Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System : A Population-Based Cohort Study

Abstract

Background: In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. The clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain.

Objective: To assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages.

Design: Population-based cohort study analyzed to emulate a clinical trial using inverse probability-weighted models to account for anticipated bias in treatment.

Setting: A large health care system providing care for 1.5 million patients in Massachusetts and New Hampshire during the Omicron wave (1 January to 17 July 2022).

Patients: 44 551 nonhospitalized adults (90.3% with ≥3 vaccine doses) aged 50 years or older with COVID-19 and no contraindications for nirmatrelvir plus ritonavir.

Measurements: The primary outcome was a composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis.

Results: During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]).

Limitation: Potential residual confounding due to differential access to COVID-19 vaccines, diagnostic tests, and treatment.

Conclusion: The overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but nirmatrelvir plus ritonavir reduced this risk further.

Primary funding source: National Institutes of Health.

Visual Abstract.. Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System.

The clinical impact of coadministration of the oral SARS-CoV-2 protease inhibitor nirmatrelvir and the pharmacokinetic booster ritonavir among vaccinated populations is uncertain. This study emulated a clinical trial to assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages.

Figure 1.. Study cohort.

eGFR = estimated glomerular filtration rate.

Figure 2.. COVID-19 cases, treatment with nirmatrelvir plus ritonavir, and hospitalization or death among study patients.

The figure includes infections and treatment initiation from 1 January to 17 July 2022, hospitalizations through 31 July 2022, and deaths through 14 August 2022.

Figure 3.. Cumulative primary and secondary end points among outpatients with COVID-19, by study group.

Patients with hospitalization or death on the day of diagnosis or the next calendar day are not considered outpatients and were excluded. The primary end point (hospitalization within 14 days or death within 28 days of diagnosis) is shown in panel A. Hospitalization (B) and death (C) are secondary end points.

Figure 4.. Subgroup analysis comparing cumulative incidence of hospitalization or death among patients who were prescribed nirmatrelvir plus ritonavir and those who were not.

Estimates, risk differences, and CIs were calculated with an inverse probability–weighted model performed within each stratum. BMI = body mass index.