example of what happens when a new medication — probably the most closely watched drug in recent memory, second only to COVID vaccines — starts to get used widely in the real world and elicits outcomes that may not have been observed during clinical trials at such high levels. This doesn’t mean the drug is failing, scientists and doctors noted, but rather that it needs to be studied further and that its dosage or duration of usage may need to be tweaked.
It’s not clear why rebound is happening, or how often it occurs in the real world. In Pfizer’s clinical trials, it occurred in 2% of the people who took Paxlovid. Many doctors who prescribe the antiviral say they hear about rebound anecdotally from patients, and that it appears to be more common than it was in trials. But that could be in part because of reporting bias, where the people who experience rebound are more likely to report it than those who didn’t have the issue.
“We’ve all heard anecdotes of patients we’ve taken care of that experience this, so it’s clearly a phenomenon,” said Jagannathan, who has prescribed Paxlovid to 25 to 30 patients and observed rebound in two of them. “What that true number is, no one knows yet.”
Pfizer and the U.S. Food and Drug Administration are tracking rebound cases for further study. Providers and patients can report cases to Pfizer’s and the FDA’s respective adverse event reporting systems.
Researchers are eyeing a few potential explanations for viral rebound.
One small study, which has not yet been peer reviewed, suggests the issue is probably not drug resistance due to viral mutation or a problem with a patient’s immune response. Rather, patients may not have been exposed to Paxlovid enough. This could mean that instead of the five-day course currently authorized by the FDA, people may need to take the drug for longer, or at a different dosage. The study, which was posted on a pre-print site this week, looked at three vaccinated and boosted adults who took Paxlovid, including one who experienced rebound. That person was infected with the BA.2 omicron subvariant.
Patients and health care providers can report instances of suspected Paxlovid rebound to Pfizer and the U.S. Food and Drug Administration, which are tracking the phenomenon for further study.
To report it to Pfizer, go to Pfizer’s COVID-19 Treatment Adverse Event Reporting website and submit a form online.
To report it to the FDA, go to FDA MedWatch and submit a form online or by fax at 1-800-332-0178. Call 1-800-332-1088 for questions.
“Our hypothesis or best guess at this point is we think there’s insufficient drug exposure to get rid of the virus,” said the study’s lead author, UC San Diego’s Dr. Aaron Carlin, who studies emerging and reemerging viral infections and how they interact with the immune system. “There’s likely going to be studies to see if people need 10 days instead of five days to try to prevent that rebound from occurring.”
Another small study, initially posted in late April and updated last week by the VA Boston Health System, also suggests the reason for relapse isn’t because the virus mutated after patients took Paxlovid. The authors said further research is needed to determine the cause of relapse.
Pfizer’s Paxlovid trials were done in vaccinated and unvaccinated people when delta and earlier variants were circulating. Now, it’s people infected with omicron and omicron subvariants who are taking the drug, including many who are vaccinated. So it’s possible their immune systems are responding to the drug a little differently, which might help explain rebound. It could also be that omicron and its subvariants lead to a longer period of viral shedding than delta, so people may now need a longer course than five days.
The UC San Diego study analyzed several coronavirus variants and their sensitivity to Paxlovid, and didn’t find significant differences in how they responded to the drug. But there is some evidence suggesting that the neutralizing antibody response in vaccinated people is lower against omicron than delta, “so there may be something about omicron and the immune system that contributes to this (rebound), but we don’t understand that yet,” Carlin said.
If it turns out the virus does become resistant to Paxlovid in the future, it may be that combining it with other antivirals may help. Treating HIV with a single drug almost immediately leads to drug resistance, but treating it with three drugs doesn’t, Carlin said.
“It’s a warning, but I don’t think it’s a reason people should not take the drug,” Carlin said. “It’s still highly effective. We just have to understand whether it can be used in a way to make it even better to avoid the rebound.”
Catherine Ho (she/her) is a San Francisco Chronicle staff writer. Email: cho@sfchronicle.com Twitter: @Cat_Ho