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Stanford Antiviral Chronic Fatigue Syndrome Trial Promises Hope, But More Study Needed

111512_0224_Valganicicl1.jpg


by Cort Johnson

Before XMRV was Kogelnik/Montoya…the 2006 unblinded Kogelnik/Montoya study, finding that 6 months of Valcyte use returned 75% of participants to full health, hit the community like a lightning bolt. Yes, the study was very small (12 people) and it was unblinded, but the stories of recovery were so dramatic that it was hard to imagine they hadn't hit gold. All that was left, it seemed, was to document the progress with a more rigorous, placebo-controlled study that appeared to be under way.
"These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect." (Kogelnik et al, 2006)

Six years later that study has still not shown up. This latest study by Montoya, which did not involve controls, is simply a retrospective analysis which examined the effect of Valganciclovir treatment on 61 patients treated at the Stanford clinic from 2004-2009 using a chart analysis.
Heavily 'infected' patients....


All patients had above normal HHV6 (>1:320), EBV VCA (1:640), EBV VCA (1:640) and EBV EA (1:160) IgG titers. The early EBV antibodies (EBV NA IGG), that Dr. Lerner and others believe are tied to aborted but simmering infections in ME/CFS, were also measured. Note that because healthy people can have similarly high titers, none of these titers are considered diagnostic of an active infection by most practitioners in the medical community.

Montoya has proposed, however, that high titers in the presence of certain symptoms are suggestive of an active infection. The authors noted that, while high titers can be found in healthy people, most healthy people have quite low herpesvirus titers while higher titers are commonly found in people with chronic fatigue syndrome. Something must be pushing those herpesvirus antibody titers higher in ME/CFS and, of course, an active herpesvirus infection is the first thing that comes to mind.

A patient was deemed a responder if self reports of cognitive and physical functioning increased by 30% or more at some point in treatment. The average patient age was 47 and the average length of illness was a hearty 10 years. The average treatment period was about 6 months - much shorter than recommended by Dr. Lerner.
Results


Almost 60% of patients responded physically and fully 80% responded cognitively - a nice response. As a group, patients rose from an average of 34/100 to 53/100 physically (56% jump) and from 43/100 to 66/100 cognitively (50% jump). (Unfortunately from the way the study was written the percentage increase could have been interpreted as 19% and 23%. Thanks to Tom Kindlon for pointing this out). Put another way, the patients jumped from being a third of normal physically to about half normal and from about 40% of normal cognitively to two-thirds normal.

This was blunted to some extent by the fact that only the highest data point, not an average, was used to assess effects. That means we know that, at least at one point in their treatment, 80% of the participants reported that they were at least 50% better cognitively, and almost 60% were improved physically by at least 50%, but we don't know how long the effect lasted.

Teasing out the responders indicated that they improved an average of 34 and 37% respectively.

A look at the charts included in the paper indicated that there were some dramatic improvements. A couple of people went from a score of about 20-30 to 80-100 on physical functioning -meaning they were effectively well. Several others experienced dramatic improvements going from 0-20 to 50-60. (Two unfortunate people went from around 20 to less than 10). It was fairly easy to find 30-40 point gains - which equate to major improvements in functionality - but many people made smaller gains.

The most significant result may have been the quite strong finding (P<.0002) that longer treatment durations (7.4 months on average) resulted in improved benefits relative to shorter treatment durations (5.5 months). Long antiviral treatment regimes are a key feature of Dr. Lerner's antiviral treatment protocol.

The authors called the findings 'clinically striking' when placed in context of how difficult it was to treat ME/CFS, and indeed most doctors would probably be very happy to see responses like this in their patients. (Their patients would be happy as well :))
Antibodies Strike Out


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The antibody results indicated how much researchers still have to learn. The researchers thought that higher antibodies would be indicative of poorer health, but they were not, and antibody levels did not drop significantly more in the responders than in the non-responders. (There was a 'trend' toward better response in patients with high baseline antibodies). Whatever the effects of the trial, it did not appear to happen at the antibody level.

Potentially obscuring the antibody results, however, was the possibility that some patients may have hypogammaglobulemia (low B-cell and antibody levels), while others may have overly strong antibody responses, and bigger studies would be needed to tease out these factors. It's possible that too many complicating factors were present for a finding of statistical significance to show up in a study of this size.

Figuring out why some people improve during antiviral treatment while others do not has been a key goal for Montoya, and he's reportedly been plowing through immune findings to see if he can pick up measurements that change significantly as people get well. Finding that would give him and the ME/CFS research community a strong biomarker to concentrate on. (Dr. Kogelnik is looking at patients for this as well). This was not that study, however, and hopefully that paper will appear in the future.
Conclusion


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Valcyte has not gone the way of XMRV. As with XMRV, the promise of an early study - in this case the 2006 unblinded one with its remarkable success rate - did not hold up, but this study was positive and many patients did improve - in many cases, it appears, significantly.

The study, though, was underpowered in many ways; it was retrospective, it was not placebo-controlled, and patients' self-reports were rudimentary to say the least - they appear to have simply rated themselves on a scale from 0-100 on their physical and cognitive functioning and only the highest scores were used. The most intriguing result was the increased likelihood of benefit in patients with longer treatment duration - a key facet of Dr. Lerner's program.

Without a blinded control group, however, all the results can be challenged - it can be argued that the responders were simply due to placebo, the benefit was transient, and the increased benefit with duration was simply an indicator that time in combination with placebo really does heal somewhat with ME/CFS.

The road to understanding the role that pathogens play in ME/CFS has been long and crooked. With all the interest in antivirals, it's remarkable that we still do not have a single well-designed, rigorously controlled ME/CFS antiviral treatment trial. Every study, from Dr. Lerner's trials to Dr. Montoya's two studies, has had enough design flaws for skeptics to be able to discount the findings. There's still a great deal of work to be done to figure out how and why antivirals are working when they do work in this disorder.

One such study was underway. In Dec 2010 we were informed that two papers from Dr. Montoya's placebo-controlled, doubled blinded study - which involved extensive immune testing, exercise testing, etc - were in process. (We were also informed that the study we've just looked at would be published 'soon' :)). At a conference that year, Dr. Montoya reported that he was on the track of several immune biomarkers (IL-5, IL17F, ENA78, EOTAXN, IP10) that improved during treatment. He also reported that an early antigen marker usually associated with cancer may be a biomarker for this group.

The big EBV/HHV6 study is still to come…
View the Post on the Blog
 
I'm curious, between the time you took Ampligen and the increase in your V02 max, had you done much additional exercise (more than you would do before Ampligen) prior to the test?

I don't mean to undermine anything, but I think a great test of treatment response would be the V02 max threshold increasing, after treatment with zero activity increase in between. This kind of evidence would make any reasonable level of improvement significant in my opinion.

it would be interesting to see a study where they also test nk and cd8 function in those patients as well as compare antivirals with combo of antiviral and immune mod with a placebo treatment and seeing the before and after results of viral titres , nk and cd8 function. Im suprised further sudies havent been done but then alot also depends on drug companies and patents for new indications etc.

cheers!!!
If the placebo controlled study was done my understanding is that they were doing immune tests, aerobic functioning tests, brain imaging tests.....lots of stuff....
 
Maybe we should call this the Montoya Lag

This is from the post in Dec 2010 which talked about what they were doing...(see below)

  • Two papers on the double-blinded Valcyte trials had been or were in the process of wrapping up
  • A paper (probably this one) that indicated that viral titers (not antibodies?) responded to Valcyte
  • A conference presentation suggesting that Dr. Montoya had discovered immune factors that several immune markers (IL5, IL17F, ENA78, EOTAXIN, IP10) improved during treatment
  • Exciting brain MRI findings
  • Lipkin pathogen study
  • EEG and exercise findings
  • Major research meeting
That was two years ago...Since then we have this paper and he participated in the XMRV study. Dr. Montoya reportedly dropped out of the Lipkin study. If he was overcommitted that's the one I would have dropped out of....
Is this a case of researcher overreach? It seems that researchers rarely make their projected due dates...(The CAA's gut metabiome study and Dr. Baraniuk's spinal fluid studies spring to mind.)....or are these projects stalled or not working out....I am going to try and ask...
Montoya has actually been publishing more than usual in the last year or so - just not so much in CFS....

Recent work - they have recently wrapped up a number of longstanding projects and have or are submitting the results for publication. These include two papers on the double-blinded Valganciclovir trials in EBV and HHV-6 positive ME/CFS patients that started some years ago. Another paper indicating both that clinical (symptoms) and viral titers responded to antiviral treatment in HHV-6 infected patients should be in press in the not too distant future.
(Interlude: Barcelona Conference - According to a report on the internet http://pochoams.blogspot.com/2010/11…-november.html in November Dr. Montoya presented evidence suggesting that monocytes may key a role in this type of ME/CFS patient and that several immune markers (IL5, IL17F, ENA78, EOTAXIN, IP10) improved during treatment – a potential breakthrough in demonstrating the legitimacy of antiviral treatment (and the disorder itself). He has also found that an early antigen marker usually associated with cancer may be a biomarker for this group, that HHV6 integrates into the chromosome of CFS patients, which is apparently not normal for this virus. (Viral integration into the chromosomes means that when the cell replicates the virus replicates as well).
Current Work:
The Big Pathogen Study – They are currently collaborating with Dr. Lipkin and other colleagues on a comprehensive analysis of the pathogens in ME/CFS
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Immune Signatures - They are analyzing the immune response using gene expression, cytokine profiles and phosph immune-flow to look for biomarkers and immune signatures correlated with these infections. These biomarkers could be used both to diagnose and to assess improvements during treatment.

Biomarkers in the Brain – Finally? – in a novel approach that reminds one of the attempts to correlated MRI findings with disease early on in the history of CFS, the Montoya team is doing sophisticated new MRI techniques to see if they can use brain imagining to identify unique abnormalities in infected individuals. Several of these pathogens are able to access the central nervous system.
A New Website - a new website explaining their work should be open early next year and a patient forum has been set up.
Quantifying Impairment -Legitimizing ME/CFS - they are also using sub-maximal exercise testing and EEG readings to quantify (and make real) the physical and cognitive impairments in ME/CFS.
Education and Outreach
  • A Major Research Meeting – will be held to change information on and educate investigators on ‘chronic inflammatory diseases.
  • Biennial Education Meeting – will educate researchers, students, etc. on their progress
 
Why was Ampligen the only "placebo" to work for me? I took it after being ill for seven years. After taking it, my anaerobic threshold and VO2 max came up. My neuropsychological test performance, attention span, and performance IQ rose.

I'm curious, between the time you took Ampligen and the increase in your V02 max, had you done much additional exercise (more than you would do before Ampligen) prior to the test?

I don't mean to undermine anything, but I think a great test of treatment response would be the V02 max threshold increasing, after treatment with zero activity increase in between. This kind of evidence would make any reasonable level of improvement significant in my opinion.
I did not have my activity levels monitored before and during Ampligen treatment; actigraphy was not commonly used in ME/CFS studies at that time, and still isn't used enough.

I think what you are getting at is whether the increase might result from training. I'm not sure your assumption that training will increase the VO2 Max in ME/CFS is correct. I was one of those people who made all efforts to stay active after my diagnosis. I was diagnosed early.

When my illness was first diagnosed, I had only mild disability and my symptoms were mostly cognitive; in May 2003 my VO2 max was 42 ml/kg/min, which was in the low normal range for a 20 year old man (age predicted median is 48 with a standard deviation of 7).

Reading and actually believing the studies about graded exercise being helpful, I continued to do 20 minutes of moderate-intensity bike riding twice a day, five days a week. Over the ensuing year I did not stop the bike riding, regardless of symptoms. I slowly deteriorated and was having to spend more and more time in bed when I wasn't exercising, and my orthostatic intolerance and cognitive problems (such as difficulty reading and memory loss) kept getting worse and worse. I retook the VO2 max test in March 2004 and my VO2 max was 23.8 ml/kg/min, more than three standard deviations below age norms. I eventually was not able to do the bike riding anymore in mid-2004, but I continued to walk and do lighter forms of exercise as I was able. My ability to work never returned until I took Ampligen. The lowest my VO2 max got was 19 ml/kg/min, which met the SSDI disability criterion.

When I started Ampligen, my VO2 max rose to 25.9 ml/kg/min within 8 months and was 31 ml/kg/min a year after stopping the drug. I was relatively sedentary during Ampligen, more cautious with exercise by this point, but continued to walk regularly.

Look, many people in America are very sedentary. They never ride their bikes or walk like I did. But they never suffer a catastropic decrease in VO2 max like I did. The CBT/GET theory is simply wrong. No matter how much exercise you do and how good you are at persistence and toughing out the pain, it will not improve functional capacity if you have this disease.
 
I did not have my activity levels monitored before and during Ampligen treatment; actigraphy was not commonly used in ME/CFS studies at that time, and still isn't used enough.

I think what you are getting at is whether the increase might result from training. I'm not sure your assumption that training will increase the VO2 Max in ME/CFS is correct. I was one of those people who made all efforts to stay active after my diagnosis. I was diagnosed early.

When my illness was first diagnosed, I had only mild disability and my symptoms were mostly cognitive; in May 2003 my VO2 max was 42 ml/kg/min, which was in the low normal range for a 20 year old man (age predicted median is 48 with a standard deviation of 7).

Reading and actually believing the studies about graded exercise being helpful, I continued to do 20 minutes of moderate-intensity bike riding twice a day, five days a week. Over the ensuing year I did not stop the bike riding, regardless of symptoms. I slowly deteriorated and was having to spend more and more time in bed when I wasn't exercising, and my orthostatic intolerance and cognitive problems (such as difficulty reading and memory loss) kept getting worse and worse. I retook the VO2 max test in March 2004 and my VO2 max was 23.8 ml/kg/min, more than three standard deviations below age norms. I eventually was not able to do the bike riding anymore in mid-2004, but I continued to walk and do lighter forms of exercise as I was able. My ability to work never returned until I took Ampligen. The lowest my VO2 max got was 19 ml/kg/min, which met the SSDI disability criterion.

When I started Ampligen, my VO2 max rose to 25.9 ml/kg/min within 8 months and was 31 ml/kg/min a year after stopping the drug. I was relatively sedentary during Ampligen, more cautious with exercise by this point, but continued to walk regularly.

Look, many people in America are very sedentary. They never ride their bikes or walk like I did. But they never suffer a catastropic decrease in VO2 max like I did. The CBT/GET theory is simply wrong. No matter how much exercise you do and how good you are at persistence and toughing out the pain, it will not improve functional capacity if you have this disease.

My scepticism has a bias in that, I'd like to prove you right heh. I'm particularly interested in V02 max at the moment. I gather someone like Dr Klimas might argue that your 20 minute bike riding took you into anaerobic respiration and the decline is consistent with that (which appears based on Dr Klimas and Professor Newton's work, to be a destructive factor in CFS).

Their belief holds that a small amount of exercise, really small, that respects the patient's aerobic limits may recondition the body to some degree. I guess what I'm looking for is an absolute gold standard of proof, which shows the Ampligen interfering (via inteferon - *ahem*) with the neurological condition that in my vague hypothesis, caused your decline in vo2 max threshold.
 
I think skepticism is warranted, but not the stifling kind of skepticism that squelches research and prevents it from moving forward.

Since there is a lack of Federal funding, the best way to make sure your gold standard research gets done would be for the FDA to give provisional approval to Ampligen and make full approval conditional on a much more thorough vetting of the drug's efficacy and mechanism of action.

Hemispherx has the only viable drug candidate with patent protection for ME/CFS at this point. But the company is nearly bankrupt; the drug was invented in the 1970s. The only way we are going to know more about it is to make it more widely available.
 
Thanks for this, Cort, another great post and discussion.

"Everybody who studies this disorder ends up concluding its much more complex than they originally thought."

So true!!

"It seems that researchers rarely make their projected due dates…(The CAA’s gut metabiome study and Dr. Baraniuk’s spinal fluid studies spring to mind.)….or are these projects stalled or not working out….I am going to try and ask…"

Just what I thought. Where IS the Baraniuk study...??

Thanks for keeping us up to date. More posts please!! :)
 
Thats a big difference when we talk about viral titres, antibody titres are dependent on a healthy immune system. So viral titres coming down with improvement is a good indicator that the viruses have a large role in these viral sub groups. Very interesting, thanks for posting this cort.
 
Thanks for this, Cort, another great post and discussion.

"Everybody who studies this disorder ends up concluding its much more complex than they originally thought."

So true!!

"It seems that researchers rarely make their projected due dates…(The CAA’s gut metabiome study and Dr. Baraniuk’s spinal fluid studies spring to mind.)….or are these projects stalled or not working out….I am going to try and ask…"

Just what I thought. Where IS the Baraniuk study...??

Thanks for keeping us up to date. More posts please!! :)
Dr. Baraniuk put out some abstracts at the Ottawa conference last year and told me the papers would start flooding our over the next year....(He felt he would get quite a few papers out of it.) At least that's what I remember. I guess its going to be 2013...
 
Cort,
Is there any news on valcyte becoming generic, outside of india as i think they have ignored the patent. i suppose so its more affordable to more of the cfs/me community. Also any News on peterson and the antiviral cmx(ithink thats what its called) or any other new antivirals being developed for these herpes viruses.
 
Cort,
Is there any news on valcyte becoming generic, outside of india as i think they have ignored the patent. i suppose so its more affordable to more of the cfs/me community. Also any News on peterson and the antiviral cmx(ithink thats what its called) or any other new antivirals being developed for these herpes viruses.
Don't know about valcyte but the CMX001 trial just pooped out. It sounded like Dr. Peterson just stopped hearing from them...and they lost interest or went in another direction...Hopefully the drug will get approved for something and then it will be available for use in ME/CFS.

They are moving forward...They've complete a couple of trials...

This is what their website says...

Chimerix has established a pipeline of therapeutics addressing life-threatening viral diseases. Our lead compound, CMX001, is currently being developed to treat dsDNA viruses – potentially deadly diseases for immunocompromised patients. A second compound, CMX157, is being advanced to treat human immunodeficiency virus (HIV). In addition, we have identified highly active compounds against hepatitis C and influenza. We are also screening our proprietary Chimerix Chemical Library for compounds with activity against dengue virus, malaria and tuberculosis.

CMX001-201 Phase 2 Trial
CMX001 has completed a Phase 2 randomized, double-blind, placebo-controlled, dose-escalation study designed to assess the safety, tolerability and ability of CMX001 to prevent or control cytomegalovirus (CMV) infection in 230 hematopoietic cell transplant (HCT) recipients (Study 201). CMV, a member of the herpesvirus family of dsDNA viruses, is present in more than two-thirds of the population and typically causes manageable disease in individuals with responsive immune systems. However, in immunosuppressed and immunocompromised transplant recipients, CMV is a major cause of morbidity and mortality.
CMX001-202 Phase 2 Trial (AdV HALT Trial)
CMX001 is being studied in a randomized, placebo-controlled, Phase 2 trial evaluating the safety and efficacy of preemptive treatment with CMX001 versus placebo for the prevention of adenovirus (AdV) disease in 48 pediatric and adult hematopoietic cell transplant (HCT) recipients with asymptomatic AdV viremia (Study 202). Adenoviruses are responsible for respiratory diseases, including pneumonia and bronchitis, as well as other infections, including gastroenteritis and acute diarrheal diseases. In immunocompromised patients who have undergone HCT, AdV infections are recognized as a significant cause of morbidity and mortality. Immunocompromised pediatric HCT patients are particularly susceptible to serious and/or fatal AdV infections. The U.S. FDA has granted CMX001 Fast Track designation status for the AdV development program.
CMX157
CMX157 demonstrated a favorable safety, tolerability and drug distribution profile in a first-in-human clinical trial. The Phase 1 study was a randomized, blinded, single dose, dose-escalation trial to evaluate safety, tolerability and pharmacokinetics of CMX157 in healthy volunteers.
 
Don't know about valcyte but the CMX001 trial just pooped out. It sounded like Dr. Peterson just stopped hearing from them...and they lost interest or went in another direction...Hopefully the drug will get approved for something and then it will be available for use in ME/CFS.

They are moving forward...They've complete a couple of trials...

This is what their website says...

Chimerix has established a pipeline of therapeutics addressing life-threatening viral diseases. Our lead compound, CMX001, is currently being developed to treat dsDNA viruses – potentially deadly diseases for immunocompromised patients. A second compound, CMX157, is being advanced to treat human immunodeficiency virus (HIV). In addition, we have identified highly active compounds against hepatitis C and influenza. We are also screening our proprietary Chimerix Chemical Library for compounds with activity against dengue virus, malaria and tuberculosis.

CMX001-201 Phase 2 Trial
CMX001 has completed a Phase 2 randomized, double-blind, placebo-controlled, dose-escalation study designed to assess the safety, tolerability and ability of CMX001 to prevent or control cytomegalovirus (CMV) infection in 230 hematopoietic cell transplant (HCT) recipients (Study 201). CMV, a member of the herpesvirus family of dsDNA viruses, is present in more than two-thirds of the population and typically causes manageable disease in individuals with responsive immune systems. However, in immunosuppressed and immunocompromised transplant recipients, CMV is a major cause of morbidity and mortality.
CMX001-202 Phase 2 Trial (AdV HALT Trial)
CMX001 is being studied in a randomized, placebo-controlled, Phase 2 trial evaluating the safety and efficacy of preemptive treatment with CMX001 versus placebo for the prevention of adenovirus (AdV) disease in 48 pediatric and adult hematopoietic cell transplant (HCT) recipients with asymptomatic AdV viremia (Study 202). Adenoviruses are responsible for respiratory diseases, including pneumonia and bronchitis, as well as other infections, including gastroenteritis and acute diarrheal diseases. In immunocompromised patients who have undergone HCT, AdV infections are recognized as a significant cause of morbidity and mortality. Immunocompromised pediatric HCT patients are particularly susceptible to serious and/or fatal AdV infections. The U.S. FDA has granted CMX001 Fast Track designation status for the AdV development program.
CMX157
CMX157 demonstrated a favorable safety, tolerability and drug distribution profile in a first-in-human clinical trial. The Phase 1 study was a randomized, blinded, single dose, dose-escalation trial to evaluate safety, tolerability and pharmacokinetics of CMX157 in healthy volunteers.

Here's a list of past or present trials involving CMX 001 from clinicaltrials.gov

Not yet recruiting A Multiple Ascending Dose-Finding Pharmacokinetic and Pharmacodynamic Study of CMX-001 in Infants With Neonatal Herpes Simplex Virus (HSV)
Condition: Herpes Simplex Virus
Interventions: Drug: CMX 001; Drug: Placebo

2 Completed Comparative Bioavailability and Effect of Food on CMX001 in Healthy Volunteers
Condition: Healthy
Intervention: Drug: CMX001

3 Completed CMX001 in Post-transplant Patients With BK Virus Viruria
Condition: Viruria
Interventions: Drug: Placebo; Drug: CMX001

4 Active, not recruiting A Multicenter, Open-label Study of CMX001 Treatment of Serious Diseases or Conditions Caused by dsDNA Viruses
Conditions: Male or Female Patients With a Serious or Immediately Life-threatening; Disease or Condition Caused by CMV, ADV, HSV, VAVC, VARV or; Monkeypox Viruses(s) Who Have a Life Expectancy of ≥ 2 Weeks and for; Whom no Comparable or Satisfactory Alternative Therapy is Available
Intervention: Drug: CMX001

5 Recruiting The Adv Halt Trial
Condition: Adenovirus Disease
Intervention: Drug: CMX001

6 Completed Dose-escalation Study of the Safety, Tolerability and Ability of CMX001 to Prevent or Control Cytomegalovirus (CMV) Infection in R+ Hematopoietic Stem Cell Transplant Recipients
Condition: Cytomegalovirus Infection
Interventions: Drug: CMX001; Drug: Placebo
 
Cort, it's late and I did a quick read of the paper but I think your statement about all subjects having "high" titers (as they defined it) is incorrect.

I see this papers as an attempt to make use of all the data they have; outside of the Valganciclovir trial, some patients were getting treated on an individual clinic basis (i.e. not in a study) who did not fit the definition of high titers from the first randomized trial although some did. Inclusion criteria for this paper's patients did not include a particular level of titers. (just Fukuda/ Valcyte treatment/ and titer/ self-report availability were used as inclusion) Those who did fit the "high" titers were classified as "high" here and their responses were compared to those who did not fit (i.e. lower titers or did not have all "high" values). So the surprise was that even people WITHOUT high titers were just as likely to respond (62% high vs. 41% low) and respond the same degree as those with "high" titers. [The differences were statistically non-signficant.]

This issue with what Tom pointed out -- this is what is technically called "absolute" vs. "relative" difference. So the change in physical status from 34% to 53% --- 19% (53-34)) is the absolute difference whereas 56% (e.g. 19%/ 34%) is the relative. In some research circles, the trend is going away from using relative difference since it can be misleading and that is prob. why they use absolute instead. For example, saying exposure to XYZ substance leads to a tripling of risk of cancer sounds scary until you realize the tripling (relative) is from 0.00001% to 0.00003%. Absolute diff here would be 0.00002%.

In terms of them using the highest physical/ cognitive function as the outcome, it can be debated whether that is the best outcome measure but other studies, including the Norwegian rituxmab trial, also used maximum improvement. The problem is that subjects improved/ disimproved at different times and different rates.
 
Cort, it's late and I did a quick read of the paper but I think your statement about all subjects having "high" titers (as they defined it) is incorrect.

I see this papers as an attempt to make use of all the data they have; outside of the Valganciclovir trial, some patients were getting treated on an individual clinic basis (i.e. not in a study) who did not fit the definition of high titers from the first randomized trial although some did. Inclusion criteria for this paper's patients did not include a particular level of titers. (just Fukuda/ Valcyte treatment/ and titer/ self-report availability were used as inclusion) Those who did fit the "high" titers were classified as "high" here and their responses were compared to those who did not fit (i.e. lower titers or did not have all "high" values). So the surprise was that even people WITHOUT high titers were just as likely to respond (62% high vs. 41% low) and respond the same degree as those with "high" titers. [The differences were statistically non-signficant.]

This issue with what Tom pointed out -- this is what is technically called "absolute" vs. "relative" difference. So the change in physical status from 34% to 53% --- 19% (53-34)) is the absolute difference whereas 56% (e.g. 19%/ 34%) is the relative. In some research circles, the trend is going away from using relative difference since it can be misleading and that is prob. why they use absolute instead. For example, saying exposure to XYZ substance leads to a tripling of risk of cancer sounds scary until you realize the tripling (relative) is from 0.00001% to 0.00003%. Absolute diff here would be 0.00002%.

In terms of them using the highest physical/ cognitive function as the outcome, it can be debated whether that is the best outcome measure but other studies, including the Norwegian rituxmab trial, also used maximum improvement. The problem is that subjects improved/ disimproved at different times and different rates.

You're right - my mistake...I said all patients had above normal titers but that wasn't true...Dr. Montoya's thesis has been that high titers in presence of certain symptoms is suggestive of active infection but here we find that antibody titer level at baseline is not significantly associated with treatment response.

They also used the highest titer prior to the start of the trial rather than an average or the most recent measurement..Then they say that EBV titers are remarkably stable over time...which makes one wonder why they had to pick the highest one...In any case, it appears that alot of 'work' went into making this study as positive as possible.

titer within 1 year prior to starting treatment. The highest titers prior to treatment (rather than the average of all available titers) were chosen because high titers of a certain threshold were considered to have the greatest pathological impact and because EBV titers have been shown to be remarkably stable over long-term follow-up of healthy individuals [Amanna et al., 2007]. Final titers were defined as those closest to the cessation of treatment but no later than 6 months after stopping treatment. If no such value

Thanks for explaining why they choose to use absolute difference instead of relative..In that case they chose a method which did not shed a more positive light on their results (even though to me it would have made sense to do so )
 
Thanks Cort - very encouraging following the research coming out here. Looking forward to some conclusion on brain imaging (mine abnormal - high spots/lesions whatever) if they are included.
 
Look at this study...

4 Active, not recruiting A Multicenter, Open-label Study of CMX001 Treatment of Serious Diseases or Conditions Caused by dsDNA Viruses
Conditions: Male or Female Patients With a Serious or Immediately Life-threatening; Disease or Condition Caused by CMV, ADV, HSV, VAVC, VARV or; Monkeypox Viruses(s) Who Have a Life Expectancy of ≥ 2 Weeks and for; Whom no Comparable or Satisfactory Alternative Therapy is Available

It looks almost like last-ditch efforts for some of these folks. You can see looking at the list that it's perhaps not surprising that Chimerix pulled out of Dr. Peterson's trial; Chimerix is focusing on pretty well defined and accepted problems....ie transplant patients and these folks...I'm sure some ME/CFS patients could fit into this study via the CMV route...but HHV6 is not there and neither is EBV and Peterson sees more of those than CMV...The adenovirus trial is ending this January....
 
Please, read my post. I am not so informed like you all for getting into a deep detailed discussion, I have followed a more simplistic way of investigating all about my health condition, but for a long time I got very good results. Even that, if I were to participate in any medical protocol, I would definitely go for Montoya´s aproach. Viruses, bacteria and fungus are in the bottom line of this, as well as our inmunologic system.
When I had excelent results for my phisical state I went from no exercise at all in 15 years to runing from 3 to 4 kms every other day and runing a 6 kms race for the first time in my whole life. Even though my problems began many years ago, they got acute with Herpes-2 infection when I got married, 20 years ago. So I believe that the issue is not one sigle microorganism, but the agregation of them, or the imbalance betwenn microorganisms and our inmune system.

Nutritional and alternative protocols, trying to have a healthy holistic life help by improving our inmune system, balance and equilibrium is important: too much exercise is as bad as none. Staying in bed is as bad as going to bed too late. Etc. ( All this is HIGLY IMPORTANT to control in scientific trials because a disfunctional nervous system is very much energy-drained for little adaptations!). One single day staying late in the computer and my sugar level next day is out of control, in normal people this happens after many nights, we have very strong changes after very little efforts.

Antivirals are an extra help for our body for controlling viruses, like antifungals and antibiotics, but they also have downsides, like killing our friendly bacteria in the gut, making us more constipated or the contrary, etc.

I hope you don´t mind reading this very plain text, but I thing that sometimes we underestimate simple things, and we fall into microscopic problems, medical terms, etc., and we fail in observing little things...

One single glass of wine can lead me to 3 or 4 days of constipation, poor sleep and terrible foginess. The more carbohidrates I eat, the more chills I get. The more sugar I take, the more emotional changes I suffer, the more fat I take, the more times I wake up in the night to use the wc... and the list goes on!!!

Do you want to stop having leg cramps? avoid refined flour... and there´s much more about at what time we eat what... I take a baby with a inmature inmunological and neurological systems for examples... one extra hour without sleep and you have a cranky baby next day...

Ok, I hope these simple arguments and observaciones help somehow.
 
I wanted to say in response to a comment that when I stated that Montoya and Kogelnik are digging through results to find immune markers...I think they're just doing a variety of immune and probably other tests and then seeing that improves as their patients...(they are getting substantial improvement in some patients). Then they can design a study to test out whether they're correct...