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When Berkeley resident Myriam Misrach tested positive for the coronavirus last month, she started taking the COVID antiviral pill Paxlovid the same day. During the five days of treatment, her cough and shortness of breath mostly went away, but a few days after taking the last pill, her symptoms returned.
Afterward, she had a fever, headache, nausea, a runny nose, and lost her sense of taste for 48 hours, she said. And she tested positive for the virus again – despite having tested negative just days before and feeling much better.
“I had everything under control,” said Misrach, 66, who is vaccinated and refreshed. “It wasn’t a mild case at all.”
Misrach continued to test positive for two weeks after that and is still coughing today, although the other symptoms have subsided. What was even more puzzling, she said, was that her husband had also just taken Paxlovid and it “worked beautifully” for him – he felt better almost immediately and stayed that way, despite also testing positive after initially testing negative.
“I don’t blame Paxlovid, but I think they need to study it more,” she said.
As the number of Americans taking the Pfizer drug skyrockets, many people — including some — are reporting a similar “rebound” after taking the drug vaccine scientist and doctors who have documented their experiences on Twitter. In addition to a return of symptoms, rebound also means someone who thought they had recovered may still be contagious and should isolate for more days.
All known cases of Paxlovid virus rebound appear to have resolved without requiring patients to be hospitalized, say doctors who prescribe the drug and researchers studying the problem. They overwhelmingly agree that this doesn’t stop them from prescribing the antiviral drug that in clinical trials has reduced the risk of COVID hospitalization and death by nearly 90%. They say if someone is eligible for Paxlovid, despite the possibility of rebound symptoms, the patient should still get it because it delivers on its promise by actually keeping people out of the hospital.
Rebound, also called recurrence, is not uncommon in infectious diseases. Doctors often see it in patients who have been taking antibiotics or antiviral drugs where the infection returns after treatment is complete because the virus or pathogen has not been completely eliminated, Dr. Prasanna Jagannathan, Immunologist and Infectious Disease Physician from Stanford.
The Paxlovid rebound phenomenon is an example of what happens when a new drug — probably the most closely watched drug in recent times, second only to COVID vaccines — becomes widely available in the real world and produces results that which may not have been observed during clinical trials at such a high level. This doesn’t mean the drug is failing, scientists and doctors noted, but that it needs further study and that its dosage or duration of use may need to be adjusted.
It’s not clear why a rebound occurs or how often it occurs in the real world. In Pfizer’s clinical trials, it occurred in 2% of people taking Paxlovid. Many doctors who prescribe the antiviral drug say they’ve heard of rebound anecdotally from patients and that it’s more common than studies show. But that could be partly due to reporting bias, where people who experience a rebound are more likely to report it than those who didn’t have the problem.
“We’ve all heard anecdotes from patients we’ve cared for, so it’s clearly a phenomenon,” said Jagannathan, who has prescribed Paxlovid to 25 to 30 patients and seen recovery in two of them. “What this true number is, no one knows yet.”
Pfizer and the US Food and Drug Administration are pursuing rebound cases for further investigation. Providers and patients may report cases to the Pfizer and FDA adverse event reporting systems.
Researchers are looking for some possible explanations for the viral rebound.
A small study that has not yet been peer-reviewed suggests it is unlikely to be drug resistance due to a viral mutation or a problem with a patient’s immune response. Rather, patients may not have been adequately exposed to Paxlovid. This could mean people may need to take the drug longer or at a different dosage instead of the current FDA-approved five-day course. The study, published on a preprint site this week, looked at three vaccinated and boosted adults taking Paxlovid, including one who experienced a rebound. This individual was infected with the Omicron subvariant BA.2.
Patients and healthcare providers can report cases of suspected Paxlovid rebound to Pfizer and the US Food and Drug Administration, who are tracking the phenomenon for further study.
To report it to Pfizer, visit 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 fax it to 1-800-332-0178. Call 1-800-332-1088 with questions.
“Our hypothesis, or best guess at this point, is that we believe drug exposure is not sufficient to clear the virus,” said study lead author Dr. Aaron Carlin of UC San Diego, who studies emerging and re-emerging viral infections and how they interact with the immune system. “Probably there will be studies to see if it takes people 10 days instead of 5 to try and prevent this setback.”
Another small study, originally published in late April and updated by the VA Boston Health System last week, also suggests the reason for relapse isn’t because the virus mutates after patients take Paxlovid. The authors said more research is needed to determine the cause of the relapse.
Pfizer’s Paxlovid studies were conducted in vaccinated and unvaccinated subjects when Delta and earlier variants were in circulation. Now it’s people infected with Omicron and Omicron subvariants who take the drug, including many who are vaccinated. So it’s possible that her immune system is reacting slightly differently to the drug, which could help explain the rebound. It could also be that Omicron and its subvariants result in a longer virus shedding period than Delta, so people may now need a longer cycle than five days.
The UC San Diego study analyzed multiple coronavirus variants and their susceptibility to Paxlovid and found no significant differences in response to the drug. But there is some evidence that the neutralizing antibody response in vaccinated individuals is lower to Omicron than to Delta, “so there might be something to do with Omicron and the immune system (rebound), but we don’t understand that yet.” ‘ said Karlin.
If the virus turns out to be resistant to Paxlovid in the future, combining it with other antivirals may help. Treating HIV with a single drug leads to drug resistance almost immediately, but treating it with three drugs doesn’t, Carlin said.
“It’s a warning, but I don’t think it’s a reason people shouldn’t take the drug,” Carlin said. “It’s still very effective. We just need to understand if it can be used in a way that makes it even better to avoid the rebound.”
Catherine Ho (she/she) is a contributor to the San Francisco Chronicle. Email: [email protected] Twitter: @Cat_Ho
