Tuesday, August 10, 2010

FDA/NIH PAPER in PRESS


"The Alter paper is now in press, but I don't know when it will go online and until then there will be a press embargo," says Dr. Randy Schekman, editor of the journal Proceedings of the National Academy of Sciences, where the FDA/NIH XMRV paper on ME/CFS patients had been accepted and then pulled by higher-ups in the department of Health and Human Services.  The NIH's Dr. Harvey Alter is the principal investigator of the FDA/NIH study and one of the discoverers of hepatitis C.  



On Monday I emailed the CDC press office about this question that Dr. Monroe didn't answer in our interview:  "One of the CDC slides from this week’s Blood Safety Advisory Committee meeting showed that the CDC tested 20 samples from CFS patients that the Whittemore Peterson Institute found to be positive for XMRV.  But, according to the slide, the CDC didn’t find any positives among those 20. Why was this piece of information—that the agency was unable to find positives in any of those 20 samples—left out of the CDC’s XMRV study?"  No word back.  

Sunday, August 8, 2010

Q & A with CDC's
STEVE MONROE

The CDC says it's found XMRV in prostate tissue but omits a crucial fact from its XMRV study on CFS patients


Below are the emailed answers to the questions I posed, by email, to Dr. Stephan Monroe, head of the CDC’s division of High Consequence Pathogens and Pathology.  More problematic than the non-answers to most of the questions on the CDC's present and future course for CFS research is that Monroe didn’t answer one of my questions on the CDC study.

That question was why did the CDC XMRV scientists omit in their paper that they had tested 20 samples that the Whittemore Peterson Institute found to be XMRV positive but didn't find any positives themselves?  Rather than answer it, Monroe simply ran up the next question—deleting its bullet point, thereby altering the questions as posed.  The CDC press office sent Monroe’s responses at 4:42 p.m. Friday, making a Friday follow-up unfeasible.  However, I’m resubmitting the question to Dr. Monroe and will report his reply on CFS Central.

Published in July, the CDC's study failed to find the retrovirus in any CFS patients the researchers tested, unlike the October 2009 Science study by the Whittemore Peterson Institute, the National Cancer Institute and the Cleveland Clinic that found 67 percent of CFS patients positive for XMRV, and the as-of-yet unpublished FDA/NIH study, which reportedly found 80 percent of CFS patients positive for the retrovirus.  The 2010 XMRV studies in Europe have failed to find the retrovirus in patients with either CFS or prostate cancer, the two diseases in which U.S. scientists have reported an XMRV link.

Here are the two questions on the CDC’s XMRV study that CFS Central submitted to Monroe:
  • One of the CDC slides from this week’s Blood Safety Advisory Committee meeting showed that the CDC tested 20 samples from CFS patients that the Whittemore Peterson Institute found to be positive for XMRV. But, according to the slide, the CDC didn’t find any positives among those 20. Why was this piece of information— that the agency was unable to find positives in any of those 20 samples—left out of the CDC’s XMRV study? 
  • Given that the CDC couldn’t confirm any of the Whittemore Peterson Institute’s 20 positive samples, why did the CDC scientists conducting the study conclude that the CDC’s methods were accurate? My sources have confirmed that three independent labs found these samples to be positive.
Here is the one question and answer back from Monroe.  I've highlighted his reply in red: 
  • One of the CDC slides from this week’s Blood Safety Advisory Committee meeting showed that the CDC tested 20 samples from CFS patients that the Whittemore Peterson Institute found to be positive for XMRV.  But, according to the slide, the CDC didn’t find any positives among those 20.  Why was this piece of information— that the agency was unable to find positives in any of those 20 samples—left out of the CDC’s XMRV study?  Given that the CDC couldn’t confirm any of the Whittemore Peterson Institute’s 20 positive samples, why did the CDC scientists conducting the study conclude that the CDC’s methods were accurate?  My sources have confirmed that three independent labs found these samples to be positive. 
The information in the Retrovirology paper was consistent with the specifics of the study design. The results, and methodology, have been confirmed by three different independent laboratories.
    Below are the rest of the questions and answers.  I've deleted the bullets because editing with bullets has proved too problematic in Blogger.
CFS Central: Who decides what research the CDC will pursue when it comes to Chronic Fatigue Syndrome?  Is it you, Dr. Monroe?  Is it Mr. Bill Switzer [principal investigator of the CDC XMRV study]?  Is it Dr. William Reeves [who has long held that CFS is a psychogenic illness and served as the former head of CFS research for 20 years until his transfer in February to Mental Health Surveillance]?  Is it Dr. Elizabeth Unger [acting head of CFS research]? Is it Dr. Thomas Frieden [the head of the CDC]?  Or is it from higher-ups in the HHS organization?  Who decides?

Dr. Steve Monroe: As there is still much to learn about CFS, CDC pursues a broad approach to research related to CFS. Decisions about the direction of CFS research are primarily guided by the insights gained from our continued scientific investigations. 

CFS Central: There are one million people with HIV/AIDS in the U.S. There are one million people with CFS in the U.S. (using the original 1994 Fukuda definition, not the Empirical definition).  The two diseases became widespread in the 1980s.  Some believe that the CDC pursued psychiatric research where CFS is concerned because the agency had its hands full with HIV and didn’t want to deal with another infectious epidemic in this country.  And now decades later, the agency remains in that mode and will continue in that mode.  Do you believe there’s validity to this argument? Why or why not?

SM:  The direction of CFS research has, and will continue to be, based on the best available scientific information and insights gained from our research and the findings of others.

CFS Central: On patient forums in the U.S. and abroad, many bloggers voice that they have no confidence in the CDC’s CFS policies and research.  Patients post on my blog, CFS Central, or address emails to me directly about their disappointment and outrage when it comes to the CDC.  One of the most important reasons CFS patients say that they have no confidence in the CDC is because the agency is pursuing a psychological cause, when much of the evidence, including 2,500 journal articles, points to a physiological cause. Is the CDC aware that many patients have no confidence in the agency when it comes to CFS research and policy?  Does the CDC care that patients have lost confidence in the agency?

SM:  CDC is deeply committed to reducing the morbidity and societal costs associated with CFS to enable a better quality of life for CFS patients. 

CFS Central: As a follow-up to this question, three CFS patients whom I interviewed in 1994 for an investigative article on the experimental [HIV and CFS] drug Ampligen called “The AIDS Drug No One Can Have” for Philadelphia magazine have since died of the disease, including one at age 43, and another at 59 from mantle cell lymphoma, a rare cancer in the general population but one that’s remarkably common in CFS patients. While some patients are dying and many others are bed-bound or house-bound and experiencing seizures, chronic infections, heart failure and short-term memory loss, the CDC is advocating cognitive therapy, antidepressants and “sleep hygiene.”

These mild interventions may help the 38 percent of patients  with major depression who were misdiagnosed as having CFS under the Empirical definition, according to studies done by Dr. Leonard Jason.  These mild interventions, however, aren’t helping most patients who meet the original 1994, including three CFS patients whom I interviewed in 1994 who have since died of the disease: Nancy Kaiser, Jerry Crum and LeAnne Hyneman.  Does the CDC see the disconnect in what the CDC is advocating—antidepressants, “sleep hygiene” and cognitive therapy—and what patients, at least those who meet the original 1994 Fukuda definition—are experiencing? What should the CDC do to help these patients now and over the next five years?

SM: Unfortunately, there are very few double-blind, placebo-controlled studies of interventions for alleviating symptoms of CFS. CDC recommends that people with CFS work with a healthcare professional to develop a treatment plan that is highly individualized and addresses their particular constellation of symptoms. 

CFS Central: At the first international workshop on XMRV in September, the CDC’s William Switzer will be speaking on assay development to test for XMRV.  Has he ever found XMRV in any blood or tissue from any patients? 

SM: CDC has detected XMRV in samples from patients with prostate cancer.  Preliminary results were reported at a scientific conference and the findings are being prepared for publication in a peer-reviewed journal.

CFS Central: As I understand it from the CDC website, the foster-care study, which will begin in late 2010 and continue to 2013, will explore whether foster children are at higher risk for CFS than the general population of youths. 

What happens if a child doesn’t want to participate? What rights do the children have?
Who is advocating for these children? 
Will there be a court-appointed lawyer for these children? 
Or will it be only the state? 
Or will it be the foster parents plus the state? 
On the CDC website, it discusses “pharmacologic intervention trials” with these children. What kind of medications will be used? 

SM: The 5-year strategic research plan for CFS was developed in 2009 and is periodically updated. The foster-care study is not included in the current plan. 

CFS Central:  Dr. William Reeves, who was transferred from the head of CFS research to senior adviser for Mental Health Surveillance in February, is still authoring studies on CFS. His latest, released last week, is “Personality Features and Personality Disorders in Chronic Fatigue Syndrome.”  Will Dr. Reeves continue to do research into CFS over the next few years? 

SM:  CFS research will continue to be inclusive of many scientists, including those within and outside the agency, whose expertise can help us learn more about this illness.

CFS Central: The CDC says the revised 1994 Fukuda definition is the equivalent of the original 1994 Fukuda (AKA Empirical) definition. The CDC has been using the revised definition in its studies since 2005.  The CDC reported in 2003 that the estimated occurrence of CFS under the original definition in the U.S. was .23 percent.  In 2007, the CDC reported the occurrence with the new definition broadened to 2.5 percent, a 10-fold increase.  Likewise, Dr. Leonard Jason’s studies found the same 10-fold increase in the new definition over the old definition.  In addition, Jason found that in contrast to the original definition, 38 percent of patients characterized as having CFS under the revised definition actually had “major depression.”  Therefore, how can these two definitions of CFS be equivalent? 

SM:  The CDC uses quantitative assessment tools to reproducibly identify those individuals who meet the 1994 international research case definition of CFS.  The defining symptoms and criteria for exclusion have not changed. 

CFS Central:  The CDC devised the 1988 name Chronic Fatigue Syndrome to describe the symptoms of patients in the outbreak on Lake Tahoe, Nevada, among other clusters. Many of those patients had neurological symptoms and all had physical symptoms.  In the CDC’s XMRV study, it says: 

“The Lombardi et al. study [AKA the October 2009 Science study that found XMRV in 67 percent of CFS patients] specifies that samples were selected from patients fulfilling the 1994 international CFS case definition and the 2003 Canadian Consensus Criteria for CFS/ME…. Most notably, the Canadian Criteria include multiple abnormal physical findings such as spatial instability, ataxia, muscle weakness and fasciculation, restless leg syndrome, and tender lymphadenopathy. The physical findings in persons meeting the Canadian definition may signal the presence of a neurologic condition considered exclusionary for CFS and thus the XMRV positive persons in the Lombardi et al. study may represent a clinical subset of patients.”

Dr. Monroe, not only the Canadian Criteria, but the 1994 Fukuda definition—listed on the CDC’s website as the agency’s official definition for the disease—includes multiple physical findings.  Indeed “tender lymph nodes” is listed as a diagnostic criterion for CFS on the CDC website.  In addition, “difficulty maintaining upright position, dizziness, balance problems or fainting” are neurological findings listed as common CFS symptoms on the CDC website. 

Is the CDC now saying that the patients who exhibit these physical and neurological symptoms may no longer meet the CDC definition of the Chronic Fatigue Syndrome?

If the patients with physical and neurological symptoms who meet the original 1994 Fukuda definition of Chronic Fatigue Syndrome don’t have CFS, what, then, do they have?

SM:  People with CFS generally experience a variety of symptoms, many of which are consistent with other health conditions. 

Similarly, people who do not meet the diagnostic criteria for CFS may experience symptoms that are common among people who suffer from this illness.


Dr. Mary Schweitzer contributed to this post.
 
This article is copyright CFS Central 2010. All Rights Reserved. You may quote up to 150 words from this article as long as you indicate in the body of your post (as opposed to a footnote or an endnote) that the excerpt is by Mindy Kitei for CFS Central. You may not reprint more than 150 words from this article on blogs, forums, websites or any other online or print venue. Instead, refer readers to this blog to read the article.
 

Monday, August 2, 2010

3 HIV DRUGS WITH POSSIBLE EFFICACY AGAINST XMRV

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This past spring, Dr. Ila Singh at the University of Utah conducted one of three recent studies testing HIV antiretrovirals against XMRV in vitro (in the test tube).  Singh discovered that two drugs—tenofovir and raltegravir—killed the XMRV retrovirus, and corroborated an earlier study by the Mayo Clinic that concluded that AZT is also effective against XMRV.  In addition, Singh found any two combinations of these three drugs were synergistic.  She didn’t test all three drugs together, so it’s not known if a triple cocktail would be even more effective.  It’s also possible that the triple cocktail could be less effective than a two-drug combo.

Likewise, a June 2010 study by the National Cancer Institute also found that AZT, tenofovir and raltegravir inhibit XMRV in vitro.  Here’s a capsule view of the three drugs:

Nucleoside Analogue Reverse Transcriptase Inhibitors
Zidovudine (brand name AZT).  FDA-approved in 1987, AZT was the first drug used to treat HIV/AIDS, though it was developed in the 1960s as a cancer drug.  In 1974, German scientist Max Planck discovered that AZT was active against a mouse retrovirus called Friend murine leukemia virus, a close cousin of XMRV.  In HIV, AZT works by stopping the enzyme reverse transcriptase from converting the retrovirus’s RNA into DNA, which is then integrated into the genetic material of the host’s cells. Normally DNA transcribes (converts) RNA.  Reverse transcription is the reverse: RNA transcribes DNA.  Nucleoside analogue reserve transcriptase inhibitors are often abbreviated NRTIs.

Common side effects of AZT include:  nausea, loss of appetite, headache, tiredness, vomiting, constipation, asthenia (weakness).  Less common side effects:  anemia, bone-marrow suppression, bruising, muscle pain and myopathy (muscle weakness), mitochondrial toxicity and lactic acidosis, body-fat redistribution, elevated liver enzymes and liver damage, a bluish discoloration of fingernails and toenails, and allergic reactions.  Nausea is the most common side effect from AZT and can be minimized by taking the drug with food.  However, high-fat meals tend to exacerbate the nausea.

Nucleotide Analogue Reverse Transcriptase Inhibitors
Tenofovir (brand name Viread).  Nucleoside analogs are converted into nucleotide analogs by the body. If you take nucleotide analog reverse transcriptase inhibitors (often abbreviated NtRTIs), you bypass that step.  FDA-approved in 2008, Tenofovir, like AZT, blocks the retroviral attack on the host’s healthy cells by preventing the reverse transcriptase enzyme from doing its job of transcribing single-stranded viral RNA into double-stranded viral DNA.

Common side effects of tenofovir include: diarrhea, headache, pain, depression, rash, asthenia (weakness), nausea.  Less common side effects:  vomiting, gas, loss of appetite, weight loss, insomnia, dizziness, sweating, muscle pain and myopathy (muscle weakness), mitochondrial toxicity and lactic acidosis, kidney and liver damage, Fanconi syndrome, exacerbation of hepatitis, decrease in bone density, elevated blood sugar, fast or irregular heartbeat, and allergic reactions.  Kidney toxicity can occur within the first few months of taking Tenofovir, so kidney function must be monitored.  Dehydration contributes to kidney toxicity and can be minimized by drinking more water.

Integrase Inhibitors
Raltegravir (brand name Isentress):  FDA-Approval in 2007, it’s the first and only approved integrase inhibitor, though others are in the pipeline.  Integrase inhibitors block a later phase of retroviral integration than NtRTIs or NRTIs do.  Raltegravir prevents the enzyme called integrase from inserting double-stranded viral DNA into the host cells’ DNA. 

Common side effects of raltegravir include: rash, headache, nausea, asthenia (weakness) and fatigue.  Less common side effects:  gastritis, abdominal pain, insomnia, dizziness, fever, anemia, diarrhea, insomnia, rash, kidney damage, kidney failure, high blood sugar, depression, and allergic reactions.

With HIV patients, one drug is started and a second drug in added one to two weeks later, and a third drug is added one to two weeks after that. 

Dr. Ila Singh discussing XMRV and the HIV drugs being tested in animals inoculated with XMRV:

Video Courtesy of KSL.com

This post should not be construed as medical advice.  Nor is this post an endorsement of the use of antiretrovirals for ME/CFS patients and an XMRV diagnosis.  I am a science writer, not a physician or a researcher.  Consult your health-care professional before beginning any treatment plan.

Coming up:  Drugs that may help clear XMRV reservoirs.  Plus an interview with the CDC's Dr. Steve Monroe, director of the CDC’s division of High Consequence Pathogens and Pathology.

This article is copyright CFS Central 2010.  All Rights Reserved. You may quote up to 150 words from this article as long as you indicate in the body of your post (as opposed to a footnote or an endnote) that the excerpt is by Mindy Kitei for CFS Central.  You may not reprint more than 150 words from this article on blogs, forums, websites or any other online or print venue.  Instead, refer readers to this blog to read the article.
 

Monday, July 26, 2010

DR. ERIC KLEIN'S
XMRV LECTURE


Dr. Eric Klein, chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic and co-author of the first study linking prostate cancer to the retrovirus XMRV, recently gave an excellent 17-minute lecture on the retrovirus XMRV entitled, "Is prostate cancer an infectious disease?"  The lecture covered ME/CFS as well.  At about eight minutes into his talk, Klein says: "We think XMRV probably infects everybody, but it persists in those who are deficient in their antiviral defenses."  

I asked Klein about that, and he clarified in an email:  

"What I meant was that anyone, regardless of the structure of their RNaseL gene [which helps fight viruses], can be infected.  Initially we thought only those who have a specific mutation in that gene were susceptible to infection.  I did not mean to imply that the whole population is infected; it is likely that they are not.  Current studies suggest that 3 [percent] to 7 percent of control patients (non-prostate cancer and non-CFS) have evidence of prior infection as determined by the presence of antibodies to XMRV in their blood." 

Klein is the editor-in-chief of Urology and has authored more than 200 journal articles.  He is listed in Best Doctors in America.

Here's the link to Klein's lecture, though there seems to be a glitch in that the audio is sometimes in Spanish--even when you choose English:
http://webcasts.prous.com/AUA2010/html/1-en/template.aspx?section=7&p=7,11872#

A two-minute segment with Dr. Eric Klein and Dr. Robert Silverman (coauthor of the first study linking XMRV to prostate cancer):