Nirmatrelvir-Ritonavir Has Variable Impact on Incidence of Post-COVID-19 Condition

Two new studies recently published in PLOS Medicine and Open Forum Infectious Diseases have highlighted pitfalls of treatment with nirmatrelvir-ritonavir (Paxlovid; Pfizer) for the prevention of post-COVID-19 condition (PCC), known as long COVID.

The first trial found that nirmatrelvir-ritonavir treatment during acute COVID-19 had no impact on subsequent PCC incidence, though a slight protective effect was observed in higher-risk patients. In the second trial, nirmatrelvir-ritonavir induced protection during acute illness and lowered PCC risk among older adults but not adolescents.^1,2

Taken together, the research raises questions regarding the feasibility of PCC protection with nirmatrelvir-ritonavir. Research has established the efficacy of the antiviral regimen for patients with mild-to-moderate symptoms of COVID-19, though new investigations have established that said efficacy may not stretch to certain age groups. This is the case for vaccinated older adults, for which research conducted by UCLA investigators found that nirmatrelvir-ritonavir has a significantly weaker impact regarding hospitalizations and mortality.³

Despite variable data, it is pertinent to investigate the use of nirmatrelvir-ritonavir in the setting of long COVID given the epidemiology of the condition and practicality of its use. Though the exact mechanisms of action behind PCC remain unknown, studies have demonstrated that more severe acute infection is linked to a higher risk of developing PCC.

Because nirmatrelvir-ritonavir is indicated to prevent progression to severe COVID-19 in high-risk patients, it is plausible that use of the regimen could simultaneously provide long-term protection against the development of PCC and its associated physical and neurological effects.⁴

These trials—conducted by Preiss et al and Dalton et al, respectively—sought to elucidate the potential effects of nirmatrelvir-ritonavir in PCC prevention.^1,2

Nirmatrelvir-Ritonavir Has Marginable Protective PCC Effect in Older Adults

Investigators from the electronic health record data team of the Researching COVID to Enhance Recovery (RECOVER) initiative sought to evaluate nirmatrelvir-ritonavir as a PCC preventive using a large, nationally sampled cohort. A total of 445,738 patients were included in the cohort, including 151,180 (33.92%) with a nirmatrelvir-ritonavir prescription and 18,663 (4.20%) with PCC.¹

The authors found that nirmatrelvir-ritonavir treatment during acute COVID-19 had no effect on the overall incidence of PCC or incident respiratory symptoms, with only a minor effect on incident fatigue and cognitive symptoms. Patients treated with the regimen had an adjusted cumulative incidence of 4.53% (95% CI, 4.40—4.66), while untreated patients had an incidence of 4.60% (95% CI, 4.51—4.68).¹

A stratified analyses among the age strata found that nirmatrelvir-ritonavir had a protective effect on overall PCC onset only among patients aged 65 and older (risk ratio [RR]: 0.92 [95% CI, 0.88—0.97]; P < .001). The authors found that the regimen had an anti-protective effect in patients aged 18 through 24 years (RR: 1.31 [95% CI, 1.06—1.62]; P = .03) and among patients aged 35 through 49 years (RR: 1.08 [95% CI, 1.01—1.16]; P = .03).¹

“Although it may have a small protective effect among higher-risk patients and on certain symptoms, the effect sizes are negligible,” the authors concluded. “[Nirmatrelvir-ritonavir] remains an important tool to reduce the pandemic’s public health burden by preventing hospitalization and death due to acute COVID-19. However, broadly effective interventions to prevent PASC remain elusive.”¹

Older Adults, High-Risk Patients Benefit Most From Paxlovid in PCC Prevention

Another investigator group conducted a retrospective cohort study utilizing real-world, closed claims data to assess the relationship between nirmatrelvir-ritonavir and PCC by age group, with groups stratified into ages 12 through 17, 18 through 49, 50 through 64, and 65 years and older. Patients eligible for inclusion had a COVID-19 index date from April 1 through August 31, 2022, in the outpatient, telehealth, or emergency department setting. These patients also had a higher risk of severe COVID-19, based on age or underlying risk factors.²

For the study protocol, treated patients—those who received a prescription of nirmatrelvir-ritonavir within 5 days of the COVID-19 index date—were matched 1:2 on age, sex, month of index date, and region with untreated patients. The authors defined PCC as the presence of 1 or more of 45 various symptoms of conditions recorded 60 or more days following the index date.²

A total of 291,433 treated patients were matched to 582,866 untreated patients. Nirmatrelvir-ritonavir treatment reduced the risk of PCC in adults aged 50 through 64 years (adjusted hazard ratio [aHR]: 0.93 [95% CI, 0.92—0.95]) and adults aged 65 and older (aHR: 0.88 [95% CI, 0.87—0.90]). However, treatment had minimal effect among high-risk adults aged 18 through 49 (aHR: 0.98 [95% CI, 0.97—0.99]), with no effect observed among high-risk adolescents aged 12 through 17 years (aHR: 1.06 [95% CI, 0.66—1.13]).²

“Results using real-world data suggest a protective relationship between nirmatrelvir-ritonavir during acute illness and PCC risk among older adults, but not among adolescents,” the study authors concluded. “Consideration may be given to outpatient treatment of mild to moderate COVID-19 with nirmatrelvir-ritonavir to reduce the risk of severe disease and PCC.”¹

These studies indicate that nirmatrelvir-ritonavir cannot be relied on to prevent PCC in individuals with acute COVID-19. Pharmacists should counsel patients that the best way to prevent the development of PCC is to protect themselves from being infected with COVID-19 and experiencing severe symptoms through vaccination.

REFERENCES

1. Preiss A, Bhatia A, Aragon LV, et al. Effect of Paxlovid treatment during acute COVID-19 on Long COVID onset: An EHR-based target trial emulation from the N3C and RECOVER consortia. PLOS Medicine. 2025. doi:10.1371/journal.pmed.1004711

2. Dalton AF, Baca S, Raykin J, et al. Risk of Post-COVID Conditions among adolescents and adults who received nirmatrelvir-ritonavir for acute COVID-19: a retrospective cohort study. Open Forum Infectious Diseases. 2025:ofaf567. doi:10.1093/ofid/ofaf567

3. Halpern L. Nirmatrelvir-Ritonavir Has Little Impact on COVID-19 Hospitalization, Mortality in Vaccinated Older Adults. Pharmacy Times. Published March 3, 2025. Accessed September 18, 2025. https://www.pharmacytimes.com/view/nirmatrelvir-ritonavir-has-little-impact-on-covid-19-hospitalization-mortality-in-vaccinated-older-adults

4. Xie Y, Bowe B, Al-Aly Z. Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status. Nature Communications. 2021;12:6571. doi:10.1038/s41467-021-26513-3