Paxlovid Might Not Be the Long COVID Cure We Hoped For

Taking the COVID-19 antiviral Paxlovid does not appear to improve Long COVID symptoms in a meaningful way, a new study finds. Those results are a blow to the millions of people living with the condition, which currently has no approved treatment or cure.

Paxlovid has long been a source of hope for those with Long COVID. Scientists don’t know exactly what causes Long COVID, but many have hypothesized that viral material lingers in the body, potentially causing long-lasting symptoms including fatigue, the inability to exercise, brain fog, and more. Given that theory, a drug like Paxlovid, which stops the virus from multiplying and reduces the amount of it in the body, seemed to many like a promising treatment.

But the new study, which was published June 7 in JAMA Internal Medicine, found that taking Paxlovid for 15 days was safe but did not improve key Long COVID symptoms better than a placebo.

“I would have loved to bring forward a paper that said, ‘Great benefit,’” says senior author Dr. Upinder Singh, a professor of infectious diseases at Stanford University. Even though that wasn’t the result, Singh says, the study adds to scientists’ collective understanding of Paxlovid and Long COVID, and does not rule out the possibility of more positive results in the future. “Science is generative,” she says. “Data sometimes changes.”

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Singh and her colleagues enrolled 155 adults with Long COVID in the trial. All of them had previously tested positive for COVID-19, lived with Long COVID symptoms for at least 90 days, and currently experienced at least two of six major symptoms: fatigue, brain fog, body aches, cardiovascular issues, shortness of breath, and gastrointestinal issues. Most people in the study had been sick for longer than a year and almost all had been vaccinated against COVID-19. Three-quarters of participants were white and about 60% were female.

About 100 people were randomly assigned to receive the full Paxlovid regimen, which consists of two medications: the antiviral nirmatrelvir and ritonavir, which prevents nirmatrelvir from breaking down too quickly. The rest of the group took a placebo with ritonavir, which doesn't work against the SARS-CoV-2 virus on its own. Ritonavir enhanced the placebo because it's linked to a telltale side effect of Paxlovid—a bad aftertaste—so participants couldn’t necessarily guess whether they’d gotten the active treatment or not.

Both groups took their drugs twice a day for 15 days, three times longer than patients are currently prescribed Paxlovid. Researchers then tracked them for 15 weeks to assess safety and look for differences in Long COVID symptoms over time.

On the plus side, the researchers concluded that it’s generally safe to take Paxlovid for 15 days, although non-life-threatening side effects like diarrhea and bad aftertaste were common. That’s important to know, because some experts believe taking the drug for longer could help prevent outcomes like Paxlovid “rebound.” A longer course may also be more effective for some high-risk patients, Singh says.

But “we didn’t find an obvious benefit” to taking Paxlovid for symptom relief, Singh says. People in the Paxlovid group didn’t fare significantly better than those taking the placebo.

That said, people in both groups saw improvements in their symptom severity over the course of the study. Symptoms often get better over time, Singh says, but participants may also have had some expectation of feeling better simply because they were enrolled in a clinical trial. And, despite the relative improvement, moderate and severe symptoms were still common at the end of the study, which underscores the need for more research on treatments.

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Whether Paxlovid, or another antiviral drug, ends up being a viable treatment remains to be seen. While the results from this study aren’t encouraging, other teams are also studying Paxlovid’s efficacy as a Long COVID treatment. It’s possible the drug could work better when taken for a longer length of time, among certain groups of Long COVID patients, or among those who haven’t been sick as long as the participants in the current study, Singh says.

Another outstanding question: can taking Paxlovid during a case of COVID-19 help prevent Long COVID from ever developing? Some data suggest it may, but other studies have found that it doesn’t work as a preventive measure.

The new study didn’t address that possibility, and more research is needed before anyone should take Paxlovid for that reason alone—but, Singh says, patients should take comfort in the fact that scientists are actively tackling these questions, recognizing the massive unmet need for therapies targeted toward Long COVID treatment and prevention.

“People are working on this,” she says. “People are motivated.”