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Blood Products Advisory Committee Meeting Background Material

Discussion in 'XMRV Testing, Treatment and Transmission' started by ixchelkali, Jul 15, 2010.

  1. ixchelkali

    ixchelkali Senior Member

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    http://www.fda.gov/AdvisoryCommitte.../BloodProductsAdvisoryCommittee/ucm218968.htm

    July 26-27, 2010: Blood Products Advisory Committee Meeting - Xenotropic Murine Leukemia Virus-Related Virus (XMRV) Informational Presentation

    BLOOD PRODUCTS ADVISORY COMMITTEE MEETING
    98 th Meeting, July 26-27, 2010
    Hilton Washington D.C./North
    620 Perry Parkway, Gaithersburg, MD
    Topic: Xenotropic Murine Leukemia Virus-Related Virus (XMRV) Informational Presentation
    Issue: FDA is updating the committee on XMRV, the newly identified human retrovirus (a gammaretrovirus), and FDAs collaborative efforts with other public health agencies and blood establishments to determine whether XMRV poses a safety concern for the blood supply.

    Background:
    Xenotropic Murine Leukemia Virus-Related Virus (XMRV) is a newly identified retrovirus and the first gammaretrovirus of the Retroviridae family detected in humans. It is unrelated to HIV but highly similar to mouse retroviruses. Gammaretroviruses are widespread in vertebrates, but do not establish infection readily in immunocompetent hosts. Gammaretroviruses in animals are implicated in a wide range of diseases including cancers, immunodeficiency, and neurological disorders. XMRV is a simple retrovirus with gag, pol and env genes and unlike HIV or HTLV, has no accessory or regulatory genes. The genome is a dimer of linear, positive-sense, single stranded RNA about 8,300 nucleotides long.

    XMRV was identified using a viral detection DNA microarray composed of oligonucleotides corresponding to the most conserved sequences of all known viruses (1). Using this array, gammaretroviral sequences were identified in samples from 7/11 prostate cancer (PC) patients that were homozygous (QQ) for the R462 mutation for RNAse L which is an important molecule in the innate antiviral response (2). A survey of an additional 86 PC tumors by RT-PCR specific for XMRV showed that 40% of QQ cases were positive for XMRV compared with 1.5% of heterozygous RQ and homozygous wild type RR cases. Subsequently an analysis of 334 consecutive prostate resection specimens using a quantitative PCR assay and immunohistochemistry showed that 6% were positive for XMRV DNA and 23% for protein expression. Taken together, these findings suggest an association of XMRV with prostate cancer (3).

    A subsequent study showed that XMRV could also be detected in patients with Chronic Fatigue Syndrome (CFS), a disease of unknown etiology, known to affect several million people worldwide (4). DNA from peripheral blood mononuclear cells (PBMCs) of CFS patients and healthy controls was tested for the presence of XMRV sequences. XMRV sequences were found in 68 out of 101 CFS patients (67%), compared with 8 of 218 (3.7%) healthy US controls. The viral gene sequences identified in CFS patients clustered with sequences from PC and both sequences were virtually identical. Further investigation using activated CFS patient PBMC co-cultured with susceptible PC cells (LNCaP) showed that virus could be transmitted by cells and supernatant, as indicated by protein expression and transmission electron microscopy, suggesting that the virus being detected by protein expression was infectious. Virus could also be transmitted from 10/12 CFS patient plasma samples. Taken together, these studies suggested that both cell associated and cell-free transmission of XMRV is possible. Finally, antibodies to XMRV were detected in 9/18 CFS patients using a test based on the envelope of a closely related virus, spleen focus forming virus (SFFV).

    Preliminary data from a limited study of XMRV in an animal model (rhesus macaques) showed disseminated infection but only low but detectable transient viremia between 4-14 days. Seroconversion occurred at 11-14 days following inoculation, with titers peaking around day 95. Virus was isolated from T- and B- lymphocytes and NK cells in blood (but not macrophages), prostate epithelial cells, vaginal tissue, and there was evidence for viral replication in spleen, lung, lymph nodes and liver (5).

    Since the discovery of XMRV there have been several controversial reports about the association of XMRV with PC and CFS. Studies of an Irish PC cohort of 139 patients with the R462Q mutation showed no evidence of XMRV (6). In a German study, only 1/105 tissue samples were positive for XMRV DNA from non-familial PC while 1/70 samples were positive from men who did not have PC (7). In a different study of German PC patients, 589 PC tissues with the RNaseL R462Q mutation were tested using nested RT-PCR and all were found to be negative (8).

    In regard to CFS, several recent studies have reported negative findings of XMRV in blood. A Dutch study failed to detect XMRV in PBMC of patients with CFS (9) and similar findings were reported in two studies from the UK although a few samples showed XMRV neutralizing activity in one study (10,11). Studies conducted by CDC scientists in a US population of CFS cases and blood donors showed no evidence of XMRV infection in PBMC and plasma. These data do not lend support to an association of XMRV with CFS or its presence in blood donors. (13)

    Among other related findings are those recently reported by investigators in Germany that XMRV could be detected in respiratory secretions (14). In this study, 267 respiratory samples taken from German patients were screened for XMRV infection by PCR assay. The prevalence of XMRV DNA was 2.3% (3/75) in travelers from Asia who had respiratory tract infections; 3.2% (1/31) in patients with chronic obstructive pulmonary disease; 9.9% (16/161) in immunosuppressed patients with severe respiratory tract infections; 3.2% (2/62) in the healthy control group. It is not clear whether finding XMRV in the respiratory tract indicates that the virus can be transmitted by the respiratory route (14). In general, retroviruses, like HIV-1, are rarely transmitted through respiratory secretions.

    A compilation of all the XMRV studies done so far is shown in appendix I. The reasons for discrepancies between findings are not clear. Differences in cohorts, populations and test methods have been considered as potential causes. In addition, differences in geographic prevalence, genetic variation of the virus or other factors could also potentially contribute to these conflicting findings. Additional studies are needed to confirm disease association of XMRV and to fully understand the role of XMRV in disease causation.
    Discussion:
    (a) Detection methods:
    Currently there are no commercially approved/licensed tests for detection of XMRV infection. The assays used for research studies include PCR, EIA, Western blot, and immunohistochemical methods. The relative sensitivity and specificity of various assays have not been determined and standards for performance of assays have not yet been established.
    (b) Evaluation of Transfusion Risk in the US:
    Transmission through transfusion has not been shown, but is theoretically possible since virus has been detected in blood cells and there is evidence of cell-free virus. A seroprevalence study in Japan found 1.7% of random donors to be positive (12). Preliminary studies have shown that 3/2851 US blood donors (0.1%) were anti-XMRV antibody positive using a research immunoassay based on gag and env proteins (5).
    A Blood XMRV Scientific Research Working Group, led by the National Heart Lung and Blood Institute (NHLBI), has been established to identify and design research studies to evaluate whether XMRV poses a threat to blood safety. An evaluation of blood safety risks includes 1) an evaluation of the prevalence of XMRV in blood donors; 2) if prevalent in blood donors, a determination of whether the virus is transfusion-transmitted; and 3) if transfusion-transmitted, whether clinical manifestations occur. An evaluation of the prevalence of XMRV in blood donors necessitates a way to measure or identify the agent in blood specimens. The fact that different laboratories obtain different results for XMRV detection in patients specimens and different prevalence estimates in normal controls strongly suggests the need for the development of standard XMRV reference and clinical case and healthy donor prevalence panels for XMRV detection. Thus, development of XMRV nucleic acid test (NAT) analytical and clinical panels was identified as the first priority by the Working Group. As a first step towards this goal, an analytical reference panel was developed to validate NAT assays for use in donor survey studies . The panel was developed by the Blood Systems Research Institute which is the Central Laboratory for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II). Virus stocks were prepared from culture supernatants of the chronically infected prostate cancer cell line, 22Rv1. Following titration, reference infected cell preparations were established by spiking known numbers of infected cells into whole blood. Similarly, reference infected plasma preparations were established by spiking pedigreed-negative plasma with known viral titers of cell-free culture supernatants at serial dilutions. These coded analytical reference panels of specimens containing varying concentrations of XMRV virus as well as clinical panels which include biospecimens from blood donors, patients with Chronic Fatigue Syndrome whose blood was previously found to be positive for XMRV by the Whittemore Peterson Institute, and positive and negative control specimens are in the process of being tested by up to six participating laboratories to compare the sensitivity of their respective assays for XMRV. The study participants include laboratories from the NCI, FDA (two laboratories), CDC, Blood Systems Research Institute and the Whittemore Peterson Institute.
    Summary:
    The BPAC session will include several informational presentations on XMRV including a background and review of studies that led to the identification of the virus, ongoing validation studies of XMRV panels, updates of research efforts on test/panel development and other studies.
    Finally, FDA will periodically update the committee on progress in our understanding of XMRV and transfusion safety. As additional data are obtained on prevalence in blood donors and any associated transfusion risks, BPAC may be asked to advise FDA on appropriate measures to maintain the safety and availability of the blood supply.
  2. ixchelkali

    ixchelkali Senior Member

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    This is one of the most encouraging things I've read lately, especially the part about what the Blood XMRV Scientific Research Working Group is doing. That sounds like the kind of controlled study we need.
    I'll sure be glad to hear the results.
  3. George

    George waitin' fer rabbits

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    This is an excellent summary of where we are right now IX, Thank you so much for posting it. Only 3 months ago we read the transcript from the FDA and Blood working group filled with statements like, "perceived problem" and "unknown", "unknown","unknown". This sounds like the first step in the direction of taking this virus seriously. Enough of the big guns are involved that the tide is turning.
  4. Otis

    Otis Señor Mumbler

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    Great stuff ixchelkali!

    I found one point troublesome.

    While I understand this point is important, I hope they don't put too much weight on step #3 or we'll wait way to long to protect the blood supply.
  5. ixchelkali

    ixchelkali Senior Member

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    I know. It could be the place they drag their feet ("Sure it's in the blood supply, but we don't know that it does any harm. Lots of microbes are in the blood supply that are harmless..."). But based on the studies so far, it looks like only about 8 - 34% of people who test positive for XMRV show "clinical manifestations" of ME/CFS. They're going to have to look at what the difference is between those who do and those who don't. Although it could be that when they start testing people with other diseases (MS, autism, Gulf War Syndrome, fibromyalgia, IBS, MCS, chronic Lyme, etc), it could raise the percentage of those showing some kind of "clinical manifestation" much higher.

    One group that I haven't heard mentioned, that I hope they'll start looking at, is cancer patients who develop long-term fatigue with brain fog, neuropathy, etc. following treatment. For instance, as many as 20% of breast cancer survivors suffer from these long-term aftereffects. Nobody knows why, or how to help them, and it doesn't seem like anyone's doing much research on it. The symptoms are so similar to ME/CFS that if they weren't cancer survivors, they'd probably get an ME/CFS diagnosis, so I wonder if they might have XMRV, too.
  6. Otis

    Otis Señor Mumbler

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    Interesting. I bet those symptoms are even more downplayed before treatment, even if they may be part of why they went to a Dr. in the first place.

    Neuro symptoms with cancers elsewhere in the body. May not be an obvious smoking gun but I bet your thought has crossed the minds of Mikovits's, Silverman, etc.

    Can they rule out chemo and other treatments?
  7. Rrrr

    Rrrr Senior Member

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    this is great stuff. is this the same meeting where anyone is allowed to comment during a public session?
  8. George

    George waitin' fer rabbits

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    Think so. (big grins)
  9. Rafael

    Rafael XMRV+ Member

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    Please correct me if I am missing something but it seems that neither the recently published CDC study nor the Delayed FDA/NIH study are mentioned.
    The cynical part of me fears that that the actual discussion at the meeting will be all anal and formal (like a court of law) where evidence that is not yet published cannot be considered.
    If so, the likely positive results from the FDA/NIH will not be considered in evaluating the danger to blood supply.
    The results of this meeting will be published and widely referred to from all over the place for quite some time.
    The cynical side of me wonders if the timing of this particular meeting wasn't considered by those who delayed the FDA/NIH study.
    OK, this episode of the X(MRV)-Files is over. I am going out to enjoy the sun and be optimistic and happy for the rest of the day.
  10. usedtobeperkytina

    usedtobeperkytina Senior Member

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    The CDC study is mentioned, but not FDA / NIH, that I see.

    Also, there is mention of the test that says .1% of blood contaminated. That is labeled a "preliminary study."

    Also, I have heard NPR cover the post chemotherapy "syndrome" if you will. Ha, similar symptoms, but because they have had cancer, it is legitimate. {tina is shaking her head}

    Tina
  11. ukxmrv

    ukxmrv Senior Member

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    In the "And the band played on" movie, there was a scene with some members of the public speaking at what looked like a blood advisory meeting. This was very powerful and people spoke up eloquently about the officials dragging their heels.

    From the transcript of what looked like the last meeting(?) that was published a while back it sounded as if the XMRV danger wasn't being taken seriously as the CFS link was not "proven".

    I keep getting deja vu back to that movie.
  12. Otis

    Otis Señor Mumbler

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    We need an advocate to speak (or better yet 50) and a spy to report back. I think Rrrr was trying to find a local to attend.
  13. VillageLife

    VillageLife Senior Member

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    yep we really, really need to get someone to attend this that has CFS.
  14. ukxmrv

    ukxmrv Senior Member

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    Someone with CFS after a blood transfusion would be ideal. As many as possible.
  15. Rrrr

    Rrrr Senior Member

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    in terms of the public comment session of this meeting: i asked a family member to go, but she will be out of town. boo hoo. i also sent the info to the wash dc/VA CFS support group leader and never heard back. (maybe she has a new email address?)

    AND i emailed Judy M. just as an FYI, and she emailed back that SHE IS GOING TO BE THERE!!!!!!!!!!!!!!!

    once again, superwoman judy mikovits is our savior. that woman is unstoppable, and i could cry just knowing she exists. i know i sound all on-my-knees-and-bowing infatuated, but that is only because i am!

    rrrr
  16. Gemini

    Gemini Senior Member

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    Rrrr,

    Thanks for letting us know Dr. Mikovits is attending the meeting!

    OUTSTANDING!!!!!!

    Gemini
  17. Otis

    Otis Señor Mumbler

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    Rrrr,

    Thanks for your efforts and the update on our superhero. Just don't tell anyone she's susceptible to kyptonite. :)
  18. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    Is this baby gonna be on TV or what. Like on the web. I'm guessing no, because it doesn't say so, and because it's a political hot potato kind of.
  19. Gemini

    Gemini Senior Member

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    Might journalists attend to provide press coverage?

    Should we e-mail the meeting announcement to Health Editors at various papers?

    Gemini
  20. VillageLife

    VillageLife Senior Member

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    Thanks for finding this out!!

    A message I saw on the CFIDS facebook page yesterday said, With the FDA's Blood Products Advisory Committee meeting on Monday (July 26), there is likely to be plenty of information to share on XMRV & Blood Safety. Hear it directly from expert Dr. Louis Katz.https://www1.gotomeeting.com/register/143320272

    Thats good news then, that CFIDS expect there to be plenty of information from the meeting to discuss in the webinar!

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