Paxlovid doesn’t reduce hospitalization, death rates in vaccinated high-risk COVID outpatients, trial shows

COVID-19
Paxlovid box and caplets

Kches16414 / Wikimedia Commons

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.

While people feel better sooner from treatment with this important antiviral drug, we found no reduction in the already low rate of hospitalisations or deaths.

Christopher Butler, MBChB, MD

Paxlovid recipients had a shorter median time to early sustained recovery than the usual-care group (14 vs 21 days in PANORAMIC and 6 vs 9 days in CanTreatCOVID). In the PANORAMIC trial, early sustained recovery was reported by 33.0% of Paxlovid recipients and 22.1% of those in the usual-care group (aOR, 1.74). In the CanTreatCOVID trial, early sustained recovery was reported by 69.0% and 53.1% of participants, respectively (aOR, 1.99). 

Sensitivity analyses of the effect of prior distribution, missing data, and treatment received confirmed that the results for the primary outcome were robust in both trials.

“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,” the researchers wrote.

In a University of Oxford news release, Christopher Butler, MBChB, MD, who led the PANORAMIC trial, said the benefits of Paxlovid have changed amid today’s highly vaccinated populations. “While people feel better sooner from treatment with this important antiviral drug, we found no reduction in the already low rate of hospitalisations or deaths,” he said. “This provides essential evidence for optimal, cost-effective targeting of this treatment.”

‘Prudent to consider antivirals on a case-by-case basis’

In an editorial by 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, former NIAID director and now a distinguished professor at Georgetown University, the authors write the 89% relative reduction in severe outcomes seen in the previous EPIC-HR trial doesn’t apply to current circumstances, in which most adults have some pre-existing immunity and different variants are circulating.

But they cautioned against overinterpreting the new data and concluding that Paxlovid is no longer of value. 

“The enhanced recovery and more-rapid reduction in viral load indicate a degree of clinical efficacy and antiviral activity,” Lane and Fauci wrote. “Clinicians may become more selective regarding which patients to refer for treatment, 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.”

This week's top reads

  1. Osterholm on hantavirus: We’re missing ‘main point of this outbreak’

    "Respiratory person-to-person transmission is not new with the Andes hantavirus," Osterholm points out.

    Stephanie Soucheray
    Mike Osterholm

  2. Hantavirus outbreak grows to 11 cases, 9 confirmed

    So far no cases have been identified in anyone other than passengers on the Dutch cruise ship.

    Stephanie Soucheray

  3. More hantavirus cases emerge as passengers debark cruise ship

    Among those who debarked yesterday are 18 Americans, 1 of whom has tested positive for the virus. 

    Stephanie Soucheray
    MV Hondius

  4. Cancer patients seek unproven antiparasitic treatments after actor's podcast appearance

    Study finds that prescriptions of ivermectin and benzimidazole surged in the first 6 months of 2025.

    Sarah Boden
    Ivermectin tablets seized by the Austrian Federal Ministry of Finance Customs agency.

  5. WHO declares Ebola outbreak an emergency as CDC restricts travel, confirms US doctor infected

    Six other Americans are in the process of being evacuated. 

    Stephanie Soucheray
    ebola

  6. Virus in the vents: Study traces COVID spread in high-rise apartment

    Everyday activities like opening windows and running kitchen fans triggered reverse air flow in bathroom vents, spreading the virus to other units. 

    Laine Bergeson
    high-rise apartment building

  7. CDC: Risk to general public from hantavirus is low

    A French patient’s condition worsened overnight.

    Stephanie Soucheray
    cleaning contamination

  8. CIDRAP Op-Ed: Why the FDA tried to bury studies showing vaccines are safe

    The COVID and shingles vaccine studies were suppressed because they showed the vaccine-safety system works.

    Jake Scott, MD
    3 vaccine vials and 1 syringe

  9. Hantavirus outbreak reduced to 10 cases as ship passengers return to home countries

    A case previously labeled as inconclusive has tested negative, WHO officials said.

    Chris Dall

  10. Many older adults who died of COVID weren’t close to death before infection, study suggests

    In fact, 28% would likely have lived at least another 5 years if they hadn't contracted the virus. 

    Mary Van Beusekom

Our underwriters

Unrestricted financial support provided by

Become an Underwriter