Valganciclovir research paper - Jose Montoya & Andreas Kogelnik

[Bob]

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome

Jose G. Montoya, Andreas M. Kogelnik, Munveer Bhangoo, Mitchell R. Lunn, Louis Flamand, Lindsey E. Merrihew, Tessa Watt, Jessica T. Kubo, Jane Paik, Manisha Desai

Article first published online: 19 AUG 2013

DOI: 10.1002/jmv.23713

Journal of Medical Virology

http://onlinelibrary.wiley.com/doi/10.1002/jmv.23713/abstract


Abstract

There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) 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 (VGCV) 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 (MFI-20) and Fatigue Severity Scale (FSS) 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 (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). 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 (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.

 

[Bob]

The results don't seem too great...
"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."

Better results were reported in terms of 'trajectories', but I'm not exactly sure what this means without access to the full paper:
"However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025)."

It concludes:
"Further investigation with longer treatment duration and a larger sample size is warranted."

 

[Legendrew]

Interesting - does anyone know the immunomodulatory effects of valcyte? I suspect the majority of responses would come from this element of the drug but its hard to say without knowing any more.

 

[Sushi]

Bob, Let's try to get a copy of the full article. Is this the one we have been waiting for?

Sushi

 

[Bob]

Is this the one we have been waiting for?

I'm not sure if I knew we were waiting for one!

(I'm trying to activate my memory cells, right now! But without much success! )

 

[Sushi]

Bob

We have been waiting for a published Montoya study on Valcyte. I put in a request for the full paper.

Best,
Sushi

 

[beaker]

Confusion : They say the drugs were given for 6mo in the first bit, and then go on to say improvement seen after 9months. Which is it ? Does anyone know ?

I guess that might be cleared up in the full paper that others have mentioned gettting ahold of .

Thank you for any clarification.

 

[Sushi]

Confusion : They say the drugs were given for 6mo in the first bit, and then go on to say improvement seen after 9months. Which is it ? Does anyone know ?

I guess that might be cleared up in the full paper that others have mentioned gettting ahold of .

Thank you for any clarification.

As I remember the study was done in 2 phases.

Sushi

 

[beaker]

As I remember the study was done in 2 phases.

Sushi

Thank you .

 

[Sasha]

As I remember the study was done in 2 phases.

Sushi

I've seen slides of this - I think the drug was given for a certain amount of time but the patients were followed up for a longer period.

 

[Firestormm]

So. Are we saying the results were crap then? Am having trouble understanding them. 'Not significant' is never good. But like Bob I don't understand what 'statistically significant differences in trajectories' means either. I think this is the one we had been waiting for. Thanks

 

[Simon]

Confusion : They say the drugs were given for 6mo in the first bit, and then go on to say improvement seen after 9months. Which is it ? Does anyone know ?

Looks like the primary outcome was at 9 months, but they also measured outcomes at 3 months and probably other points too.

The results don't seem too great...
"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."

Better results were reported in terms of 'trajectories', but I'm not exactly sure what this means without access to the full paper:
"However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025).

First off, they are digging into their data when the primary outcome wasn't significant, which is always a bit of a concern: basically, the more outcomes you measure, the more you have to correct p values for multiple comparisons (if you measured 20 outcomes, you would expect at least one [edit: should be 6 in 20] to be significant at 0.05 just by chance). so they would have needed to use a lower p value, maybe p=0.01, or lower, depending on how many comparisons they were making.

I'm guessing that by trajectory they mean that eg mental fatigue subscore increased significantly over time (for the first three months) in the drug group but not the controls - but the difference between the two grops was not signiiicant. This probably seems a bit counterintuitive, but for statistical reasons you can detect smaller differences within groups than between groups.

But this is all guesswork without seeing the full text.

So. Are we saying the results were crap then? Am having trouble understanding them. 'Not significant' is never good. But like Bob I don't understand what 'statistically significant differences in trajectories' means either. I think this is the one we had been waiting for. Thanks

Basically, it doesn't look good.

VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.

If Stephen Holgate is right about ME/CFS being many different illnesses, then such a small study wouldn't have a prayer of finding a real results in one subset of patients, unless it was a large subgroup and the treatment was basically curative.

 

[Ecoclimber]

To avoid any confusion over the Stanford Research Projects, the projects are listed below.​

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http://chronicfatigue.stanford.edu/about/projects.html​

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1. Detection of pathogens such as herpes viruses, the Lyme disease agent, xenotropic murine leukemia virus-related virus (XMRV), Toxoplasma gondii, or any unknown pathogen that may be a trigger for chronic diseases such as CFS, CLD or other diseases. We are looking for such pathogens in a broad population of CFS patients at Stanford and comparing the findings to age- and sex-matched controls. Towards this aim we are collaborating with Manisha Desai, PhD, clinical associate professor of medicine, and Holden Maecker, PhD, director, Human Immune Monitoring Center, here at Stanford, and W. Ian Lipkin, MD, Director, Center for Infection & Immunity, John Snow Professor of Epidemiology, and Professor of Neurology and Pathology, and Mady Hornig, MA, MD, Associate Professor of Epidemiology, at Columbia University in New York City. We have met our recruitment goal of over 600 study participants, and are in the process of testing our blood samples for numerous pathogens, both known and unknown.​

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2. Gene Expression and Immune System Dynamics of Infection in Acute and Chronic Diseases. Our team is working on new studies to understand the immune response and possible immune dysfunction observed in our patients. We are looking at gene expression, cytokine profiles, and phospho immunoflow to learn whether our patients’ immune response correlates with the presence of an infectious agent, organism, or pathogen, and to identify new markers from the blood that may help predict changes in disease over time and response to changes in medication. Thus far, we have analyzed 51 cytokines in over 600 individuals. Towards these goals we are collaborating closely with the Human Immune Monitoring Center facility at Stanford, including Mark Davis, PhD, professor of medicine in the division of microbiology and immunology, and Holden Maecker, PhD​

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3. Is qEEG Resting State Peak Alpha Activity in Chronic Fatigue Syndrome Patients Different than Healthy Controls? A Pilot Study of the Clinical Utility of PAF Measurement in CFS. Marcie Zinn, Ph.D, an experimental neuropsychologist, focuses her research on the cognitive neuroscience of cognitive dysfunction in our patients. Through this project, we are evaluating peak alpha frequency measurements of CFS patients and healthy controls. We hope that our efforts will lead to validated tests that will improve our capacity to diagnose cognitive impairment as well as to evaluate treatment interventions.​

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4. Immune System Dynamics in Cardiovascular Disease. Francois Haddad, MD, clinical assistant professor of medicine in the division of cardiovascular medicine, is working with our patients using a sub-maximal effort exercise testing machine to find an objective method to assess fatigue and physical impairment. Additionally, Dr. Haddad and his team of cardiologists utilize a device which evaluates endothelial dysfunction. Ultimately, we hope to improve our diagnostic capability as well as better evaluate the effects of CFS on cardiovascular health.​

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5. Review of Magnetic Resonance Venography (MRV) Images of the Cerebral Venous System of Patients with Chronic Fatigue Syndrome. In collaboration with Michael Dake, MD, professor of medicine in the division of cardiothoracic surgery, we are investigating the correlation between the symptoms associated with Chronic Fatigue Syndrome and abnormal cerebral venous drainage.​

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6. Collaborating with the Neuroradiology department at Stanford to investigate the role of novel magnetic resonance imaging (MRI) techniques (e.g. using a 3T magnet) in the hope of discovering biomarkers in the brain for infection-associated CFS. These MRI tests are not available for routine clinical use. Michael Zeineh, MD, Assistant Professor of Radiology at the Stanford University Medical Center, and his neuroradiology fellows are helping us analyze preliminary imaging data to apply for an NIH grant to begin a larger study on neuroimaging in CFS patients.​

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7. Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and Murine Leukemia Virus (MLV) in Patients with Chronic Fatigue Syndrome. Under the leadership of W. Ian Lipkin, MD, Director, Center for Infection & Immunity, John Snow Professor of Epidemiology, and Professor of Neurology and Pathology at Columbia University, we engaged in a National Institutes of Health (NIH) funded, multi-site study analyzing the prevalence of XMRV and MLV in CFS patients. Results have recently been published. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus of polytropic murine leukemia virus. (please note this link will direct you to a webpage unaffiliated with Stanford University)​

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Recent Publication​

1. Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. Watt T, Oberfoell S, Balise R, Lunn MR, Kar AK, Merrihew L, Bhangoo MS, Montoya JG. J Med Virol. 2012 Dec;84(12):1967-74. doi: 10.1002/jmv.23411. PMID: 23080504 [PubMed - in process]

2. A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus. Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff, AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. MBio. 2012 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. PMID: 22991430 [PubMed - in process]

3. Antiviral therapy of two patients with chromosomally-integrated human herpesvirus-6A presenting with cognitive dysfunction. Montoya JG, Neely MN, Gupta S, Lunn MR, Loomis KS, Pritchett JC, Polsky, B, Medveczky PG. J Clin Virol. 2012 Sep;55(1):40-5. doi: 10.1016/j.jcv.2012.05.016. Epub 2012 Jul 5. PMID: 22770640

 

[SOC]

I'm a bit puzzled about why they did only 6 months when clinical evidence is that most patients need about 18 months to see substantial benefit from valgancyclovir.

My own experience is that at 6 months I was still in (or just coming out of) an IRIS-like reaction and was feeling pretty crumby. My daughter was feeling better at 6 months, but not hugely so. So, we would have not shown a big improvement at 6 months, either. However, at 12-18 months, my daughter was fully functional and I was significantly improved.

 

[Legendrew]

I think this data raises what could be a very interesting point - it is clear that some people do improve on this drug but this study clearly implies that these people are not in the majority which to me has to imply that in the majority these viruses are not the causative issue. Perhaps the longer term benefit comes from the immunomodulatory benefits of the drug in the long term instead of the antiviral properties. Suffice to say I think a longer study as SOC suggests is something that could be useful to see whether this slow action could the reasoning for the disappointing results.

 

[Sasha]

I think this data raises what could be a very interesting point - it is clear that some people do improve on this drug but this study clearly implies that these people are not in the majority which to me has to imply that in the majority these viruses are not the causative issue. Perhaps the longer term benefit comes from the immunomodulatory benefits of the drug in the long term instead of the antiviral properties. Suffice to say I think a longer study as SOC suggests is something that could be useful to see whether this slow action could the reasoning for the disappointing results.

I don't have the papers to hand but I had thought that in the prospective/retrospective studies of their clinical records that Lerner/Montoya did, they were finding strong improvements in fatigue in patients at 6 months, which may have led Montoya to choose this 6 month period of treatment for this study. If this RCT doesn't reflect that clinical experience, it raises the question of what else might have been going on with those patients in the clinic, such as other treatments, perhaps.

I might be wrong on the timing issue though, so don't take my word for it!

 

[Guido den Broeder]

According to Lerner, it takes 5 to 7 years of treatment to see the final result.

Also, they need a more accurate patient selection to draw conclusions about the effect on ME.

 

[Legendrew]

According to Lerner, it takes 5 to 7 years of treatment to see the final result.

Have you got a link to that?
To me that sounds like an awfully long time

 

[Sasha]

Have you got a link to that?
To me that sounds like an awfully long time

That also sounds like an ineffective therapy. I don't know how you'd distinguish between the action of the drug and other factors, in such a long timeframe.

 

[heapsreal]

I know valcyte definately helped me and when i came off i crashed within 8 weeks. The quick fall has shown me how much it helped as many symptoms have returned or intensified since i stopped. I think for those who respond, the issue maybe how to maintain this improvement when off valcyte. I think this is where they need to look into ways of improving immune function.