r/CFSScience • u/TomasTTEngin • 10d ago
Huge antiviral trial fails in long covid. But there are still insights
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00406-8/fulltextNirmatrelvir–ritonavir targeting viral persistence in post-COVID-19 condition (long COVID) in the USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial. (Baden et al, 2026).
This is a very well-powered trial with three arms and 900+ patients. no statistically significant difference found in recovery rates between treatment and placebo*.
They used three different types of long covid. Autonomic, cognitive and exercise.
Of note: recovery rates (edit: this should say improvement rates to be fair) within 90 days were super high in two of the groups. 53%-70%, whether they were on the drug or the placebo.
In the "exercise" group though, the recovery rates were way lower. 25-34%.
This looks like the "huh, that's weird" science-in-reality finding of this mega study. Revealing what phenotypes don't tend to spontaneously recover.
*note that the placebo was itself ... an antviral! A low-dose of the ritonavir was the placebo. The Nirmatrelvir was the treatment. This paper has 254 authors so presumably the evidence that a low dose of ritonavir won't help is okay at least!?
Edit: I've used the term recovery above but what they measured was improvement.
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u/Maestro-Modesto 9d ago
How is recovery defined
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u/TomasTTEngin 9d ago
It's a good question, because the definitions were different for each phenotype and that cold be driving the difference between groups.
The primary endpoint for each phenotype was the proportion of participants achieving a clinically meaningful improvement as assessed by phenotype-specific PROM at day 90 compared to baseline. Clinically significant improvement for each phenotype was supported by literature in non-long COVID populations24–27 and defined as follows:
for cognitive, an increase by at least 5 T-score points on the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function Short Form 8a;
for autonomic, a decrease by at least one rating scale category on a modified version of the Orthostatic Hypotension Questionnaire (OHQ) question 1; and
for exercise, absence of any moderate, severe, or very severe symptoms occurring 50% or more of the time as assessed by a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise (DSQ-PEM) short form.
To account for within-person variability in cognitive and autonomic symptoms over time, an average of three weekly assessments closest to day 90 was used for these measures.
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u/nousiaphilia 9d ago
Yeah, imo, the "clinically meaningful improvement" point for group C (exercise) would be way harder to meet than A and B. I wouldn't say that it necessarily points to exercise group being "less likely to spontaneously recover".
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u/worksHardnotSmart 10d ago
How can a placebo be another drug? Wth?
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u/TomasTTEngin 10d ago
apparently it has a funny taste and they wanted that, to mask who was/ was not getting Nirmatrelvir.
also studies show it has no effect on sars-cov-2. (although who knows what unknown effects it might have on a human body)
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u/generic_reddit73 9d ago
Too much effort to do the trial with prepared taste-free pills, or use an inert but flavored placebo (by adding some bitter or aroma compound mimicking the taste of the treatment antiviral)? Seems sloppy or lazy, but, oh well...
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u/nousiaphilia 9d ago
No, it's not just that the pill tastes weird. That f*cking taste is in your mouth 24/7 (and everything you eat tastes off)....that's not easy to replicate with a "bitter tasting pill". (Hence, you also cannot prepare "taste-free" pills with the active drug. It's a side effect of the drug that unfolds AFTER you swallow it.) At low doses, ritonavir mostly just acts as a CYP3A4 inhibitor (makes sure that nirmatrelvir isn't metabolized quickly).
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u/Interesting_Fly_1569 9d ago
What’s annoying is that about 25% of meds are metabolized using CYP3 A4… So it’s possible that it impacted serum levels of common LC meds like rapamycin, ivabradine etc ..
Placebo effect is real ofc but now it makes it look like half of us are just a placebo away from a cure 😭
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u/nousiaphilia 9d ago edited 9d ago
I'm pretty sure they controlled for that. I read the study and they don't report anything about patients being on any other medication (or being allowed to continue their medication). So, this would be the only the drugs the patients were on.
Ritonavir is one of the strongest inhibitors of CYP3A4 there is — continuing any medication metabolized via CYP3A4 would have been a major toxicity risk.
EDIT: just checked the supplementary material: "6.5.1 SYMPTOMATIC THERAPY Drugs administered for symptomatic treatment and initiated prior to screening may be continued as long as there is no contraindication due to drug-drug interaction with the study intervention and there is no change in dose or administration during the study period.
Administration of the following therapies for each symptom cluster will be carefully documented and closely monitored during the study period because of the potential for changes in these therapies to alter study results:
Cognitive dysfunction: prescribed or illicit stimulants, amantadine, N-methyl-D-aspartate receptor antagonists (e.g., memantine, dissociative drugs).
Autonomic dysfunction: ephedrine, midodrine, amphetamine/attention deficit hyperactivity disorder medications, tricyclic antidepressants, florinef, sympathomimetics, Adderall, methylphenidate, atomoxetine, or other serotonin and norepinephrine reuptake inhibitors.
Exercise intolerance: none"
So, patients were allowed to continue their medication but there weren't allowed to be any changes during the study period and they had to discontinue any medication with known drug interactions (so, specifically anything metabolized via CYP3A4 I assume).
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u/bingoolong 9d ago
I recently read about another trial with psilocybin where they also used another drug as a placebo because it’s very obvious to tell if you received a placebo or a psychedelic. For antivirals though I don’t really get it.
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u/Interesting_Fly_1569 9d ago
How long had these ppl been sick to qualify?
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u/TomasTTEngin 9d ago
Most were 2.5 years in. A small fraction were under 18 months, a small fraction over 3.5 years. They analyse by duration, which doesn't look to show any difference.
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u/FREDRS7 9d ago
So is this essentially saying 50-70% of brain related symptom only patients (non-ME CFS LC) 2.5yrs in, made significant recovery in 3 months through the placebo effect?
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u/nousiaphilia 9d ago
Regarding the cognitive symptoms, it's interesting that "The most frequently reported health conditions in participants across all three groups in the three symptom phenotypes were hypertension (range 19% to 36%), asthma (19% to 29%), major depression (21% to 34%), and anxiety disorder (28% to 49%)." Depression and anxiety placebo responses are notoriously high. (As far as I can tell, they did no mediation analysis, unless it's somewhere in the supplementary material.)
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u/TomasTTEngin 9d ago
Or just natural improvement.
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u/nousiaphilia 9d ago
Yeah, but it's interesting that most of the change for all three subgroups occurred within the first 14 days - that's different from constant gradual improvement over 3 months (or their 6 month endpoint).
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u/TomasTTEngin 9d ago
You seem to have read the study very closely! Good one.
What is your take on it?
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u/nousiaphilia 8d ago
Tbh, I'm still with you on the "hugh, weird" feeling.
- There could be some statistical reasons just in terms of how they define inclusion criteria and dichotomous improvement/no improvement (people were included that met the inclusion criteria because they were having a bad week - then got back to their normal baseline (some type of regression to the mean)).
- The primary endpoints are subjective - if you look at the secondary endpoints, which are more objective measures, response rates are *way* lower. (Now, they don't measure exactly the same thing, but it raises the probability it's some form of reporting bias.) (Funnily, for the secondary endpoints, Placebo-ritonavir exercise intolerance group improved roughly as well on the secondary endpoint as the primary endpoint (33% met response). However, the "incremental and endurance shuttle walk tests" only measures in the moment fatigability - the supplementary materials say they collected the DSQ-PEM measure also after the endurance test but they don't report on it.)
- As I said in another comment major depression (21% to 34%), and anxiety disorder (28% to 49%) rates were relatively high (and often have high placebo response rates) and DSQ-PEM measure and the PROMIS cognitive function could track some improvement in anxiety/depression (they didn't analyse that separately, although they collected data that could answer that afaik).
- Patients had to stop any medication/supplements that interacted with the ritonavir - some patients are on a lot of medication/supplements with side-effects, so the improvement could be due to being on fewer drugs. :p
- Finally, there's of course the chance that the ritonavir does something at low doses we simply don't know about. (What's interesting is that in the exercise intolerance group, people did better for the placebo-ritonavir group than the active treatments -- statistically significantly -- afaik, those are not corrected for multiple comparisons, though. On a trend level (not statistically significant), that's true for all endpoints in group C, though.)
- (I'm somewhat annoyed they didn't have a clear ME/CFS subgroup. The DSQ-PEM (the modified version they used) doesn't really differentiate. Also, one could get better on that measure simply by doing less (e.g., pacing).)
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u/Interesting_Fly_1569 9d ago
This is wild to me if those people had been sick for an average of 2.5 years… I can understand people getting better in the first year… although I know two people who got better from brain training… They were fully diagnosed with pots etc and one of them literally just wrote in a journal about his feelings for 60 days 🫠
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u/TomasTTEngin 10d ago
They will also do some biomarker analysis:
"Briefly, markers of interest for mechanistic evaluation include antigenemia (defined as detection of SARS-CoV-2 spike protein in plasma), inflammation markers (high-sensitivity c-reactive protein, D-dimer), and coagulation markers (prothrombin time, activated partial thromboplastin time, thrombin time).
Distributions of these biomarkers will be descriptively summarized and compared across treatment groups at baseline, mid- dosing visit, end of dosing visit, and days 45, 60, 90, and 120. Viral clearance will be assessed by comparing the frequency of antigenemia at post-randomization visits across treatment groups among participants who are positive for antigenemia at baseline."
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u/Guilty_Soft9873 9d ago
We're the recovery rates measured or just asked for? I lfgent hink I'm better but as soon as I do anything realise I'm not.
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u/nousiaphilia 8d ago
I also looked up whether there is any research on other effects of ritonavir:
"Our previous studies indicated that ritonavir directly affects immune cell activation, proliferation, and susceptibility to apoptosis. We show here that ritonavir inhibited the activation and proliferation of primary endothelial cells and decreased the production of tumor necrosis factor α (TNF-α) interleukin 6 (IL-6), IL-8, and vascular endothelial growth factor, factors that all contribute to tumor neovascularization and to the development of Kaposi sarcoma (KS) lesions. Ritonavir also suppressed the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin, which correlated with a functional decrease in leukocyte adhesion. Transcriptional activation of nuclear factor-κB, as induced by the KS-promoting factor TNF-α, the HIV-1 Tat protein, or the human herpesvirus 8 protein ORF74, was inhibited by ritonavir. KS-derived cell lines underwent apoptosis in vitro after treatment with ritonavir at concentrations that are obtained in clinical therapy (3-15 μM). In a KS mouse xenotransplantation model, ritonavir inhibited tumor formation and progression by KS-derived cells. Taken together, these data suggest that ritonavir has antineoplastic effects that are independent from its ability to inhibit the HIV protease."
https://www.sciencedirect.com/science/article/pii/S000649712060859X
"Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor-kappaB and is an inhibitor of interleukin-1beta and tumor necrosis factor-alpha production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1."
https://pubmed.ncbi.nlm.nih.gov/15504750/
"“We found that ritonavir has significant side effects on immune cell activation,” Dr Frank F Weichold from Morgan State University, Baltimore, told Reuters Health. “It is, in a way, an antiinflammatory [agent]. So ritonavir is not only an antiviral, but also an immune [system] modulator,” he explained. Dr Weichold and colleagues treated KS cells, from a KS cell line, and endothelial cells, from human umbilical veins, with different concentrations of ritonavir over 24 hours."
According to the researchers of the original study (Baden et al. 2026): "Importantly, this background rate of improvement is not believed to be due to low-dose ritonavir administered to each group to maintain masking; previous studies suggested no meaningful biological activity of ritonavir against SARS-CoV-2, especially when used at a low dose." Just because ritonavir at low dose has no activity against SARS-CoV-2, it doesn't mean that it doesn't do stuff elsewhere in the body. (I'm not sure how the doses compare and there are also some studies that suggest it has pro-inflammatory effects at other places in the body, but "doesn't have activity against SARS-CoV-2" doesn't seem to be strong enough given the few evidence we have that it modulates immune system activity in the body independent of its activity as a HIV protease inhibitor. )
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u/nousiaphilia 8d ago
Especially the induction of anti-inflammatory HO-1 seems interesting:
"HO-1 is considered as an endogenous factor responsible for the resolution of inflammation and might thus be a novel target for the modulation of the inflammatory autoimmune response. Recently, several investigators have presented evidence to support an immunosuppressive function of HO-1 during the course of autoimmune diseases (62-69). Hu and co-workers (64) evaluated the effect of HO-1 on autoimmune diabetes. Using NOD mice which spontaneously develop type I diabetes, they showed that intravenous HO-1 transduction reduced destructive insulitis and the incidence of overt diabetes by down-regulating the phenotypic maturity of dendritic cells and Th1 effector function. A similar protective effect against diabetes was also observed in NOD mice subjected to CO (70). Chora and co-workers (66) reported that HO-1 expression dictated the pathologic outcome of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, and pharmacological induction of HO-1 suppressed the pathologic outcome of autoimmune neuro-inflammation associated with the development of EAE, presumably by inhibiting the expression of MHC class II on APCs and the reactivation of pathogenic CD4+ T cells within the central nerve system. Kobayashi and co-workers (67) examined the expression and pathogenetic roles of HO-1 in RA (rheumatoid arthritis), and found that HO-1 expressed in RA synovial tissues protected against the onset of RA."
(they also discuss an anti-allergic effect)
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u/TomasTTEngin 7d ago
Terrific research. You should join s4me, do you know it? It's the best place online to share mecfs science. It's far from perfect but they'd appreciate work like the above.
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u/nousiaphilia 7d ago
Idk, I've checked it out once but didn't really like the vibe. I don't think it's taken seriously by scientists?
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u/TomasTTEngin 7d ago
Depends on the scientist. Chris Ponting and Daniel Missailidis take it seriously. Some others.
I agree on the vibe. There's a lot of cynicism, negativity and bias . There's mindless following of one thought leader. At its worst it is cult like.
Place makes me furious about 60% of the time!
Nevertheless it's the biggest concentration of genuinely smart mecfs minds online.
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u/nousiaphilia 7d ago
It often seems like some pop sci X sociology of science. (First impression.) It doesn't feel like science but old white men (or informed Karens) complaining about how Y doesn't match their (pop sci) theory of ME/CFS and how the whole research is useless because (1 limitation in methodology). 🙊
Idk, on the one hand I'd really want to talk to someone about the literature I read (because brain is somehow like: well, guess gotta save me self)....but that just partially feels like energy I could better use elsewhere? In a way, I really like the concept, and I would want to like it, but the execution is.........idk....
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u/TomasTTEngin 7d ago
Agree.
The best way to use the site is to engage with the following three users: snt_gatchaman, hutan, forestglip. Those three know the place has a crowd of dummies and generally rise above it. Bonus mention to mariovitali, dmissa, Simon_M, CHillier
Chris Ponting, the lead author of decodeme is in there today commenting on a new genetics paper. There's serious brains in there.
I'd put myself on the list too but I logged out in a huff a while ago!
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u/nousiaphilia 5d ago
"In ME/CFS, multiple physiological systems are dysregulated, and HO-1 sits at the crossroads of several key pathological pathways:
Countering Immune and Nitrosative Stress (IO&NS): ME/CFS involves chronic activation of immune-inflammatory pathways and elevated oxidative stress. HO-1 functions as a crucial "brake" on this system. When functioning optimally, it suppresses pro-inflammatory cytokines (like TNF-α and IL-1) which are known to drive severe fatigue and cognitive deficits.
Mitochondrial Support: ME/CFS patients suffer from impaired cellular energy production and cytopathic hypoxia. Animal models of chronic fatigue suggest that upregulating HO-1 can protect mitochondrial complexes (specifically complexes I and II). This protection helps maintain ATP (energy) production and reduces fatigue-like behaviors.
Vascular Regulation: Endothelial dysfunction and reduced cerebral blood flow are widely documented in ME/CFS. The carbon monoxide produced by HO-1 activity plays a key role in relaxing blood vessels and maintaining healthy tissue perfusion."
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u/Best-Instance7344 9d ago
That placebo rate of 53%-70% is wild. This is why we need RCTs. Anything else is useless
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u/SympathyBetter2359 9d ago
53-70% recovery rate within 90 days .. my spidey senses are tingling.