Learning CFS: the Lerner Antiviral Treatment Trial Succeeds

Comments

K
  • _Kim_

What criteria does Lerner use to decide whether to add cimetadine or not.
At the physicians discretion, cimetidine (400 mg every 12 hours) and/or probenecid (500 mg every 12 hours) which inhibit(s) acyclovir tubular secretion were given to increase acyclovir serum levels
I'm also curious about his prescribed dosages of AVs. Does every six hours mean 2X/day?? If that's right, then he gives 2g if you are under 175 lbs and 3g if you are over.
Both valacyclovir and famciclovir were given as 1 gm (14.3 mg/kg) every six hours. When the patient weighed 79.5 kg, 1500 mg valacyclovir (or famciclovir) was given every six hours.
 
What criteria does Lerner use to decide whether to add cimetadine or not. I'm also curious about his prescribed dosages of AVs. Does every six hours mean 2X/day?? If that's right, then he gives 2g if you are under 175 lbs and 3g if you are over.
His 2007 paper says "After three months of valacyclovir, if the EI point score had not improved, oral cimetidine (500 mg bid) or probenecid (500mg bid) were added to valacyclovir (11)." Now this is interesting because not only does cimetidine increase serum concentrations of the drug but it also has immune modulating and antiretroviral effects (Bourinbaiar and Jirathitikal), so I wonder how many patients he did this for. Every six hours means four times per day.
 
G
  • Gerwyn

This

"

indicates that you can have positive EBV, retroviral, HHV-6, enteroviral and Candida tests and still fit the definition of CFS - which is a good thing because a considerable portion of patients do have positive test results.



I don't understand the focus on diagnosis - there was little focus on diagnosis in this paper; the focus was on the average 2+ mean increased rate of progress according to the EPIS scale. The question of where Dr. Lerner places a diagnosis of CFS on his scale really has very little bearing on the outcome of the study.

I don't see how the criteria for who's a responder matters either. The responders made up 75% of the patients - it was a large group of people. What matters to me is that those people moved up the scale rather dramatically - they improved greatly.



I don't know if Dr. Lerner cares if EBV is 'active' in the sense that you mean. If he cared about that - if his years of studying these patients had indicated that traditional measures of EBV activity was the pertinent he would have measured it - but that's not what he found. He found other measures were important and those were the ones he used. The scientific community was all over 'active' EBV at one time - it doesn't appear to make a difference in CFS.

Most people have been exposed to EBV, HHV6 and CMV. The question here is do they have the kind of nonpermissive infection that Dr. Lerner has found in these patients and if they do - how important is it to their health.
dr Lerner has not found any evidence of non permissive infection he hypothesises that there could be.that is entirely different.if the other viruses in the study normally latent were active then because of that fact alone EBV would have been.That alone would invalidate the study because a formal diagnosis of CFS could not be givem.Responders were someone with an eips scale of 1.that is entirely arbitary figure and totally subjective.The improvement was 1 point on the Eips scale.I would not call that a great improvement.There was no formal diagnostic measures used.That is my point they were completely arbitrary.An Eips scale of 0 to 5 constituted a diagnosis of CFS.An eipsvalue of 6 to 10 did not.There is no evidence that nonpermissive infection actually exists.There are non permissive cells.That is an entirely different .The eips scale inquestion is not validated in any way apart from Dr Lerner. I am quite happy to post the "validation" if that would be helpful.No one diagnoses ME,cfs based on disability.that disability could be caused by anything.In that study 5 was CFS 6 was not.If 6 was CFS then there would have been nothing positive to report.To my eyes there is nothing to justify the assertation that level six does not apply to patients with CFS and that level of disability does not qualify for a diagnosis of ME,cfs

This is all "non permissive" infection means

Somatic cell hybrids between rat XC(HPRT-) cells, non-permissive for herpes
simplex virus type 1 (HSV-1) infection, and permissive mouse L(TK-) cells were
constructed and karyotyped. Infection of these hybrid cells by HSV-1 strains F and MP
revealed that they were susceptible to the virus. The amounts of virus produced by the
hybrid cells, as well as the cytopathic effect observed, was very similar to that of the
parental L(TK-) cells. Our results suggest that failure of HSV-1 to replicate in XC cells
is more likely to be due to the absence of cellular elements required for efficient virus
multiplication rather than to the presence of blocking or inhibiting factors.

It just means that those cells do not support replication of the virus.
 
There was no formal diagnostic measures used. (snip) That is my point they were completely arbitrary.An Eips scale of 0 to 5 constituted a diagnosis of CFS.
"International criteria for diagnosis of CFS were used.2" (footnote 2 is the Fukuda criteria). Dr. Lerner is a coauthor of the Canadian Consensus Criteria, so I think he is diagnosing CFS properly, although Fukuda was used presumably because CCC was not published until after the study began. The EIPS was not used to diagnose patients, but was used to track patient treatment progress.

EBV does not preclude a diagnosis of CFS. CFS was a name given to a disease that seemed like it was active EBV but was not quite it.

To me the study shows that herpes viruses probably are a factor in CFS but probably not the primary cause and that antiherpetics can improve symptoms in some patients.
 
Hi Gerwyn

I am currently rereading the paper very slowly and carefully, I do have episodic memory issues so i have to take time. I will reply when I have finished, and I will definitely give consideration to your arguements. If I find the the same result, I will report that on this forum later. Maybe someone else who is capable of reviewing this faster can comment on this?

I may have been commenting based on interview claims (my memory is sometimes that bad) which would make it anecdotal and unpublished in the scientific sense.

Bye
Alex

no alex the final finding was 6 + 0r minus 1.2.Dr lerners avowed intent was to show that EBV caused CFS.This was not achieved.without a placebo arm it is impossible to say whether the drug treatments caused any benefit that would not have occured anyway because the infectious phase of the pathogens in question is self limiting.I have no doubt that the patients inquestion were ill anyone with that pathology would be.Everyone with that pathology in terms of viral infection would eventually recover anyway.
 
G
  • Gerwyn

I think Gerwyn is talking about mono, which is not CFS, people get over mono. But a certain percent does go on to acquire CFS so even if not a cause it can be a trigger for CFS.

however, Learner looked at other herpes viruses as well, and at multiple herpes, co-infections, etc. His argument is not reliant only on EBV.

Yes Kurt he did.That is why I noticed the flaws

I dont appear to be making myself clear so perhaps I had better start from the basics.

Everyone has cells in their body which are non permisive for viral infections.This is what is meant by non permissive infections.It just means that the virus can enter the cell but wont replicate.

In order for that to happen the virus obviously has to infect the person in the first place

RNA viruses quickly establish latency

That persons cells will contain latent viruses bound to the DNA

Yet in Dr lerners study the majority of RNA viruses were active(By IgG values)

Active viruses trigger latent viruses.So any EBV present would also become active even though for some reason IgG levels for this virus was not measured.

this level of active viral infection would easily account for the disability and formally exclude a diagnosis of CFS fUKUDA even if the diagnosis was accurate in the first place.

The level of pathogenic activity in group B would also account for the disability found there.We do not know if the pathogenicity of that group was resolved in any way.This level of pathogenicity would also account for the fatigue levels presented and preclude a diagnosis of CFS FUKUDA.

All these viral infections are self limiting so we do not know without a placebo that the treatments were not more effective than placebo.

Something is keeping normally latent viruses active.The question is what?

DR learner himself concedes that point

Disability scales even if internationally validated are not diagnostic tools.Yet Dr Learner uses them as such in this study

If one decides before hand what a significant result will be then a very low P value automatically ensues when this absolute level is reached even when the clinical effect is small.

For example the improvement in EIPS 5 to 6 attracts a p value of 0000.1 even when the changes are not significant.i would argue that they are actually different ways of wording the same level of dysfunction

In similar vein a cut off point of point of 5 for diagnosis of CFS and 6 as not having CFS is arbitrary and I would argue clinically incoherent.If the cut off point of 6 was set for example then the results would be entirely different!

Diagnosis by FUKUDA criteria is notoriously unreliable unless PEM is used.DR learner did not use that as a diagnostic criteria in this study.

I am very uncomfortable about the fact that the study took two years to publish and ultimately the study was published ina journal owned by one of the researchers.

The quality(or even the existence ) of peer review in Dovepress is the subject of much controversy and heated debate

Best wishes

Gerwyn
 
Hi kurt,

I have long been wondering about this issue of why our viral response might be different. I have an hypothesis that might explain it for at least a subset of CFS patients. Numerous other researchers are also saying something similar, but they tend to be less specific and more cautious, as practicing scientists should be.

The interferon response, resulting in RNaseL and other mechanisms, is a common antiviral response. We know from the Dubbo study that 10% of acute infection patients go on to develop long term problems that might be CFS. I suspect that the acute nature of the infection is critical, and that if the body starts sensing something serious. like a brain or cardiac infection or massive viral load, it initiates an emergency antiviral response. This causes massive amounts of elastase to be released, cleaving the RNaseL into fragments. One of these fragments is very effective at cleaving viral RNA. Several of the others slow and inhibit cellular metabolism, or at least are hypothesised to do so. In an acute viral infection, this will usually result in rapid removal of the virus, In people who develop CFS the virus is not removed, so the acute antiviral response is often retained, long term, which does secondary damage to energy production and vascular function. The work of DeMeirleir and others points to this possibilty.

Now the cause of this viral nonclearance is still a quandery, and there are four further hypotheses, all or none or some of which may be right. Lerner's arguement about nonpermissive viral infection could explain this, and is the first hypothesis.

The second hypothesis is that my RNase L arguement explains Lerner's nonpermissive hypothesis (rather than the other way around), because the hyper active RNaseL fragment is cleaving the virus RNA and preventing proper virus particles from being formed. This will not completely stop presentation of viral fragments on the cell surface (thus alerting the immune system), nor will it completely stop production of viral toxins, thus continuing to poison the body.

The third hypothesis is that this could be caused by the XMRV toxic protein envelope. So little is known about this at the moment that I can say very little about this.

The fourth hypothesis is that this could all be due to the decreased natural killer cell cytotoxicity. I doubt this is the complete answer, but I could be wrong. It is very likely part of the answer, however, and could be linked to the XMRV immune toxin hypothesis etc. There are at least several studies on this in the works, so expect to hear a lot more about NK cells in the medium term.

None of these hypotheses have been proven, but I am not aware that any is disproven either. We really need more understanding of the underlying biochemistry, and hence even more science, which requires even more funding. This is why I am both a science and political advocate, although I am a late comer to politics and still learning the basics.

bye
Alex


There are many good clues to that difference. Most CFS patients are pathological detoxifiers, for example. And we have a host of gene abnormalities including immune, adrenal, methylation, etc. Full genomic profiling is becoming less an less expensive, one company says they will have a $100 full genomic profile test by the end of the year. That is the entire human genome for a given patient. I think the answers are coming.
 
G
  • Gerwyn

Epstein Barr virus

I thought that this might help


Epstein Barr Virus (EBV) 90% of adults in W.Europe and N. America carry EBV. Infection persists for life with virus regularly shed by salivary gland. Salivary fluid transmits the virus e.g. infected eating utensils and kissing. It is a mark of how well adapted to us this virus is,that it can persist for a lifetime in an asymptomatic state.T cells effectively control it.In vitro it is the most potent transforming virus known.Definition of transformation in this system is the conversion of non-dividing B lymphocytes from (EBV-) individuals to indefinitely proliferating lymphoblasts. It is linked to at least 4 different types of tumour:

* Burkitt's lymphoma (African manifestation)
* Nasopharyngeal cancer (common Chinese & SE Asian manifestation)
* B cell lymphomas in immune suppressed individuals (organ transplantation or HIV)
* Hodgkin's lymphoma, clonal form exists in 40% of afflicted individuals

A link with Burkitt's lymphoma was first established when virus isolated from cultured Burkitt's cells, and linked to the disease sero-epidemiologically. EBV DNA can be isolated from tumours, viral specific antigens can be detected in the tumours, infection with EBV induces a lymphoma like disease in new world primates. In vitro EBV immortalization of B cells further supports the link.

The mechanism by which the virus transforms cells is still uncertain. The transforming gene(s) have not been unambiguously identified (large virus). Possible candidates include EBNA-1 (Epstein Barr nuclear antigen) and EBNA-2. EBNA-1 associates with a transcriptional enhancer element in the EBV origin of replication. Also suggested that EBNA-1 activates the lymphoid recombinase RAG genes. Activation of these genes may be required for viral integration into the host genome. It could also result in chromosomal rearrangements and translocations. EBNA-1 Tg mice have an increased incidence of lymphoma. EBNA-2 is a transcriptional transactivator for both viral and cellular genes. It upregulates the LMP-1 and LMP-2 genes, as well as markers for B cell activation e.g CD23 as well as CD21, the EBV receptor. Another candidate is LMP, the latent membrane protein which acts as a constitutively activated receptor. It is the only latent viral gene product which can transform cell lines in vitro. It induces the expression of many cellular genes including markers for B cell activation. LMP-1 interacts with cellular proteins that transduce signals from the TNF family of receptors e.g TRAFF and TRADD (TNF receptor associated factor and TNF receptor associated death domain).
 
I'm happy to see any study that reports improvements in CFSers, or in any "subset" of the disease that's commonly called CFS.

I wonder, though, about the distinction between subjects with vs. without co-infections.

This study makes it seem that the co-infections are the problem.

However, I think it's not unreasonable to speculate that perhaps the difference between the two groups is some other factor that's causing some people to be more likely to have the co-infections active as well as to not be able to benefit from the antiviral treatment.

An even vaguely healthy immune system should be able to keep babesia under control, for instance.

Lyme is notoriously hard to find on tests. If it comes up on any, it generally suggests not just the presence of the bacteria but a particularly active presence.

Conceivably the presence of XMRV could make some people more vulnerable to co-infections being active, for instance.

I'd thus like information on the XMRV status of all the patients in the study.

Living in an especially moldy home also has the potential of causing otherwise unproblematic infections to become active, due to the immunosuppressive characteristics of the mold.

As an anecdotal report, I recently heard that a patient of Dr. Lerner's who was living in a moldy home did not respond to an antiviral treatment. She said he accused her of not taking the drug, even though she actually was.

And I had horrific die-off symptoms to antivirals and antibiotics when living in my own moldy home (needing to immediately discontinue the drugs) and had very few after moving out.

Thus, I would like to hypothesize that Dr. Lerner might have more success with ALL of his patients if he ensured that they weren't living in horrifically moldy conditions first.

It certainly would be worth his going back and looking at the patients in this study to see the extent to which their homes indeed were or were not severely moldy anyway.

Best, Lisa
 
Controlling for XMRV, Mold and other Third Variables

(I put this on another thread about this study, but it seems this one is more active.)

I'm happy to see any study that reports improvements in CFSers, or in any "subset" of the disease that's commonly called CFS.

I wonder, though, about the distinction between subjects with vs. without co-infections.

This study makes it seem that the co-infections are the problem.

However, I think it's not unreasonable to speculate that perhaps the difference between the two groups is some other factor that's causing some people to be more likely to have the co-infections active as well as to not be able to benefit from the antiviral treatment.

An even vaguely healthy immune system should be able to keep babesia under control, for instance.

Lyme is notoriously hard to find on tests. If it comes up on any, it generally suggests not just the presence of the bacteria but a particularly active presence.

Conceivably the presence of XMRV could make some people more vulnerable to co-infections being active, for instance.

I'd thus like information on the XMRV status of all the patients in the study.

Living in an especially moldy home also has the potential of causing otherwise unproblematic infections to become active, due to the immunosuppressive characteristics of toxic mold.

As an anecdotal report, I recently heard that a patient of Dr. Lerner's who was living in a moldy home did not respond to an antiviral treatment. She said he accused her of not taking the drug, even though she actually was.

And I had horrific die-off symptoms to antivirals and antibiotics when living in my own moldy home (needing to immediately discontinue the drugs) and had very few after moving out.

Thus, I would like to hypothesize that Dr. Lerner might have more success with ALL of his patients if he ensured that they weren't living in horrifically moldy conditions first.

I think it would be worth his going back and looking at the patients in this study to see the extent to which their homes indeed were or were not severely moldy anyway.

Best, Lisa
 
Good study. I don't know why it's so difficult for mainstream doctors to understand the concepts of coinfection and multifactorial etiology.
 
does anybody know if/when/how often t-cell counts (cd4&cd8) were taken from group A&B patients in the study?

i didnt noice that info in reading through several times. thanks, j
 
The Placebo Response in the Treatment of Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis
Psychosomatic Medicine 67:301-313 (2005)

The impact of placebos on physiological processes are well documented. This review looked at the placebo response in a series of ME CFS intervention studies. The results are pertinent not only to the discussion of Lerner's study but also to judging the validity of any ME CFS intervention claims.

In an analysis of 27 intervention studies in ME CFS, although it was found that the overall placebo response in ME CFS was lower than in other medical conditions, further analysis showed that the differences seen within the placebo response was due to the intervention type. Psychological interventions had the lowest placebo response while anti infectious and immunological interventions had a high placebo response.

"Psychological-psychiatric interventions were shown to have a low placebo response, whereas neutral interventions had a medium placebo response. Finally, infectious-immunological and alternative-complementary interventions were shown to have a high placebo response."

Of course all of us can take from this what they wish, however I think that discussion of this issue might prove very helpful to all of us as a separate thread....
 
Gerwyn - this level of active viral infection would easily account for the disability and formally exclude a diagnosis of CFS fUKUDA even if the diagnosis was accurate in the first place.
Gerwyn - The level of pathogenic activity in group B would also account for the disability found there.We do not know if the pathogenicity of that group was resolved in any way.This level of pathogenicity would also account for the fatigue levels presented and preclude a diagnosis of CFS FUKUDA.
You keep repeating this yet you've been shown several times that the Fukuda definition does not exclude CFS patients who have an EBV infection. Could you respond to the posts indicating that Fukuda does not exclude EBV positive patients from having CFS?

It seems to me that you're implying that the results don't apply here because they had an active infection and therefore can't be defined as having CFS. That's an amazing statement - given all the people on this Forum and elsewhere have active infections.

The critical critical question for me would be if they're results apply to me? I would guess that they very well might; that the people seeing Dr. Lerner had a mysterious fatiguing problem, had difficulties standing and exercising, etc. they had seen scads of doctors, and they finally got to Dr. Lerner.

You can parse the definition question all you want but my assumption is that people who make their way to Dr. Lerner, or Cheney or Bateman or Lapp, etc - have what I have which makes me interested in which treatments work for them.
 
anyone want to "translate" deans data for me? (sorry, severe PEM at work!) i hate to "drop out" this far into the thread, but the info is a blur of words...thanks, j

(cant even figure which emotie to use!...is there a "I sincerely want to understand what everybody is talking about today!" one? )
 
"Psychological-psychiatric interventions were shown to have a low placebo response, whereas neutral interventions had a medium placebo response. Finally, infectious-immunological and alternative-complementary interventions were shown to have a high placebo response."
That is interesting; I didn't know that certain types of treatments had a high placebo response.
 
I dont appear to be making myself clear so perhaps I had better start from the basics.
Actually I think you've been quite clear. I think all of the issues you have brought up have been thoroughly addressed here.
 
The Placebo Response in the Treatment of Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis
Psychosomatic Medicine 67:301-313 (2005)

The impact of placebos on physiological processes are well documented. This review looked at the placebo response in a series of ME CFS intervention studies. The results are pertinent not only to the discussion of Lerner's study but also to judging the validity of any ME CFS intervention claims.
This study (out of Britain....wouldn't you know it?) seems designed to demonstrate that CFS patients are biased against psychological interventions, due to their overzealous beliefs that CFS/ME is not "all in your head" (my words).

Indeed, the study does show that people were more likely to have placebo effects to immunological-oriented drug treatments or alternative ones.

More interestingly, NONE of the treatments had a very high placebo rate compared to that observed in other diseases.

The authors suggest that this lack of placebo effect is a bad thing, due to CFSers having "bad attitudes" (again my term) with regard to being optimistic that treatments are going to work. That's especially true for the "validated treatments" (their words this time) of Graded Exercise Therapy and Cognitive Behavioral Therapy. It also is true for antidepressants since those SHOULD work since CFSers suffer from "comorbid depression" (again their words).

With this kind of researcher bias, I have a hard time taking anything they say seriously.

This is the first time I've actually bothered to read a study by Simon Wesseley. I can see why so many CFSers hate him so much.

With regard to placebo usage in antivirals: I would imagine that most CFSers embarking upon an antiviral trial are aware that these drugs generally produce an initial die-off response.

If I were in a clinical trial and I didn't get a die-off, I would assume that I was in the placebo group. I tend to think that most CFSers would make the same conclusion.

Just because people get the die-off doesn't mean that the drug is going to eventually help them. That seems to have been the problem with Montoya's Valcyte study: people suffered through horrendous die-off and then eventually didn't get much better or any better.

It's my understanding that in many cases, placebo effects tend to be limited in terms of how long they last. People may show immediate positive gains, but those gains are less likely to last than those experienced by people who actually have been helped.

Observing how CFS patients on antivirals do long after they take the drugs thus seems important.

Maybe there are other ways to deal with the methodological problems created by the die-off. Thoughts?

Best, Lisa
 
However, I think it's not unreasonable to speculate that perhaps the difference between the two groups is some other factor that's causing some people to be more likely to have the co-infections active as well as to not be able to benefit from the antiviral treatment.

An even vaguely healthy immune system should be able to keep babesia under control, for instance.

Lyme is notoriously hard to find on tests. If it comes up on any, it generally suggests not just the presence of the bacteria but a particularly active presence.

Conceivably the presence of XMRV could make some people more vulnerable to co-infections being active, for instance.
I am severly affected by CFID's...debilitating, fatigue, pain, NMH/OI. I must be in a reclined position 95% of the day. I have been dx'd w/CFID's by Dr. Cheney, Montoya and Kogelnick plus all of the PCP's and ID's I have seen.

I also test positive for Borrelia, Babesia, Bartonella, MycoPneumonia, CPN. I have hi viral titres to EBV, HHV-6, Coxsackie, Parvo, CMV. My NK Cell count is 8, my CD4a and CD8a are extremely low.

My husband also tests positive for all these things...he however is NOT sick. His NK Cell count is the highest the testing Dr had ever seen, 1000+. Looks like my husbands immune system keeps all these bacteria and viruses at bay.

My immune system does not....or on the other hand does, since I'm not dead, but makes me feel very very ill while fighting them.

Just some food for thought.

thanks.
 
More interestingly, NONE of the treatments had a very high placebo rate compared to that observed in other diseases.
This is what I remembered. I agree about Wessely; that article should have been such a big win for us but by the time he was done spinning it - at least in the media - we looked like nuts again. Still I imagine that the researchers can read and understand the paper.