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SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy

Of people treated for acute COVID-19 with nirmatrelvir–ritonavir (N-R), 20% experienced virologic rebound (VR), according to a Boston-area multicenter health system study. Many patients with VR had no symptoms indicating the virus had returned, and VR was associated with the shedding of replication-competent virus.

In the observational cohort study, ambulatory adults with acute COVID-19 were grouped based on receipt of 5 days of N-R or nonreceipt of COVID-19 therapy. VR was defined as a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL.

“Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression,” the authors write. “Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected.”

Editorial: “Nirmatrelvir–ritonavir and other oral agents are critical treatment options for mild and moderate COVID-19, so strategies to eliminate rebound are important for both personal and public health,” editorialists write. “[One study] suggested that delaying (but not prolonging) N-R treatment would reduce rebound. Pfizer is studying the benefits of a second course of N-R treatment for patients with rebound (ClinicalTrials.gov: NCT05567952). The French research agency ANRS | Emerging Infectious Diseases is comparing 5 versus 10 days of N-R in immunocompromised patients (ClinicalTrials.gov: NCT05587894). Until recently, the U.S. government provided N-R free of charge. However, with full FDA approval of the drug, a price of about $1390 for a 5-day course has been established; therefore, added days of treatment would be very expensive in the absence of a change in the standard treatment plan.”

Source: Annals of Internal Medicine