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Viral Finding May Open Treatment Possibilities for 15-20K Chronic Fatigue Syndrome Patients in the U.S.

More Viral Funny Business in ME/CFS

Persistent human herpesvirus-6 infection in patients with an inherited form of the virus. Pantry, S, Medveczky, M, Arbuckle, J, Luka, J, Montoya, J., Hu, R. Renne, H., Peterson, D., Pritchett, J., Ablashi, D. and P. Medveczky. Journal of Medical Virology.

A lot of interesting viral possibilities have been raised in chronic fatigue syndrome (ME/CFS) over time, but this virus, possibly found in every cell of a persons body, might just take the cake.

ciHHV-6 – The Wrong Kind of Integration

Most people are exposed to HHV-6 early in life and carry a latent form of the virus in their body. Usually benign, immune suppression can allow HHV-6 to become reactivated causing fever, seizures, encephalitis, cognitive problems, heart disease and more.

gene model

Some people have HHV-6 integrated into every cell of their body

ciHHV-6 is different though. Two HHV-6 viruses (HHV-6A and HHV-6B) that probably jumped into the human germ at some unknown point several hundred thousand years ago, now some people carry a copy of it in the DNA of every cell of their body; that’s right – every cell of their body.

Does the thought of having a potentially harmful herpesvirus genome present in the DNA of every cell of your body send a little shiver up your spine? It certainly does mine, but before anyone panics let’s recognize that our DNA is larded with all sorts of weird stuff including many old (mostly beaten up) viruses. (Fragments of retroviruses make up about 8% of our genome) Almost all of us have also been infected by 5-8 of the 9 herpesviruses that can smack us hard if our immune systems let them get out of line. We carry toxic species of bacteria in our guts. We’re full of surprises, but the idea that a potentially damaging herpesvirus exists – fully intact – in some people’s DNA calls for more research.

Studies of approximately 6,000 blood and cord blood donor tests indicate 0.8% or slightly less than 1% of the US population, most of whom are in good health, have ciHHV-6. Tests on people with chronic illnesses are less extensive, but early studies suggest increased rate of ciHHV6 integration are present in numerous neurological disorders including children suspected of encephalitis (3.26%), non-Hodgkins Lymphoma (3.13%) and multiple sclerosis (2.86%).

The first of its kind in chronic fatigue syndrome, this study, led by a respected herpes virus researcher (and in collaboration with Dr. Jose Montoya  of Stanford University and Dr. Dan Peterson of Simmaron Research), determined whether a kind of human herpes virus 6 infection called ciHHV-6A or ciHHV-6B was present in a subset of patients diagnosed with chronic fatigue syndrome.

Misdiagnosis Presents Dangers

Even in its benign, unactivated state ciHHV-6 can produce lab test results that make it look like you have roaring HHV-6 infection when you do not. The high viral loads that are a distinctive feature of ciHHV-6 present a danger when physicians, believing the patient has a raging HHV-6 infection, prescribes unneeded and potentially dangerous antivirals.

stethoscope with question mark

Misdiagnosing ciHHV-6 as an active HHV-6 infection can lead to unneeded and possibly dangerous antiviral -treatment

In fact, high levels of HHV-6 (> 5.5 log10 copies/ml of HHV-6 in whole blood) on quantitative PCR tests are considered a definitive indication that ciHHV-6 is present unless a patient is acutely ill. HHV-6 appears to be largely localized in the tissues in ME/CFS, and therefore doesn’t leak a lot of HHV-6 into the blood. (Very high levels of HHV-6 DNA can be found during primary (or first) infections, but this type of infection is not usually seen in ME/CFS).

Even in primary infections HHV-6 loads will diminish over time in the blood. That doesn’t happen with ciHHV-6.

Since a latent ciHHV-6 infection is contained within the cellular DNA, the result on a serum or plasma PCR test is much lower because the cells are separated from the plasma and only DNA from cells that die in the process will show up.

The Study

Three hundred and thirty seven people suffering from neurological problems and long-term fatigue were tested using quantitative PCR for the presence of ciHHV-6. Very, very high levels of HHV6 indicated that two percent (7/337) had chromosomally integrated HHV-6. mRNA tests indicated the virus was actively replicating in their blood.

Two percent (2.1%) of the ME/CFS population translates into about 15-20,000 people with ME/CFS in the US.

Findings

Not Homegrown After All

This study suggests that, in symptomatic ciHHV-6 patients, infection with an exogenous HHV-6 virus may be a frequent occurrence.

The second part of the study involved four ciHHV6 patients suffering from symptoms consistent with ME/CFS including debilitating fatigue, headache, blurred vision, cognitive impairment, pain, etc. who were given further testing to determine the type of HHV-6 present. All had an active infection of different strain of HHV-6 virus than found in their genome. That suggested their illness was not due to ciHHV-6 reactivation but to another strain of HHV-6 they’d been exposed to.

It also suggested that people with ciHHV-6 and neurological symptoms such as fatigue and cognitive problems may very well have two HHV-6 infections; the ciHHV-6 in their DNA and an outside infection.

Long-Term Antiviral Treatment Provides Hope 

The good news…Is that antiviral drugs improve the severe neurological symptoms, including dysfunction and long-term fatigue, suffered by a certain group of patients with CFS. Dr. Peter Medveczky

Two treatment regimes, a short-term regime (900 mg/valganciclovir 2x’s/day) lasting 3 weeks and a longer term (900 mg/valganciclovir 2x’s/day for first three weeks then 450 mg twice daily for three weeks or more) lasting greater than or equal to six weeks. The short-term treatment had no effect on viral load (U100 RNA) or symptoms while the long-term treatment eliminated both. A blood test five weeks after the end of the treatment for one patient, however, indicated the virus was back in full force.

(Note that Valtrex, an antiherpesvirus drug commonly used in ME/CFS, is not effective against HHV-6)

valcyte molecule

Valganciclovir (Valcyte) is effective against HHV-6; (valaciyclovir) Valtrex is not

Kristin Loomis, the Executive Director of the HHV-6 Foundation, suggested patients with active ciHHV-6 infections may also benefit from supplements that enhance their cellular immune response such as AHCC, ImmunoPro, and Avemar, or the prescription drug Immunovir that can be ordered legally from Canada with a prescription.

Last year Medveczky and Montoya reported successfully resolving the neurological symptoms and fatigue of two ciHHV6 patients experiencing cognitive problems, depression, fatigue, and abnormal qEEG readings. Their qEEG readings normalized and their DNA load declined although, (as expected), it did not disappear. According to the Pantry study they remain symptom free.

Kristin Loomis suggested one reason these patients may need longer than normal treatment regimes is a long lasting immunosuppression caused by HHV-6. She noted that the beta herpesviruses (HHV-6, 7 and CMV (HHV-5)) found in ME/CFS all cause immunosuppression that can last up to six months. Until the immune system is restored, these virsues will continue to reactivate during stressful periods or in response to another illness.

She also encouraged patients with ciHHV6 to join the CIHHV6 registry.

ciHVV-6 Opens The Door?

Why the ciHHV-6 patients were infected with a different HHV-6 strain than they were harboring isn’t clear, but several possibilities exist. Findings of reduced antibody rates to an HHV-6 protein suggest ciHHV-6 may somehow have switched off some immune factors that target HHV-6, thereby opening the door for new HHV-6 infections.

kicking door open

Some preliminary evidence suggests ciHHV-6 could open the door for more HHV-6 infections

Kristin Loomis, the President of the HHV-6 Foundation that helped fund the study, noted that many people with recurring herpesvirus infections (ciHHV-6 or not) probably have an undiagnosed immune deficiency such as hypogammaglobulinemia, impaired CD4 or NK cell responses, reduced lymphoproliferative response and/or low NK cell counts. The following tests at a lab such as Quest can identify these some of these immune ‘holes’.

  • IgG Subclasses Panel
  • Lymphocyte Subset Panel (CD4, CD8, CD3, CD19 and CD16/56)
  • ImmuKnow Immune Cell Function (measures CD4 cell response)
  • Natural Killer Cell Functional Assay, FC

Other causes of viral reactivation include stress. (Hydrocortisone activates virus in the laboratory.)

Drugs Open the Door?

Laboratory cell culture studies suggest the possibility that in some cases drugs may have opened the door for ciHHV-6 reactivation. Antibiotics such as Amoxicillin, Minocycline, Vancomycin, Dapsone, Trichostatin; NSAIDS such as ibuprofen and naproxen; immunosuppressants such as hydrocortisone; anti-inflammatories such as sulfasalazine, anticonvulsants such as carbamazepine, phenobarbital, valproic acid and HDAC inhibitor Trichostatin A have all been found in laboratory culture tests or in case reports, to enhance the risk of HHV-6 reactivation. (Click here for more drugs – Table Four).

Extreme drug allergies (also known as Drug Induced Hypersensitivity Syndrome or DRESS) result in HHV-6 reactivation in about 85% of cases. Steroids can also activate HHV-6; it is unknown if they present a unusual risk to individuals with ciHHV6, however.

Tested Positive for HHV-6? You Probably Have ciHHV-6

A team of ciHHV-6 experts does not recommend routine screening for ciHHV-6 for the general population but does recommend that patients with ‘suspiciously high’ serum or plasma HHV-6 levels get screened using quantitative PCR using whole blood or PBMC’s.

Kristin Loomis suggested ME/CFS patients who’ve tested positive for HHV-6 (via quantitative PCR) probably have ciHHV-6. The question then becomes whether they also have an active infection or if your test merely reflected the fact that you have ciHHV-6.

This is the tricky part. ciHHV-6 infection can result in false positives for active HHV-6 infection but this study involved four ME/CFS patients with inherited ciHHV-6 infection. This suggests ciHHV-6 infected ME/CFS patients may be at greater risk of succumbing to an outside strain of HHV-6.

The Missing Test

We have two questions here. If you’ve tested positive for HHV-6 do you actually ciHHV-6?  And if you have ciHHV-6, do you also have another HHV-6 infection?

Question mark

Since tests to determine if active HHV-6 infections are not available commercially, doctors will have to make informed judgments regarding treatment

The first question is relatively easy to answer. Quantitative PCR tests offered by commercial laboratories can suggest you have ciHHV-6. Since ciHHV-6 is expected to produce high DNA copy numbers, and CFS patients with persistent low-level HHV-6 infections almost always test negative (or fall below the level of detection) for HHV-6, any quantitative PCR DNA lab tests indicating high HHV-6 loads very strongly suggests that you have ciHHV-6.

(Note: This does not apply to persons testing positive on the qualitative nested PCR tests at VIP Laboratories or Redlabs.)

Unfortunately, no commercial laboratories offer tests that can tell if you have an active HHV-6 infection.

Physicians will need to rely on their clinical assessments (ie do your symptoms suggest you  have an active infection? Do immune lab tests suggest your body is fighting off an infection, etc.)  to determine if antivirals are indicated.

Kristin Loomis suggested that those with a positive plasma test in the past should send blood samples to the clinical lab University of Washington to confirm CIHHV6 status, using a form that can be downloaded from the HHV-6 Foundation page on CIHHV6 testing. The University of Washington has a new third generation PCR test that is highly accurate and designed to identify ciHHV6 samples.

Testing Must Be Done on Whole Blood (Not Plasma)

Alternatively, samples can be sent to Viracor or Quest but physicians need to contact the lab director at each lab in advance to request that the testing be done on whole blood instead of plasma.

The test used in this study, a real-time PCR assay for HHV-6 U100 mRNA, can differentiate between latent and active infections but is not available in commercial labs.

A New Subset 

An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from … this research including antiviral therapy. Dr. Peter Medveczky

pie chart with subsets

Researchers propose subsetting out a category of ME/CFS patients with ciHHV-6 and HHV-6 infections.

The authors proposed to call ciHHV-6 with an outside HHV-6 infection “inherited herpesvirus six syndrome” or IHS. When asked why the ‘syndrome’ tag, Kristin Loomis replied that too much is unknown to pin the disorder down more. Several different HHV-6 scenarios, it turns out, could be causing similar symptoms. An abortive HHV-6 infection, reactivation of the integrated genome even if it is not fully replicating, or even ciHHV-6’s interference with genetic functioning of the chromosomes its found in, could all potentially cause similar symptoms.

Medveczky explains that IHS patients are:

  1. ciHHV-6 positive
  2. suffer from an illness similar to ME/CFS,
  3.  have HHV-6 mRNA  (late mRNA) present in their blood indicating the virus is active
  4. respond to six weeks of antiviral treatment with the disappearance of the active virus and experience symptom improvement

Since ciHHV-6 is found in all the cells of the body it’s potential to wreak mischief either genetically or through reactivation is high. It will take future studies to determine if it does, however. Medveczky found that HDAC inhibitor Trichostatin A activates CIHHV6 in the test tube. Many of the new cancer treatments, such as Vorinostat, are HDAC inhibitors.

Good Pedigree

The senior author of the study, Dr. Peter Medveczky, has been publishing herpesviruses papers since the 1980’s. HHV-6 Foundation president, Kristin Loomis, noted that Medveczky was completely skeptical when he first heard about ciHHV-6 but he’s now convinced, and he’s actively linking a subset of ME/CFS to a viral disorder. With his long stint of herpesvirus research behind him, Medveczky is the kind of researcher other researchers listen to – a vital need.

Conclusion

Doubled rates of ciHHV-6 in ME/CFS relative to the general population suggest ciHHV-6 could contribute to ME/CFS. The high viral loads in laboratory tests, present in people with benign ciHHV-6 infections, can lead to unneeded courses of antivirals. On the other hand, some evidence suggests ciHHV-6 associated immune dysfunction may open the door for further herpesvirus infections.

This early study indicates new HHV-6 infections may be commonly found (and effectively treated) in ME/CFS patients with ciHHV-6. Further study is needed but the success of long term antiviral treatment regimes (@ 6 weeks)  in these patients suggests from 15-20,000 ME/CFS patients in the U.S. could ultimately benefit from appropriate courses of antivirals. Shorter-term courses are not effective.

Since persistently high levels of HHV-6 are associated with ciHHV-6 status but not chronic HHV-6 infection, further testing, while not definitive, can help determine whether ciHHV-6 is present. Physicians will need to decide on a case-by-case basis if antiviral treatment is warranted. Quantitative PCR tests done on whole blood can suggest whether ciHHV-6 is present. No commercial laboratory tests at this time can determine if an active HHV-6 infections are present.

Further Studies

All one study can do is open the door; it takes confirmatory studies to make the findings stick. If a sub-category of ME/CFS called Inherited Human Herpesvirus Six Syndrome is to take hold substantial research is needed. Small research foundations like the HHV-6 Foundation can only do so much. Thus far the work has been done on a shoestring; now it needs full funding and that means NIH funding.

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12 Comments

  • Questus

    August 1, 2013 at 10:42 pm - Reply

    Cort,

    This is an important finding.

    This comment stood out: Kristin Loomis, the President of the HHV-6 Foundation that helped fund the study, noted that many people with recurring herpesvirus infections (ciHHV-6 or not) probably have an undiagnosed immune deficiency such as hypogammaglobulinemia, impaired CD4 or NK cell responses, reduced lymphoproliferative response and/or low NK cell counts. The following tests at a lab such as Quest can identify these some of these immune ‘holes’. –

    I have 4 to 6 times the viral load of HHV6, CMV, and EBV as a ‘normal’ person but Dr. Klimas did not recommend antivirals in my case. ( I do have impaired CD4 and NK cell responses.) She noted that my chronic low white count (leukopenia) is a concern with antivirals. She did though suggest that IVIG might be helpful.

    Think this article is important in many ways. I’ve seen people ‘jump’ on the antiviral program over the years, but haven’t seen a lot of progress. Many have taken Famvir for HHV6 without results, and CIHHV6 may be part of the issue. Those people now have concerns about the effectiveness of using Famvir in the future due to resistance.

    Hope to learn more about CIHHV6, and how those infected do with with Valcyte treatment in the future. It sounds promising, but anti virals have been sounding promising for how long now? The cost of Valcyte is roughly 2000.00 monthly.

    I’ll be interested in how future studies on CIHHV6 unfold.

    Good story!

    Best,

    Questus

  • Cort Johnson

    August 1, 2013 at 11:40 pm - Reply

    Thanks Questus,

    We definitely need more studies but it was intriguing that Valcyte, which is probably not used a lot because of its potential side effects, appears to have been effective in all six patients reported. I know of two people who failed on Valtrex, one of whom was fading fast, who did very, very well on Valcyte.

  • Questus

    August 2, 2013 at 2:44 am - Reply

    Cort, It is intriguing.

    Can you tell me more about the person you’ve communicated with who was fading and did ‘very, very well on Valcyte.’? Was that person taking it for HHV6 or a combination of viruses?

    What was his/her situation prior to medicating if you know? Wondering about Immune status and the doctor that oversaw their treatment.

    Am sure we both know more people than we can count who didn’t have a positive reaction to Valtrex. (or Famvir)

    Valcyte is a different animal, and I think this piece of the viral puzzle is intriguing. Wish the puzzle were smaller…sigh.

    Best,
    Questus

  • Cort Johnson

    August 2, 2013 at 3:03 am - Reply

    I believe but am not sure that that person had HCMV. I don’t know about HHV-6; I do remember thinking at least one of the viruses (and I don’t know if there were several or not) was an odd one.

    .He had gotten much better at one point in his illness but then relapsed and kept relapsing….But the time he got to where he got to he really seemed like he was on his way out. No physical stamina left at all. One thing I remember are some sort of viral caused weals on his back. He’s really a brilliant guy and had devised these sophisticated charts that monitored his progress but when Montoya saw him last, he was babbling; all Montoya had to do was look at him to become very concerned; he immediately put him on a stronger drug – Valcyte – and he IMMEDIATELY began to recover. When last I talked to him my impression was that he was healthy….It really fit into the miracle recovery camp for me..

    So there’s Vistide and Valcyte – two drugs with potentially serious side effects that aren’t really used alot (understandably) but do really help some people. Some people can’t handle Valcyte, that’s for sure. We really could use some more effective and less toxic alternatives. Hopefully they are coming.

  • katherine

    August 2, 2013 at 5:29 am - Reply

    I am intrigued, I came down with CFS post-virally (had adult onset mono was the diagnosis), but then did not recover the energy aspect of the disease.
    I had one remission after getting a severe flu, when the flu went away so did the CFS symptoms. This lasted 3 months, I wonder if it “jumpstarted” my immune system? And now with the possibility of an anti-viral course have a little hope, I will follow your results more before going for more testing and treatment, but sounds intriguing.

  • Issie

    August 2, 2013 at 6:58 am - Reply

    There’s two things that came to my mind when I read this —–Lysine and Colostrum.

    As I read more about this, I ran across information showing that one needs to lower arginine and up lysine to help with different kinds of viral problems.

    I have hypogammaglobulinemia and IVIG was suggested to me. But, I don’t want to go that route. I have chosen to go with high doses of Colostrum. Some people are using Transfer Factors – but,, I found an Immune Formula of Colostrum (Symbiotics – it also has olive leaf and some other things to support the immune system in it), and think this may work as well and maybe better. It gives a die off when you first start it – as I have read the antivirals do.

    Interestingly, my doctor who is treating me for a protozoa – believes that arginine feeds it. (If lysine helps to kill the herpes virus and lowers arginine levels in the body. It seems this might would help with lots of issues.) It lives in a biofilm (like a force field around these things)- which is where virus and other bacteria also live. I think the key would be to breakdown the biofilms and take something to make the immune system recognize these unwanted “creatures (and virus) within”. If we could get the immune system to recognize things – that ultimately would be the long term best solution.

    Here is a forum thread of others talking about their experience with some of these medicines spoken of.

    http://forums.dinet.org/index.php?/topic/19720-considering-anti-virals/

    Go for what will help the immune system to work and then there won’t be virus.

    Issie

  • Mary Jane

    August 2, 2013 at 3:20 pm - Reply

    I was on Valcyte for 6 months and thought I would die! Stupid me kept taking it and was determined to see it through! $5,000 later, it did nothing but age me. And my labs indicate reactivation every so often.

    • Cort Johnson

      August 2, 2013 at 3:26 pm - Reply

      It’ hard to give up on something even when it isn’t working. I know who that is……I don’t like to think how much money I wasted (or rather my insurance company wasted at times.) These case reports suggest you should have at least started seeing results after 6 weeks…. and then it would have been good to stay on it for six months to ensure your immune system had returned to health.

      I think we can safely scratch you off of the Valycte responder list! :)

  • readyforlife

    August 2, 2013 at 7:26 pm - Reply

    Last night I was visiting my nephew at the University of Washington hospital and I pulled up your site on my IPHONE to see if anything was new. And it was strange to read about this test that can be done while I was sitting at the hospital that they recommend sending the blood work to. I called my doctor this morning and i’m having a blood draw on Thursday the 8th. Will be interesting to see the results. I have tested positive many times for HHV6 and its usually through the roof. Thanks you for all the hard work you do to keep us informed. It gives some of us some hope.

    • Cort Johnson

      August 2, 2013 at 10:00 pm - Reply

      A bit off serendipity there :). Good luck with the test. I’d love to hear how it turns out..:)

  • Andrea

    August 8, 2013 at 6:17 am - Reply

    I very much doubt that doctors in the Uk would fund investigations or treatment. They do not even send you to Rheumatologists now when they make a diagnosis of Fibromyalgia :-(

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