No study has systematically reviewed published risk of real-world baseline hospitalization and mortality among untreated COVID-19 patients at high-risk for progression to severe COVID-19. This poses challenges to understanding the current value of antivirals.

OBJECTIVES: To characterize the baseline risk of hospitalization and mortality in real-world US clinical practice for nirmatrelvir/ritonavir (NMV/r) eligible patients.

METHODS: A systematic literature review was conducted using PubMed, Embase, MedRxiv, SSRN and grey literature to identify real-world evidence US studies (December 21, 2021, through January 30, 2024) of patients aged ≥12 years with mild-to-moderate COVID-19, at high risk for progression to severe COVID-19 and treated with NMV/r or untreated/best supportive care. Study and patient characteristics, and one-month risks of hospitalization, mortality, and composite outcomes of hospitalization and mortality were extracted for NMV/r and untreated patients. To address inherent clinical and demographic differences between the treated and untreated patients within each study, we calculated the baseline risks from the NMV/r group by dividing the reported risk in the NMV/r group by the adjusted or matched treatment effect from each study.

RESULTS: Of 1023 studies initially screened, data from 33 publications which met selection criteria were extracted. Studies differed in populations characteristics, comparators, and approaches to address confounding. Before adjusting for real-world NMV/r prescribing practice, adjusted baseline (untreated) risk of all-cause hospitalization (n=11 studies) ranged from 0.5-7.7%, median 2.1%, mortality (n=11) ranged from 0.1-3.1%, median 0.4%, and combined hospitalization/mortality risk (n=10) ranged from 0.6-14.4%, median 3.5%. Adjustment for within study heterogeneity resulted in adjusted baseline (untreated) risk of all-cause hospitalization ranging from 1.0-4.1%, median 2.1%, and mortality ranging from 0.1-0.9%, median 0.4%, and combined hospitalization/mortality ranging from 2.1-15.5%, median 3.5%. Outlier values were attributable to higher risk populations (e.g., elderly age, more comorbidities, etc.).

CONCLUSIONS: Understanding risk of hospitalization among untreated patients with COVID-19 contextualizes the current value of antiviral treatments.