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Nirmatrelvir/ritonavir (Paxlovid) appeared to alleviate long COVID symptoms in two patients but was unable to prevent the development of long COVID in another, a small case series found.

Two of the individuals took nirmatrelvir/ritonavir weeks after testing positive -- one following COVID re-exposure -- but both patients' symptoms eased following treatment, reported Michael Peluso, MD, of the University of California San Francisco, and colleagues.

A third patient took nirmatrelvir/ritonavir within 24 hours of COVID symptom onset, yet experienced a rebound of symptoms and went on to develop long COVID, the authors wrote in a pre-print

"It seems that Paxlovid may benefit patients with long COVID," said Peluso in a statement, "but there is no way to access the drug unless a doctor is willing to break the rules, which we are not advocating."

Peluso's group offered two hypotheses: one, that early antiviral therapy may prevent severe disease, but not long COVID in high-risk patients. The second is that nirmatrelvir/ritonavir helps to treat and even reverse persistent SARS-CoV-2 sequelae of "inflammation, local tissue damage, and end-organ disease."

Peluso's group examined data from three patients in the Long-Term Impact of Infection With Novel Coronavirus study who reported long COVID symptoms as well as nirmatrelvir/ritonavir use.

A 42-year-old man and a 43-year-old woman with no significant medical history were both vaccinated and boosted 2 to 4 months previously before testing positive for COVID-19. Neither patient initially received antiviral therapy. But 2 to 3 weeks after symptom resolution, both patients began to experience worsening myalgia and fatigue. Over the next 3 to 7 weeks, the patients experienced severe fatigue and myalgia, as well as malaise and trouble concentrating, or so-called brain fog.

After the man was re-exposed to the virus, he initiated a 5-day course of nirmatrelvir/ritonavir. The woman began her prescription 25 days following initial symptom onset.

Both patients' conditions improved dramatically, with both reporting gradual resolving of symptoms. The man reported "gradually approaching his baseline health" and the woman said she was able to re-engage in activities of daily living, though she still experiences shortness of breath and myalgias.

The third patient, however, had a different clinical course. He was a 48-year-old man with a prior medical history of presumed Behcet's disease. He was also vaccinated and boosted 5 months prior when he tested positive for COVID. The man was prescribed nirmatrelvir/ritonavir within 24 hours of symptoms. Within 4 days of completing his treatment, he experienced recurring fever, fatigue, rhinorrhea, cough, chest pain, rash, and brain fog.

Three weeks after testing positive, he had worsening fatigue, along with chest soreness, palpitations, and malaise lasting 30 days following symptom onset.

"The key aspect of this case is that longer courses of Paxlovid may be needed, and giving it too early might not be optimal," Peluso said. "Only by doing rigorous studies will we get answers."

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