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A 15-day course of the antiviral nirmatrelvir-ritonavir (Paxlovid) didn't improve symptoms of long COVID, according to a randomized controlled trial that was stopped early for lack of efficacy.

The STOP-PASC trial showed no difference in improvement on a combined outcome of fatigue, brain fog, shortness of breath, body aches, and gastrointestinal and cardiovascular symptoms for nirmatrelvir-ritonavir compared with placebo-ritonavir over 10 weeks, Upinder Singh, MD, of Stanford University, and colleagues .

The study was also presented at the in Boston.

"I don't think we've shown that Paxlovid doesn't work," Singh told MedPage Today. "We've shown that 15 days of Paxlovid given to this highly vaccinated patient population who has had symptoms for a long time, didn't show any statistically significant difference in the composite [outcome]."

Singh noted that future studies of nirmatrelvir-ritonavir in long COVID could assess patients with a shorter duration of long COVID symptoms -- the median duration in this study was 17.5 months -- and could assess combinations of drugs, and perhaps be targeted to specific symptoms.

Ziyad Al-Aly, MD, of the VA St. Louis Health Care System in Missouri, who was not involved in the study, agreed that this shouldn't be the last study of nirmatrelvir-ritonavir in long COVID.

"This is the first-ever trial and I think we need to do a whole lot more to understand this," Al-Aly told MedPage Today. "I don't think the door is closed at all on the idea of viral persistence, or on Paxlovid's effectiveness" in long COVID.

The rationale for using nirmatrelvir-ritonavir in long COVID is built on the hypothesis that long COVID is driven by viral persistence, though this is just one of several hypotheses. SARS-CoV-2 RNA and proteins have been shown to persist in blood and tissues, though there's never been definitive evidence of a reservoir of live, replicating virus, the researchers wrote.

As nirmatrelvir-ritonavir's primary mechanism of action is stopping viral replication, it would be thought to work in long COVID by wiping out any replicating virus, Singh explained.

For the Selective Trial of Paxlovid for Postacute Sequelae of SARS-CoV-2 infection (STOP-PASC) trial, Singh and colleagues enrolled 155 patients with long COVID. They were aiming for 200 patients, but cut enrollment short after a review by the data safety monitoring board suggested stopping for a lack of efficacy, Singh said. The trial also caught flak when participants became upset that some researchers were not wearing masks during clinic visits.

Patients were studied from November 8, 2022 to September 12, 2023. At enrollment, they were randomized in a 2:1 fashion to nirmatrelvir-ritonavir (300 mg/100 mg) or placebo-ritonavir twice daily for 15 days.

The median age was 43, and 59% were female. Only one person in each group hadn't been vaccinated against COVID. The most common long COVID symptoms at enrollment were fatigue, which was reported by all participants, and brain fog, reported by 95.5%.

As with the primary endpoint, there were generally no differences between groups on individual symptoms at any time point, though the researchers noted that there were slightly higher odds of greater severity of the "most bothersome" symptom for the nirmatrelvir-ritonavir group at 10 weeks (OR 1.99, 95% CI 1.06-3.72, P=0.03) and 15 weeks (OR 2.42, 95% CI 1.27-4.60, P=0.01).

Singh noted that severity scores generally improved in both groups, but she warned that symptom burden still remained high at the end of the study for many patients. For instance, about 60% of people still had moderate-to-severe fatigue at the end of the 15-week study, she said.

Adverse events were similar in both groups, and mostly low grade. There were four serious adverse events, three in the nirmatrelvir-ritonavir group (blood loss anemia, forearm fracture, and melanoma) that were determined not to be related to the drug, and one in the placebo-ritonavir group: hepatitis, which was possibly related to the intervention.

The study was limited by its single-center nature, and a smaller sample size than originally planned due to early enrollment closure. The high rate of exclusion due to eligibility criteria also limited its generalizability and potentially missed subgroups of patients who could be responders.

Singh and colleagues concluded that "longer treatment durations, dose variations, optimal timing, and different phenotypes of PASC should be investigated in larger studies. Additionally, multiple pathways may contribute to PASC pathogenesis; therefore, in addition to testing single therapies, combination therapies (e.g., antivirals with immunomodulators) warrant exploration."

Further light will also be shed by at least three other trials of nirmatrelvir-ritonavir in long COVID, including the NIH's , which is aiming to enroll 900 patients, the at Yale, and a trial at the in Sweden aiming to enroll 400 patients.

"The challenge with long COVID is that it's very heterogeneous, and it's unlikely that one drug is going to ameliorate all these long COVID symptoms," Al-Aly told MedPage Today. "I think the value of this trial is teaching us how to better think about designing trials for long COVID."

Singh told MedPage Today that her group is still analyzing biomarker data and data from participants' wearables, which should shed further light on long COVID.

Future analyses could "group responders and non-responders according to biomarkers, and that would help inform the development of future trials in a smarter way," Al-Aly said.

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