John Farley, MD, MPH, director of the FDA’s Office of Infectious Diseases

BOSTON — Concerns raised by VA clinicians have played a central role in discussions of rebound cases of COVID-19 after treatment with the antiviral combination marketed as Paxlovid.

Researchers from the VA Boston healthcare system and colleagues advise in a preprint report how the initiation of treatment with nirmatrelvir combined with ritonavir (NM/R) appeared to be associated with relapse of COVID-19 symptoms and SARS-CoV-2 viral load in eight non-immunocompromised patients.1

The Food and Drug Administration granted emergency use authorization to Paxlovid (nirmatrelvir and ritonavir) in December 2021 for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing who are also at high risk for progression to severe COVID-19, including hospitalization or death.

In the VA study, the patients, aged 31 to 71 years old, improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 of their illness.

“Relapse symptoms were described most frequently as cold symptoms, though some patients experiencing a recurrence of fatigue and headache,” the authors advised. “All relapses resolved without additional antiviral treatment. Viral load during relapse was comparable to levels during initial infection.”

The study noted that sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain.

In one case, a patient transmitted SARS-CoV-2 to two family members during relapse. “The presence of high viral load and the occurrence of one transmission event suggest that patients with relapse should isolate until antigen testing is negative,” the researchers emphasized.

“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 wrote in an early version of the preprint.

John Farley, MD, MPH, director of the FDA’s Office of Infectious Diseases, said the agency was 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 press release in May, Farley pointed out that the benefit of a five-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 added 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 noted. “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 emphasized 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 added. “However, there is no evidence of benefit at this time for a longer course of treatment (e.g., 10 days rather than the five 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.”

Length of Course

That comment was in response to a statement by Pfizer CEO Albert Bourlato to 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 concluded 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.”

In the first case they reported, the authors noted that “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.”

At a briefing in late May, Ashish Jha, MD, the White House COVID-19 Response Coordinator, cited the data about rebounds in the Paxlovid clinical trials, asking, “But that was with delta. And so the question is: Is this more common with omicron?  We’re actually doing a lot of work right now to try to sort that out. We’re talking to health systems, getting real-world experience data.”

Jha added, “If you have, you know, 20,000 people getting Paxlovid every day, that would mean that about—even if it was only still 2%—that would mean 400 people are having rebound every day. So it is hard to know exactly how often it happens.”

He added that the patients who are rebounded “are not getting particularly sick, are not ending up in the hospital. If the goal of this treatment, which it was, was to prevent hospitalizations and deaths, it is doing that incredibly well.”

 

  1. Charness M, Gupta K, Stack G, et. al. Rapid Relapse of Symptomatic Omicron SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir, 13 May 2022, PREPRINT (Version 2) available at Research Square [https://doi.org/10.21203/rs.3.rs-1588371/v2]