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Taking Pfizer’s blockbuster COVID-19 pills, Paxlovid, at the same time as a rival’s treatment for the virus might be safe and more effective than either drug alone, federal scientists have found. 

The combination might also offer a solution to so-called “rebound” cases, when patients see a return of symptoms after finishing off a course of Paxlovid. 

But more research is needed, and the Food and Drug Administration does not currently allow doctors to prescribe both drugs to a patient.

The findings, published this month as a preprint that has yet to be peer-reviewed, come from a study run by the National Institutes of Health in monkeys.

After being infected by the Delta variant, some were given both Paxlovid and Lagevrio — the COVID-19 antiviral drug produced by Merck and Ridgeback Biotherapeutics. 

Animals who got both treatments saw “decreased SARS-CoV-2 shedding and replication” early on in their infection, and “milder disease” compared to those who got only one drug or the other. The researchers saw no concerning reactions among animals who got the two drugs.

However, the study’s authors cautioned that there were key questions that will need to be addressed in future human trials and experiments with the two drugs. And for now, the FDA says doctors are not allowed to prescribe Paxlovid to patients at the same time as Lagevrio. 

Greenlighted last year under the name molnupiravir, Lagevrio is only authorized by the FDA for use in patients where alternative options “are not accessible or clinically appropriate.” 

Lagevrio carries additional warnings that Paxlovid does not, like risks it could pose to reproduction — it should not be taken during pregnancy — and the chance it could lead to new, worrying variants.

“Therefore, if a patient is taking Paxlovid, an alternative COVID-19 treatment option authorized by the FDA, they would not be eligible for Lagevrio,” Chanapa Tantibanchachai, a spokesperson for the agency, said in a statement. 

Another treatment option, Eli Lilly’s bebtelovimab, carries the same kind of requirement, which effectively bars providers from combining the monoclonal antibody drug with Pfizer’s pills.

“No data” on how to treat rebound

Earlier this year, South Korean researchers reported in a preprint that they had found a “profound” improvement in mice who were given both drugs. 

The NIH’s study tested the two drugs in rhesus macaques, the “closest surrogate to humans.” 

But while the study’s authors speculated the combination might “counteract the ‘rebound effect’,” the animals in their experiment only received four days of treatment before autopsies were conducted. 

By contrast, rebound cases in COVID patients have generally been reported a few days after the person finishes the full five-day course of Paxlovid.

In an email, the National Institutes of Health’s Dr. Heinz Feldmann blamed the early end to the study on “viral kinetics”: Before the animals’ virus levels dropped too low, the scientists wanted to be able to compare samples from of the viral load in different parts of the body. 

“We went for peak virus replication (day 3 or 4) to better show the efficacy of the treatment,” Feldmann wrote.

The approach has sparked interest in part because the two drugs work in different ways. Paxlovid works by blocking the process by which the virus replicates in the body. Lagevrio aims to battle the virus by creating too many errors as it replicates. 

“Combination antivirals are the rule in other viral diseases, for example HIV and hepatitis C.  The combination of antivirals can enhance the potency and decrease the risk of the emergence of resistant viruses,” Dr. Roy Gulick, chief of the division of infectious diseases at Weill Cornell Medicine, said in an email. 

Gulick is co-chair of the NIH’s COVID-19 Treatment Guidelines panel, which has continued to publish updated recommendations for doctors treating patients throughout the pandemic. 

He also pointed to other viruses that do not need more than one antiviral, like herpes and hepatitis B.

“It’s potentially worth studying in humans, but it may be challenging to improve upon the 89% success rate of Paxlovid,” Gulick wrote, citing Pfizer’s initial results in high-risk unvaccinated adults.

In August, the FDA said it would amend Pfizer’s emergency use authorization to require a clinical trial to study rebound cases. The company says it plans to study “retreatment” with another course of Paxlovid for these patients.

So far, the NIH panel’s recommendations for doctors treating rebound cases say that there is “currently no data on the efficacy of administering longer courses or a second course of ritonavir-boosted nirmatrelvir.” 

Dr. Anthony Fauci, the president’s outgoing chief medical adviser, is among the Americans who have reported battling a COVID rebound. 

The 81-year-old told the “NIH Record” that he sought out a second course of the pills, after he came down with the return of symptoms.

“I got much more sick than I was the first time around,” said Fauci.