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FDA Discusses Rebound Cases of COVID-19 After Paxlovid Therapy

Prescriptions for Paxlovid, the antiviral treatment for COVID-19, are up considerably in recent weeks. Find out how concerned pharmacists and other clinicians should be about reports of rebound cases after therapy with nirmatrelvir combined with ritonavir.

BOSTON – Concerns are being raised about rebound cases of COVID-19 after treatment with the antiviral combination marketed as Paxlovid.

Researchers from the Department of Veterans Affairs (VA) Boston healthcare system advise in a preprint report how the initiation of treatment with nirmatrelvir combined with ritonavir (NM/R) in a 71-year-old vaccinated and boosted male “resulted in rapid resolution of COVID-19 symptoms followed one week later by the development of typical cold symptoms.”

The study team points out that SARS-CoV-2 viral load fluctuated along with the symptoms, “with two distinct peaks on Day 1 and Day 9 of illness. No other respiratory pathogens were identified.”

Viral sampling showed sequence identity for the omicron subvariant BA.1 on Days 1, 7, and 11.

“Our findings suggest that viral replication and COVID-19 symptoms may recur after very early treatment with NM/R before natural immunity is sufficient to fully clear SARS-CoV-2,” the authors write.

John Farley, MD, MPH, director of the Office of Infectious Diseases, says the Food and Drug Administration is aware of the reports of “some patients developing recurrent COVID-19 symptoms after completing a treatment course of Paxlovid. In some of these cases, patients tested negative on a direct SARS-CoV-2 viral test and then tested positive again.”

In an FDA release, Farley points out that the benefit of a 5-day treatment course of Paxlovid was demonstrated in the clinical trial that Pfizer provided to support EUA; among non-hospitalized patients at high risk of progression to severe disease, treatment with Paxlovid reduced the risk of hospitalization or death by 88%.

He adds that reductions in hospitalization and death were also demonstrated in clinical trials of other available approved (Veklury [remdesivir]) or authorized (Lagevrio [molnupiravir]) antiviral agents.

“In light of these reports, additional analyses of the Paxlovid clinical trial data have been performed,” he notes. “In the Paxlovid clinical trial, some patients (range 1-2%) had one or more positive SARS-CoV-2 PCR tests after testing negative, or an increase in the amount of SARS-CoV-2 detected by PCR, after completing their treatment course. This finding was observed in patients treated with the drug as well as patients who received placebo, so it is unclear at this point that this is related to drug treatment. Additional analyses show that most of the patients did not have symptoms at the time of a positive PCR test after testing negative, and, most importantly, there was no increased occurrence of hospitalization or death or development of drug resistance.”

Farley emphasizes that the reports do not change the conclusions from the Paxlovid clinical trial which demonstrated a meaningful reduction in hospitalization and death.

“We are continuing to review data from clinical trials and will provide additional information as it becomes available,” he adds. “However, there is no evidence of benefit at this time for a longer course of treatment (e.g., 10 days rather than the 5 days recommended in the Provider Fact Sheet for Paxlovid) or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course.”

That comment was in response to a statement by Pfizer CEO Albert Bourlato media outlets that, in cases where virus levels do rebound, “then you give a second course, like you do with antibiotics, and that’s it.”

The VA researchers conclude their report by recommending that “clinicians should note the potential for a rapid relapse of COVID-19 symptoms following the completion of early, effective treatment with NM/R. Treatment with NM/R was started on the first full day of symptoms, just one day after a negative PCR. The resumption of SARS-CoV-2 replication after the completion of NM/R treatment may have triggered the delayed onset of cold symptoms, which are thought to be immune-mediated. No other respiratory viruses were identified at the peak of cold symptoms, and vaccine and developing natural immunity may have minimized symptom severity and duration.”