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Background: The effectiveness of the novel oral antiviral agents, nirmatrelvir plus ritonavir and molnupiravir, in treating COVID-19 in patients with nonalcoholic fatty liver disease is unclear.

Objective: To assess the effectiveness of novel oral antiviral agents against COVID-19 among patients with nonalcoholic fatty liver diseases.

Methods: This retrospective cohort study used the TriNetX Research Network to identify non-hospitalized patients with COVID-19 and nonalcoholic fatty liver disease between 1 January 2022, and 30 June 2023. Propensity score matching was used to form two matched cohorts treated with or without nirmatrelvir-ritonavir or molnupiravir.

Results: In the two matched cohorts of 6,358 patients each, the use of novel oral antiviral agents was associated with a significantly lower risk of all-cause emergency department visits, hospitalization, or mortality (6.59% versus 8.24%; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.70–0.91). The novel antiviral group had a significantly lower risk of all-cause emergency department visits (HR, 0.85; 95% CI, 0.74–0.99). Additionally, the incidence of hospitalization was significantly lower in the oral antiviral group than in the control group (HR, 0.71; 95% CI, 0.55–0.90). There were no deaths in the oral antiviral group but 12 deaths in the control group.

Conclusion: Novel oral antiviral agents are beneficial for treating COVID-19 in patients with nonalcoholic fatty liver disease.