Why Long COVID Won't Resolve: A Mechanistic Reading of Viral Persistence, Mitochondrial Dysfunction, and the Gut–Brain Axis the Standard Model Is Missing — Part 3: Why Single-Mechanism Treatment Fails

If the mechanistic convergence above is correct, the failure profile of current long COVID treatment becomes predictable. Paxlovid for chronic long COVID has produced disappointing results in randomized trials (RECOVER-VITAL and STOP-PASC have failed to demonstrate significant benefit in chronic long COVID populations, though acute Paxlovid likely reduces incident long COVID). The pharmacologic mechanism is antiviral — protease inhibition that suppresses viral replication. If chronic long COVID is sustained primarily by persistent antigen rather than replicative infection, and by the downstream bioenergetic state of the gut epithelium that the persistent antigen initiated, antiviral therapy will not resolve the established lesion. The fire is out; the smoke damage remains. Metformin has demonstrated modest benefit in reducing incident long COVID when given during acute infection (COVID-OUT trial), and modest benefit in some chronic long COVID cohorts. Its mechanism includes mitochondrial complex I modulation, AMPK activation, and microbiome effects. The signal fits the mitochondrial component of the convergent lesion, which is why the benefit is modest rather than null and why it is also modest rather than curative — metformin partially addresses one of the convergent mechanisms. Low-dose naltrexone produces modest benefit in some patients, consistent with its immune-modulatory