COVID virologic rebound may occur in patients treated with nirmatrelvir-ritonavir

1. In this retrospective cohort study, the virologic rebound (VR) of coronavirus disease 2019 (COVID-19) occurred far more frequently in patients treated with nirmatrelvir-ritonavir (N-R) than in those who did not use any therapy.

2. VR in patients treated with N-R was associated with a substantially longer shedding period of replication-competent virus.

Evidence Rating Level: 1 (Excellent)

Study Rundown: N-R is a widely used oral antiviral that inhibits the main protease of SARS-CoV-2. However, previous studies have reported VR, characterized by recurrence of symptoms and positive COVID-19 testing after initial recovery with treatment. In this observational cohort study, the effect of five days of N-R treatment versus no therapy on the frequency and duration of VR in ambulatory adults with acute COVID-19 was observed.  In the end, VR occurred in approximately one in five people taking N-R and was associated with a longer shedding period of replication-competent virus in such patients, with potential implications for monitoring and isolation recommendations. The study is limited by its observational design and relatively small sample size, however. As well, contagiousness and transmission events were not measured directly but rather inferred from VR results. Overall, this retrospective cohort study demonstrated that patients with N-R treatment had higher rates of VR than those who did not use any therapy.

Click to read the study in AIM

Relevant Reading: Rebound of COVID-19 With Nirmatrelvir–Ritonavir Antiviral Therapy

In-Depth [retrospective cohort study]: Participants and data for this study were drawn from POSITIVES (Post-vaccination Viral Characteristics Study), a prospective observational cohort study that enrolls persons with acute COVID-19 for longitudinal assessment of quantitative viral load, viral culture, and symptom data collection. A total of 173 ambulatory persons with acute COVID-19 from March 2022 to May 2023 were initially enrolled; 127 remained after all exclusion criteria and dropouts had been considered. The two strategies of interest were either a) receipt of five days of N-R therapy (n=55), or b) no receipt of therapy for COVID-19 (n=72). The primary outcome of interest was VR within 20 days of the participant’s initial positive COVID test result, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or sustained elevated viral load. Fifteen persons (20.8%) taking N-R had VR versus one (1.8%) untreated person (absolute difference, 19.0 percentage points; 95% CI, 9.0 to 29.0 percentage points; p=0.001). Overall, recipients of N-R achieved initial culture conversion sooner than those who were not treated (p<0.001). However, the number of days to final culture conversion differed between those taking N-R who had VR (median, 14 days; IQR, 13 to 20 days) and those taking N-R who did not have VR (median, 3 days; IQR, 2 to 4 days). In summary, VR occurred more frequently in those COVID patients taking N-R than those who did not, and in patients in which VR occurred, they tended to have longer shedding periods of replication-competent virus if they had taken N-R than if they had not.

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