Nirmatrelvir-Ritonavir Shows No Outcome Benefit in Vaccinated High-Risk COVID-19 Patients: NEJM

A recent study published in The New England Journal of Medicine found that treatment with Nirmatrelvir-ritonavir did not reduce the incidence of hospitalization or death among vaccinated, higher-risk individuals with COVID-19, suggesting limited additional benefit in this population.

The drug combination, commonly known by its brand name Paxlovid, previously demonstrated strong effectiveness in reducing hospitalizations and deaths among unvaccinated people at high risk of complications from COVID-19. However, its benefits in populations with existing immunity, either through vaccination, prior infection, or both, have remained uncertain.

Thus, these two large open-label platform trials, the PANORAMIC trial in the UK and the CanTreatCOVID trial in Canada were conducted. These studies focused on higher-risk adults in the community, including those aged 50 and older or younger adults with underlying health conditions. All participants had tested positive for the virus and had been experiencing symptoms for 5 days or less.

The participants were randomly assigned to receive either standard care alone or standard care plus a five-day course of nirmatrelvir–ritonavir. The primary goal was to determine whether the antiviral reduced the risk of hospitalization or death within 28 days.

Between December 2021 and September 2024, over 4,200 participants were enrolled across both trials. The results showed no significant reduction in severe outcomes among those who received the antiviral treatment when compared to those who received usual care alone.

In the PANORAMIC trial, 0.8% of participants in the treatment group were hospitalized or died, when compared to 0.7% in the control group. In the CanTreatCOVID trial, 0.6% of treated participants experienced severe outcomes when compared to 1.2% in the usual-care group. While the Canadian trial suggested a possible benefit, the results were not statistically conclusive.

A smaller substudy involving 634 participants did find that the drug effectively reduced viral load by the end of treatment, which indicated that it still has biological activity against the virus. However, this reduction did not translate into a measurable decrease in severe illness or mortality.

Serious adverse events were rare but did occur in a small number of participants across both trials. Overall, these findings illuminate the need for continued evaluation of COVID-19 treatments in the context of changing immunity levels and emerging variants, as health systems refine strategies to protect the most vulnerable populations.

Source:

Butler, C. C., Pinto, A. D., Harris, V., Holmes, J., Rahman, N. M., Cureton, L., Hayward, G., Richards, D. B., Lowe, D. M., Standing, J. F., Breuer, J., Hood, K., Png, M. E., Petrou, S., Dorward, J., Patel, M. G., Thomas, N. P. B., Evans, P., Hart, N. D., … PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups. (2026). Oral nirmatrelvir-ritonavir for covid-19 in higher-risk outpatients. The New England Journal of Medicine, 394(16), 1583–1594. https://doi.org/10.1056/NEJMoa2502457