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

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)

 

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.

 

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)

 

Thanks for the info. I didn't know that metformin reduced the viral load.