J Korean Med Sci.  2023 Oct;38(42):e347. 10.3346/jkms.2023.38.e347.

Effectiveness and Adverse Events of Nirmatrelvir/Ritonavir Versus Molnupiravir for COVID-19 in Outpatient Setting: Multicenter Prospective Observational Study

  • 1Division of Infectious Diseases, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
  • 2Korean Physician’s Association, Seoul, Korea
  • 3Division of Infectious Diseases, Department of Internal Medicine, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
  • 4Division of Infectious Diseases, Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea
  • 5Division of Infectious Diseases, Department of Internal Medicine, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea
  • 6Division of Infectious Diseases, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea


In this study, we aimed to compare the effectiveness and adverse reactions of nirmatrelvir/ritonavir and molnupiravir in high-risk outpatients with coronavirus disease 2019 (COVID-19).
This multicenter prospective observational study evaluated the rate of hospitalization, death, and adverse events within 28 days of oral antiviral agent prescription (molnupiravir, n = 240; nirmatrelvir/ritonavir, n = 240) to 480 nonhospitalized adult patients with COVID-19 from August 2, 2022 to March 31, 2023.
Patients receiving molnupiravir had a higher prevalence of comorbidities (85.8% vs. 70.4%; P < 0.001) and a higher Charlson comorbidity index (2.8 ± 1.4 vs. 2.5 ± 1.5; P = 0.009) than those receiving nirmatrelvir/ritonavir. Three patients required hospitalization (nirmatrelvir/ritonavir group, n = 1 [0.4%]; molnupiravir group, n = 2 [0.8%]; P = 1.000). Nirmatrelvir/ritonavir was associated with a higher risk of adverse events than molnupiravir (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.27–3.03), especially for patients aged 65 years and older (OR, 3.04; 95% CI, 1.71–5.39). The severity of adverse events in both groups was mild to moderate and improved after discontinuation of medication. In the molnupiravir group, age ≥ 65 years (OR, 0.43 95% CI, 0.22–0.86) and appropriate vaccination (OR, 0.37; 95% CI, 0.15–0.91) reduced the occurrence of adverse events.
The rates of hospitalization and death were low and not significantly different between high-risk patients who received either nirmatrelvir/ritonavir or molnupiravir. Although adverse events were more frequent with nirmatrelvir/ritonavir than with molnupiravir, none were severe. Nirmatrelvir/ritonavir can be safely used to treat COVID-19, while molnupiravir could be considered as an alternative treatment option for high-risk groups.


COVID-19; Nirmatrelvir and Ritonavir Drug Combination; Molnupiravir


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