Preprint Effect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C, 2024, Preiss et al.

SNT Gatchaman

SNT Gatchaman

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Effect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C
Alexander Preiss; Abhishek Bhatia; Chengxi Zang; Leyna V Aragon; John M Baratta; Monika Baskaran; Frank Blancero; M Daniel Brannock; Robert F Chew; Ivan Diaz; Megan Fitzgerald; Elizabeth P Kelly; Andrea G Zhou; Mark G Weiner; Thomas W Carton; Fei Wang; Rainu Kaushal; Christopher G Chute; Melissa Haendel; Richard Moffitt; Emily Pfaff; N3C; RECOVER

Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. In this study, we examined whether treatment with Paxlovid in the acute phase of COVID-19 helps prevent the onset of PASC.

We used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,461 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. Our primary outcome measure was a PASC computable phenotype. Secondary outcomes were the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period.

Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.99, 95% confidence interval [CI] 0.96-1.01). However, its effect varied across the cognitive (RR = 0.85, 95% CI 0.79-0.90), fatigue (RR = 0.93, 95% CI 0.89-0.96), and respiratory (RR = 0.99, 95% CI 0.95-1.02) symptom clusters, suggesting that Paxlovid treatment may help prevent post-acute cognitive and fatigue symptoms more than others.


Link | PDF (Preprint: MedRxiv)
 
Adjusted relative risk was 0.85 (95% CI 0.79-0.90) for the cognitive symptom cluster, 0.93 (95% CI 0.89-0.96) for the fatigue symptom cluster, and 0.99 (95% CI 0.95-1.02) for the respiratory symptom cluster.
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In the “VA-like cohort” subanalysis, the cohort included 61,604 male patients 65 years or older with a COVID-19 index between January 3, 2022, and December 31, 2022 (the same study period used in Xie et al, 2023). 17 Of this cohort, 15,846 (25.72%) were treated with Paxlovid. Adjusted relative risk for the primary outcome was 0.95 (95% CI 0.86-1.03). For the cognitive, fatigue, and respiratory GBD symptom clusters, adjusted relative risk was 0.74 (95% CI 0.63-0.85), 0.89 (95% CI 0.78-0.99), and 0.92 (95% CI 0.84-0.99), respectively.
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We found that Paxlovid had a protective effect against the onset of novel cognitive and fatigue symptoms in the post-acute period, which suggests that Paxlovid may have more impact on the underlying causes of those symptoms. [...] Our findings allow us to generate the hypothesis that cognitive symptoms (against which Paxlovid is most protective) may be caused by mechanisms that Paxlovid would affect (e.g., viral load).
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The problem with PASC is that it is a collection of all symptoms ranging from anosmia to kidney/lung damage to diabetes, etc, etc, with MECFS related ones (fatigue, fog, PEM) being only a part. It sounds like Paxlovid helped preventing MECFS symptoms but not other damages.

The lower viral load may have lead to less violent response by the innate immune system, which in turn lead to lower MECFS symptom prevalence. I wish they would now look into why Meformin cuts the chance for long-COVID by 40%. Since Metformin doesn't do anything about the viral load, triangulating the two may lead to some answers for the trigger. My guess would be: metformin's anti-inflammatory property may have lead to it by saving the immune system from over-reacting too much to the novel virus, similar to baricitinib helping severely ill patients and then lowering their long COVID prospect.
 
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poetinsf said:
The problem with PASC is that it is a collection of all symptoms ranging from anosmia to kidney/lung damage to diabetes, etc, etc, with MECFS related ones (fatigue, fog, PEM) being only a part. It sounds like Paxlovid helped preventing MECFS symptoms but not other damages.

The lower viral load may have lead to less violent response by the innate immune system, which in turn lead to lower MECFS symptom prevalence. I wish they would now look into why Meformin cuts the chance for long-COVID by 40%. Since Metformin doesn't do anything about the viral load, triangulating the two may lead to some answers for the trigger. My guess would be: metformin's anti-inflammatory property may have lead to it by saving the immune system from over-reacting too much to the novel virus, similar to baricitinib helping severely ill patients and then lowering their long COVID prospect.
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Unfortunately, the data is pointing towards exactly the opposite direction. It seems to reduce nothing in regards to ME/CFS and only things related to a severe acute infection.

In this recent presentation by the lead author of the Metformin studies the researcher is very open about the fact they they have no idea whether Metformin actually reduces the risk of Long COVID, whether it only works in overweight people by affecting things associated with being overweight or whether there are virological effects (there is data on Metformin reducing viral load see https://www.s4me.info/threads/prepr...led-clinical-trial-2023-bramante-et-al.33640/, they think being an mTOR inhibitor could be the leading effect).
 
Adding to @EndME's comment. Viral replication depends on metabolic reprogramming (subverting host cellular machinery to its own requirements), so if metformin limits that it may act to reduce viral load. Some references on just the lipid aspects of that for viruses and metformin.

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Innate metabolic responses against viral infections (2022, Nature Metabolism)

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis (2022, Viruses)

Viral hijacking of cellular metabolism (2019, BMC Biology)

SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target (2019, Nature Communications)

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Lipidomics Profiling of Metformin-Induced Changes in Obesity and Type 2 Diabetes Mellitus: Insights and Biomarker Potential (2023, Pharmaceuticals)

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort (2023, Journal of Pharmacology and Experimental Therapeutics)

Lipids Alterations Associated with Metformin in Healthy Subjects: An Investigation Using Mass Spectrometry Shotgun Approach (2022, International Journal of Molecular Sciences)

Metformin induces lipid changes on sphingolipid species and oxidized lipids in polycystic ovary syndrome women (2019, Nature Scientific Reports)
 
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EndME said:
Unfortunately, the data is pointing towards exactly the opposite direction. It seems to reduce nothing in regards to ME/CFS and only things related to a severe acute infection.
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What do you mean by this? It seems to be the opposite of what you're saying. Paxlovid was associated with decreased risk of cognitive and fatigue, but not respiratory phenotypes.
 
New preprint version 4 with slightly different numbers. The numbers are also slightly different from data presented in a webinar today. I'm not sure why.

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

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Background
Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. Researchers have begun to explore whether Paxlovid treatment in the acute phase of COVID-19 could help prevent the onset of PASC.

Methods and Findings
We used electronic health records from the National Clinical Cohort Collaborative (N3C) to define a cohort of 410,026 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation framework to estimate the effect of Paxlovid treatment on PASC incidence. The treatment group was defined as outpatients prescribed Paxlovid within five days of COVID-19 index, and the control group was defined as all patients meeting eligibility criteria not in the treatment group. The follow-up period was 180 days. We estimated overall PASC incidence using a computable phenotype. We also measured incident cognitive, fatigue, and respiratory symptoms in the post-acute period.

Paxlovid treatment had a small effect on overall PASC incidence (relative risk [RR] 0.94; 95% CI [0.90, 0.99]; p=0.011). It had a slightly stronger protective effect against cognitive (RR 0.86; 95% CI [0.77, 0.95]; p<0.001) and fatigue (RR 0.92; 95% CI [0.86, 0.97]; p=0.002) symptoms.

Conclusions
In this study, Paxlovid had a weaker preventative effect on PASC than in prior observational studies, suggesting that Paxlovid is unlikely to become a definitive solution for preventing PASC. Differing effects by symptom cluster suggest that the etiology of cognitive and fatigue symptoms may be more closely related to viral load than that of respiratory symptoms. Future research should explore potential heterogeneous treatment effects across PASC subphenotypes. 1

Link | PDF (Preprint: MedRxiv) [Open Access]
 
forestglip said:
What do you mean by this? It seems to be the opposite of what you're saying. Paxlovid was associated with decreased risk of cognitive and fatigue, but not respiratory phenotypes.
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I cannot remember what I was trying to say and reading my comment doesn't make it clearer (I'm unsure whether my statements are supposed to be Paxlovid or Metformin). If my initial statements were to have been about Paxlovid my guess to what I was trying to say is that all initial evidence to suggest that Paxlovid may be a suitable prevention for Long-Covid was based on studies of hospitalised patients (so all things tied to severe acute infections) and I recall at least one study of non-hospitalised patients, where it might make slightly more sense to make comments about ME/CFS (although not much), where there was no relationship between Paxlovid and LC (https://pubmed.ncbi.nlm.nih.gov/38175151/).

That is, I don't think that there is any evidence to suggest that Paxlovid has any influence on ME/CFS prevalence even though the symptoms that were most reduced in the above study could be considered to be ME/CFS symptoms, because there is no indication that this study is of any relevance to discussing ME/CFS (fatigue might be a symptom of ME/CFS but it is also a symptom of PICS etc).
 
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