Authors: Arielle Dreher Axios September 2, 2022

Paxlovid, once hailed as a “game-changer” for its ability to treat COVID-19 infections at home, is becoming one of the pandemic’s biggest enigmas.

The intrigue: There’s growing concern about the link between Pfizer’s antiviral pill and COVID rebound, in which patients test positive or have symptoms days after a course of the drug is completed. President Biden, First Lady Jill Biden and NIAID Director Anthony Fauci have each relapsed.

• The FDA has asked Pfizer to investigate whether a second five-day course of the drug will prevent the virus from returning.
• Pfizer executives in May suggested patients who can’t clear the virus with the first course should take more, Bloomberg reported.

The big picture: Paxlovid use surged over the summer, with as many as one-third of reported coronavirus cases treated with the drug.

• But uncertainty over what’s causing the relapses, and whether the drug helps younger patients, is making some people wary of taking the treatment, physicians say.
• At least part of the problem is that people are not routinely tested after taking Paxlovid, which makes it hard to establish how often rebound happens or why the virus lingers in some people, Leana Wen, an emergency physician and a professor at George Washington University, told CNN.
• A large study of more than 109,000 people in the New England Journal of Medicine concluded the drug significantly reduced hospitalizations and deaths among patients aged 65 and older but that there was no evidence of benefit in younger adults.
• The prospect of reinfection shouldn’t discourage older or high-risk patients from taking the pills, said Yale infectious diseases specialist Scott Roberts.
• “Rebound is almost always more mild than initial course,” Roberts told Axios.
• Paxlovid could have the added benefit of warding off long COVID, or symptoms that linger beyond the first 30 days after testing positive, and studies to determine this are underway.

But availability of the drug could change before clear answers emerge.

• The Biden administration has only bought enough pills to supply Paxlovid through the middle of next year, after which it will transition to the commercial market, HHS Assistant Secretary for Preparedness and Response Dawn O’Connell wrote in a blog post on Tuesday.

Between the lines: COVID rebound has also been observed in people who have not taken Paxlovid, and some experts believe it might be a natural course of the infection to see symptoms ebb, then return.

• COVID’s course “is not a purely linear process; it waxes and wanes a little bit,” said Jonathan Li, a Harvard Medical School researcher and co-author of a pre-print that found high levels of rebound in people who hadn’t been treated with the drug.

State of play: The CDC recommends Paxlovid for those over the age of 50, and for those with medical conditions like lung or heart disease that makes them high-risk, although the drug’s emergency authorization covers anyone 12 years old and up.

• Research in Clinical Infectious Diseases found the drug remains effective for vaccinated people who contract COVID-19, reducing emergency room visits by lowering the risk of complications like lower respiratory tract infection and cardiac arrhythmia.
• Beyond the Pfizer study requested by the FDA, a clinical trial of immunocompromised people is evaluating if Paxlovid should be used for five, 10 or 15 days.

What they’re saying: “The consensus by the vast majority of people caring for COVID patients is that the rebound is not really a side effect of Paxlovid, it is more that are we really treating people for long enough or not?” Sarju Ganatra, a cardiologist at Lahey Hospital and co-author of the Clinical Infectious Diseases study, told Axios.

Yes, but: “This is where having a well-designed, well-controlled study helps us understand disease better, and this is the challenge of anecdotal reports. Without a control, it’s really hard to know what’s actually happening,” said Kara Chew, an infectious disease physician at University of California Los Angeles.

The bottom line: Paxlovid remains an important tool to keep some people out of the hospitals, especially with the highly contagious Omicron variant still circulating and many people not staying current on boosters, experts said.

• Isolation will also be critical as long as enough people are experiencing COVID rebound and stay infectious beyond the five-day isolation period recommended by the CDC.