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SEATTLE -- While SARS-CoV-2 rebound can occur in patients not taking nirmatrelvir-ritonavir (Paxlovid), it was rare and usually only lasted a day, according to a retrospective analysis of the randomized ACTIV-2 trials.

Across the placebo arms of three trials, 31% of untreated patients with mild to moderate COVID-19 had a viral rebound, and 26% had a symptomatic rebound, at a median of 11 days after initial symptoms appeared, reported Rinki Deo, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, during the Conference on Retroviruses and Opportunistic Infections.

Viral rebound and high-level viral rebound were seen in 31% and 13% of participants, respectively, and both symptomatic and viral rebound was seen in 3%, they noted in the study, which was also published in the .

"The main take-home point from this study is that the symptom resolution from acute COVID-19 often times is not a linear process, but it waxes and wanes," Deo said during a press conference. "Symptom relapse is not unexpected even without treatment and is only very rarely connected with viral rebound."

"It is important to keep this context in mind when interpreting the results of Paxlovid rebound data," she added.

Of note, 89% of symptomatic rebounds and 95% of viral rebounds in untreated patients lasted only 1 day before improving.

"This is in contrast to the more prolonged symptom and viral rebound after nirmatrelvir-ritonavir treatment in previous case reports that may indicate differences in the characteristics of the rebound episodes occurring with or without antiviral therapy, or bias in reported cases," the authors wrote.

Viral rebound has previously been detected at different levels across different trials. In the study of nirmatrelvir-ritonavir for mild to moderate COVID, there was an increase of 0.5 log₁₀ copies/mL or greater in nasal SARS-CoV-2 RNA levels from post-treatment levels in approximately 4% of placebo participants and 7% of treated participants. However, viral RNA levels were only evaluated at two time points.

In the current trial, nasal RNA was quantified daily for the first two weeks, and once a week thereafter, "which likely explains the substantially higher rates of viral rebound (31%) in our analysis," Deo and team noted.

The authors proposed several potential causes of rebound. "One possibility is that viral dissemination into different anatomical compartments over time could cause an evolving series of symptoms," the authors wrote. "Another explanation is infection with 2 separate SARS-CoV-2 variants, which has been described but is still believed to be a rare occurrence. In addition, co-infection with another respiratory virus is a possibility, along with symptom rebound from a noninfectious cause."

For this analysis, Deo and colleagues included 563 participants receiving placebo in the ACTIV-2/A5401 trial. The viral rebound analysis was conducted among participants who enrolled from November 2020 to July 2021 in the placebo groups of the following phase II studies: bamlanivimab 7,000 mg (n=46); bamlanivimab 700 mg (n=112); and amubarvimab plus romlusevimab (n=109) monoclonal antibodies. An additional 296 participants were included from the placebo group of the phase III trial of amubarvimab plus romlusevimab for the symptom rebound analysis.

Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28, and daily symptom diaries were used to record the severity of 13 symptoms for 29 days.

Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log₁₀ RNA copies/mL from the preceding time point to a viral load of 3.0 log₁₀ copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log₁₀ RNA copies/mL to a viral load of 5.0 log₁₀ copies/mL or higher.

Median participant age was 49, 51% were women, and 81% were considered to be at high risk for severe COVID. Participants enrolled at a median 6 days after symptom onset.

Five percent of participants were considered to have symptom rebound due to hospitalization.

Untreated patients who had symptom rebound were more likely to be women, at high risk for progression to severe disease, and had higher symptom scores and higher anterior nasal viral levels on day 0.

Viral rebound was more likely to be seen in older patients at low risk for severe disease and with a higher median anterior nasal viral level at day 0.

The authors noted that their results could be affected by the underlying study population because the ACTIV-2/A5401 study enrolled mostly unvaccinated people infected with pre-Omicron variants.

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