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Only a very small number of high-risk patients with COVID-19 experienced "rebound symptoms" after being treated with nirmatrelvir/ritonavir (Paxlovid), a retrospective study found.

Among nearly 500 patients, 93% of whom were fully vaccinated, two patients were hospitalized due to symptoms that were not directly related to "rebounding" within a month and required care in the intensive care unit (ICU), and four experienced rebound symptoms at a median of 9 days (interquartile range [IQR] 7-14.5), reported Nischal Ranganath, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

All rebound symptoms were resolved with symptom-directed treatment, and no deaths were reported in any patients after 30 days following their initial COVID-19 diagnosis, the group noted in .

"We found that rebound phenomenon was uncommon in this group of patients," said co-author Aditya Shah, MBBS, also of the Mayo Clinic, in a statement. "The four individuals who experienced rebound represent only 0.8% of the group, and all of them recovered quickly without additional COVID-directed therapy."

Of the four patients who experienced rebound symptoms:

• A 75-year-old fully vaccinated man with coronary artery disease, chronic obstructive pulmonary disease, and diabetes started taking nirmatrelvir/ritonavir 3 days after receiving a positive COVID-19 test. Initial symptoms subsided 5 days after finishing treatment and returned 19 days later. He developed COVID pneumonia and received symptom-directed therapy.
• A 40-year-old fully vaccinated woman with obesity, chronic kidney disease, and hypertension started nirmatrelvir/ritonavir 3 days after a positive test. Her initial symptoms resolved at the completion of treatment, with symptoms returning 6 days later.
• A 69-year-old fully vaccinated man with obesity and hypertension started nirmatrelvir/ritonavir just 1 day after receiving a positive test result. His initial symptoms cleared upon completing therapy, but resurfaced 10 days later.
• A 70-year-old fully vaccinated man with hypertension, dyslipidemia, obesity, and a history of prostate cancer started nirmatrelvir/ritonavir 1 day after testing positive. His initial symptoms resolved at completion of treatment, and returned 8 days later.

All four patients had received boosters for their mRNA vaccines no more than 185 days prior to infection and subsequent treatment.

The study defined rebound symptoms as "a recurrence of COVID-19 symptoms following successful completion of 5 days" of nirmatrelvir/ritonavir, a co-formulated treatment that received an emergency use authorization from the FDA for high-risk people with mild-to-moderate symptoms of COVID-19 infection.

Among the four patients, rebound symptoms included cough and wheezing, dyspnea, pharyngitis, fatigue and malaise, rhinorrhea, and sinus congestion.

For this study, Ranganath and team included individuals with confirmed diagnosis of symptomatic COVID-19, a positive response to a completed course of nirmatrelvir/ritonavir, and clear evidence that there were no other causes for the symptoms they were experiencing. Patients who failed to complete the 5-day course, lacked significant improvement in symptoms, or had persistent symptoms indicating long COVID were excluded.

Among the 483 patients included in the study, median age was 63 and 56% were women. The median Monoclonal Antibody Screening Score was 3 (IQR 1-5), which suggested a high risk for severe disease progression. Most patients were not immunocompromised, which was a limitation to the study.

While the number of patients with rebound symptoms was ultimately small in this study, it is a phenomenon that the authors believe warrants further study.

"Identifying risk factors may help distinguish patients who are more likely to experience rebound phenomenon," Ranganath and colleagues wrote. "We are unable to define risk factors in this study due to a small number of cases, but it is notable that the four patients with rebound had multiple underlying medical comorbidities and had received SARS-CoV-2 vaccine more than 90 days prior to nirmatrelvir/ritonavir therapy."

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