Nirmatrelvir/ritonavir reduces the risk of hospitalization for COVID-19 even in the era of predominant omicron subvariants BA.4 and BA.5

Introduction

Nirmatrelvir is an oral antiviral with activity against the M^pro protease, which is essential for the replication of SARS-CoV-2. In the EPIC-HR study, its administration in combination with ritonavir, initiated within 5 days of the onset of COVID-19 symptoms, reduced the risk of progression to severe disease compared to placebo by 89%. The treatment was administered in this study to unvaccinated adults during the period of predominant pre-delta and delta variants. Based on these results, the US Food and Drug Administration (FDA) approved nirmatrelvir/ritonavir in December 2021 for the treatment of adults and pediatric patients with mild to moderate COVID-19 and a high risk of hospitalization or death. Real-world practice data show similar benefits of this antiviral treatment, but they originate from the period before the emergence of subvariants BA.4 and BA.5.

Authors from the University of Colorado utilized data from the largest health database in the state and evaluated the impact of outpatient COVID-19 treatment with nirmatrelvir/ritonavir on the risk of hospitalization, emergency room visits (as a surrogate parameter for disease relapse), and mortality within 28 days of starting treatment during the period when the SARS-CoV-2 omicron BA.2, BA2.12.1, BA.4, and BA.5 variants predominated.

Analyzed Data and Patient Population

This was a retrospective observational study in which data from the state-wide health database of Colorado from the period 26 March – 25 August 2022 were analyzed. Patients with a positive test result for SARS-CoV-2 or a prescription for nirmatrelvir/ritonavir were included. They were not allowed to have been prescribed any other antiviral treatment for COVID-19 within 10 days of a positive test, they were not hospitalized at the time of testing, and the positive test must have been performed no more than 10 days before the prescription of the evaluated antiviral. Two cohorts with corresponding propensity scores were created. One included patients with nirmatrelvir/ritonavir, and the other included infected patients without this treatment. The primary monitored parameter was hospitalization for any cause within 28 days.

The decision to prescribe nirmatrelvir/ritonavir in routine practice was based on the clinical recommendations of the US National Institutes of Health (NIH). The treatment was administered at a dose of 300 mg of nirmatrelvir (150 mg in patients with moderately severe renal failure) and 100 mg of ritonavir 2× daily for 5 days.

A total of 21,493 individuals met the inclusion criteria, with individual cohorts with corresponding propensity scores including 7,168 individuals treated with nirmatrelvir/ritonavir and 9,361 without antiviral treatment. Patients older than 65 years were represented by 32% in the nirmatrelvir/ritonavir cohort and 21% in the cohort without treatment, 27% vs 19% were obese, and at least 2 comorbidities were present in 31% vs 21% of participants in these cohorts.

Results

Patients with nirmatrelvir/ritonavir had a 55% lower risk of hospitalization within 28 days (0.9% with this antiviral vs. 1.4% without antiviral treatment; adjusted odds ratio [OR] 0.45; 95% confidence interval [CI] 0.33–0.62; p < 0.0001).

Treatment with nirmatrelvir/ritonavir was also associated with a lower need for emergency room visits (3.9 vs. 4.7%; adjusted OR 0.74; 95% CI 0.63–0.87; p = 0.0002).

Last but not least, there was a significant reduction in 28-day mortality (< 0.1 vs. 0.2%; adjusted OR 0.15; 95% CI 0.03–0.50; p = 0.0010) 

Conclusion

According to current standards, nirmatrelvir/ritonavir is recommended for the outpatient treatment of patients with mild/moderate COVID-19 with a high risk of hospitalization or death. This new work provides real-world data from the USA, expanding the evidence of the benefits of antiviral treatment even in the era of predominant BA.4 and BA.5 subvariants of SARS-CoV-2, including vaccinated individuals and those over 65 years of age.

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Source: Aggarwal N. R., Molina K. C., Beaty L. E. 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 2023 Jun; 23 (6): 696–705, doi: 10.1016/S1473-3099(23)00011-7.