On June 3rd, U.S. Senator Jeff Merkley announced that he had a “rebound” Covid-19 infection after taking Pfizer’s antiviral, Paxlovid. In a statement he posted on Twitter, Merkley wrote: “After recovering and feeling better, some COVID symptoms have returned I have again tested positive. This is occurring in a modest percent of folks who used Paxlovid and is called ‘COVID-19 rebound.”
Paxlovid was the first Covid-19 oral antiviral granted Emergency Use Authorization (EUA) by the FDA, in late December of 2021. Manufactured by Pfizer, the novel drug showed impressive outcomes in clinical trials, reducing hospitalization or death in people with Covid-19 by 88 percent when given within five days of symptom onset.
During clinical trials, researchers had noted that the antiviral can cause rebound infection — where someone with Covid-19 feels better and tests negative, only to have symptoms and detectable levels of the virus reoccur within days — but those instances seemed to be rare. Saralyn Mark, an endocrinologist, gerontologist, and Covid-19 Lead for the American Medical Women’s Association, tells Inverse that in the clinical trials for the EUA, 1 to 2 percent of participants experienced rebound infections but “nothing that raised red flags.”
There is no official estimate of how often rebound infections occur in the real world. Researchers are still trying to determine the frequency as well as causation, but here’s what we know so far.
How does Paxlovid work?
Paxlovid is prescribed for people who are within the first five days of testing positive for Covid-19 and who have one or more risk factors for complications from the virus.
“Paxlovid inhibits the viral replication and stalls more severe infection while the immune system works,” Mary Jo Ondrechen, a professor of chemistry and chemical biology at Northeastern University who works on developing potential anti-viral drugs, tells Inverse.
It does so through the use of two medications: Nirmatrelvir and ritonavir. When the SARS-CoV-2 virus infects a human cell, it uses a specific enzyme to make copies of itself, thereby spreading the virus to other cells in the body. Nirmatrelvir blocks that enzyme, which prevents the virus from replicating.
The other medication inside Paxlovid is ritonavir. Initially developed to treat HIV/AIDS, ritonavir boosts levels of antiviral medicines, allowing nirmatrelvir to work better.
Why does a rebound infection happen?
Rebound illness can happen any time between 2 and 8 days after completing treatment with Paxlovid. Importantly, it doesn’t mean someone has been infected with a new strain of the virus, says Mark. Researchers think that Paxlovid is able to get the levels of virus in the body so low that someone with Covid-19 both feels better and tests negative. But this virus, in particular, is known to linger in some places in the body, like the GI tract. Whatever remnants of the virus left after a course of Paxlovid may then be able to replicate and reach detectable levels over several days.
Mark likens it to stopping a course of antibiotics early. “People feel better so they stop taking the antibiotics early and before they complete their course. But if you don’t do the full course, the bacteria may not be completely eliminated and can continue to replicate.” This might suggest that the dose of Paxlovid isn’t high enough to eliminate the infection, she says. Or some people might need a longer course of the drug for full effectiveness. “We don't have a long history with this medication,” she says. “So we're learning as we go forward.”
Another possibility is that people aren’t taking it in the precise five-day window indicated.
“How many people really know that it's only been five days since they became positive for the virus? How many people know the exact day? Almost nobody,” Donald Alcendor, an Adjunct Associate Professor of Pathology, Microbiology, and Immunology at Vanderbilt University School of Medicine, tells Inverse. “ More than likely, you could have a drug that is meant to be given early in the course of infection being given to some people that are in a later stage of infection, where the drug is not as effective.”
Another factor, Alcendor says, is that all of the people in the EUA trials were unvaccinated. So while instances of rebound infections were only 1 to 2 percent in the trials, that may be different among people who are vaccinated.
Because the drug has only been available to the public for about six months, Ondrechen says researchers simply need more data to better understand and identify what the root cause or causes of rebound infections could be. “We need data on outcomes for persons treated with Paxlovid,” she says. “Paxlovid is generally prescribed only to those with one or more risk factors for severe disease. It is possible that the treated population is more susceptible.”
Do rebound infections put you at higher risk of severe disease?
The good news about rebound infections, says Alcendor, is that thus far, it doesn’t seem like they’re causing more severe disease than the initial infection did. However, early data from the VA suggests that people can transmit the virus once the rebound infection happens.
If you’ve taken Paxlovid and experienced a rebound infection, the CDC recommends masking for 10 days following the onset of rebound symptoms.
In many ways, rebound infections are a bit like breakthrough infections after vaccination. The topline, most important goal of vaccination and treatment is to prevent the worst outcomes of Covid-19: Hospitalization and death. By and large, both Paxlovid and the vaccines have achieved this. While rebound infections can be frustrating and can have public health consequences, just like breakthrough infections do, it’s still a much-needed and largely effective tool for people who are at high risk of complications from Covid-19.
“Imagine if we’d had something like Paxlovid when the pandemic started,” Alcendor says. “An oral medication that if taken in the first five days that’s highly effective at preventing the worst outcomes for high-risk people. It would have been a game-changer. And it still is.”