CLINICAL QUESTION
In patients who are fully vaccinated and have a risk factor or in those who are unvaccinated without a risk factor who have COVID-19 and are symptomatic, does nirmatrelvir/ritonavir (Paxlovid) reduce the duration of symptoms or the likelihood of hospitalization?
BOTTOM LINE
Mortality and hospitalization rates due to COVID-19 have fallen since the beginning of the pandemic because of a combination of past infection, vaccination, and improved treatments. The 1% rate of hospitalization in this study is consistent with the hospitalization rate in a series of 19,456 outpatients with the Omicron variant. Although there was a numerical reduction in hospitalizations with treatment in the current study, it was not statistically significant. Even if it were significant, the number needed to treat (100) would be relatively high. (Level of Evidence = 1b)
SYNOPSIS
Nirmatrelvir/ritonavir was shown in a randomized trial to reduce hospitalization by 89% and death by 86% in patients who were unvaccinated and had at least one risk factor for severe disease when the ancestral variant of SARS-CoV-2 was predominant. But it is important that drugs be evaluated in the correct target population, which now includes patients who have been vaccinated and are sick with the Omicron variant. This industry-sponsored study enrolled two groups of patients: (1) fully vaccinated adults with symptomatic, confirmed infection with SARS-CoV-2 and at least one risk factor for severe disease; and (2) unvaccinated adults with a symptomatic infection and no risk factors. Later in the trial, the authors included patients at average risk who had not received a vaccine in the past 12 months.
Patients were recruited between August 2021 and July 2022, corresponding with the Delta wave and the Omicron wave, respectively. The onset of symptoms was in the past 5 days. Patients (N = 1,296) were randomized to receive the standard 5-day course of nirmatrelvir/ritonavir or matching placebo. At baseline, 46% were male, 22% were non-White, 41% identified as Latino, and 77% had mild- to moderate-severity disease. Approximately one-half were vaccinated and had a risk factor, and one-half were unvaccinated and had no risk factors. Of the 1,440 patients who were initially randomized, 144 were excluded because of data quality issues, but they were evenly divided between groups. There was no difference in duration of symptoms between groups and no significant difference in the likelihood of hospitalization or death (0.8% vs. 1.6% for placebo; difference = −0.8%; 95% CI, −2.0 to 0.4). There was only one death (a vaccinated patient in the placebo group). In a prespecified subgroup analysis of vaccinated patients with a risk factor, hospitalization or death occurred less often with nirmatrelvir/ritonavir, but the difference was not statistically significant (0.9% vs. 2.2%; difference = −1.3%; 95% CI, −3.3 to 0.7).
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Allocation: Concealed
Setting: Outpatient (any)
Reference: Hammond J, Fountaine RJ, Yunis C, et al. Nirmatrelvir for vaccinated or unvaccinated adult outpatients with Covid-19. N Engl J Med. 2024;390(13):1186-1195.
Editor's Note: Editor’s Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.
