Paxlovid Regimen Safe, But Not Effective for Postacute Sequelae of COVID-19


A newly published study suggests that a 15-day regimen, while safe, did not statistically separate from a placebo comparator group in main outcomes for PASC of SARS-CoV-2 infection.

Linda N. Geng, MD, PhD   Image credit: Stanford Medicine

Linda N. Geng, MD, PhD

Image credit: Stanford Medicine

Data suggest that a 15-day course of nirmatrelvir-ritonavir (Paxlovid; Pfizer) is generally safe, but failed to demonstrate any significant benefit for improving certain symptoms of postacute sequelae (PASC) of SARS-CoV-2 infection, according to the newly published results of the STOP-PASC randomized clinical trial (NCT05576662).1,2 Notably, the study population was mostly vaccinated (98%) with a protracted symptom duration of about 3 months.

The data were published in JAMA Internal Medicine1 by Linda N. Geng, MD, PhD, an associate professor of primary care and population health at Stanford Medicine, and colleagues, including senior author Pinder Singh, MD, professor and chief of infectious disease and geographic medicine and of microbiology and immunology. Geng noted in a statement that, “we’ve demonstrated the overall safety of a 15-day course of Paxlovid—that’s 3 times as long as it’s being taken for acute COVID. While there are now improved therapies and treatment practices for acute COVID, there’s nothing FDA-approved for long COVID, people continue to suffer, and the numbers keep piling up.”2

“Some studies suggest that viral particles and molecular debris could be responsible for some long-COVID sufferers’ ongoing symptoms,” Singh said in a statement.2 “We figured if that’s the case, maybe treating them with Paxlovid could relieve some of these symptoms.”

In total, 155 patients were randomly assigned to either oral 300-mg nirmatrelvir–100-mg ritonavir (n = 102) or placebo-ritonavir (n = 53) in 2:1 fashion. Patients were given therapy twice daily for 15 days. Patients were a median age of 43 years (IQR, 34-54) and were mostly women (59%; n = 92). The mean time between SARS-CoV-2 infection indexing and randomization in the study was 17.5 months (SD, 9.1). Only a single patient in each group had not received an initial COVID-19 vaccination series. Prior to enrollment, 26.5% (n = 41) of patients had used SARS-CoV-2 actue antiviral medication, including nirmatrelvir-ritonavir.

After 10 weeks, 99 of 102 patients in the nirmatrelvir-ritonavir group and 49 of 53 in the placebo-ritonavir group had primary outcome data available. Of those, there were no indications of statistically significant differences in the pooled symptom severity scores for 6 core symptoms assessed: fatigue, brain fog, body aches, cardiovascular symptoms, shortness of breath, and gastrointestinal symptoms). Those core symptoms progressed toward lower severity levels in both groups.

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On secondary outcomes measures at the 15-week time point, the most bothersome core symptoms reported by those in the trial were fatigue (45.2%; n = 70) and brain fog (24.5%; n = 38). Although no significant differences in severity were reported between the groups at the 5-week measurement point, there were slightly higher odds of a more severe score for the nirmatrelvir-ritonavir group compared with the placebo-ritonavir group at the 10-week (OR, 1.99; 95% CI, 1.06-3.72; P = .03) and at 15-week time points (OR, 2.42; 95% CI, 1.27-4.60; P = .01). No significant differences were reported at the 5-, 10-, or 15-week time points for the proportion of patients experiencing relief of most bothersome symptom; nor was there a between-group difference for time to relief of the core symptoms or most bothersome symptom.1

As for safety, only 1 serious, possibly trial-related adverse event (AE)—hepatitis—was reported among the placebo recipients, while the 3 cases of serious AEs were reported by the treatment group recipients: blood loss anemia, forearm fracture, and melanoma. Those 3 latter AEs were deemed unrelated to the treatment. “One reasonable implication of our results is that Paxlovid can be given safely for a longer period of time, for example, in instances where a newly infected patient is immunocompromised,” Singh said in a statement.2

It has been estimated that 10% to 20% of those infected with SARS-CoV-2—a number ultimatelu in the tens of millions in the United States alone—develop long COVID, though the somewhat unclear long COVID definition makes that estimation difficult to make. Additionally, upward of 200 separate symptoms, many of which overlap with other diagnosis have been ascribed to the syndrome, making a definitive diagnosis similarly challenging.2

The investigators noted additional results from a number of chemical and immunological tests, as well as measurements take from wearables taken throughout the trial may help determine if certain subgroups benefited more than others, and how they might be distinguished in advance of treatment or enrollment in another trial. “We hope to report on our analyses of these measurements in 4 to 6 months,” Singh said in a statement.2

1. Geng LN, Bonilla H, Hedlin H, et al. Nirmatrelvir-ritonavir and symptoms in adults with postacute sequelae of SARS-CoV-2 infection: The STOP-PASC randomized clinical trial. JAMA Intern Med. Published online June 7, 2024. doi:10.1001/jamainternmed.2024.2007
2. Stanford Medicine trial:15-day Paxlovid regimen safe but adds no clear long-COVID benefit. News release. Stanford Medicine. June 7, 2024. Accessed June 7, 2024.
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