STUDY EVALUATES RETREATING COVID IN PATIENTS WITH REBOUND SYMPTOMS
January 2026
Some patients experience a rebound of COVID-19 symptoms after completing a 5-day course of nirmatrelvir/ritonavir (Paxlovid). COVID-19 rebound is defined as a return of symptoms or SARS-CoV-2 positivity 3-7 days after symptomatic or viral recovery. Symptoms of COVID-19 rebound are generally mild and occur in both treated and untreated individuals. Across clinical and observational studies, symptomatic or viral rebound has been reported to occur in 0.8%-32% of individuals receiving nirmatrelvir/ritonavir. However, the safety and clinical benefit of retreatment with nirmatrelvir/ritonavir for patients experiencing COVID-19 rebound had not been investigated.
To examine this question, researchers performed a Phase 2, randomized, double-blind, placebo-controlled trial where 436 participants with symptomatic mild to moderate COVID-19 who had rebound symptoms and SARS-CoV-2 positivity within 14 days of completing an initial 5-day course of nirmatrelvir/ritonavir were randomized to a second 5-day course of nirmatrelvir/ritonavir (300 mg nirmatrelvir plus 100 mg ritonavir orally every 12 hours) or placebo/ritonavir (292 and 144 participants, respectively). Participants were ≥12 years of age, weighed ≥40 kg, and had ≥1 risk factor for severe COVID-19. The median age was 55 years, 80.5% were vaccinated (59.9% received their last COVID-19 vaccination >6 months before randomization), and 71.8% had ≥2 risk factors for severe COVID-19. The primary efficacy endpoint was the change in SARS-CoV-2 viral RNA levels from baseline to Day 5. At the end of the study, the nirmatrelvir group had a significant reduction in viral RNA levels at Day 5 compared with the placebo group (least squares mean change -3.87 vs -3.17 log10 copies/mL, difference -0.71, 95% CI -1.09, -0.32, P=0.0004). In the nirmatrelvir and placebo groups, the median time to 2 consecutive negative rapid antigen test results was 4 versus 5 days (hazard ratio 1.24, 95% CI 0.98, 1.55, P=0.0697), and the median time to sustained alleviation of all targeted symptoms was 8 versus 9 days (hazard ratio 1.08, 95% CI 0.85, 1.39, P=0.5202), respectively. The nirmatrelvir group had a greater incidence of dysgeusia (10.0% vs 1.4%) and diarrhea (3.0% vs 0.7%) than the placebo group.
Retreatment with nirmatrelvir/ritonavir reduced viral loads and shortened symptom duration by approximately one day compared with placebo. However, there were no COVID-19-related hospitalizations or deaths in either group through Day 28, and retreatment did not affect severe disease outcomes. Retreatment was safe and well tolerated, with dysgeusia (10.0% vs 1.4%) being the most common adverse event.
In summary, this study found no clear benefit of retreating rebound COVID with Paxlovid, as rebound disease was transient and mild and did not lead to severe complications.
