March 2024
Does treatment with nirmatrelvir/ritonavir raise risk for COVID-19 rebound?

In a community-based study, clinical and virologic rebound was more common in patients who received nirmatrelvir/ritonavir than in those who did not receive antivirals.

While symptomatic rebound after a five-day course of nirmatrelvir/ritonavir (Paxlovid) has been reported, this phenomenon appears to occur infrequently and independently of antiviral administration (NEJM JW Infect Dis Jan 3 2024). Now, investigators for a prospective, multicentre, community-based study examined the frequency of symptomatic and virologic rebound in a cohort of patients with virologically documented infection who maintained daily diaries and swabs to assess SARS-CoV-2 viral load. Patients who received nirmatrelvir/ritonavir according to US Food and Drug Administration Emergency Use Authorization guidelines were propensity-matched with those who did not receive the medication despite meeting the criteria for treatment.

Symptomatic rebound occurred in 32% of 130 patients who received nirmatrelvir/ritonavir as compared with 20% of 241 untreated patients (p=0.009). Virologic rebound occurred in 27% of treated vs 7% of untreated patients (p<0.001). Patients with more-severe COVID-19 were more likely to experience rebound. The average daily number of symptoms throughout follow up was similar in the treated and untreated groups, but the average viral load was lower in treated patients. 

Comment: This careful analysis confirms my clinical impression that rebound is common. The prospect of worsening symptoms after a five-day course of nirmatrelvir/ritonavir may discourage patients from pursuing antivirals. However, although nirmatrelvir/ritonavir reduces risk for severe outcomes and may reduce risk for long COVID, this treatment remains underutilised in patients who would benefit from it. Still unanswered is whether a five-day course is too short, and whether a longer course – or a second course in patients with rebound (such as Dr Anthony Fauci) – would be beneficial.

Anna Wald, MD, MPH, Professor, Department of Medicine, Epidemiology and Laboratory Medicine, and Division Head, Allergy and Infectious Diseases, University of Washington; and Professor, Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, USA.

Smith-Jeffcoat SE, et al. Symptoms, viral loads, and rebound among coronavirus disease 2019 (COVID-19) outpatients treated with nirmatrelvir/ritonavir compared with propensity score-matched untreated individuals. Clin Infect Dis 2023 Nov 14; e-pub (https://doi. org/10.1093/cid/ciad696).

This summary is taken from the following Journal Watch titles: Infectious Diseases, General Medicine, Hospital Medicine.

Clin Infect Dis