Early Nirmatrelvir/Ritonavir Linked to Lower Long COVID Risk in High-Risk Outpatients

Treatment with nirmatrelvir/ritonavir (Paxlovid; Pfizer) within 5 days of SARS-CoV-2 infection was associated with modestly lower risks of long COVID, post-acute hospitalization, and death among high-risk, nonhospitalized adults, according to a target trial emulation study published in PLOS Global Public Health. However, investigators observed no clear reduction in long COVID risk among individuals without documented risk factors for severe COVID-19.^1,2

Although nirmatrelvir/ritonavir has been shown to reduce severe acute COVID-19, evidence on whether it prevents post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has been mixed in high-risk patients and largely absent in low-risk patients, the study authors noted.¹

Study Drew on a Large, Diverse Patient Population

The researchers analyzed electronic health records from 29 repositories within the Patient-Centered Clinical Research Network (PCORnet) as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative. The study included 497,499 adults with a first SARS-CoV-2 infection between March 1, 2022, and February 28, 2023. Among individuals with at least 1 risk factor for severe illness, 159,659 received nirmatrelvir/ritonavir within 5 days of infection and 272,048 received no COVID-19 treatment.¹

Investigators used stabilized inverse probability of treatment weighting to balance baseline characteristics and ran negative control outcome analyses to assess residual confounding. Outcomes were measured 30 to 180 days after infection.¹

The previous largest study on the topic, conducted in 281,793 US veterans, found that nirmatrelvir was associated with a reduced risk of post–COVID-19 condition (relative risk, 0.74; absolute risk reduction, 4.51%). However, that population was older and predominantly White and male, leaving questions about generalizability.^1,3

Benefits Observed Across Organ Systems and Subgroups

At 180 days, the estimated risk of long COVID was 30.51 events per 100 individuals in the treated group versus 33.50 in the untreated group (HR, 0.88; 95% CI, 0.87-0.89), an absolute risk reduction of 2.99 events per 100 individuals. Treatment was also associated with lower risks of all-cause hospitalization (HR, 0.70; 95% CI, 0.68-0.73) and all-cause death (HR, 0.53; 95% CI, 0.46-0.60) in the post-acute period.¹

Reduced risk was observed across neurological, pulmonary, hematologic, metabolic, digestive, and musculoskeletal conditions, as well as general symptoms such as fatigue and changes in smell and taste. No conclusive association was found for hair loss.¹

Greater absolute risk reductions were seen in men (3.53 events per 100 individuals) than in women (2.61) and in individuals aged 65 years and older (3.27) than in those younger than 65 (2.73). By geography, the largest reduction occurred among patients in small towns (6.90 events per 100 persons), followed by micropolitan (5.69) and metropolitan areas (2.19). The study authors noted that, compared with the veterans study, the benefits extended to women, Black patients, and metropolitan residents. However, there was no evidence of benefit among pregnant individuals.^1,3

Notably, treated patients were less likely than untreated patients to be Black or Hispanic.¹

No Clear Benefit in Low-Risk Individuals

Among individuals without documented risk factors, the association between nirmatrelvir/ritonavir and long COVID was inconclusive (HR, 1.03; 95% CI, 0.95-1.11). The study authors said this aligns with the phase 2/3 EPIC-SR trial (NCT05011513), in which nirmatrelvir/ritonavir did not significantly shorten time to sustained symptom alleviation among standard-risk patients and vaccinated patients with risk factors. The investigators attributed the null finding to lower baseline risk, which limits the absolute benefit achievable and the statistical power to detect differences.^1,4

Implications for Pharmacy Practice

Because treatment must begin within 5 days of symptom onset, timely access is critical. In July 2022, the FDA authorized state-licensed pharmacists to prescribe nirmatrelvir/ritonavir to eligible patients, with limitations. Under that authorization, pharmacists review recent health records for renal and hepatic function and screen patients’ full medication lists for potentially serious drug interactions, referring patients for clinical evaluation when information is insufficient.⁵

The study’s findings suggest these early assessments may carry benefits beyond the acute phase for high-risk patients. “Current guidelines recommend the use of Paxlovid for treating acute COVID-19; our findings suggest that its potential to reduce the risk of Long COVID conditions among high-risk patients should also be considered,” the study authors wrote.¹

Study Limitations

The study authors acknowledged that the observational design leaves room for residual confounding. Structured electronic health record data may be incomplete and subject to misclassification, and the analysis captured only new conditions rather than worsening of preexisting ones. The investigators also could not determine whether patients completed their prescribed course.¹

REFERENCES

1. Zang C, Li H, Khullar D, et al. Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: a target trial emulation study from the RECOVER Initiative. PLOS Glob Public Health. 2026;6(10):e0005771. doi:10.1371/journal.pgph.0005771

2. Early Paxlovid treatment was associated with modestly lower risks of Long COVID, post-acute hospitalization, and death among high-risk, nonhospitalized patients with COVID-19. News release. PLOS—EurekAlert! October 28, 2026. Accessed October 30, 2026. https://www.eurekalert.org/news-releases/1149287

3. Xie Y, Choi T, Al-Aly Z. Association of treatment with nirmatrelvir and the risk of post–COVID-19 condition. JAMA Intern Med. 2023;183(6):554-564. doi:10.1001/jamainternmed.2023.0743

4. Hammond J, Fountaine RJ, Yunis C, et al. Nirmatrelvir for vaccinated or unvaccinated adult outpatients with Covid-19. N Engl J Med. 2024;390(13):1186-1195. doi:10.1056/NEJMoa2309003

5. Coronavirus (COVID-19) update: FDA authorizes pharmacists to prescribe Paxlovid with certain limitations. News release. FDA. July 6, 2022. Accessed October 30, 2026. https://www.prnewswire.com/news-releases/coronavirus-covid-19-update-fda-authorizes-pharmacists-to-prescribe-paxlovid-with-certain-limitations-301581671.html