Rebound of SARS-CoV-2 Infection after Nirmatrelvir–Ritonavir Treatment

Rebound of SARS-CoV-2 Infection after Nirmatrelvir-Ritonavir TreatmentTo the Editor: Nirmatrelvir is an inhibitor of the main protease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has been shown to block viral replication and reduce disease severity in unvaccinated persons at risk for the progression of coronavirus disease 2019 . 1 Here, we describe the occurrence of rebound symptoms and viral replication after treatment with nirmatrelvir combined with ritonavir.Patient 1, a 71-year-old man with asthma, reported having rhinorrhea, sore throat, congestion, cough, fatigue, malaise, chills, fever (temperature, 38.4°C), and a positive rapid antigen test for SARS-CoV-2.A 5-day course of nirmatrelvirritonavir was started on the same day.He was asymptomatic from day 2 through day 8. On days 9 through 12, while the patient was still isolating, he had a return of typical cold symptoms with rhinorrhea, sore throat, and congestion along with increased asthma symptoms.SARS-CoV-2 viral load was determined from anterior nasal swabs according to the cycle threshold (Ct) on quantitative reverse-transcriptasepolymerase-chain-reaction (RT-PCR) assay and indirectly from results of antigen testing.Peaks of symptoms and viral load coincided on days 1 and 9 (Fig. 1 and Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).Whole-genome viral sequencing identified the BA.1.20subvariant of the SARS-CoV-2 B.1.1.529(omicron) variant from day 1 through day 11.Patient 2, a 69-year-old man, had cold symptoms and positive results on rapid antigen testing and PCR assay on day 0 through day 3.A 5-day course of nirmatrelvir-ritonavir was started on day 1.The patient was asymptomatic with negative results on rapid antigen testing and intermittent PCR assays from day 4 to day 9. Mild cold symptoms and positive results on both rapid antigen testing and RT-PCR assay recurred on day 10 and lasted for 3 days.Patient 3, a 50-year-old woman who lived in the same household with Patient 2, had a similar pattern of rebound symptoms and viral load after treatment with nirmatrelvir-ritonavir.Viral sequencing identified the omicron BA.2.9 subvariant in these two patients.In all three patients who have been described here, there were no muta-The New England Journal of Medicine Downloaded from nejm.org