Individuals with acute COVID-19 who receive prompt antiviral treatment, such as ensitrelvir, nirmatrelvir, or molnupiravir, in the outpatient setting may be less likely to experience post–COVID-19 condition (PCC) compared with those who receive no treatment.
In a prospective, nationwide, registry-based cohort study conducted at acute-care hospitals across Japan during the predominance of Omicron sublineages JN.1 and KP.3, the estimated risk of PCC was 21.5 percent among participants receiving antivirals within 5 days of symptom onset and 25.1 percent among those not receiving antivirals, with an absolute risk difference of –4.14 percentage points (95 percent confidence interval [CI], −6.34 to −1.94 pp; p<0.001) and a number needed to treat (NNT) of 24.2. [JAMA Netw Open 2026;9:e2611983]
Antiviral use was associated with a 14-percent lower risk of PCC compared with no antiviral treatment (adjusted risk ratio [aRR], 0.86, 95 percent CI, 0.78–0.93; p<0.001). Results were consistent for ensitrelvir (aRR, 0.86, 95 percent CI, 0.79–0.95) and molnupiravir (aRR, 0.81, 95 percent CI, 0.67–0.98).
Additionally, antiviral use was associated with a lower likelihood of failure to return to usual health by day 84 compared with no antiviral treatment (9.9 percent vs 12.9 percent; aRR, 0.77, 95 percent CI, 0.67–0.89; p<0.001; NNT, 31.4). This benefit was observed for ensitrelvir (aRR, 0.75, 95 percent CI, 0.64–0.88).
In terms of symptom-specific outcomes, significantly fewer participants who received antiviral therapy reported symptoms relatively specific to COVID-19 at days 28 and 84 compared with those who did not receive antiviral therapy. These symptoms included smell disorder (aRR, 0.43, 95 percent CI, 0.32–0.58) and taste disorder (aRR, 0.59, 95 percent CI, 0.45–0.78).
“Prompt antiviral treatment can reduce the duration and severity of COVID-19 symptoms, decrease SARS-CoV-2 viral load, prevent progression to severe disease, and lower the risk of developing PCC in patients with risk factors for severe disease,” the investigators said.
The findings suggest that early antiviral use may help mitigate the long-term burden of COVID-19 across a broad outpatient population, including younger individuals and those without risk factors for severe disease, they added.
The present data differ from those presented in recent trials evaluating treatment for established PCC, which did not demonstrate a benefit of antiviral therapy. [JAMA Intern Med 2024;184:1024-1034; Lancet Infect Dis 2025;25:936-946] This difference, according to the investigators, may be attributed to intervention timing, such that treatment during the acute phase could influence PCC development, whereas later-stage viral suppression may have limited impact once symptoms are established.
“Although viral load was not evaluated in this study, the lower proportions of smell and taste disorders—hallmark symptoms of COVID-19—in participants receiving antivirals are consistent with findings from previous reports of accelerated viral clearance and symptom recovery with ensitrelvir,” they pointed out. [Antiviral Res 2024;229:105958; JAMA Netw Open 2024;7:e2354991]
“Because olfactory dysfunction is often underestimated and may contribute to neurocognitive sequelae, these results, together with accumulating evidence linking COVID-19–related olfactory dysfunction to structural and functional brain alterations, raise the possibility that early antiviral treatment may have broader clinical implications,” the investigators said.
The analysis included 7,699 participants aged ≥12 years who had laboratory-confirmed COVID-19, symptom onset of ≤5 days, and no recent anti–SARS-CoV-2 treatment. Of these, 2,181 received antivirals (median age 58 years, 51.9 percent male), and 5,518 did not receive antiviral therapy (median age 45 years, 53.1 percent female).
Overall, most participants had mild COVID-19 (98.7 percent) and had received at least two COVID-19 vaccine doses (89.6 percent). Those who did vs did not receive antivirals were older and had more comorbidities.