15-day Paxlovid regimen safe but shows no clear long-COVID benefit, trial finds

A study led by Stanford Medicine researchers evaluated the extended use of Paxlovid, an antiviral drug effective against acute COVID-19, for treating long COVID symptoms. The findings, published in JAMA Internal Medicine, indicate that while a 15-day Paxlovid course was safe, it did not significantly alleviate symptoms associated with long COVID.

Study Overview

Paxlovid combines two antiviral drugs, nirmatrelvir and ritonavir, and is approved by the FDA for managing acute COVID-19 in high-risk adults. Typically prescribed for five days, this regimen has shown an over 85% reduction in hospitalization and mortality rates among recipients. However, the Stanford trial tested a 15-day course of Paxlovid to determine its efficacy in treating long COVID, a condition characterized by the persistence or reappearance of COVID-19 symptoms three months post-infection.

Dr. Linda Geng and Dr. Upinder Singh led the trial, known as STOP-PASC (Selective Trial of Paxlovid for Post-Acute Sequelae of COVID). The study aimed to explore if lingering viral particles or molecular debris might cause ongoing symptoms in long COVID patients.

Trial Design and Results

The randomized, placebo-controlled, double-blinded phase 2 trial included 155 participants who tested positive for SARS-CoV-2. Most had been vaccinated and reflected the ethnic diversity of the San Francisco Bay Area, with a median age of 43 years. Participants reported moderate to severe cases of at least two out of six core long COVID symptoms: fatigue, brain fog, shortness of breath, body aches, cardiovascular issues, and gastrointestinal problems.

Participants were randomized to receive either a 15-day course of Paxlovid or a placebo. To maintain blinding, the placebo included low doses of ritonavir, which can cause a metallic taste, a side effect also seen with Paxlovid. Preliminary analysis showed no significant safety concerns but also no evident benefits, leading researchers to continue the trial without recruiting new participants.

At the 10-week mark, analysis revealed no statistically significant difference between the Paxlovid and placebo groups regarding the primary endpoint: reduction in the severity of the six core symptoms. Secondary outcomes, such as blood pressure, heart rates, and performance on physical tests, also showed no noticeable differences. However, the extended use of Paxlovid was deemed safe, with few serious adverse events reported.

Challenges and Future Directions

Dr. Singh noted that the lack of a clinical response does not negate possible benefits in specific subsets of patients. Questions remain about the optimal timing and duration of treatment, as well as whether certain symptom clusters may respond better to antiviral therapy.

Routine testing for cryptic SARS-CoV-2, which might hide in deep tissues, was impractical due to the lack of noninvasive and cost-effective tests. Interestingly, both the Paxlovid and placebo groups experienced overall symptom improvement, hinting at potential natural symptom resolution or a placebo effect.

The researchers aim to analyze various chemical, immunological, and wearable measurements collected during the trial to identify if certain individuals benefited more from Paxlovid. These insights could refine future trials and treatments for long COVID, sponsored by entities including the National Institutes of Health and Pfizer, Paxlovid's developer.

Conclusion

While the trial showed Paxlovid's safety for extended use, it did not demonstrate significant benefits in reducing long COVID symptoms. Ongoing research and future trials will be crucial in uncovering effective treatments for this complex condition.

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