J Korean Med Sci.  2023 Sep;38(35):e272. 10.3346/jkms.2023.38.e272.

Real-World Effectiveness of Nirmatrelvir-Ritonavir and Its Acceptability in High-Risk COVID-19 Patients

  • 1Division of Infectious Diseases, Department of Internal Medicine, National Medical Center, Seoul, Korea
  • 2Public Health Research Institute, National Medical Center, Seoul, Korea
  • 3Seoul Veterans Hospital Medical Center, Seoul, Korea
  • 4Department of Pediatrics, National Medical Center, Seoul, Korea
  • 5Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
  • 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Medical Center, Seoul, Korea
  • 7National Institute of Infectious Diseases, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Korea
  • 8Division of Infectious Diseases, Department of Internal Medicine, Seoul Medical Center, Seoul, Korea


Nirmatrelvir-ritonavir is highly effective in preventing severe coronavirus disease 2019 (COVID-19) in high-risk patients with mild-to-moderate severity. However, real-world performance data are limited, and the drug is not so acceptable to the COVID-19 patients at high risk who need it in Korea.
To evaluate the effectiveness of nirmatrelvir-ritonavir, we conducted a propensity score-matched retrospective cohort study on patients with mild-to-moderate COVID-19 at high risk for a severe disease who were hospitalized at four hospitals in South Korea from February 2022 to April 2022. A total of 236 patients in the treatment group (administered nirmatrelvir-ritonavir) and 236 in the matched control group (supportive care only) were analyzed for the primary outcome, i.e., the time to oxygen support-free survival. The secondary outcome was a composite result of disease progression. The reason for not prescribing nirmatrelvir-ritonavir to the indicated patients was also investigated.
The treatment group showed significantly longer oxygen support-free survival than the matched control group (adjusted hazard ratio [aHR], 0.07; 95% confidence interval [CI], 0.01–0.31; P < 0.001). Multivariate Cox regression analysis showed that age (aHR, 1.03; 95% CI, 1.00–1.07), National Early Warning Score-2 at admission (aHR, 1.36; 95% CI, 1.08–1.71), nirmatrelvir-ritonavir treatment, female sex (aHR, 0.37; 95% CI, 0.15–0.88), and time from symptom onset to admission (aHR, 0.67; 95% CI, 0.48–0.95) were significantly associated with oxygen therapy. However, none of the factors were related to the composite outcome. In the unmatched control group, 19.9% of 376 patients had documented explanations for nirmatrelvir-ritonavir non-prescription, and 44.0% of these were due to contraindication criteria. In the treatment group, 10.9% of patients discontinued the medication primarily because of adverse events (71.4%), with gastrointestinal symptoms being the most common (50.0%).
Nirmatrelvir-ritonavir treatment significantly reduced oxygen therapy requirements in high-risk patients with COVID-19 during the omicron variant surge in South Korea. Physicians are encouraged to consider the active use of nirmatrelvir-ritonavir and to be watchful for gastrointestinal symptoms during medication.


Nirmatrelvir-Ritonavir; COVID-19; Effectiveness; Retrospective Cohort Study


  • Fig. 1 Flowchart for selection of study participants.SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

  • Fig. 2 Oxygen support-free survival analysis in the propensity score–matched cohort. Kaplan–Meier survival curves of oxygen-free survival with a follow-up duration of 11 days from the hospital admission. Patients who were discharged without oxygen therapy were censored at the discharge date or on hospital day 12, whichever came first. The nirmatrelvir-ritonavir treatment group showed significantly longer oxygen-free survival (P < 0.001) than the control group.

  • Fig. 3 The forest plot of multivariate Cox proportional analysis of oxygen therapy with nirmatrelvir-ritonavir treatment. The following variables were included in the model: age, sex, BMI, CCI score, immunosuppressant use, coronavirus disease 2019 vaccination status, NEWS2, and days from symptom onset to admission. Inappropriate vaccination indicates patients who were never vaccinated or received only one dose of vaccine or a second dose more than 180 days prior to enrollment date. Appropriate vaccination indicates patients who received a third dose of vaccine within 8 days or a second dose between 8 and 180 days before the enrollment date.BMI = body mass index, CCI = Charlson Comorbidity Index, NEWS2 = National Early Warning Score-2.*P < 0.05, **P < 0.01, ***P < 0.001.


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