A pair of new observational studies by the same research group links early oral antiviral drug use to both a 14% lower risk of long COVID in nonhospitalized patients with Omicron infections and better patient-reported and functional outcomes after infection.

Lower risk of long COVID in early antiviral recipients

For the first study, published late last week in JAMA Network Open, researchers in Japan analyzed registry data from 51 Japanese hospitals during the period dominated by Omicron sublineages JN.1 and KP.3. Participants were COVID-19 outpatients aged 12 to 98 years who became ill no more than five days before enrollment from February to October 2024, with follow-up through February 2025.

Of 7,699 participants, 28.3% received antiviral drugs (ensitrelvir, molnupiravir, or nirmatrelvir-ritonavir [Paxlovid]), 98.7% had mild infections, and 89.6% had received at least two COVID-19 vaccine doses. Post–COVID-19 condition (PCC), or long COVID, was defined as the persistence of at least one of five symptoms (cough, shortness of breath, malaise, impaired smell, and impaired taste) on surveys on days 28 and 84. 

After adjustment, the estimated risk of long COVID was 21.5% in antiviral recipients and 25.1% in those not receiving antivirals. Antiviral use was tied to a lower risk of long COVID than no antiviral use (adjusted risk ratio [aRR], 0.86), with an adjusted risk difference (aRD) of −4.14 percentage points and a number needed to treat (NNT) of 24.2. 

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.

A lower risk of long COVID was observed among 1,698 ensitrelvir recipients (aRR, 0.86; aRD, −3.85 percentage points; NNT, 26.0) and 385 molnupiravir recipients (aRR, 0.81; aRD, −5.58 percentage points; NNT, 17.9). The direction of associations was consistent across all studied subgroups. 

Point estimates favored nirmatrelvir-ritonavir use, but the association wasn’t statistically significant (98 recipients; aRR, 0.88; aRD, −3.53 percentage points). 

Among patients who completed the 84-day survey, failure to return to usual health was less common among antiviral recipients than among those who didn’t receive antivirals (9.9% vs 12.9%; aRR, 0.77; aRD, −3.19 percentage points; NNT, 31.4). Antivirals were consistently linked to lower proportions of participants reporting COVID symptoms such as impaired smell or taste. 

“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 authors wrote. 

“Early antiviral use was associated with a lower risk of PCC across a broad outpatient population, including younger participants and those without risk factors for severe disease,” they added.

The team called for future studies to confirm longer-term antiviral effectiveness and assess the associations in diverse populations.

Antiviral recipients more likely to return to usual health

In the second study, published this month in the International Journal of Infectious Diseases, the investigators studied a subset of the same patient cohort over the same period to compare rates of medical reconsultation, recovery from illness, and work productivity and activity through 28 days between those with and without early use of ensitrelvir, nirmatrelvir, or molnupiravir. 

In total, 2,271 participants received an antiviral, and 5,768 didn’t. The most commonly used antiviral was ensitrelvir (77.7%), followed by molnupiravir (17.8%) and nirmatrelvir-ritonavir (4.5%).

“Many patients require repeated medical visits or re-consultations, experience prolonged symptoms that hinder return to pre–COVID-19 health, and face reductions in quality of life and productivity,” the researchers wrote. “Secondary bacterial infections and associated antibiotic use pose additional challenges with respect to clinical management and antimicrobial stewardship.”

These findings highlight the potential role of antiviral treatment in supporting individual recovery, healthcare resource utilization, and workforce productivity, beyond traditional virological and disease progression endpoints.

After adjustment, unscheduled COVID-related medical reconsultations were documented in 16.2% of the antiviral group and 17.4% in the no-antiviral group. Although re-consultation rates were numerically lower in antiviral recipients, the difference was not statistically significant (aRR, 0.93). 

Ensitrelvir was associated with lower odds of reconsultation compared with no antiviral use (aRR, 0.88; NNT, 44.4). The estimates for nirmatrelvir-ritonavir (aRR, 1.32) and molnupiravir (aRR, 1.09) weren’t statistically significant. 

After adjustment, 25.6% of participants in the antiviral group experienced failure to return to usual health by 28 days, compared with 33.7% in the no antiviral group. Antiviral use was associated with a lower risk of failure to return to usual health by 28 days (aRR, 0.76; NNT, 11.4).

Ensitrelvir (aRR, 0.75; NNT, 10.7) and molnupiravir (aRR, 0.78; NNT, 13.0) were linked to a lower risk of failure to return to usual health compared with no antiviral, but the estimate for nirmatrelvir wasn’t statistically significant (aRR, 0.88). 

The antiviral group was associated with larger reductions in presenteeism, work impairment, and activity impairment but not absenteeism. While ensitrelvir was tied to larger reductions in presenteeism and activity impairment, the estimates for molnupiravir and nirmatrelvir-ritonavir weren’t statistically significant.

After adjustment, the frequency of additional antibiotic prescriptions by 28 days was low in both groups (3.4% and 3.1% in the antiviral and no-antiviral groups, respectively), with no statistically significant between-group difference (aRR, 1.07).

Molnupiravir was linked to a higher rate of additional antibiotic prescriptions than the no- antiviral group (aRR, 1.86), but estimates for ensitrelvir and nirmatrelvir didn’t reach statistical significance.

“Early antiviral use was associated with more favorable patient-reported and functional recovery outcomes during the early recovery period, alongside a trend toward reduced healthcare utilization; however, these findings should be interpreted in the context of underlying prescribing patterns and potential differences between individual agents,” the study authors wrote.

“In the current post-Omicron era, where severe outcomes are less frequent, these findings highlight the potential role of antiviral treatment in supporting individual recovery, healthcare resource utilization, and workforce productivity, beyond traditional virological and disease progression endpoints,” they concluded. “Further research is warranted to assess the economic consequences and cost-effectiveness of early antiviral treatment and to optimize treatment strategies for different patient subgroups.”