‘Paxlovid rebound’ raises questions over how long antiviral COVID treatment should last

President Biden testing positive for COVID-19 again days after completing a course of Paxlovid has raised the question of whether the length of the antiviral treatment should be reconsidered.

Just days after he completed a five-day round of Pfizer’s COVID-19 antiviral treatment, Biden’s physician Kevin O’Connor said in a letter on Saturday that the president had tested positive once again. As of Wednesday, Biden is still testing positive for COVID-19.

This phenomenon has come to be known as “Paxlovid rebound,” when a person tests positive for coronavirus again even after initially testing negative following a round of treatment with the antiviral. A recent preprint study found that Paxlovid rebound occurred among 3.5 percent and 5.4 percent of coronavirus infections at the 7-day and the 30-day mark after treatment respectively. Biden’s chief medical advisor Anthony Fauci also experienced Paxlovid rebound after contracting the virus and started a second round of treatment.

Some experts have called for studies into extending Paxlovid treatments to be prioritized, as early research has suggested that Paxlovid rebound could occur due to insufficient exposure to the drug. Researchers from the University of California San Diego School of Medicine said last month that the drug may not be reaching enough infected cells in the allotted time.

Paxlovid, under an emergency use authorization issued by the Food and Drug Administration (FDA), is administered in two doses taken daily over the course of five days. Physicians are not permitted to prescribe longer rounds of treatment and clinical data on courses lasting more than five days has yet to be completed.

Earlier this year, Fauci said the National Institutes of Health was in talks with Pfizer about studies looking into longer courses of Paxlovid, though any updates on these possible trials have not been disclosed.

“I’m actually still flabbergasted that we have not set up a clinical trial to figure this out. It’s an easy thing to do,” Robert M. Wachter, chair of the Department of Medicine at the University of California, San Francisco, told The Hill.

“Wouldn’t cost that much to be able to accumulate enough patients in a week or two and follow them for a few weeks so we could have an answer,” Wachter said, adding that the data needed to potentially extend the length of a round of Paxlovid could have been collected already if trials had been started just a few months ago.

According to Wachter, there aren’t any​ similar antiviral “analogies” to compare Paxlovid to. Viral rebound isn’t usually tested for and other antiviral treatments aren’t administered in the same manner.

Eric Toner, Senior Scholar at the Johns Hopkins Center for Health Security at the Bloomberg School of Public Health, noted that viral rebound has rarely been studied as much as it is now in the context of COVID. ​However, Toner said instances of viruses or bacterial infections still lingering after treatment do occur.

Instances of viral rebound of coronavirus are also not unique to Paxlovid. Cases of rebound with molnupiravir, the COVID-19 antiviral created by Merck and Ridgeback, have been observed as well.

People who experience cases of antiviral rebound are still at risk of transmitting COVID-19 to other people. Michael Charness, a researcher from the Veterans Administration Medical Center in Boston, recently told CNN that he and his colleagues had observed at least two instances of people infecting others after their symptoms reoccurred. Both cases involved people who tested positive again after taking Paxlovid.

People tend to have much milder symptoms that resolve fairly easily on their own after testing positive again, Toner said. For this reason, he said a second round of treatment, even in cases of Paxlovid rebound, is probably unneeded. O’Connor, Biden’s physician, has provided regular updates on the president’s health, but has not disclosed whether he has started a second course of Paxlovid like Fauci did.

While the need for and feasibility of longer Paxlovid rounds remains uncertain, the U.S. may find itself relying on antivirals more going forward as new variants of COVID-19, more infectious and better at evading immune protection, continue to crop up.

“If we do see more variants and they’re more evasive and we have more people with infections who are at risk of a serious outcome, then antivirals will become increasingly important,” Wachter said, though he added, “As far as we know, none of that is really true.”

He noted that even with subvariants like BA.5 spreading and causing more infections, the current vaccines are still offering strong protection against severe cases, hospitalizations and deaths.

Researchers have previously said that it would be difficult, but not impossible, for COVID-19 to become resistant to Paxlovid treatment, as the drug targets a part of the virus that does not change easily.

When reached for comment, a Pfizer spokesperson pointed to a health advisory from the Centers for Disease Control and Prevention (CDC) released earlier this year that stated a brief return of COVID-19 symptoms following the completion of Paxlovid treatment “may be part of the natural history of SARS-CoV-2.”

“While further evaluation is needed, we have not seen any viral resistance emerge to date in patients treated with PAXLOVID, and we continue to monitor data from our ongoing clinical studies and post-authorization safety surveillance,” said the spokesperson. “We remain very confident in PAXLOVID’s clinical effectiveness at preventing severe outcomes from COVID-19 in patients at increased risk.”

The spokesperson for Pfizer did not comment on the possibility of longer Paxlovid courses.

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