Infectious Disease

Paxlovid reduces hospitalization, risk of death in vaccinated patients

December 19, 2022

3 min read


Anesi reports receiving salary and research support from the NIH, royalties from UpToDate, and honoraria from Westchester Medical Center, as well as serving as an expert witness for various law firms. Dryden-Peterson reports receiving financial support on behalf of his institution from the NIH. Please see the study for all other authors’ relevant financial disclosures.


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Real-world data on Paxlovid showed it was associated with a reduced risk for hospitalization or death in outpatients with early COVID-19 “in the context of high vaccination prevalence and an intense omicron epidemic,” researchers reported.

In April, WHO recommended Paxlovid (nirmatrelvir plus ritonavir; Pfizer) for patients at highest risk for hospitalization, and advised against use of the treatment in “most vaccinated or lower-risk persons,” Scott Dryden-Peterson, MD, MSc, an assistant professor of medicine at Harvard Medical School, and colleagues wrote in Annals of Internal Medicine. However, “emerging data involving the initial omicron variants show a potential benefit of nirmatrelvir plus ritonavir regardless of vaccination status,” they added.

Data derived from: Dryden-Peterson S, et al. Ann Intern Med. 2022;doi:10.7326/M22-2141

In the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) randomized clinical trial, unvaccinated outpatients with early COVID-19 who received nirmatrelvir plus ritonavir had an 89% reduced risk for hospitalization and death.

Dryden-Peterson and colleagues conducted a population-based cohort study to further assess the efficacy of nirmatrelvir plus ritonavir in the context of prevalent SARS-CoV-2 immunity. The researchers used observational data to emulate a hypothetical trial similar to EPIC-HR, where a total of 44,551 outpatients aged 50 years and older and diagnosed with COVID-19 from Jan 1. to June 17 were randomly prescribed nirmatrelvir plus ritonavir or not.

Among the 12,541 outpatients who were prescribed the treatment, 43% (n=5,446) were aged 65 to 79 years, 36% (n=4,482) were immunocompromised and 79% (n=9,869) were vaccinated and boosted against COVID-19.

Patients who received nirmatrelvir plus ritonavir were exposed to treatment within 2 days of their diagnosis. A composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis was used as the primary outcome.

Dryden-Peterson and colleagues found that the primary outcome of hospitalization or death occurred in 69 patients (0.55%) who were prescribed nirmatrelvir plus ritonavir and 310 patients (0.97%) who were not (RR = 0.56; 95% CI, 0.42-0.75 ).

Compared with patients who did not receive nirmatrelvir plus ritonavir, those who did had a lower risk for:

  • hospitalization (RR = 0.6; 95% CI, 0.44-0.81); other
  • death (RR = 0.29; 95% CI, 0.12-0.71).

Nirmatrelvir plus ritonavir was also associated with “increased protective activity among incompletely vaccinated persons and patients who had received their most recent vaccine dose more than 20 weeks prior,” the researchers wrote.

Dryden-Peterson and colleagues noted that both the current study and EPIC-HR demonstrated reductions in hospitalizations and deaths in the treatment groups, but the differences in study contexts may have resulted in a smaller risk reduction size in the current analysis. The EPIC-HR trial used only unvaccinated participants and had a 7% reduction in hospitalization rate, while Dryden-Peterson and colleagues’ study consisted of mainly vaccinated participants and resulted in a 1% hospitalization risk reduction.

“It is possible that hospitalization risk cannot be reduced much further, particularly among vulnerable patients,” they wrote.

The researchers acknowledged that adherence to nirmatrelvir plus ritonavir may be lower in their study, thus potentially lowering the perceived effectiveness.

The study also uncovered ethnic disparities, with Black patients (2%; n=234) and Hispanic patients (4%; n=445) seeing lower rates of nirmatrelvir plus ritonavir prescriptions compared with white patients.

Dryden-Peterson and colleagues concluded that “although these data suggest its clinical impact may be reduced in the context of high levels of prior immunity and consequently lower risk, the estimated 40% reduction in hospitalization and 71% reduction in death could have large population benefits if nirmatrelvir plus ritonavir is widely used.”

In a related editorial, George L.Aniti, MD, MSCE, MBE, an assistant professor of medicine at the University of Pennsylvania Perelman School of Medicine, and Christina MaGuire, PharmD, BCIDP, an infectious disease clinical pharmacy specialist at Penn Presbyterian Medical Center, noted that the retrospective nature of the study is an asset in that it measures real-world efficacy, “which is perhaps what matters most from a population health standpoint.”

The timing of the study coincides with emerging data that, according to Anesi and Maguire, suggest new convergent mutations from rising omicron strains will create immune evasion against Evusheld (tixagevimab-cilgavimab, AstraZeneca) and bebtelovimab (Eli Lilly & Co.).

“These developments are particularly concerning for immunocompromised persons who rely most on antibody-based prevention and treatment due to poor immunogenicity from vaccines and prior infection and high risk for severe disease,” they wrote.

Because of that, Anesi and Maguire pointed out that clinicians will continue to face challenges in providing therapy while accounting for “severe and sometimes insurmountable” drug-drug interactions, and will need to rely on multidisciplinary collaboration.

“Uptake of prescription of nirmatrelvir plus ritonavir is suboptimal, sometimes in ways that exacerbate pandemic disparities,” they wrote. “The present study and the state of the evolving pandemic offer further motivation to rectify that.”



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