Nirmatrelvir, Ritonavir Treatment Associated With Reduced Risk of COVID-19 Hospitalization, Death in Extremely Vulnerable Patients


Study authors suggest that immunocompromised patients may greatly benefit from nirmatrelvir and ritonavir; however, there was no significant benefit shown in lower-risk patients.

Key Takeaways

1. Nirmatrelvir and Ritonavir Efficacy: The combination of nirmatrelvir and ritonavir has shown promise in reducing the risk of death or hospitalization due to COVID-19, especially in clinically extremely vulnerable (CEV) individuals.

2. Treatment Efficacy in Patients With COVID-19: The study evaluated the efficacy of the antiviral drug combination nirmatrelvir and ritonavir in reducing the risk of death or hospitalization due to COVID-19 in 4 CEV cohorts.

3. Effectiveness Varies with Vulnerability: Although nirmatrelvir and ritonavir were associated with a reduced risk of death or hospitalization in CEV patients, this association was not found in lower-risk individuals (unvaccinated patients aged ≥70 years) who did not show a statistically significant benefit from the treatment when comorbidities were considered.

Nirmatrelvir and ritonavir (Paxlovid; Pfizer) is an oral antiviral drug combination that targets a significant protease enzyme in SARS-CoV-2. This treatment was approved based on interim efficacy and safety data that was conducted prior to the Omicron variant’s emergence.

A prior study found that, nirmatrelvir and ritonavir significantly reduced the primary composite end point of 28-day risk of death or hospitalization due to COVID-19, and by day 28, there were 0 deaths in the nirmatrelvir and ritonavir patient cohorts. To further evaluate the combination’s efficacy, a retrospective cohort study published in JAMA Network Open analyzed the 28-day risk of death or hospitalization due to COVID-19 in 4 groups with elevated risk of complications who received nirmatrelvir and ritonavir.

The study observed individuals who had increased vulnerability to complications as a result of COVID-19 infection, with any cause of death and COVID-19-related hospitalization being compared between individuals who were either prescribed or not prescribed nimatrelvir and ritonavir. Demographic, diagnostic, and medical procedure data were used to identify clinically extremely vulnerable (CEV) cohorts for the trial. Further, the primary outcome was a composite result of COVID-19-related emergency hospital visit or admission, or death from any cause within 28 days of a patient’s enrollment. A secondary outcome was emergency department visit for any reason, with or without subsequent admission to a hospital.

Woman holding oral nirmatrelvir and ritonavir treatment

Image credit: Lost_in_translation |

A total of 6866 patients with COVID-19 were divided into 4 groups: CEV people who were either severely (CEV1; 560 patients) or moderately immunocompromised (CEV2; 2628 patients), and individuals who were not immunocompromised but had medical conditions that are associated with a high risk of COVID-19-induced complications (CEV3; 2100 patients). CEV1 and CEV2 included individuals 18 years of age and older. Further, a group to expand eligibility (EXEL; 1578 patients) was added to allow wider access to nirmatrelvir and ritonavir for individuals at lower risk of COVID-19-related symptoms than CEV patients, but who had factors (eg, unvaccinated, aged ≥70 years) that put them at higher risk of complications compared with the general population. Individuals who received nirmatrelvir and ritonavir were not required to have a positive polymerase chain reaction (PCR) test and were matched to individuals with COVID-19 who were not exposed to nirmatrelvir and ritonavir that needed a positive PCR test.

The study results indicate that nirmatrelvir and ritonavir exposure was associated with a lower risk of death or hospitalization due to COVID-19 in patients with extreme vulnerability to COVID-19-related complications; however, this association was not present in lower-risk individuals in the EXEL group. There was a statistically significant risk difference (RD) of −2.5% in the CEV1 group (95% CI, −4.8% to −0.2%), a −1.7% RD in the CEV2 group (95% CI, −2.9% to −0.5%), a non-statistically significant −1.3% RD in the CEV3 group (95% CI, −2.8% to 0.1%), and a non-statistically significant RD of 1.0% in the EXEL group (95% CI, −0.9% to 2.9%).

The primary outcome w as met for the subgroups of individuals aged 70 years and older and for male patients compared to female patients. RDs were nominally—but not statistically significant—further from the null in the subgroup aged 70 years and older compared with the main analysis. Further, RDs were more protective in male participants compared to female participants, though these differences were insignificant, according to the study authors.

Although event counts could not be reported, the RD in 98 nirmatrelvir and ritonavir-exposed and 98 unexposed individuals was -8.2% (95% CI, -13.6% to -2.7%) in individuals aged 70 years and older. In the CEV1 group, the RD of 179 nirmatrelvir and ritonavir-exposed and 179 unexposed women was -1.1% (95% CI, -2.7% to 0.4%), and the RD of 101 nirmatrelvir and ritonavir-exposed and 101 unexposed men was -5.0% (95% CI, -10.6% to 0.7%). Among vaccinated individuals, RD estimates in the 4 CEV groups were similar to estimates for the whole study group. Further, small cell restrictions had prevented reporting the association in unvaccinated individuals in the 3 CEV groups; however, in the EXEL group, there were 7 events in 210 unvaccinated nirmatrelvir and ritonavir-exposed individuals, and 6 events in 170 unvaccinated individuals who were not exposed to nirmatrelvir and ritonavir. The RD in this subgroup was -0.2% (95% CI, -3.9% to 3.5%), and there weren’t any significant differences between nirmatrelvir and ritonavir-exposed and unexposed individuals in emergency department visits.

Individuals who were exposed to nirmatrelvir and ritonavir were not required to take a PCR test because COVID-19 was the only requirement for receiving nirmatrelvir and ritonavir; however, a sensitivity analysis required positive PCR tests for these individuals, resulting in a subgroup of 1362 individuals from the original 6866 study population. The estimated RD for 480 patients in the CEV2 group was the same as the main analysis (-1.1% [95% CI, -6.0% to 3.7%]), whereas the RD for 352 individuals in the same group was -1.1% (95% CI, -6.0% to 3.7%), compared with -1.3% in the main analysis. Compared to 1.0% in the main analysis, the RD for 470 individuals in the EXEL group was 3.4% (95% CI, -1.3% to 8.1%).

The current study’s results are consistent with prior research on nirmatrelvir and ritonavir; however, older age (≥70 years of age) did not present a statistically significant, beneficial association with nirmatrelvir and ritonavir after taking additional comorbidities into account.

Limitations of the study include the lack of generalizability due to the EXEL group requiring a positive PCR test, and reliance on data that may not have captured every factor that physicians take into consideration when choosing nirmatrelvir and ritonavir for treatment. Further, study results may not be applicable to all COVID-19 variants because Omicron was the main variant during the study’s duration. The study authors note that future research should focus on creating an approach to accessing COVID-19 vulnerability that is more granular than the 4 vulnerability groups involved in the current study.


Dormuth CR, Kim JD, Fisher A, Piszczek J, Kuo IF. Nirmatrelvir-Ritonavir and COVID-19 Mortality and Hospitalization Among Patients With Vulnerability to COVID-19 Complications. JAMA Netw Open. 2023;6(10):e2336678. doi:10.1001/jamanetworkopen.2023.36678

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