Early-Phase Oral Antiviral Use and Post-COVID-19 Condition in Outpatients

Post-COVID-19 condition (PCC) contributes substantially to long-term morbidity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Information about the effectiveness of oral antivirals in preventing PCC in outpatient populations remains limited.

To evaluate the association between early oral antiviral use and PCC risk among outpatients with COVID-19, with and without risk factors for severe disease.

Prospective, nationwide, multicenter, registry-based cohort study conducted at 51 acute-care hospitals across Japan during the predominance of Omicron sublineages JN.1 and KP.3. Outpatients aged 12 years or older with laboratory-confirmed COVID-19, symptom onset of 5 days or less before enrollment, and no recent anti-SARS-CoV-2 treatment were enrolled between February and October 2024, with follow-up through February 2025. The primary analysis population included participants with complete baseline covariates and valid day 28 and day 84 assessments.

Oral antiviral use (ensitrelvir, nirmatrelvir, or molnupiravir) at enrollment vs no antiviral use.

The primary outcome was PCC, defined as persistence of 1 or more of 5 prespecified symptoms (cough, shortness of breath, malaise, smell disorder, or taste disorder), with the same symptoms reported on both days 28 and 84. Exploratory outcomes included failure to return to usual health by day 84.

Among 7699 participants (2181 receiving antivirals: 1131 [51.9%] male; median [IQR] age, 58.0 [41-71] years; and 5518 without antivirals: 2928 [53.1%] female; median [IQR] age, 45.0 [29-57] years), most had mild COVID-19 (7599 participants [98.7%]) and received 2 or more vaccine doses (6902 participants [89.6%]). Participants receiving antivirals were older and had more comorbidities; other baseline characteristics were similar between groups. After prespecified adjustment, antiviral use was associated with a lower risk of PCC (adjusted risk ratio [aRR], 0.86; 95% CI, 0.78-0.93). Results were consistent for ensitrelvir (aRR, 0.86; 95% CI, 0.79-0.95) and molnupiravir (aRR, 0.81; 95% CI, 0.67-0.98). Failure to return to usual health by day 84 was less common among participants receiving antivirals than among participants without antivirals (9.9% vs 12.9%; aRR, 0.77; 95% CI, 0.67-0.89).

In this cohort study of outpatients with COVID-19, early oral antiviral use was associated with a lower risk of PCC. These findings suggest that early antiviral treatment may help mitigate long-term consequences of SARS-CoV-2 infection.