Nirmatrelvir-Ritonavir Effective Against Omicron BA.4, BA.5 SARS-CoV-2 Variant

Study results support the use of nirmatrelvir-ritonavir as a first-line treatment for adult outpatients acutely infected with COVID-19.

Real-world evidence from the Omicron period of the COVID-19 pandemic shows the benefit of nirmatrelvir-ritonavir for vaccinated outpatients and those younger than 65 years of age with nonsevere COVID-19 at high risk of hospitalization or death, according to study findings published in The Lancet Infectious Diseases.

Investigators sought to examine the real-world effect of nirmatrelvir-ritonavir treatment on emergency department visits, 28-day hospitalization, and mortality among outpatients with early symptomatic COVID-19 during a SARS-CoV-2 Omicron predominant (BA.2, BA2.12.1, BA.4, and BA.5) period. The primary endpoint was 28-day all-cause hospitalization.

This propensity-matched, retrospective, observational cohort study of non-hospitalized adult patients infected with SARS-CoV-2 was conducted from March 2022 through August 2022. Investigators analyzed data from electronic health records from the University of Colorado Health (a 13-hospital system with 141,000 annual admissions and numerous ambulatory sites and affiliated pharmacies). The analysis included data from outpatients with a nirmatrelvir-ritonavir order or a positive SARS-CoV-2 test; those treated with nirmatrelvir-ritonavir were propensity score matched with patients who were untreated.

A total of 21,493 patients infected with SARS-CoV-2 between the last week in March and the last week in August 2022 met inclusion criteria; 11,612 were untreated and 9881 received nirmatrelvir–ritonavir treatment (300 mg nirmatrelvir [150 mg with moderate renal impairment] and 100 mg ritonavir orally, twice daily, for 5 days). Because most of those who received nirmatrelvir-ritonavir treatment did not have a positive SARS-CoV-2 test in their electronic health records, and nirmatrelvir-ritonavir prescription requires a positive SARS-CoV-2 test, investigators assumed testing occurred outside the health system.

Real-world evidence reported during a BA.2, BA2.12.1, BA.4, and BA.5 omicron surge showed an association between nirmatrelvir-ritonavir treatment and reduced 28-day all-cause hospitalization, all-cause mortality, and visits to the emergency department.

The 16,529 patients in the propensity matched cohort were stratified by age (ie, <65 years and ≥65 years), sex, number of vaccinations at time of infection, obesity status, immunocompromised status, number of comorbid conditions other than obesity and immunocompromised status, and race and ethnicity (ie, non-Hispanic White vs other). Significant baseline differences in characteristics in the treatment cohort vs the control cohort included older age, higher rate of Medicare insurance, and more participants with 2 or more comorbidities. Among patients in the treatment group, 26.8% were obese, 24.6% were immunocompromised, 32.1% were at least 65 years of age, 30.5% had at least 2 additional comorbid conditions, 20.4% had no vaccinations prior to their positive SARS-CoV-2 test, and 60.7% had at least 3 vaccinations prior to a positive test.

Compared with no antiviral treatment, nirmatrelvir-ritonavir treatment was associated with reduced 28-day all-cause hospitalization (61/7168 [0.9%] in treatment group vs 135/9361 [1.4%] in control group; adjusted odds ratio [aOR], 0.45; 95% CI, 0.33-0.62; P <.0001) and with 28-day all-cause mortality (2/7168 [<0.1%] in treatment group vs 15/9361 [0.2%] in control group; aOR, 0.15; 95% CI, 0.03-0.50; P =.0010).

Similar results were seen for COVID-19-related 28-day hospitalization (0.7% of treatment group vs 1.2% of control group; aOR, 0.40; 95% CI, 0.28-0.57; P <.0001). Post hoc sensitivity analysis of only patients with observed SARS-CoV-2 positive tests showed no statistical significance in the association with 28-day hospitalization.

As a surrogate for clinically significant relapse, investigators used subsequent emergency department visits. They found a decrease in such visits in among those in the treatment group vs control group (283/7168 [3.9%] vs 437/9361 [4.7%], respectively; aOR, 0.74; 95% CI, 0.63-0.87; P =.0002).  

Study limitations include the collection of hospitalization data within a single health system with low representation of different races/ethnicities; inability to confirm symptom onset within 5 days of treatment; possible residual confounding and unmeasured confounders; the lack of laboratory test results from a large number of patients treated with nirmatrelvir-ritonavir; and unaccounted-for bias from untreated patients hospitalized outside the study’s health system or treated patients who did not fill their prescription or took less than the full 5-day treatment course.

Investigators concluded that “Real-world evidence reported during a BA.2, BA2.12.1, BA.4, and BA.5 omicron surge showed an association between nirmatrelvir-ritonavir treatment and reduced 28-day all-cause hospitalization, all-cause mortality, and visits to the emergency department.” They added that “it is reassuring that rebound symptoms after nirmatrelvir-ritonavir treatment appear to be rarely severe.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Pulmonology Advisor


Aggarwal NR, Molina KC, Beaty LE, et al. Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study. Lancet Infect Dis. Published online February 10, 2023. doi:10.1016/S1473-3099(23)00011-7