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Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein

heapsreal

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Abstract

Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients. An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ≥1:320, EBV viral capsid antigen (VCA) IgG ≥1:640, and EBV early antigen (EA) IgG ≥1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response. After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response. J. Med. Virol. 84:1967–1974, 2012. © 2012 Wiley Periodicals, Inc.

http://onlinelibrary.wiley.com/doi/10.1002/jmv.23411/abstract

anyone has access to the full article for free, a link would be good.

cheers!!!
 

heapsreal

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It states longer treatments were associated with improved response. Be nice to know the treatment length but i also take it that its longer then montoya's initial study length of 6 months?

cheers!!!
 
Messages
46
It states longer treatments were associated with improved response. Be nice to know the treatment length but i also take it that its longer then montoya's initial study length of 6 months?

cheers!!!


Valganciclovir Treatment
Patients followed one of two valganciclovir treatment
regimens based on clinical judgment (e.g., history
of side effects to antimicrobials). Fifty-eight
patients took 900 mg of valganciclovir twice daily (induction
dose) for 3 weeks, followed by 900 mg of valganciclovir
once daily (maintenance dose). Six
patients only took the maintenance dose for the duration
of their treatment.
The length of treatment varied among patients
according to the treating physician’s clinical judgment.
If patients were treated with valganciclovir
more than once and the two treatment regimens were
more than 1 month apart, then the first treatment
regimen was used for analysis as well as for establishing
baseline and final functioning levels and antibody
titers. If, however, multiple treatments with valganciclovir
were

<
1 month apart, these were considered a
single treatment course for analysis purposes.
 

anniekim

Senior Member
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Location
U.K
Apologies if this has been posted elsewhere on here. Are the HHV6 titres mentioned 1 :336 lower than Montoya has used before?

Also sorry for my ignorance but does this study say response could not be predicted by how high titres were just if one had positive serology?

http://www.meassociation.org.uk/?p=13221

EDIT

Sorry see this has been posted elsewhere so moderators please feel free to delete this. (threads have been merged)
 

anniekim

Senior Member
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Location
U.K
Were the titre numbers for HHV6 that were considered high in this study 1 :360 lower than other studies Montoya has done?

Also sorry for my ignorance but is this piece of work saying response to valcyte couldn't be predicted by higher titres but purely if there was positive serology?

Sorry I don't understand what this means, 'mean treatment in months was 6.5 (SD = 2.0)'. What is it in months? Many thanks
 

heapsreal

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I think its saying higher the tires doesnt mean a better response to treatment or the worse the condition is eg someone with lower titres could be more ill then someone with higher titres and the one with lower titres could respond better then the person with higher titres and vice versa. I suppose theyare saying its not an indication if they will respond or not. I think theyare saying if u have titres above the minimum then these viruses can be an issue for you??
 

anciendaze

Senior Member
Messages
1,841
Notice that improvements were associated with reduced viral titers. This points to a useful therapeutic goal, even if valgancyclovir is not the drug used. They failed to validate their hypothesis about patients with high titers being more likely to respond.

The problem which seems to have turned up is that a high titer may be either the result of an especially active infection or an especially active immune response to a lesser infection. Both these and other viruses in the herpes group are immunotropic, and have immunomodulatory characteristics. It seems very likely that there is damage to the immune system over time. If immune response does not decline, the result may be an autoimmune disease. On the other hand, if it does, you have a situation where you can't tell if you are looking at a serious infection. Simply looking at the numbers doesn't tell you.

This kind of problem is common in chronic infectious diseases.

We know that long-term infection with some strains of EBV is associated with several cancers. We have also seen that HHV-8 is associated with Kaposi's sarcoma. We don't have a "smoking gun" for HHV-6, but it is looking like this is only a matter of time. Association between CMV and a number of cancers is also under investigation. All these are human herpes viruses.

It is no longer safe to assume that active infections by these common viruses are harmless. If your immune system is holding them latent you are probably in good shape. If they are reactivated something should be done to change the situation.
 

SOC

Senior Member
Messages
7,849
These results are consistent with what my daughter and I saw with our valganciclovir treatment. I had been continuously sick longer than she had, I was sicker, but she had higher HHV-6 and EBV titres. We both responded well to valganciclovir. My daughter is now in remission. I'm improved, but still significantly impaired.

It appears that my immune system was damaged by the illness and was not producing sufficient antibodies, so my titres weren't very high. My daughter's immune system seemed to be still fighting and she recovered faster, but I still got a huge improvement.

So, I can easily see why titres are not directly related to response. Antibody titres don't tell the full story for patients with immune impairment.
 

anciendaze

Senior Member
Messages
1,841
I want to add that these problems with tests are not peculiar to weird conditions easily confused with mental illness. Even though tuberculin testing for TB infection was suggested (by A. Conan Doyle!) soon after tuberculin was discovered as an antigen provoking immune response to those bacteria it was not used as a test for many years. (During this time it was the basis of attempted treatments, most of which failed.) After the incidence of TB was reduced various tests with tuberculin became standard for diagnosis. It worked well for cases of recent onset TB.

I know of at least one much later case in which a tuberculin test was administered, and failed, though an autopsy later revealed extensive TB which was hard to see on X-rays. The patient's immune system was simply too far gone, and the doctors involved were not familiar with long-standing TB infections.

Our whole healthcare system has problems coping with chronic infectious disease.
 

Dolphin

Senior Member
Messages
17,567
After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001).

The percentages reported could be reported in another way.

"Physical and Cognitive Functioning

To assess response to treatment, self-reported physical and cognitive functioning levels were obtained at every clinic visit. Functioning levels were evaluated on a scale of 0-100%. A score of 100% indicated that the patient was completely well."



"Before valganciclovir treatment, the average baseline physical and cognitive functioning levels were 34% (standard deviation; SD 6.9%) and 43% (SD 5.4%), respectively, for all patients (responders and non-responders). After treatment, the mean of all patients' physical and cognitive functioning levels improved by an average of 19% (P <
0.0001) and 23% (P < 0.0001), respectively (Table I, Fig. 2a-c)."

As the figures show, this means the final scores were 53%* and 66%* (i.e. a 19-point increase from 34 to 53 would be described usually as a 56% increase and a 23-point increase from 43 to 66 would be described usually as a 53% increase).

[*Dolphin: because of rounding, the figures could actually be anywhere between 52-54% and 65-67% respectively]

One point to note is that the analysis is slightly unusual:


"Baseline physical and cognitive functioning levels were determined by averaging up to three levels within 1 year prior to starting valganciclovir treatment. Final functioning levels were determined by identifying the highest level within 6 months of stopping treatment. The highest levels after treatment (rather than the average of all available levels) were chosen in order to capture the largest effect of treatment on functioning. Additionally, a wide variation in time to treatment benefit was observed (e.g., functioning may improve during treatment course or after treatment cessation). The average of post-treatment functioning levels, therefore, may not present an accurate depiction of improvement."
---------

Also, as the authors say,
---------
"It was, however, not possible to assess the possibility of placebo or Hawthorn effects due to the single-arm, historical study design."
---------
 
Messages
95
One part of this study I'd like to commend is in this simple quote:-

"in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) IgG antibody titers."

Ok, the CFS part is still there but, I am desperate to see more research that focuses in on biological abnormalities previously discovered in patients and using them to refine a cohort.

I've read some pretty heavy debates about the virtues of lumping and splitting, but I think you have to commit to a lot of the splitting type of research before you can actually answer that question anyway.
 

Simon

Senior Member
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Location
Monmouth, UK
It's worth pointing out that this study failed to find any difference in response between high-anitbody titre and low-antibody titre patients.

Very little can be read into the improvements since, as the authors say, there was no placebo control group. Also, as Dolphin points out, they used PEAK scores to measure improvements, not mean or final scores; this means that even if there was no overall improvement across patients they would still appear to be one if fatigue scores fluctuated over time (above average scores give the peaks, below average scores are ignored). As Dolphin also points out, they reported the improvements in a conservative way so the results do actually look interesting, but without a control group its impossible to draw any conclusions. Does anyone know if they plan to publish a controlled trial?

ps I think the Research1st report on this has it about right:
Responder Characteristics Elusive: A team led by Dr. Jose Montoya at Stanford University published results of a chart review of 61 CFS patients treated with Valcyte to identify differences between the 32 “responders” and 19 “nonresponders.” No significant differences were found in the baseline antibody titres to HHV-6 or EBV or other variables analyzed.[my underlining] Longer treatment correlated with an improved response as judged by patient’s self-reported physical and cognitive functioning. (Journal of Medical Virology, Oct. 10, 2012)

I should point out that I haven't read the full text, just the abstract and Dolphin's analysis - but that's surely at least as good? :)
 

RustyJ

Contaminated Cell Line 'RustyJ'
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There was a significant improvement in a significant number of patients, however was this due to treatment? Also was the treatment affecting some other biological agent, if herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) titres were not significantly changed. Have I got this wrong, lol? To me it seems that the treatment was very helpful, just not for the reasons he thought it would be. Also, it's possible I guess that the titres may not change because of other factors, including dysfunctional immune system. In other words it might seem that HHV-6 and EBV are a problem in these patients, but that might be a false reading.
 

Dolphin

Senior Member
Messages
17,567
There was a significant improvement in a significant number of patients, however was this due to treatment? Also was the treatment affecting some other biological agent, if herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) titres were not significantly changed. Have I got this wrong, lol?
The titers did change:

Change in Titers
Mean antibody titers for EBV VCA IgG
(P ¼ 0.0165) and HHV-6 IgG (P < 0.0001) decreased
with valganciclovir treatment in all patients (responders
and non-responders). No significant difference was
found in the change of antibody titers after treatment
between the responder and non-responder groups
(Table II).
and

Valganciclovir treatment caused all mean antibody
titers to decrease in responders and non-responders.
The decline in both EBV VCA and HHV-6 antibody
titers observed in this open-label cohort suggests that
our patients might have had a substantial reactivation
that was amenable to antiviral intervention
against both viruses. The decline in EBV VCA and
EBV EA antibody titers was more pronounced in responders
than non-responders; however, this distinction
was not statistically significant. This study was
not powered to detect significant differences in the
mean change between these groups.

If one looks at the paragraph in the discussion that starts:
In contrast to this study’s original hypotheses
they give possible reasons for the lack of association with baseline titers. I have no idea if some are plausible or not (e.g. some with reactivated virus may have borderline
hypogammaglobulinemia).
 

heapsreal

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Non responders could be apart of the non responders dr lerner found, they were the ones with bacterial co-infections like lyme,mycoplasma etc but he does get improvement with this group when he treats with abx as well.

Also i think whats being misunderstood is that the titre levels didnt neccessarly correspond with patient severity ie some with low titres were sicker then those with high titres.

Antibody titres are also dependent on a healthy(to a degree) immune system being able to pump out alot of these titres as well.
 

satoshikasumi

Senior Member
Messages
113
This means the average treatment was 6 and a half months
67% of the study population were treated from 4-8 months
95% of the study population were treated from 2-10 months.

Were the titre numbers for HHV6 that were considered high in this study 1 :360 lower than other studies Montoya has done?

Also sorry for my ignorance but is this piece of work saying response to valcyte couldn't be predicted by higher titres but purely if there was positive serology?

Sorry I don't understand what this means, 'mean treatment in months was 6.5 (SD = 2.0)'. What is it in months? Many thanks