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Background: Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir., Methods: We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5-30 days) of oral nirmatrelvir/ritonavir outside (n = 11) of and within (n = 2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir., Results: Among those who take an extended course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experience a meaningful reduction in symptoms, although not all benefits persist. Others experience no effect on symptoms. One participant stopped early due to intense stomach pain. For the two participants who took an extended course of nirmatrelvir/ritonavir within the context of an acute reinfection, both report eventually returning to their pre-re-infection baseline., Conclusions: Extended courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study how and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID., Competing Interests: Competing interests: Dr. Peluso has served as a consultant for Gilead Sciences and AstraZeneca, outside the submitted work. The remaining authors have no conflicts of interest to declare., (© 2025. The Author(s).)

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence. We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued. Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes. Third, studies should have multiple illness comparator cohorts for IACCIs such as myalgic encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses. Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity. Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Long COVID is a chronic and often disabling illness with long-term consequences. Although progress has been made in the clinical characterization of long COVID, no approved treatments exist and disconnects between patients and researchers threaten to hinder future progress. Incorporating patients as active collaborators in long COVID research can bridge the gap and accelerate progress toward treatments and cures., Competing Interests: Declaration of interests The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir., Methods: We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5-30 days) of oral nirmatrelvir/ritonavir outside (n=11) of and within (n=2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir., Results: Among those who took a long course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experienced a meaningful reduction in symptoms, although not all benefits persisted; others experienced no effect on symptoms. One participant reported intense stomach pain that precluded her from continuing her course. Among the two participants who took a long course of nirmatrelvir/ritonavir within the context of an acute reinfection, both eventually returned to their pre-re-infection baseline., Discussion: Long courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study who, how, and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID., Competing Interests: Conflicts of interest to declare: Dr. Peluso has served as a consultant for Gilead Sciences and AstraZeneca, outside the submitted work. The remaining authors have no conflicts of interest to declare.