Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection

Abstract

ImportanceThere is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC).ObjectiveTo assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms.Design, Setting, and ParticipantsThis was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration.InterventionsParticipants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days.Main Outcomes and MeasuresPrimary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline.ResultsOf the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade.Conclusions and RelevanceThe results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC.Trial RegistrationClinicalTrials.gov Identifier: NCT05576662

Is Antiviral Treatment with Remdesivir at the Acute Phase of SARS-CoV-2 Infection Effective for Decreasing the Risk of Long-Lasting Post-COVID Symptoms?

“…It is important to consider that this study, in agreement with our study, also found that the effects of antivirals were more pronounced for some specific post-COVID symptoms such as fatigue, muscle pain, or dyspnea [ 30 ]. The STOP-PASC Randomized Clinical Trial has recently observed that oral administration of Nirmatrelvir-Ritonavir in COVID-19 survivors with post-COVID symptoms did not show a significant benefit to their symptoms [ 31 ]. Similarly, the effects of Nirmatrelvir-Ritonavir on post-COVID sequalae are also controversial since Wang et al [ 32 ] found a decrease in the long-term risk of death and the development of post-acute cardiovascular and respiratory sequelae in a large sample of inpatient COVID-19 survivors, whereas Ioannou et al [ 33 ] did not find this protective effect in a sample of non-hospitalized veterans.…”

COVID-19 Booster Vaccination Status and Long COVID in the United States: A Nationally Representative Cross-Sectional Study

“…Finally, surveys did not include the number of past infections per respondent, information on anti-viral medication, or when the worst symptomatic infection occurred in relation to the most prevalent virus variant. If available, data on participants’ use of antiviral treatments (i.e., nirmatrelvir) would likely have a greater impact on our symptom-severity analysis, as research on the effectiveness of antiviral drugs for preventing long COVID has been mixed [ 40 , 41 , 42 ]. An increase in the number of times a patient has had a COVID infection is associated with an increase in the likelihood of experiencing long-term symptoms, thus participant reinfection statistics are more likely to influence our long-COVID analysis [ 43 ].…”

Effect of Paxlovid Treatment During Acute COVID-19 on Long COVID Onset: An EHR-Based Target Trial Emulation from the N3C and RECOVER Consortia

“…In Stanford University's STOP-PASC trial, which included 155 participants, Paxlovid did not show significant benefit in improving extant fatigue, brain fog, body aches, cardiovascular symptoms, shortness of breath, or gastrointestinal symptoms. 13 In addition to treating PASC, researchers have begun to explore whether Paxlovid treatment in the acute phase of COVID-19 infection could help prevent the onset of PASC. One plausible pathway could be reducing infection severity.…”