Two open-label, multicenter randomized controlled platform trials show that early treatment with the antiviral drug nirmatrelvir–ritonavir (Paxlovid) doesn’t cut hospitalization or all-cause death rates in vaccinated high-risk COVID-19 patients, although it does speed recovery.

For the trials, one each in the United Kingdom (PANORAMIC trial) and Canada (CanTreatCOVID), a team led by University of Oxford researchers randomly assigned high-risk, vaccinated adult COVID-19 outpatients to receive either usual care plus nirmatrelvir (300 milligrams [mg])–ritonavir (100 mg) twice a day for five days, or usual care alone from April 2022 to September 2024. Paxlovid is indicated for the treatment of mild-to-moderate COVID-19 in adults at increased risk for severe illness.

A total of 3,516 adults were enrolled in PANORAMIC, and 716 participated in CanTreatCOVID. High-risk patients were those aged 50 years or older, or younger adults who had underlying medical conditions such as asthma or diabetes. All participants had been ill for no more than five days, and over 98% were vaccinated against COVID-19. Follow-up was 28 days. The CanTreatCOVID trial was stopped early owing to slow recruitment and because its Paxlovid supply was discontinued. 

The findings were published this week in the New England Journal of Medicine.

“Nirmatrelvir–ritonavir has been shown to reduce progression to severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unvaccinated high-risk outpatients,” the study authors wrote. “The effectiveness of nirmatrelvir–ritonavir in persons who have been vaccinated, infected naturally, or both is unclear.”

Different efficacy in today’s highly vaccinated populations

In the PANORAMIC trial, 14 of 1,698 (0.8%) Paxlovid recipients and 11 of 1,673 participants (0.7%) in the usual-care group were hospitalized or died (adjusted odds ratio [aOR], 1.18; probability of superiority, 0.334). 

In the CanTreatCOVID trial, 2 of 343 (0.6%) participants in the Paxlovid group and 4 of 324 (1.2%) participants in the usual-care group were hospitalized or died (aOR, 0.48; probability of superiority, 0.830). 

In a substudy involving 634 participants who submitted nose-throat swabs, SARS-CoV-2 viral load was lower by the end of Paxlovid treatment. Most Paxlovid recipients reported adverse events, which primarily involved taste and gastrointestinal side effects, and treatment discontinuation was relatively common. Serious adverse events were reported in nine Paxlovid recipients in the PANORAMIC trial and in four in the CanTreatCOVID trial.