‘Insufficient drug exposure’ may be to blame for Paxlovid ‘COVID rebound’

SAN DIEGO — Paxlovid has been a key medication in preventing severe cases of COVID-19, but symptoms have returned in some patients after taking the pills. That’s why the Centers for Disease Control and Prevention issued a health advisory concerning “COVID-19 rebound” symptoms. Now, researchers from the University of California San Diego School of Medicine may have an answer for why patients on Paxlovid are experiencing this.

Researchers found the relapse wasn’t caused by resistance to the drug or impaired immunity against COVID. Instead, the rebound is likely the result of insufficient exposure to Paxlovid. Simply put, not enough of the drug reached the infected cells to stop the virus from replicating.

The U.S. Food and Drug Administration granted Paxlovid emergency use authorization in December 2021, after a clinical trial showed the drug reduced the risk of hospitalization and death from COVID-19 by 89 percent. Paxlovid is easier to take at home compared to drugs like Remdesivir, which requires intravenous injection.

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Human lung epithelial cells (blue) infected by SARS-CoV-2 BA.2 virus (red) isolated from a patient with COVID-19 rebound after Paxlovid treatment. CREDIT: UC San Diego Health Sciences

Should patients stay on Paxlovid longer?

For the study, researchers first isolated the SARS-CoV-2 BA.2 variant from a COVID-19 rebound patient and tested whether it developed any drug resistance. Following the Paxlovid treatment, the virus was still sensitive to the drug and showed no relevant mutations that would reduce the drug’s effectiveness.

“Our main concern was that the coronavirus might be developing resistance to Paxlovid, so to find that was not the case was a huge relief,” says Dr. Aaron Carlin, the study’s first author and assistant professor at UC San Diego School of Medicine, in a university release.

Next, researchers sampled the patient’s plasma to test their immunity against SARS-CoV-2 and found the patient’s antibodies were still effective at blocking the virus from entering and infecting new cells. This suggests that a lack of antibody-mediated immunity was also not the cause of the patient’s rebound symptoms.

With this evidence in hand, researchers concluded that the rebound symptoms are likely due to insufficient drug exposure. The team adds that this may be due to Paxlovid being metabolized more quickly in some patients or that the drug needs a longer treatment period. Currently, Paxlovid patients take three pills twice daily for five days, for a total of 30 pills.

“The goal of Paxlovid is to prevent serious illness and death, and so far no one who has gotten sick again has needed to be hospitalized, so it’s still doing its job,” says Dr. Davey Smith, the study’s senior author and chief of Infectious Diseases and Global Public Health at UC San Diego School of Medicine. “We simply need to understand why the rebound happens in some patients and not others. More research is needed to help us adjust treatment plans as necessary.”

The study is published in the journal Clinical Infectious Diseases.

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