If It’s COVID, Paxlovid? Studies Suggest a Rethink These Days

Oral nirmatrelvir-ritonavir (Paxlovid) failed to spare COVID-19-vaccinated individuals from the worst outcomes if they got sick, though it may have helped speed recovery time and cut viral loads, according to two community-based clinical trials.

In the U.K.-based PANORAMIC trial, the incidence of all-cause hospitalization or death after 28 days was 0.8% among those receiving the antiviral combination plus usual care, which was comparable to the 0.7% of peers receiving only usual care (adjusted OR 1.18, 95% Bayesian credible interval [CrI] 0.55-2.62).

With an estimated 33% chance of superiority over usual care, nirmatrelvir-ritonavir fell well short of the superiority threshold of 97.5% in this trial of over 3,000 higher-risk people.

In the smaller Canadian CanTreatCOVID trial, the same outcome of hospitalization or death reached 0.6% in the nirmatrelvir-ritonavir group and 1.2% with usual care. The between-arm difference was again not significant (adjusted OR 0.48, 95% CrI 0.08-2.23), and the antiviral treatment’s 83% probability of superiority over usual care once more fell short of the 97.5% threshold.

The two studies were reported together by Christopher Butler, MD, of the University of Oxford, England, and colleagues in the New England Journal of Medicine.

“We found no evidence that early treatment with nirmatrelvir-ritonavir reduced the already-low incidence of hospitalization or death in either trial and were unable to identify any prespecified subgroup with compelling evidence of treatment effect,” Butler and colleagues wrote.

Nirmatrelvir-ritonavir was first made available under emergency use authorization by the FDA in late 2021, and was FDA approved in 2023 as a 5-day regimen for treating adult outpatients with mild to moderate COVID-19 at risk for severe disease. Approval was based on efficacy data in symptomatic, unvaccinated adults testing positive for SARS-CoV-2 infection in the EPIC-HR trial.

Now, the PANORAMIC and CanTreatCOVID results reflect a COVID-19 landscape that’s shifted since the pandemic’s early period, said H. Clifford Lane, MD, former deputy director for clinical research and special projects at the National Institute of Allergy and Infectious Diseases (NIAID), and Anthony Fauci, MD, the former NIAID director.

“These new data indicate that the 89% relative risk reduction seen in the analysis of hospitalizations or death associated with the use of nirmatrelvir-ritonavir in the EPIC-HR trial does not apply to the current circumstances, in which most adults have varying degrees of preexisting immunity and the circulating variants are different,” Lane and Fauci wrote in an accompanying editorial.

That doesn’t mean nirmatrelvir-ritonavir’s therapeutic time has come and gone, they cautioned. PANORAMIC and CanTreatCOVID participants who took the combination drug saw enhanced recovery and faster viral load reductions, they noted, which points to both clinical efficacy and antiviral activity.

Indeed, Butler’s group reported that early sustained recovery, defined as recovery by day 14 of treatment that was sustained to day 28, reached 33% and 22.1% in PANORAMIC’s treatment and control arms, respectively (adjusted OR 1.74, 95% CrI 1.48-2.04), and 69% and 53.1% in CanTreatCOVID (adjusted OR 1.99, 95% CrI 1.40-2.87). Median time to recovery with the antiviral was 3 to 7 days shorter in the two studies.

Furthermore, in a PANORAMIC virology substudy of 485 participants, 29.2% of nirmatrelvir-ritonavir recipients reached a viral load below detection level at day 5, a significant improvement over the 16.5% of controls (adjusted OR 2.15, 95% CrI 1.37-3.44). Day 5 geometric mean viral load was 3,587 in the nirmatrelvir-ritonavir group and 30,267 among controls (adjusted geometric mean ratio 0.13, 95% CrI 0.08-0.21).

“Clinicians may become more selective regarding which patients to refer for treatment,” Lane and Fauci wrote. “But it still would seem prudent to consider antivirals on a case-by-case basis, particularly in older adults, persons with a compromised immune system, and persons for whom more-rapid recovery is a priority.”

The open-label, prospective PANORAMIC and CanTreatCOVID trials enrolled adults in the community at higher risk of COVID-19, which included either those age 50 years or older and younger adults with relevant coexisting conditions. Participants had to have SARS-CoV-2 infection symptoms for 5 days or less and a positive COVID test.

Patients were randomized to receive either usual care plus daily oral nirmatrelvir-ritonavir for 5 days, or usual care alone. The PANORAMIC primary analysis included 1,698 people who received nirmatrelvir-ritonavir and 1,673 who received usual care. CanTreatCOVID included 343 people in the nirmatrelvir-ritonavir group and 324 in the usual-care group.

PANORAMIC evaluated nirmatrelvir-ritonavir from April 2022 to March 2024, while CanTreatCOVID evaluated the intervention from January 2023 to September 2024. Nearly everyone in PANORAMIC and CanTreatCOVID was vaccinated, with rates reaching at least 97.8% among all participants.

Most of PANORAMIC’s nirmatrelvir-ritonavir group had adverse events (90.4%), while 0.5% had serious adverse events. The rate of serious adverse events in CanTreatCOVID was higher in the usual-care only group (3.4%) than in the nirmatrelvir–ritonavir group (1.3%).

Butler’s group acknowledged that the two studies had an open-label design that precluded estimation of placebo or nocebo effects.

Additionally, the CanTreatCOVID trial was stopped early due to slow recruitment and because the supply of nirmatrelvir-ritonavir was discontinued.