COVID-19 rebounds in one in five Paxlovid users
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Key takeaways:
- Half of patients who experienced virologic rebound after taking Paxlovid also reported symptom rebound.
- However, Paxlovid remains a critical treatment option for high-risk patients, researchers said.
About 20% of patients with COVID-19 experienced virologic rebound after receiving Paxlovid, according to an observational study published in Annals of Internal Medicine.
“We conducted this study to address lingering questions about Paxlovid and virologic rebound in COVID-19 treatment,” Mark Siedner, MD, MPH, an infectious disease clinician and researcher in the Division of Infectious Diseases at Massachusetts General Hospital, said in a press release. “We found that the [virologic rebound (VR)] phenomenon was much more common than expected ... and that individuals shed live virus when experiencing a rebound, implying the potential for transmission after initially recovering from the virus.”
There have been prior reports of VR with Paxlovid (nirmatrelvir/ritonavir; Pfizer), including in former CDC Director Rochelle P. Walensky, MD, and President Joe Biden.
However, previous research has suggested that viral RNA rebound and symptom rebound occurred at similar frequencies in patients who received nirmatrelvir/ritonavir and placebo.
For the current study, Siedner and colleagues compared VR outcomes of adults with acute COVID-19 who received a 5-day regimen of nirmatrelvir/ritonavir (n = 72) and those who did not receive treatment (n = 55).
Compared with untreated participants, those taking nirmatrelvir/ritonavir tended to be older, were vaccinated against COVID-19 and were more likely to be immunosuppressed.
The researchers found that 15 participants, or 20.8%, who received nirmatrelvir/ritonavir had VR vs. one participant, or 1.8%, left untreated, yielding an absolute difference of 19 percentage points (95% CI, 9-29).
In multivariable models that included demographics and other clinical characteristics, only nirmatrelvir/ritonavir use was linked to VR (adjusted OR = 10.02; 95% CI, 1.13-88.74).
VR was more common among participants who started therapy within 2 days of symptom onset (26.3%) compared with those who started 2 or more days after symptom onset (0%).
“Although subgroup analyses were limited by small samples, in this study, VR seemed to be less common among those who delayed therapy by 1 or 2 days after their first positive test result and among those who started therapy more than 2 days after symptom onset,” the researchers wrote. “This finding, in conjunction with the lack of drug resistance-associated mutations after VR events, raises the question of whether VR might result from incomplete viral eradication in some persons during the currently recommended 5 days of treatment. To test this hypothesis, future studies could compare the effect of longer durations of [nirmatrelvir/ritonavir] therapy on rebound incidence.”
Additionally, 50% (95% CI, 25-75) of participants with VR also reported symptom rebound, whereas two were completely asymptomatic.
Given the small sample size, the researchers said they were unable to draw conclusions on a causal association between VR and nirmatrelvir/ritonavir use.
Although VR was more frequent than expected, “Paxlovid remains a lifesaving drug I prescribe to high-risk patients,” Jonathan Li, MD, an infectious disease physician and researcher in the Division of Infectious Diseases at Brigham and Women’s Hospital, said in the release.
“This study, while informative, does not change the fact that this drug is very effective at preventing hospitalizations and death,” Li said. “Instead, it offers valuable insights to Paxlovid patients, helping them understand what to expect and how long they might be contagious.”
In a related editorial, Myron S. Cohen, MD, a Yeargan-Bate Professor of Medicine, Microbiology and Epidemiology at the University of North Carolina School of Medicine, and Elizabeth R. Brown, ScD, a professor of biostatistics, bioinformatics and epidemiology at the Fred Hutch Cancer Center, noted that patients who received nirmatrelvir/ritonavir in the study “likely had clinical benefit, and it is important to note that rebound was not observed in most treated participants.”
Still, “further consideration of the dosage, timing, and duration of treatment with [nirmatrelvir/ritonavir] is essential to inform optimal use of this drug,” Cohen and Brown wrote.
On Nov. 14, 2023, this article was updated with the correct titles and affiliations for Li and Siedner. The editors regret the error.
References:
- Cohen M, Brown E. Ann Intern Med. 2023;doi:10.7326/M23-2887.
- Edelstein G, et al. Ann Intern Med. 2023;doi:10.7326/M23-1756.
- One in five patients experience rebound COVID after taking Paxlovid, new study finds. https://www.eurekalert.org/news-releases/1007441. Published Nov. 13, 2023. Accessed Nov. 13, 2023.
Perspective
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The study, which is limited by its observational nature, provides more evidence that there is likely a real correlation between Paxlovid use and viral rebound, although the causal process is still unknown. It remains unclear why the majority of Paxlovid users don’t have rebound and a minority do. The clinical implications of rebound have to be tempered by the fact that the chief purpose of the drug is to prevent severe disease — which it does irrespective of rebound. Rebound should not dissuade anyone from using this lifesaving medication. However, it is nonetheless important to understand the causal factors surrounding rebound and whether the phenomenon can be minimized with altered dosing or longer half-life SARS-CoV-2 protease inhibitors such as ensitrelvir (Shionogi) (available in Japan).
Johns Hopkins Center for Health Security
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