Mayo Clinic researchers studied the outcomes of 483 high-risk patients  treated for COVID-19 with a five-day oral regimen of nirmatrelvir and ritonavir, together marketed as Paxlovid. Only a handful developed COVID-19 rebound symptoms, and the researchers say more studies are needed to determine why.

Overall, the treatment benefited everyone in the study. All recovered, including the patients who developed rebound symptoms, which were generally mild. The findings appear in the journal Clinical Infectious Diseases.

"We found that rebound phenomenon was uncommon in this group of patients," says senior author Aditya Shah, M.B.B.S., a Mayo Clinic infectious diseases physician and researcher. "The four individuals who experienced rebound (symptoms) represent only 0.8% of the group, and all of them recovered quickly without additional COVID-directed therapy."

Most of the patients had been vaccinated, and many had received booster vaccinations. The median age was 63. While these patients were high-risk for COVID, none was immunocompromised. Only two patients were admitted to the hospital, and it was for reasons other than COVID-19.

The study zeros in on four patients with rebound symptoms:

• A 75-year-old man with coronary artery disease who had increased cough and muscle aches 19 days after treatment.
• A 40-year-old woman with obesity, hypertension and kidney disease who developed fatigue and sore throat six days after treatment.
• A 69-year-old man with hypertension and obesity who exhibited nasal discharge and cough 10 days following therapy.
• A 70-year-old man with a history of prostate cancer, obesity, hypertension and high cholesterol, who developed significant sinus congestion 10 days after treatment.

Why did some rebound?

Researchers think one explanation could be that a replication of the SARS-CoV-2 virus — the virus that causes COVID-19 — may have triggered a secondary immune response that showed up as mild COVID-19 symptoms. They suggest further prospective studies could answer the question. They also note that all four patients with rebound symptoms had many serious health problems known as comorbidities — a factor shown to complicate recoveries. And all four patients had been vaccinated more than 90 days before becoming infected with COVID-19.

Mayo Clinic funded the study. Others on the study team include first author Nischal Ranganath M.D., Ph.D.; John O'Horo, M.D.; Douglas Challener, M.D.; Sidna Tulledge-Scheitel, M.D.; Marsha Pike, D.N.P.; Michael O'Brien; and Raymund Razonable, M.D. — all of Mayo Clinic.