TO THE EDITOR Cao and colleagues (Feb. 2 issue)1 report that the oral antiviral agent VV116 was noninferior to nirmatrelvir–ritonavir in alleviating Covid-19–related symptoms. In contrast, nirmatrelvir–ritonavir had been shown to substantially reduce progression to severe Covid-19 (hospitalization or death) in a randomized, double-blind, placebo-controlled trial.2 It is important to point out that two treatments with similar effects on symptom resolution may affect progression to severe illness differently.3 Furthermore, the reliability of the noninferiority assessment regarding VV116 was compromised because the trial population was much smaller than that in the pivotal nirmatrelvir–ritonavir trial and included patients with a lower risk of severe outcomes; in addition, the patients were aware of their treatment assignments.4 The first two factors also prevented the investigators from obtaining clues about treatment effects on progression to severe disease, since no patients had such progression by the end of the trial. It would be worthwhile to conduct a double-blind, randomized clinical trial with a sufficient number of high-risk patients to compare VV116 with nirmatrelvir–ritonavir according to a composite outcome of hospitalization or death.
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