Treating Long-COVID with Nirmatrelvir and Ritonavir
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on August 20th, 2025
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The pathogenic cause behind long COVID is poorly understood; it has been hypothesized that factors such as immune dysregulation, microbiome dysbiosis, and other factors can play a role. Viral persistence had also been suggested to be associated with long COVID. With funding from Pfizer, a study was conducted to examine whether antiviral therapy can alleviate long COVID.
The phase 2 study was conducted in the United States between April 2023 and February 2024, and it included 100 participants who had previously been infected with SARS-CoV-2. 4 weeks after the initial infection, these participants had been exhibiting long-COVID symptoms for at least 12 weeks. The participants were randomly assigned to be treated twice a day with only ritonavir or the nirmatrelvir–ritonavir combination for 15 days. Ritonavir was given at a dose of 100 mg, and nirmatrelvir at a daily dose of 300 mg. The PROMIS-29 Physical Health Summary was used to assess treatment’s effectiveness.
Assessment after 28 days found that treatment with the nirmatrelvir–ritonavir combination did not result in significant improvement in health outcomes, when compared to the ritonavir monotherapy. The researchers noted that this lack of clinical effectiveness does not refute the viral persistence hypothesis, because the viral reservoir might be inaccessible to the antiviral agents. Other factors such as low drug dose and short treatment duration might have reduced the clinical effectiveness.
The phase 2 study was conducted in the United States between April 2023 and February 2024, and it included 100 participants who had previously been infected with SARS-CoV-2. 4 weeks after the initial infection, these participants had been exhibiting long-COVID symptoms for at least 12 weeks. The participants were randomly assigned to be treated twice a day with only ritonavir or the nirmatrelvir–ritonavir combination for 15 days. Ritonavir was given at a dose of 100 mg, and nirmatrelvir at a daily dose of 300 mg. The PROMIS-29 Physical Health Summary was used to assess treatment’s effectiveness.
Assessment after 28 days found that treatment with the nirmatrelvir–ritonavir combination did not result in significant improvement in health outcomes, when compared to the ritonavir monotherapy. The researchers noted that this lack of clinical effectiveness does not refute the viral persistence hypothesis, because the viral reservoir might be inaccessible to the antiviral agents. Other factors such as low drug dose and short treatment duration might have reduced the clinical effectiveness.