Early Oral Antiviral Use Associated With Lower Risk of Post–COVID-19 Condition, Study Finds

Long after the fever breaks and the isolation period ends, many patients with COVID-19 continue to suffer. Post-COVID-19 condition (PCC), commonly known as long COVID, is defined by the WHO as the persistence of symptoms approximately 3 months after infection, lasting at least 2 months and unexplained by an alternative diagnosis. Common manifestations include fatigue, cough, shortness of breath, and olfactory or gustatory disturbances that impair daily functioning. A 2025 updated meta-analysis estimated a pooled global PCC prevalence of approximately 29% to 36% among individuals with confirmed COVID-19, with a significant symptom burden persisting up to 2 years post-infection.¹

Despite its scale, evidence supporting pharmacologic strategies for preventing PCC, rather than treating it after the fact, has remained limited and inconsistent. However, a new prospective study published in JAMA Network Open now adds meaningful data to this question.^1,2

About the ANCHOR-01 Study

The ANCHOR-01 study was a prospective, nationwide, multicenter, registry-based cohort study conducted across 51 acute-care hospitals in Japan between February and October 2024, with follow-up through February 2025. The study period coincided with the predominance of the Omicron JN.1 and KP.3 sublineages. A total of 7699 outpatients aged 12 years and older with laboratory-confirmed COVID-19 and symptom onset of 5 days or fewer were enrolled, with 2181 receiving an oral antiviral at enrollment and 5518 receiving none.²

Three antivirals were studied, including ensitrelvir (Xocova; Shionogi), in 77.9% of patients in the antiviral group, molnupiravir (Lagevrio; Merck), in 17.7% of patients, and nirmatrelvir/ritonavir (Paxlovid; Pfizer), in 4.5% of patients. Notably, the study population was broad, encompassing patients both with and without traditional risk factors for severe COVID-19, reflecting routine outpatient clinical practice. Most participants had mild disease (98.7%) and had received 2 or more vaccine doses (89.6%).²

The primary outcome was PCC, defined as the persistence of at least 1 of 5 prespecified symptoms—cough, shortness of breath, malaise, smell disorder, or taste disorder—reported at both day 28 and day 84 after enrollment, approximating the WHO's 2-month persistence criterion.²

Key Findings: A Significant Reduction in PCC Risk

In the primary adjusted analysis, early oral antiviral use was associated with a statistically significant reduction in PCC risk (adjusted risk ratio [aRR], 0.86; 95% CI, 0.78–0.93; P < .001). The estimated PCC rate was 21.5% among participants receiving antivirals versus 25.1% among those who did not, representing an adjusted risk difference of 4.14 percentage points and a number needed to treat (NNT) of 24.2.²

Among individual agents, both ensitrelvir (aRR, 0.86; 95% CI, 0.79–0.95; NNT, 26.0) and molnupiravir (aRR, 0.81; 95% CI, 0.67–0.98; NNT, 17.9) were associated with significantly lower PCC risk. For nirmatrelvir/ritonavir, point estimates favored treatment, but the association did not reach statistical significance (aRR, 0.88; 95% CI, 0.63–1.24), likely reflecting the relatively small number of participants in that subgroup (n = 98).²

Antiviral use was also associated with a significantly lower rate of failure to return to usual health by day 84 (9.9% vs 12.9%; aRR, 0.77; 95% CI, 0.67–0.89; NNT, 31.4). Particularly striking reductions were observed in smell and taste disorders, with antiviral use associated with more than a 40% lower risk of persistent smell disorder at both day 28 and day 84 (aRR, 0.43; 95% CI, 0.32–0.58 for symptoms reported on both days).²

Subgroup analyses showed consistent direction of effect across age groups, sex, and high- and lower-risk strata. Statistically significant associations were seen in participants aged 12 to 39 years and 40 to 59 years, as well as in those without risk factors for severe disease, a finding with significant implications for how treatment decisions are framed.²

Beyond Hospitalization Prevention: A Broadening Rationale

The traditional rationale for prescribing oral antivirals in the outpatient setting has focused on preventing severe disease and hospitalization in high-risk patients. The ANCHOR-01 findings suggest that longer-term outcomes, specifically recovery trajectory and PCC prevention, may also warrant consideration in the clinical conversation.²

Lead author Makoto Hibino, MD, of Shonan Oiso Hospital, framed the findings carefully in an interview with Pharmacy Times. "Preventing hospitalization and severe acute outcomes remains a critically important goal, even as the clinical landscape has evolved with viral variants and increasing population immunity through prior infection and vaccination," Hibino said. "At the same time, our findings suggest that longer-term recovery outcomes, including PCC, also deserve attention. However, as this was an observational study, it does not establish causality."

The study authors note that these findings differ from recent trials evaluating antiviral treatment for established PCC, which showed no benefit, suggesting that the window of opportunity may lie in the acute phase, when early viral suppression could limit the downstream inflammation and immune dysregulation thought to drive persistent symptoms.^2,3

The ANCHOR-01 data add to a growing body of corroborating evidence. A 2024 retrospective cohort study from Dubai found that nirmatrelvir/ritonavir was associated with a 58% reduction in long COVID symptoms (adjusted HR, 0.42; 95% CI, 0.19–0.95) among non-hospitalized outpatients during the Omicron era.³

Should Treatment Criteria Be Broadened?

Since the ANCHOR-01 study found that benefits extended to younger, lower-risk patients—including those without comorbidities—this raises a provocative clinical question: should pharmacists and providers consider offering antivirals more broadly to patients primarily seeking to avoid long-term complications?

"While our study population included a broad range of outpatients, we cannot conclude from this data alone that treatment criteria should be broadened," Hibino said. "The approved indications and real-world use of antivirals vary substantially by country and by agent. For example, in Japan, ensitrelvir has been used relatively broadly in outpatient settings, whereas medications such as nirmatrelvir/ritonavir or molnupiravir are primarily used for higher-risk patients in many other countries. Therefore, our findings should be viewed as important hypothesis-generating data regarding PCC prevention."

For US-based pharmacists, this distinction matters as nirmatrelvir/ritonavir remains authorized for patients at high risk for progression to severe COVID-19. The ANCHOR-01 results do not alter that regulatory framework, but they provide additional context for shared decision-making conversations with eligible patients, particularly those hesitant about treatment for a seemingly mild illness.

Counseling Patients: Framing the Quality-of-Life Benefit

Community pharmacists are often the first point of contact for patients navigating an acute COVID-19 diagnosis, and the ANCHOR-01 data offers a new dimension for patient counseling. Patients who are eligible for antivirals but view their illness as "mild" may not appreciate that the risk calculus extends beyond hospitalization.

"Many patients with mild acute symptoms wonder whether medication is necessary. However, the burden of COVID-19 is not limited to preventing hospitalization or severe acute illness; for many patients, how quickly they return to their usual health and whether symptoms persist also matter greatly," Hibino said. "In our study, patients receiving antivirals were more likely to report returning to their usual health by day 84."

However, Hibino added an important qualifier. "Of course, as this is observational data, this should not be communicated as a guaranteed benefit. Rather, within shared decision-making, clinicians and pharmacists may present this as information suggesting that early treatment may be associated with a more favorable recovery trajectory while also considering individual risks, concomitant medications, and patient preferences."

As the evidence base matures, PCC prevention may become a recognized and meaningful consideration alongside acute severity in the antiviral-prescribing conversation—one in which pharmacists are uniquely positioned to play a role.

REFERENCES

1. Yiren Hou, Tian Gu, Zhouchi Ni, Xu Shi, Megan L Ranney, Bhramar Mukherjee, Global Prevalence of Long COVID, Its Subtypes, and Risk Factors: An Updated Systematic Review and Meta-analysis, Open Forum Infectious Diseases, Volume 12, Issue 9, September 2025, ofaf533, https://doi.org/10.1093/ofid/ofaf533

2. Hibino M, Shintani A, Murayama H, et al. Early-phase oral antiviral use and post–COVID-19 condition in outpatients. JAMA Netw Open. 2026;9(5):e2611983. doi:10.1001/jamanetworkopen. 2026.11983

3. Saheb Sharif-Askari F, Ali Hussain Alsayed H, Saheb Sharif-Askari N, et al. Nirmatrelvir plus ritonavir reduces COVID-19 hospitalization and prevents long COVID in adult outpatients. Sci Rep. 2024 Oct 29;14(1):25901. doi: 10.1038/s41598-024-76472-0.