SARS-CoV-2 Reservoir and Antiviral Strategy in Long COVID

1 Proal et al. 2025 β€” Targeting the SARS-CoV-2 Reservoir in Long COVID

Full Citation:: Proal AD, Aleman S, Bomsel M, et al. Targeting the SARS-CoV-2 reservoir in long COVID. Lancet Infectious Diseases. 2025;25(5):e294–e306. (Proal et al. 2025) DOI:: 10.1016/S1473-3099(24)00769-2 PMID:: 39947217 Study Design:: Expert consensus review (multi-author position paper); draws on HIV and hepatitis C reservoir trial methodology Key Findings::

- No approved treatments exist for long COVID; viral persistence is a leading mechanistic candidate
- SARS-CoV-2 can persist for months to years in subsets of patients, potentially driving ongoing symptoms
- Existing antivirals (nirmatrelvir/ritonavir) target active replication and may not affect stable reservoirs
- Critical trial design considerations identified: mechanism of action, participant selection, treatment duration, reservoir biomarker standardization, and combination approaches
- Draws lessons from HIV long-term non-progressors and hepatitis C cure models for reservoir-clearing strategies

Relevance:: Highly relevant to post-COVID ME/CFS. Establishes the scientific and clinical framework for treating Long COVID as a viral reservoir disease. Authors include leading ME/CFS researchers (VanElzakker, Proal, Iwasaki, Putrino). The design considerations apply directly to proposed ME/CFS antiviral trials. Complements Peluso et al. 2024 gut tissue biopsy evidence with actionable trial design principles. Certainty Assessment::

- *Quality:* High (Lancet Infectious Diseases; expert consensus; multi-author international consortium)
- *Sample:* Review/position paper β€” no primary data
- *Replication:* Synthesises replicated findings across multiple independent groups
- *Certainty:* 0.75 (consensus framework; primary trial data awaited)
- *Limitation:* No new empirical data; trial recommendations untested at time of publication

2 Pridgen & Putrino 2026 β€” Herpes-Antiviral Combination Therapy for Long COVID

Full Citation:: Pridgen WL, Putrino D. Patient-reported improvements from use of IMC-2 alone and IMC-2 and Paxlovid in a Long COVID cohort: a case series. Frontiers in Immunology. 2026;16:1698271. (Pridgen and Putrino 2026) DOI:: 10.3389/fimmu.2025.1698271 PMID:: 41562079 / PMCID: PMC12812670 Study Design:: Single-center, open-label, prospective case series; two arms with crossover opportunity. No placebo, no control, not randomized, not blinded. Sample Size:: n=24 completed (12 IMC-2-only, 12 IMC-2+Paxlovid); 3 crossovers; 27 approached; single Alabama LC clinic (Apr 2022–Feb 2024). Intervention:: IMC-2 = valacyclovir 1500 mg BID + celecoxib 200 mg BID Γ— 120 d. IMC-2+Paxlovid arm added Paxlovid days 13–28 (valacyclovir reduced to 750 mg BID during the 15-day window). Outcome Measures:: Patient Global Impression of Change (PGIC) fatigue (primary), brain fog + dysautonomia (secondary), at days 120/305/731; 10-pt VAS in parallel. Subjective patient-reported only.

Key Findings:

  • IMC-2+Paxlovid (IP) vs IMC-2-only (IO): PGIC fatigue 2 points higher (p < 0.0001, Cohen’s d = 1.8)
  • VAS: IP group reported on average 55.3% greater reduction in fatigue than IO (p < 0.0001)
  • Dysautonomia (d=1.4, p < 0.001) and brain fog (d=1.4, p < 0.001, 7-pt) also favored IP
  • IP improvements appeared durable: no significant symptom change across 120/305/731-day follow-ups (~600 days post-protocol)
  • Regimen tolerated: no AEs in the IO arm; IP-arm side effects were transient and confined to the Paxlovid window (dysgeusia 86.7%, increased fatigue 40%, body aches 26.6%)
  • Renal/hepatic function monitored pre-protocol and q6–8 wk; medication stopped if abnormal

Conclusion:: Authors interpret the results as pilot evidence of synergy between IMC-2 and Paxlovid and call for a randomized, double-blind, placebo-controlled trial as the necessary next step.

Limitations:

  • Open-label case series β€” no placebo/control arm; placebo effect and selection bias unaddressed
  • Small n (12/arm), single site, single investigator group
  • Subjective PGIC/VAS endpoints only; no validated LC instrument or objective measures
  • Marked female bias (20 F / 4 M)
  • Major inventor conflict of interest: W. Pridgen is partner/founder of PridCor Therapeutics, holder of the patent covering IMC-2 components
  • Ethics review by Institute of Regenerative and Cellular Medicine (for-profit IRB, IRCM-2025-446)
  • Cannot support causal efficacy; low-certainty hypothesis-generating pilot

Relevance:: This is the only direct pilot data answering ch37’s open statement that combination antiviral strategies targeting multiple latent/reactivating viruses β€œhave not been tested.” It extends the valacyclovir+celecoxib concept (independently trialled by the Bateman Horne Center) by adding a Paxlovid arm targeting SARS-CoV-2 persistence alongside herpesvirus reactivation. For ME/CFS it is context/relevance only: a Long COVID cohort, research-stage, off-label, and heavily confounded β€” not a basis for clinical recommendation.

Certainty Assessment:

  • Quality: Low (open-label case series, no control, no randomization)
  • Sample: Small (n=24)
  • Replication: None yet β€” single pilot; independent Bateman Horne combination trial is separate
  • Certainty: 0.21 (discounted from raw 0.25 Γ— Long-COVID weight 0.85)
  • Limitation: Off-label; high valacyclovir dose; inventor COI; interaction burden with common ME/CFS co-prescriptions (see harm search in search log)

References

Pridgen, William L, and David Putrino. 2026. β€œPatient-Reported Improvements from Use of IMC-2 Alone and IMC-2 and Paxlovid in a Long COVID Cohort: A Case Series.” Frontiers in Immunology 16: 1698271. https://doi.org/10.3389/fimmu.2025.1698271.
Proal, Amy D., Soo Aleman, Morgane Bomsel, Petter Brodin, Marcus Buggert, Sara Cherry, Daniel S. Chertow, et al. 2025. β€œTargeting the SARS-CoV-2 Reservoir in Long COVID.” Lancet Infectious Diseases 25 (5): e294–306. https://doi.org/10.1016/S1473-3099(24)00769-2.