Three pill bottles

Dr. Pridgen is using three drugs to fight two pathogens.

The Inevitable Combination Treatment Approach?

Chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and long COVID are complex diseases that affect many systems and can cause a remarkable number of symptoms. It’s certainly possible that someone will get to the core of the problem and introduce a drug that takes care of everything.

It seems more likely, though, that each of these diseases will require combination treatments. It was a combination of drugs, after all, that throttled HIV. Multiple drug combinations, each of which features at least two drugs from different classes, are now available.

Ditto with Hepatitis C where the addition of a second drug greatly boosted treatment effectivenessZepatier, for instance, combines a protease inhibitor (Grazoprevir) and an antiviral (Elbasvir). Ninety percent recovery rates are now being touted.

So what the heck are we doing with one drug therapy in long COVID (Paxlovid) or regarding herpesvirus infections in ME/CFS.  At this point trying to knock out a complex disease with one drug seems like bringing a knife to a gunfight.

Indeed, concerning long COVID, David Putrino, the leader of the Mt Sinai Center, stated, “Everyone wants a single treatment; that’s not realistic for long COVID.” Bruce Patterson is using a CCR5 antagonist plus statins to try to knock down long COVID. Resia Pretorius had found that an unusually strong triple drug anti-platelet, anticoagulant approach is necessary to move the needle in long COVID.

Triple Coagulation Therapy Scores in Long COVID: Implications for ME/CFS, FM and POTS


Some ME/CFS researchers concur. Travis Craddock’s models at Nancy Klimas’s Institute for Neuroimmune Science, for instance, found that while using a herpesvirus antiviral by itself allowed herpesviruses to quickly rebound, adding rituximab caused the virus to flatline. Nancy Klimas is using two drugs in an attempt to knock out neuroinflammation first and then reset the HPA axis later, in Gulf War Illness and ME/CFS.

A Moonshot For ME/CFS, Knocking EBV Down and a Stuck Long-COVID Study: The 2023 INIM Conference Highlights

Given all this, it seems remarkable, in retrospect, that anyone would expect a one-drug approach (Valtrex, Famvir, Valcyte) to knock out the Epstein-Barr virus or other herpesviruses in ME/CFS. It’s perhaps not surprising that Pridgen has been able to get his duo antiviral drug approach in fibromyalgia almost to the finish line. (A phase 3 trial is waiting clearance from the FDA to start)

Early Paxlovid Long-COVID Reports Not Promising

While nothing has been published, anecdotal reports suggest that the Stanford Paxlovid (which is a two-drug combo study (nirmatrelvir and ritonavir)) – which has been completed – did not go well. (While Paxlovid is a two-drug combination, ritonavir – the second drug – does not interact with the virus itself. Instead, it stops the body from metabolizing the first drug (nirmatrelvir), thus boosting its potency. Paxlovid, then, is essentially a one-drug formulation.)

Meanwhile, a bunch of Paxlovid trials have gotten underway recently. A 900-person RECOVER Paxlovid invitation-only trial appears to have gotten underway in July, a 100-person Yale study started in April 2023, and a 400-person Karolinska study opened its doors in May 2023. We should know the results of several of these in 2024.

Time will tell how the Paxlovid trials end up, but all these duplicative trials (they seem mostly to be using the same dose) to me, point to the general disorganization, messiness, and inefficiency of our medical research system. Do we really need 4 Paxlovid clinical trials to tell if the drug is helpful or would it have been better to use our limited resources on testing other potential treatments?

Pridgen’s Combination Plus Long-COVID Trial 

And here comes Dr. Pridgen, MD. He’s gone the furthest with the duo-drug synergistic approach in our neck of the woods. Not only was his two-drug antiviral therapy (valacyclovir/celexicob) aimed at a condition – fibromyalgia – that few people associated with viruses – but as was noted that approach has made it to Phase III trials.

When Bateman Horne Center tested the duo-drug approach in a small placebo-controlled, double-blinded Phase II long-COVID study, the results appeared to be pretty good. Pridgen reported that 14 weeks of the drugs resulted in “clinically and statistically significant improvements in fatigue, pain, and symptoms of autonomic dysfunction” and that the drug combination was well-tolerated; i.e. no significant side effects or adverse events. Thirty-seven of 39 participants completed the trial.

Now comes the “IMC-2 and Paxlovid Synergy Treating Long COVID Trial” featuring three drugs: the IMC-2 combination (valtrex/celecoxib) and Paxlovid.

Study Rationale 

  • Continuous use of the IMC-2 approach “provides daily suppression of herpesviruses such as VZV, HSV-1, HSV-2, EBV, CMV, HHV6, and potentially others”.
  • Paxlovid is a combination antiviral that primarily uses nirmatrelvir – an antiviral that belongs to a family of 3C-like protease inhibitors developed in the late 2010s to fight the feline coronavirus. These 3C-like protease inhibitors block the activity of a viral enzyme called 3C-like protease (3CLpro).
  • Knocking down the coronavirus helps reverse the immune changes (exhausted T and NK cells and B-cell activation) it caused, allowing the IMC-2 protocol to be more effective at knocking the activated herpesviruses down. Pridgen has found that he can use lower doses of his IMC-2 combination to the same effect than when it’s used alone.

In his office, Pridgen treated long-COVID patients with IMC-2 (2-dose every 12 hours (valacyclovir 750mg/celecoxib 200mg pill) for 120 days plus 1-pill of Nirmatrelvir/1-pill Ritonavir (every 12 h) given for 15 days. During the time the participants were taking Paxlovid the IMC-2 dose was cut in half.

Pridgen compared their results to 13 long-COVID patients treated with IMC-2 alone. (Note that  Participants had to report that “they were substantially less healthy than before, suffered from severe or moderately severe fatigue, and at least moderately severe brain fog or palpitations (with dizziness & tachycardia) or both.

He used a five-point grading system (none, mild, moderate, moderately severe, severe) to assess fatigue, brain fog, and symptoms of dysautonomia. The primary endpoint of this prospective study was the % reduction in moderately severe and severe symptoms of fatigue.


Pridgen found substantial reductions in fatigue, brain fog, and dysautonomia in the IMC-2/Paxlovid group which were significantly better than found in the IMC-2 only group.

Fatigue results

Fatigue results – Dark grey bar – IMC-2 + Paxlovid; light grey bar – IMC-2.


Paxlovid-IMC-2 long COVID results

Dark grey bars – IMC-2 + Paxlovid; light grey bars – IMC-2.

Pridgen reported that when used with Paxlovid, he was able to cut the IMC-2 dose (750mg/celecoxib 200mg pill per side (12 h)) by half and achieve the same results. He also reported that the IMC-2/Paxlovid combination works much more quickly than IMC-2 alone. Pridgen reported that he’s treated about 50 long-COVID patients. While using just IMC-2 tended not to work in about 25% of long-COVID patients, the IMC-2/Paxlovid combination works in many more long-COVID patients. The only notable side effects were the metallic taste that Paxlovid produced which is well known and disappears when the drug is done.

Pridgen noted that with the free Paxlovid no longer being free in the U.S., in 2024, getting it will become more difficult.

Hope for Other Viral Triggers???

Pridgen reports that Paxlovid’s 3C-like protease (cysteine) formulation potentially has activity not just against the SARS-CoV-2 coronavirus but against many other viruses, including other coronaviruses (MERS and others), (picornaviruses (rhinoviruses, enteroviruses and others)), astroviruses (diarrhea), caliciviruses (gastroenteritis), hepeviruses (hepatitis including hepatitis A), alphaviruses (arthritis, encephalitis, rashes and fever), flaviviruses (West Nile virusdengue virustick-borne encephalitis virusyellow fever virusZika virus) and others.

We don’t know if Paxlovid is effective against these other viruses, but if it is, it could potentially be helpful – when applied with Pridgen’s IMC-2 protocol for herpesviruses – against other viral triggers in ME/CFS. There’s also the possibility that the viral trigger for some people with ME/CFS was another coronavirus, in particular, one that could be associated with the ACE-2 issue in ME/CFS.

Note that the study was “prospective” and was not placebo-controlled or double-blinded (the patients knew they were getting the medication). Pridgen has funding for a pilot placebo-controlled, double-blinded study and is beginning to look for a location to host the trial.


  • Long COVID is often not just about the coronavirus – there’s also often a herpesvirus reactivation to worry about. If that’s true, then why are we trying to kill two birds with one stone (two viruses with one medication – Paxlovid)? The situation seems even more untenable given that combination drug therapy is needed to knock down HIV (3 drugs) and hepatitis B (two drugs) and other pathogens.
  • Dr. Skip Pridgen brought the first duo antiviral approach to the herpesviruses in ME/CFS/FM with his IMC-2 protocol. As the penultimate phase-3 trials of that approach are taking place in fibromyalgia, Pridgen brought his herpesvirus-busting protocol to long COVID ( at the Bateman Horne Center) and reported that it worked: fatigue and other symptoms declined.
  • After Pridgen, though, was unable to make progress in about 25% of his long COVID patients, he added Paxlovid to the mix and reported – in a small non-blinded, non-placebo-controlled prospective trial – some pretty darn impressive results. Fatigue scores, in particular, shot down dramatically and significant improvements were seen in brain fog and dysautonomia symptoms.  Paxlovid plus his herpesvirus meds was far more effective than Paxlovid alone.
  • With Pridgen reporting that Paxlovid might also be helpful against many other viruses, it’s quite speculative but some possibility this triple drug combination might be helpful to those with ME/CFS/FM and other illnesses who experience herpesvirus reactivations and other viral triggers.
  • With those results in hand, Pridgen was able to raise funding for a proper trial and the search is on for a location. Pridgen’s duo antiviral approach was new for fibromyalgia and ME/CFS and his triple antiviral approach is new for long COVID but combination therapies are probably going to be needed in long COVID, ME/CFS, and similar diseases.
  • Thanks to the many people who have supported Health Rising thus far in its end-of-the-year drive!

Applying The Arseneau “Should I Try a Treatment or Not” Test

The Arseneau test assesses the factors below to help decide whether or not to try a treatment. Note that different people will get different results. For instance, people with more resources may feel more comfortable trying more expensive and unproven treatments. Likewise, people who’ve had bad reactions to treatments in the past may be less likely to try things that don’t have a strong evidence base. In other words, the final results are person-dependent.

  • The credibility of the source – While Dr. Pridgen has always been quite optimistic about his approach, for me, he is a good source. He has, after all, been able to shepherd an antiviral treatment for fibromyalgia (of all diseases), to the point where a phase III trial is awaiting clearance from the FDA. That really says something.
  • Quality of the evidence – lacking. Small study and good results but no placebo controls or blinding.
  • The benefit, the cost, and the risk–benefit analysis – the benefit appears to potentially be quite high, the cost is probably high, particularly in 2024, and since several studies have assessed the risk of IMC-2 and Paxlovid, the risk appears to be low.

Arseneau Test Conclusion – A possibly costly drug combination not covered by insurance in a small, preliminary trial with some very good preliminary results probably puts it out of the range for many of us but since it appears to be safe, others may want to give it a shot (if they can find a practitioner.) If Pridgen can get a trial going – and there’s no reason to think he shouldn’t be able to – we could have a better sense of efficacy by sometime next year.


Facing a two-pathogen situation (the coronavirus and herpesvirus reactivation) Pridgen took his combination antiviral approach to the next level.  We’re still at the very early stages but thankfully Pridgen has the funds to do what the ME/CFS field has so rarely been able to do – test out his new protocol –  and we should learn in the not-to-distant future how it went. Long COVID patients, of course, will want to know but while Paxlovid was specifically created to battle the coronavirus, the possibility that it might help against other pathogens makes the trial of interest to people with ME/CFS and/or fibromyalgia.

Overall, Pridgen’s approach and others that feature combination therapies are a good sign that the long COVID and ME/CFS/FM fields are coming to grips a bit with the complexity of these diseases.

Health Rising’s Donation Drive Update

Thanks to the hundreds of people (I am behind on my tallys) who have supported Health Rising thus far.

With 10 or so blogs under its belt, Health Rising has been providing updates on Dr. Pridgen’s work for over ten years.  Why? Drugs don’t come easy for ME/CFS or fibromyalgia and when they occur we jump on them and now that long COVID is in the mix we’re jumping on it too.

If keeping up to date with new treatments is something you’re committed to please support Health Rising in a manner that works for you.





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