Beyond Oxygen Requirement: Rethinking Patient Selection for Oral Antiviral Therapy to Inform Trial Design in the Omicron Era

Current COVID-19 therapeutic recommendations for oral antiviral therapy rely on a stage-based framework established during the first pandemic waves, restricting treatment to patients presenting within five days of symptom onset who do not require supplemental oxygen, whereas corticosteroids are recommended for hospitalized patients requiring supplemental oxygen. Although this strategy remains supported by randomized evidence, the biological and clinical landscape of COVID-19 has profoundly evolved with widespread hybrid immunity, Omicron sublineages, and an older and immunocompromised hospitalized population. We propose that oral antiviral eligibility, primarily in the context of nirmatrelvir/ritonavir, should progressively move beyond an oxygen-centered eligibility algorithm toward an integrated clinical assessment including symptom duration, host characteristics, pulmonary involvement on chest CT, virological burden (when available), and oxygen requirement. Importantly, this perspective does not challenge early antiviral initiation within the approved therapeutic window. Rather, it argues that future studies should determine whether a more integrated patient selection strategy can optimize the use of oral antiviral therapy in contemporary COVID-19 caused by Omicron sublineages.