Paxlovid may reduce long COVID risk for some patients, study finds

COVID patients who were treated with Paxlovid, the oral antiviral that has proved highly effective at preventing hospitalization and death among elderly and at-risk people, appeared less likely to suffer from several key symptoms associated with long COVID, according to a new study.

The report, which draws on databases from the Department of Veterans Affairs, examined more than 9,000 people who took Paxlovid, along with an almost 50,000-strong control group of people who tested positive but did not take the drug. It showed an approximately 25 percent reduction in 10 of the 12 symptoms studied, including the common complaints of lingering fatigue and brain fog. The results held true whether or not people had been vaccinated or had a prior infection.

“This study is very important,” said Akiko Iwasaki, professor of immunobiology and molecular, cellular and developmental biology at Yale University. “It has public health implications that are quite relevant today.”

Even as vaccines have reduced the risk of hospitalization and death from infection with SARS-CoV-2, researchers continue to worry about the individual suffering and population-wide threats from long COVID.

Data released this summer by the Centers for Disease Control and Prevention’s Household Pulse Survey suggests that close to 15 percent of adults have had long COVID, developing symptoms lasting three or more months after contracting the virus. The CDC recently enhanced the web-based survey to assess how big an impact those symptoms are having on long-haulers’ ability to carry out day-to-day activities.

Ziyad Al-Aly, chief of research and development at the VA St. Louis Health Care System and lead author of the new report, said it showed the importance of introducing an antiviral to reduce the severity of acute disease. It also lends credence to the idea that long COVID symptoms may be driven, at least in part, by viral persistence, in which the virus is not fully cleared by infected individuals.

“Suppressing the viral load may reduce the problem of viral persistence,” said Al-Aly, a clinical epidemiologist at Washington University in St. Louis.

The new study, funded by VA, was released online as a preprint, meaning it has not yet been peer reviewed as is standard protocol for academic journals. Publishing preprints has become more common in the urgent atmosphere of the pandemic, often leading to a form of almost instant online peer review. Several prominent virologists chimed in online quickly and positively.

Eric Topol, professor of molecular medicine and executive vice president of Scripps Research, tweeted that the report is “a major advance,” and reviewed the findings in an online post that emphasizes the urgency of developing treatments for what is now widely recognized as a mass-disabling condition.

“We have no treatment that has been validated to treat Long COVID,” Topol wrote. “Rigorous, randomized, definitive clinical trials are long overdue.”

There are plans to measure the impact of the Pfizer drug (nirmatrelvir and ritonavir) next year as part of the National Institutes of Health’s $1.15 billion RECOVER program, the agency announced recently. The clinical trial will enroll 1,700 adults. Results are not expected until 2024.

Some researchers said it would be useful to have access to data from Pfizer’s placebo-controlled clinical trials assessing the impact of the antiviral on acute COVID in thousands of volunteers.

“We could do a long-term follow up to determine if both groups have the same or different rates of persistent symptoms,” said David Putrino, director of rehabilitation innovation at Mount Sinai Health System in New York.

Pfizer said the company is “working with multiple institutions toward the start of studies to evaluate Paxlovid for potential use in addressing long COVID.” In its 2022 financial guidance, the company reported Paxlovid revenue of $22 billion.

Clinicians have been hampered in developing specific treatments for long COVID in large part because the mechanism – or mechanisms – behind the huge variety of reported symptoms has not been identified. Leading theories include viral persistence, the development of microclots and acute inflammation, which other studies have shown can cause long-term damage.

Iwasaki speculates that using Paxlovid to stop the virus from replicating might not only prevent viral persistence but also the other mechanisms, by containing the virus within the upper respiratory tract before it migrates to other organs.

“The virus is the trigger for all of the other hypotheses,” Iwasaki said. “Nip it in the bud as quickly as possible, and some of these things could be prevented.” She said she believes there may be advantages in taking Paxlovid as soon as possible after diagnosis.

The new study has inherent limitations.

The people who enrolled qualified to receive the drug according to the emergency use authorization issued last year by the Food and Drug Administration, which is for anyone 12 and older at risk of severe disease including those 65 and older. As a result, the study did not include previously healthy young people, who represent the majority of patients seen at many long covid clinics, according to Benjamin Abramoff, director of the Post-COVID Assessment and Recovery Clinic at Penn Medicine.

There is no data to show whether those previously healthy young people would reap the same benefits as people at risk of severe disease. Putrino cautioned that the study’s promising results may be related to the antiviral’s ability to reduce the severity of acute illness that can lead to lingering complications such as lung fibrosis from pneumonia, pericarditis from inflammation and what’s known as post-ICU syndrome, rather than the other symptoms he commonly sees.

“Many, many others with long COVID had mild/non-hospitalized acute disease but went on to develop this debilitating, syndromic, ME/CFS-type long COVID,” Putrino said, referring to chronic fatigue syndrome.

As a retrospective study rather than a randomized controlled trial, there may also be underlying differences that are unaccounted for in the study between those who took Paxlovid and the control group, including being more engaged with their physicians, said Abramoff.

“The study provides more evidence for the importance of prospective controlled studies to look into Paxlovid as a means of preventing long COVID in the broader population,” Abramoff said.

Al-Aly, the lead author, said the study also highlighted for him the remarkable underutilization of an effective therapy, with 85 percent of people who were qualified to be prescribed the antiviral not taking it. “Is it because they were not offered it, or they had concerns?” he asked.

In the short time since the study was released online, Al-Aly said he has seen lay readers draw misguided conclusions.

“We are not saying any and all people should take Paxlovid,” Al-Aly said. “At this point, we do not know that. People need to understand that.”