Paxlovid antiviral therapy reduces risk of long COVID

In a recent study posted to the medRxiv* server, researchers in Saint Louis, Missouri, examined whether nirmatrelvir treatment reduced the risk of long COVID, the disease encompassing the post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [PASC].

Study: Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19. Image Credit: p.ill.i / ShutterstockStudy: Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19. Image Credit: p.ill.i / Shutterstock


The prevention of PASC is an urgent health priority, for it has gripped millions of people globally. Although several hypotheses are doing rounds about the underlying mechanisms of long COVID, it is not yet clear whether it has something to do with the persistence of the virus, its fragments, or the intensity of the inflammation during the acute phase of coronavirus disease 2019 (COVID-19). Unfortunately, there is no approved drug for the long COVID prevention or treatment.

In December 2021, oral nirmatrelvir received approval for the treatment of acute SARS-CoV-2 infection in the United States (US). Millions of hospitalized people are at risk of progression to severe diseases benefitted from its treatment. However, there is still a lack of data regarding this drug's efficacy in reducing the risk of long COVID.

About the study

In the present study, researchers used the database of the US Department of Veterans Affairs (VA) to identify individuals who had a positive SARS-CoV-2 test between March 1, 2022, and June 30, 2022, but did not seek hospital admission. More importantly, 9,353 participants survived the first 30 days after the first positive SARS-CoV-2 test (T0) despite having at least one risk factor for progression to severe COVID-19. The risk factors included older age (>60 years),  body mass index >25 km/m2, smoking, cancer, cardiovascular and kidney disorders, chronic lung disease, diabetes, immune dysfunction, and hypertension.

The nirmatrelvir group comprised 9424 participants who received nirmatrelvir within five days of T0 and survived the first 30 days after the first positive SARS-CoV-2 test. The control group had 47,123 individuals who received no COVID-19 treatment during the acute COVID-19 phase and survived 30 days after T0.

The team created a panel of 12 post-acute COVID-19 outcomes to estimate the effect of nirmatrelvir in the study population versus controls using inverse probability-weighted survival models. The prespecified panel of PASC covered health conditions such as dysrhythmia, ischemic heart disease, deep vein thrombosis (DVT), and pulmonary embolism (PE), to name a few. The study model also estimated hazard ratio (HR) and absolute risk reduction (ARR) in percentage at 90 days. The researchers also examined the risk of PASC-related death and hospitalization separately and combined.

Study findings

Of the total study population, 9217 individuals received oral nirmatrelvir treatment within five days after T0, and the team followed up with them and 47,123 controls to August 31, 2022. The authors noted that the nirmatrelvir treatment was associated with reduced risk of PASC, with HR and ARR of 0.74 and 2.32, respectively. Additionally, it reduced the risk of 10 of 12 post-acute COVID-19 outcomes. These ten outcomes were cardiovascular system disorders, such as dysrhythmia and ischemic heart disease, and coagulation and hematologic disorders, such as DVT and PE. Additional post-acute COVID-19 outcomes were fatigue, acute kidney and liver disease, muscular pain, neurocognitive impairment, and shortness of breath. Nirmatrelvir treatment also reduced the risk of post-acute death and hospitalization at 90 days, with HRs and ARRs of 0.52, 0.28, and 0.70, 1.09, respectively. Intriguingly, its effect did not vary with vaccination status and history of SARS-CoV-2 infections, including reinfections.


Overall, nirmatrelvir treatment during the acute phase of COVID-19 reduced the risk of adverse health outcomes related to PASC. However, the magnitude of risk reduction for post-acute COVID-19 outcomes was modest compared to its efficacy during the acute phase. Thus, the clinical decision to initiate treatment with nirmatrelvir should consider its overall effectiveness in both disease phases. Another significant observation was that the benefit of nirmatrelvir treatment progressively increased gradually as the number of risk factors increased and was most pronounced in people with five or more risk factors.

Future randomized trials should investigate whether the benefit of nirmatrelvir treatments extends to people without risk factors for progression to severe disease because the current study analyses suggest that those at most risk likely derived the most benefit. Nevertheless, the benefit of nirmatrelvir treatment extends to the post-acute phase of COVID-19 when given within five days of a positive SARS-CoV-2 test (T0). Therefore, future studies should also evaluate the effect of a more extended nirmatrelivir treatment, a higher dose, or both in reducing the risk of post-acute sequelae of SARS-CoV-2.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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