Randomized Clinical Trial To Evaluate The Efficacy And Safety Of Valganciclovir In A Subset Of Patients With Chronic Fatigue Syndrome
Abstract:
There is no known treatment for chronic fatigue syndrome . Little is known about its pathogenesis. Human herpesvirus 6 and Epstein-Barr virus have been proposed as infectious triggers.
Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir or placebo for 6 months in a double-blind, placebo-controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory and Fatigue Severity Scale scores, self-reported cognitive function, and physician-determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels.
VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore , FSS score , and cognitive function . VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders . In the VGCV arm, monocyte counts decreased , neutrophil counts increased and cytokines were more likely to evolve towards a Th1-profile . Viral IgG antibody titers did not differ between arms.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00478465.
The Wrong Way To Treat Chronic Fatigue Syndrome
Now you know the conventional medical therapies that are best suited to treat chronic fatigue syndrome. A lot of them dont have great research to support their use. So, be sure to have an in-depth discussion with your doctor. Discuss whether the potential side effects of the medication are worth it for the potential benefits.
There are other treatments that are often prescribed in conventional medical settings that are known to not be effective. And they may even have dangerous side effects. Below, I detail the conventional treatments of chronic fatigue that need to be avoided. These include:
- Graded exercise therapy
- Sleeping pills
Graded exercise therapy
Graded exercise therapy or GET as its commonly referred to is an exercise plan specifically for those with chronic fatigue syndrome. Most patients with CFS report something known a post-exertional malaise this is a feeling of exhaustion or tiredness following exercise/activity. GET was developed in hopes to improve CFS patients resilience to exercise programs.
Graded exercise therapy remains a common conventional treatment for chronic fatigue syndrome. Even though patients typically remark that GET makes their symptoms worse. Thankfully, new research confirmed what CFS sufferers had been saying all along GET does not work. And it may actually make your fatigue worse.
Do not include GET in your chronic fatigue treatment. Instead, follow the recommendations I lay out for exercising with fatigue here, here, and here.
Depression Stress And Anxiety
Adjusting to a chronic, debilitating illness sometimes leads to other problems, including depression, stress, and anxiety. Many patients with ME/CFS develop depression during their illness. When present, depression or anxiety should be treated. Although treating depression or anxiety can be helpful, it is not a cure for ME/CFS.
Some people with ME/CFS might benefit from antidepressants and anti-anxiety medications. However, doctors should use caution in prescribing these medications. Some drugs used to treat depression have other effects that might worsen other ME/CFS symptoms and cause side effects. When healthcare providers are concerned about patients psychological condition, they may recommend seeing a mental health professional.
Some people with ME/CFS might benefit from trying techniques like deep breathing and muscle relaxation, massage, and movement therapies . These can reduce stress and anxiety, and promote a sense of well-being.
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Impaired Energy Metabolism In Me/cfs
Metabolomic studies have reported evidence of impaired ATP production from oxygen, glucose, fatty acids, and amino acids in multiple cell types . Not just oxidative phosphorylation but also glycolysisand possibly, the citric acid and urea cyclesare incriminated. In people with ME/CFS, there also is a more general hypometabolic state as previously proposed , characterized by depressed levels of most metabolites, as occurs in hibernating animals . Later, we speculate as to the cause of this hypometabolic state.
Both structural and functional mitochondrial abnormalities have been found in ME/CFS. Branching and fusion of mitochondrial cristae are observed in muscle biopsies of some patients . Although some studies have reported deletions of mtDNA genes, the most extensive controlled study using contemporary technology did not find mtDNA variants that correlated with susceptibility to ME/CFSalthough it did find a correlation between specific haplogroups and mtDNA single-nucleotide polymorphisms and specific symptoms . Other reports have identified a deficit in Complex V activity of the electron transport chain in lymphocytes, with a compensatory up-regulation of respiratory capacity , and a decrease in mitochondrial membrane potential in CD8+ T cells . Serum from ME/CFS patients reportedly contains a factor that induces mitochondrial fragmentation .
A Fibromyalgia Doctor Steps Out: Dr Dantini On Antivirals For Cfs And Fm
Caroline Andersons gripping novel A Chronic Fatigue Syndrome Novel portrayed a small communities fight for health in the face of a mysterious disorder. When the lead character went searching for answers she stumbled into a shadowy and even, at times, dangerous world of tainted government agencies and big corporations doing what they need to do to ensure their bottom line is met.
Caroline herself has been looking for answers for decades and her fight, fraught with misdiagnosis, confusion and even doctor neglect, has been every bit as tumultuous. Unlike many people with ME/CFS, however, it does have a happy ending and the reason for that is Doctor Dantini.
Carols treating physician, Dr. Dantini, demonstrates how large and diverse the CFS/FM universe is. A Florida physician treating FM and CFS with antivirals since the late 1980s, with a book The New Fibromyalgia Remedy out in 2008, and a website touting the viral causes and treatment of FM I was kind of astonished I?d never heard of him.
His website states that He specializes in the treatment of viruses that cause fibromyalgiaand chronic fatigue syndrome and that The advantage in diagnosing the viral cause of fibromyalgiaand Chronic Fatigue Syndrome leads us to a logical course of treatment based on laboratory diagnostics.
| Antibody |
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HERPESVIRUS ME/CFS SHORT OVERVIEW
Food Allergies a Hidden Menace?
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New Therapy For Chronic Fatigue Syndrome To Be Tested At Stanford
STANFORD, Calif. – A preliminary study suggests there may be hope in the offing for some sufferers of chronic fatigue syndrome with a new therapy being tested by researchers at the Stanford University School of Medicine.
José Montoya, MD, associate professor of medicine , and postdoctoral scholar Andreas Kogelnik, MD, PhD, have used the drug valganciclovir – an antiviral often used in treating diseases caused by human herpes viruses – to treat a small number of CFS patients.
The researchers said they treated 25 patients during the last three years, 21 of whom responded with significant improvement that was sustained even after going off the medication at the end of the treatment regimen, which usually lasts six months. The first patient has now been off the drug for almost three years and has had no relapses. A paper describing the first dozen patients Montoya and Kogelnik treated with the drug was published in the December issue of Journal of Clinical Virology.
“This study is small and preliminary, but potentially very important,” said Anthony Komaroff, MD, professor of medicine at Harvard Medical School, who was not involved in the study. “If a randomized trial confirmed the value of this therapy for patients like the ones studied here, it would be an important landmark in the treatment of this illness.”
Montoya is speaking about his efforts at the biannual meeting of the International Association for Chronic Fatigue Syndrome in Fort Lauderdale on Jan. 11 and 12.
A Town For People With Chronic
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In December of 2012, I came down with what at first looked like a bad case of mononucleosis. I felt tired and had a sore throat, a cough, and a slight fever. At the time, I was twenty-six and working as an adjunct English professor at a small college in Westchester, New York. It was Christmas break, so I thought that I would sleep it off and feel better by the New Year. But over the next few months my symptoms grew to include muscle pain, migraines, and occasional vertigo. The cough went away but the tiredness got worse, and by the summer I was spending half my time resting in bed. I was used to playing pickup basketball several times a week after work, but now a few pushups left me exhausted. I couldnt figure out what was happening. One afternoon, as an experiment, I went for a run near my apartment, in uptown Hoboken. I clipped my iPod Shuffle to my mesh shorts and jogged past Italian delis with dry-cured sausages in their windows and along a pier that hugged the Hudson. It felt amazing. But the next day, while grading papers with a few other teachers, suddenly, I became dizzy and weak. I left the office without explanation, and, for the next several days, I barely left my bedroom.
A previous version of this story incorrectly described cytokines and misstated the location of a clinic dispensing Ampligen.
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Molecular Mechanisms Behind Viral Pathogenesis In Me/cfs
Viral infection can initiate a multitude of physiological changes in host cells that can contribute to ME/CFS development . Viral pathogens frequently associated with ME/CFS are also known to alter various molecular processes in host cells that define clinical conditions of ME/CFS . Three of the most frequently discussed molecular processes, namely immune cell alterations, mitochondrial modulation and autoimmunity, are described in brief within this section.
Fig. 1
Schematic diagram showing various viral pathogens potentially associated with ME/CFS and possible molecular mechanisms altered by these pathogens that can contribute to ME/CFS development
So What Are The Criteria For Initiating Treatment With Valacyclovir And Possibly Also Valganciclovir
A high proportion of patients that I see with CFS/ME do very well on the standard regimes of diet, nutritional supplements, sleep, pacing, attention to mitochondrial dysfunction, thyroid and adrenal support. However, there is always a hard core of patients who, despite sticking to these regimes well, do not see the deserved improvements. These are the people for whom these drugs may be helpful. So what are the criteria?
An obvious initiating infection with Epstein-Barr virus and positive IgM tests and/or positive IgG tests shows that there has been exposure to Epstein-Barr in the past and there could well be ongoing non-permissive replication now.
If there is no IgG antibody to Epstein-Barr virus, then this indicates no prior infection and therefore no indication of the treatment.
Lerner also looks at other antigens, namely D and R components of EVB early antigen to indicate non-permissive incomplete virus replication. I am not sure if this test is available and I will make enquiries. However, my view at this stage would be that anybody with a viral trigger, positive IgM and/or IgG antibodies and who has not responded to the above regime would be a candidate for a trial of Valacyclovir.
In addition, for EBV and CMV chronic infections, I also have the Armin labaratories Elispot tests available – see Armin Order Form October 2018 – tests 26 and 29,
So to diagnose Epstein-Barr virus subset chronic fatigue syndrome requires the following positives:
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Altered Levels Of Tryptophan Metabolites
Tryptophan serves as a precursor for nicotinamide adenine dinucleotide biosynthesis, making it important in redox balance. Abnormalities in the pathways by which tryptophan is transformed into serotonin or kynurenine pathway metabolites have been reported in both acute COVID-19 and ME/CFS , and can cause both oxidative stress and excitotoxicity .
Abnormal Metabolism Involving The Gaseous Signaling Molecules No And Hydrogen Sulfide
The major gaseous signaling molecules include NO, carbon monoxide, and hydrogen sulfide . They play key roles in the regulation of blood pressure, inflammation, and neurotransmission . Under physiological conditions, both NO and H2S have anti-inflammatory effects . However, both deficient and excess production of these gaseous signaling molecules can create brain pathology, immune dysfunction, and redox imbalance .
NO.
NOS2 is significantly up-regulated in patients with severe and critical COVID-19 . There is evidence of nitrosative stress and disordered NO metabolism in people with ME/CFS . Levels of NO are higher in ME/CFS patients, which can accelerate nitrosative stress . Citrulline, a product of arginine metabolism by NOS, also is increased in ME/CFS .
H2S.
Normal H2S metabolism protects against inflammation and redox imbalance . One of the modes by which H2S functions is by a posttranslational modification termed persulfidation or sulfhydration , which prevents irreversible oxidation of proteins . H2S metabolism is disrupted in Alzheimers disease, Parkinsons disease, and Huntingtons disease and also, during aging . H2S inhibits tau-phosphorylation, which may explain, in part, its role in protecting against Alzheimers disease .
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A Hypothetical Association Between Ebv And Me/cfs
As mentioned above, EBV infection has been identified as a risk factor in a subgroup of ME/CFS patients . There are studies showing a statistically significant elevation of anti-EBV-dUTPase antibodies , a defective EBV-specific B and T cell response , a high rate of active EBV infection , serologic evidence of EBV reactivation with elevated IgM antibodies against late VCA antigen , and a positive up-regulation of EBV-induced gene 2 mRNA in peripheral blood mononuclear cells from a subgroup of patients with ME/CFS. However, serological observations related to EBV were not always confirmed and, accordingly, the association between EBV infection and ME/CFS is not established . Furthermore, the presence of an active EBV infection in a subgroup of ME/CFS patients has been actively debated, because most studies revealed no increase in EBV viral load in ME/CFS patients. If a third state of virus, defined as abortive/lytic/leaky replication could explain the presence of certain EBV proteins with the potential capacity to contribute to the symptomatology of ME/CFS , is an hypothesis that remains unconfirmed.
Drug And Alternative Therapies
Specific chronic fatigue syndrome symptoms such as pain, depression, and poor sleep are treated.
Many different drugs and alternative therapies have been tried to relieve the chronic fatigue itself. Although many treatments, such as antidepressants and corticosteroids, seem to make a few people feel better, none are clearly effective for all. It can be hard for people and doctors to tell which treatments work because symptoms are different in different people and because symptoms may come and go on their own.
Controlled clinical trials The Science of Medicine Doctors have been treating people for many thousands of years. The earliest written description of medical treatment is from ancient Egypt and is over 3,500 years old. Even before that, healers… read more , which compare the benefits of a drug to those of a placebo , are the best way to test therapies, and no drug therapy has been shown to be effective for the treatment of chronic fatigue syndrome in controlled trials. A number of treatments directed at possible causes, including use of interferons, intravenous injections of immune globulin, and antiviral drugs, have been mostly disappointing and potentially dangerous. Dietary supplements, such as evening primrose oil, fish oil supplements, and high-dose vitamins, are commonly used, but their benefits remain unproved. Other alternative treatments have also been ineffective. Treatments that have no proven benefits are best avoided because they can have side effects.
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A Reboot For Chronic Fatigue Syndrome Research
Name a remedy, and chances are that Elizabeth Allen has tried it: acupuncture, antibiotics, antivirals, Chinese herbs, cognitive behavioural therapy and at least two dozen more. She hates dabbling in so many treatments, but does so because she longs for the healthy days of her past. The 34-year-old lawyer was a competitive swimmer at an Ivy-league university when she first fell ill with chronic fatigue syndrome, 14 years ago. Her meticulous records demonstrate that this elusive malady is much worse than ordinary exhaustion. Last year, I went to 117 doctor appointments and I paid $18,000 in out-of-pocket expenses, she says.
Genetic Predisposition To Ebv Infection
The diversity of human leukocyte antigen molecules results from selective pressure during co-evolution with pathogens . A characteristic of HLA diversity is the long-term persistence of allelic lineages, which causes trans-species polymorphisms to be shared among closely related species . In humans, there are 13 allelic lineages of DRB1 and, according to the phylogenetic relationship between the different DRB genes of primates described by Bontrop et al, the DRB1*04, *03 and *02 lineages are the oldest, with the DRB1*04 lineage being the most ancestral . Since EBV is the only human-adapted member of the genus Lymphocryptovirus, transferred to a hominid ancestor , it could be hypothesized that immune evasion mechanisms of the EBV have more effectively evolved among older allelic lineages of DRB1. Such an hypothesis could help explaining why individuals with haplotypes DR2-DQ6, DR3-DQ2 or DR4-DQ8 are less resistant to EBV infection and are at greater risk of developing EBV-related disorders .
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Ampligen May Work In Chronic Fatigue Syndrome Because
it modulates the activity of a part of the innate immune defense that some studies suggest is disrupted in chronic fatigue syndrome . It does this through its ability to mimic the structure of viral proteins which normally stimulate the bodys immune defenses. Some chronic fatigue syndrome patients have high levels of an unusual type of a molecule which appears to disrupt the innate immune response. Ampligen appears to be able to restabilize the immune response in at least some of these patients.
Hemispherx Biopharma recently reported that Ampligen stimulates the activity of the toll-like receptors on the outer part of the cell that play an important role in the early recognition of pathogens. Some but not all studies suggest that rates of opportunistic infections are increased in chronic fatigue syndrome patients. Ampligens broad anti-pathogenic properties may be able to reduce the activity of these pathogens in some patients.
