Veteran’s Administration Joins the Long-COVID Fray
A new long-COVID preprint that recently came out just screams that times have changed. For one thing – the study is huge – 9,000 patients! It also shows long COVID has made it into the Veteran’s Administration (VA) database in the U.S. – which is a very good thing -as it’s a monster.
While we aren’t generally aware of it – because they’ve never been used in chronic fatigue syndrome (ME/CFS) – the VA has massive electronic databases that are often used in medical research. In fact, VA – which has 171 medical centers, 1,298 healthcare facilities, and 1,113 outpatient clinics – is easily the single, integrated healthcare system in the U.S.
Over the last month or so, VA researchers have published papers on e-cigarettes, sleep and brain trauma, gut microbiome enhancement and alcohol abuse, COVID-19 and neurologic disorders, and others. In the COVID-19 paper, researchers compared 150,000 VA patients who’d contracted COVID-19 with more than 11 million people who had not. (It concluded, a year later, that the people coming down with COVID-19 had a higher risk of stroke, memory disorders, nervous system disorders, episodic disorders like migraines and seizures, Guillain-Barré syndrome, and sensory disorders (ouch!). Findings like that should ensure that long COVID remains a subject of great interest for quite a while.)
Getting long COVID into the VA’s database, then, is a pretty big deal. (Similar studies are underway in the RECOVER Initiative.)
The VA Study
The title of the study, “Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19“, buries the lead for most of us. Nirmatrelvir is Paxlovid – the only antiviral drug (note the -vir) – being used in large amounts in COVID-19.
I learned about this study from Eric Topol’s recent blog post on it. Topol’s engagement with long COVID (he said it was the thing he feared most from COVID-19) is another nice sign of the condition’s emerging prominence. Topol is one of the top 10 most cited researchers in medicine and received a $207 million NIH grant to co-lead the Precision Medicine Initiative in 2016.
The “Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19” study followed 9,000 COVID-19 patients treated with Paxlovid from March-June 2022 and compared them to 47,000 COVID-19 patients who were not treated with Paxlovid or any other antivirals or antibodies.
The study used electronic records to assess 12 potential sequelae, as well as hospitalization and death. Besides things like cardiovascular, coagulation, kidney, etc. problems, the study assessed three symptoms (fatigue, musculoskeletal pain and cognitive issues) commonly found in ME/CFS and fibromyalgia.
The study results show just how powerful these big studies can be – as well as the limitations they present. The study found that people given Paxlovid in the first five days of their infection were 26% less likely to come down with long COVID. Paxlovid significantly reduced 10 of the 12 sequelae assessed, including cardiovascular disease, coagulation disorders, kidney problems, etc. as well as fatigue, musculoskeletal pain, and cognitive problems. Interestingly, if I’m reading the graph right, the drug appeared to have one of its largest effects on fatigue.
- A huge Veterans Administration study (50+ thousand) determines we are truly in a different world with long COVID. The biggest integrated health system in the US brings huge databases and lots of yummy data to medical research.
- A recent 11 million-person study (yes 11 million), for instance, found that having a COVID-19 infection produced a greater risk of coming down with a wide variety of neurological disorders.
- The study followed 9,000 COVID-19 patients treated with Paxlovid from March-June 2022 and compared them to 47,000 COVID-19 patients who were not treated with Paxlovid or any other antivirals or antibodies.
- People given Paxlovid in the first five days of their infection were 26% less likely to come down with long COVID. Paxlovid significantly reduced 10 of the 12 sequelae assessed, including fatigue, musculoskeletal pain, and cognitive problems. It also reduced the risk of death (48% reduction) and hospitalization (24% reduction). The results pertained whether a person was vaccinated or not.
- The study did not assess the incidence of ME/CFS or the effect of Paxlovid on post-exertional malaise, orthostatic intolerance, and sleep problems. Because it was also done on people with the ability to get Paxlovid (i.e. they had at least one risk factor for severe COVID-19) we don’t know if it applies to healthier people.
- Still, the results suggested that an antiviral drug can reduce the incidence of long COVID. Eric Topol suggested that because Paxlovid stops replication of the virus it may reduce the viral reservoir left behind by it resulting in less immune activation or autoimmunity directed at the virus.
- The study results came not long after the RECOVER Initiative named their first clinical trial: a 1700-person trial of Paxlovid to start in January of next year. It also comes not long after the Long COVID Research Initiative announced it was spending $15 million (and hopefully up to $100 million) to understand the role viral persistence plays in long COVID.
- Long COVID gave antiviral research a big boost and Paxlovid is just the first and almost certainly not the last or the best antiviral that is being tried out in COVID and now in long COVID.
- With EBV reactivation being found in long COVID EBV antivirals are getting more attention as well. That’s a good thing as the current drugs used are not specific for EBV or particularly effective.
- Once again, long COVID is doing what we hoped it would – force the research community to take a deep look at some prominent research themes in ME/CFS such as viral persistence and antivirals that were never fully explored.
- It’s also recruiting many allies to our and long COVID’s cause. The senior author of the VA study has published 9 papers on long COVID. In the latest he wrote: “Given the scale and the chronic nature of several of its sequelae, long COVID will reverberate with us for decades, and will have broad and deep social, economic, political and global security implications, long after the COVID-19 pandemic abates. This pandemic provides a historic opportunity not only to understand long COVID but also other post-viral conditions and infection-associated chronic illnesses…”
Whatever a person’s state of health, Paxlovid proved to be a powerful drug that prevented long COVID from appearing in about 25% of those who had taken it. Interestingly, the more risk factors a person had, the more effective it was.
Studies that rely on large electronic databases are going to have limitations, and this one did. Chronic fatigue syndrome (ME/CFS) does not appear to be in the VA’s database, as the study did not assess the incidence of ME/CFS. Nor did the study assess the effect of Paxlovid on some symptoms commonly found in ME/CFS such as post-exertional malaise, orthostatic intolerance, and sleep problems. These factors will hopefully work their way into the VA’s databases over time as it comes to grip with long COVID.
While the study focused on non-hospitalized patients (a good thing for ME/CFS), because it also focused on people who had at least one risk factor for COVID-19, we also don’t have data on how effective Paxlovid is in preventing long COVID in people without risk factors. (Paxlovid is approved for people with a risk factor for severe COVID-19).
Still, the study showed that an antiviral drug taken early in the course of a coronavirus infection was able to cut down long COVID by a quarter. So, what the heck is going on?
In his blog, Topol noted that because Paxlovid stops the replication of the virus, it likely reduces its ability to penetrate deeper into the body and leave behind a viral reservoir, or remnants of the virus, behind. Less virus in the body possibly means less immune activation or autoimmunity directed at the virus. It also suggests some sort of immune hole may be preventing people who come down with long COVID from rapidly dispatching the virus.
Of course, the findings also point a finger at the possible impact of antivirals. We should remember that as good as Paxlovid is, it isn’t the be-all and end-all of coronavirus antivirals. It’s simply the first one to break through, and others that are in development/testing may be more effective at reducing the incidence of long COVID. Plus as Dr. Peluso pointed out – it may take several different kinds of treatments to fully get at long COVID.
Dr. Michael Peluso, an assistant professor of medicine at the University of California, San Francisco, told the NY Times “The results are quite provocative and suggest that further investigation of antiviral agents and their effects on long Covid is urgently needed.”.
The VA study results were timely given the recent RECOVER Initiative announcement that its first long-COVID clinical trial will feature none other than Paxlovid.
The Paxlovid RECOVER Initiative Long-COVID Trial
At the end of October, the RECOVER Initiative announced its first long COVID clinical trial – Paxlovid (300 mg w/100 mg ritonavir). The 1,700 people participating in the trial provided yet another reminder for people with ME/CFS that “we’re not in Kansas, anymore”, and that long-COVID research can, at times, be taking place on a scale that we’re not used to.
The trial is clearly being informed by ME/CFS research, as it’s using a modified DePaul post-exertional questionnaire developed by Lenny Jason, as well as questionnaires assessing cognition and autonomic nervous system symptoms using an “active stand test” which sounds a whole heck of a lot like the NASA Lean Test the Bateman Horne Center has been promoting.
All Together Now
The VA study results suggest that the RECOVER Initiative is on the right track in trying out Paxlovid. Three major efforts – it, the RECOVER Initiative clinical trial result, and the Long COVID Research Initiative effort, all appear to be on the same page.
The Long COVID Research Initiative is starting off with $15 million to search for evidence of coronavirus persistence in long COVID and hopes to dedicate $100 million to it. Rather quickly, virus persistence – a subject which, with the exception of Epstein-Barr Virus, was basically dead in the water research-wise in ME/CFS, has become a major theme in long COVID.
And what about the Epstein-Barr virus? Several good studies have found EBV reactivation in long COVID, and the EBV field in ME/CFS is nothing if not fascinating. From a putative immune hole in ME/CFS, to an active infection, to smoldering broken forms of the virus, to EBV-triggered pathogenic genes, to EBV-triggered neuroinflammation in ME/CFS, to EBV as a kind of an autoimmune inoculator – the list of EBV-associated possibilities in ME/CFS and elsewhere seems to go on and on.
The pandemic has reportedly vastly increased interest in antivirals. Just yesterday, three possible new antivirals for COVID were announced. The coronavirus isn’t the only virus getting attention: Epstein-Barr virus and other herpes viruses are as well. EBV-specific monoclonal antibodies, for instance, are being explored.
Antivirals have worked in ME/CFS for some people, but the antivirals we have now are not specific to EBV nor very effective at knocking it down. Given that, it’s no surprise then that the antiviral recovery stories on Health Rising indicate that when antivirals work, they often take up to a year to do so. A new crop of COVID-19-inspired antivirals might do far better…
Once again, long COVID is doing what we hoped it would – force the research community to take a deep look at some prominent research themes in ME/CFS that were never fully explored. It’s also recruiting many allies to our and long COVID’s cause that we couldn’t have anticipated.
The VA paper’s senior author, Ziyad Al-Aly, for instance, has published at least 9 studies and papers on long COVID thus far. Just last week, he published “Long COVID: long-term health outcomes and implications for policy and research“, in which he documented the enormous range of other illnesses and effects (kidney disease, dysrhythmias, ischaemic heart disease, heart failure, pericarditis, myocarditis and thromboembolic disease, new-onset diabetes mellitus, structural changes in the brain, hemorrhagic stroke, seizure disorders and disruptions in cognition and memory) a COVID-19 infection is increasing the risk of getting.
“Given the scale and the chronic nature of several of its sequelae, long COVID will reverberate with us for decades, and will have broad and deep social, economic, political and global security implications, long after the COVID-19 pandemic abates. This pandemic provides a historic opportunity not only to understand long COVID but also other post-viral conditions and infection-associated chronic illnesses…“