Nirmatrelvir-Ritonavir Has Little Impact on COVID-19 Hospitalization, Mortality in Vaccinated Older Adults

Nirmatrelvir-ritonavir (Paxlovid; Pfizer), an antiviral treatment designed for patients with mild-to-moderate effects of COVID-19, was found to have a significantly weaker impact in older adults who have been vaccinated for COVID-19. The study results from a clinical trial conducted at UCLA demostrated little reductions in the key metrics of hospitalizations and mortality.^1,2

Paxlovid has shown proven effectiveness in unvaccinated adults, but questions remain surrounding efficacy in vaccinated patients.| Image Credit: © Pixel_Studio_8 - stock.adobe.com

Clinical trials of nirmatrelvir-ritonavir have shown the effectiveness of the therapy in reducing hospitalizations due to COVID-19 in patients unvaccinated against the virus but not vaccinated patients. One trial, conducted by Hammond et al, in patients at standard risk of severe COVID-19 who were fully vaccinated found an insignificant difference in sustained alleviation of symptoms between patients receiving nirmatrelvir-ritonavir and those with placebo.³

Still, given the younger ages of the participants in those past trials, it remained an open question whether nirmatrelvir-ritonavir’s effectiveness could be generalized to older and highly vaccinated adults. This was especially important for investigators to elucidate further, given that most older Americans have, at this point, received 2 or more COVID-19 vaccines.¹

“Since the strongest predictor of severe COVID-19 is advanced age, it has been crucial to obtain evidence on whether the results of the Pfizer trials generalized to older and vaccinated populations,” John Mafi, lead author of the study, said in a news release.²

Therefore, the current investigators aimed to compare hospitalization and mortality outcomes in vaccinated older adults with versus without restricted access to nirmatrelvir-ritonavir. The authors utilized a “natural experiment” in Ontario, Canada, in which Ontario instituted an age-restrictive policy on access to nirmatrelvir-ritonavir that reserved the treatment for symptomatic adults with COVID-19 who were aged 70 and older unless they were immunocompromised. The restriction, which occurred between April 1 and November 30, 2022, allowed the investigators to analyze patient outcomes within a specific time period and compare between exact age thresholds, with the assistance of data from Ontario health databases.^1,2

In total, over 1,600,000 Ontarians ages 65 to 74 years during the study period were included in the analysis, with 87.5% of the cohort having received at least 2 vaccines against COVID-19. Despite observing rising hospitalization and mortality outcomes as age increased, there were no major differences between patients just below or just above age 70 years in COVID-19-related hospitalizations (39.5 vs 42.9; absolute difference, 3.4; 95% CI, −1.3-8.1; P = .15), all-cause hospitalizations (979.6 vs 988.4; absolute difference, 8.9; 95% CI, −35.0-52.7; P = .69), or all-cause mortality (109.6 vs 115.7; absolute difference, 6.1; 95% CI, −2.7-14.9; P = .17).¹

Similarly, the differences in outcome were insignificant in 2021 prior to the widespread availability of nirmatrelvir-ritonavir. The absolute differences per 100,000 patients per month were 0.43 (95% CI, −4.5-5.4; P = .86) for COVID-19-related hospitalizations, 2.8 (95% CI, −55.5-61.1; P = .93) for all-cause hospitalizations, and −1.2 (95% CI, −16.4-14.1; P = .88) for all-cause mortality, according to the study authors. Overall, they found that more than double the rate of nirmatrelvir-ritonavir prescriptions was not associated with hospitalization or mortality reductions in highly vaccinated older adults.^1,2

“Since the study found no significant effect on COVID-19 hospitalizations and deaths among vaccinated older adults, our findings underscore the urgent need for further randomized-clinical trials investigating [nirmatrelvir-ritonavir’s] effects in higher-risk populations, such as older subgroups who are frail or immunosuppressed,” Katherine Khan, the study’s senior author, said in a news release.²

REFERENCES

1. Mafi JN, Vangala S, Kapral MK, et al. Hospitalizations and mortality among older adults with and without restricted access to nirmatrelvir-ritonavir. JAMA. Published online February 20, 2025. Accessed March 3, 2025. doi:10.1001/jama.2024.28099

2. University of California – Los Angeles Health Sciences. Paxlovid’s impact on hospitalization and death in COVID-vaccinated older adults far weaker than previously thought. EurekAlert! News Release. Released February 20, 2025. Accessed March 3, 2025. https://www.eurekalert.org/news-releases/1074346

3. Hammond J, Fountaine RJ, Yunis C, et al. Nirmatrelvir for vaccinated or unvaccinated adult outpatients with COVID-19. N Engl J Med. 2024;390(13):1186-1195. doi:10.1056/NEJMoa2309003