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Biochemical, inhibition, inhibitor resistance studies XMRV reverse transcriptase

Discussion in 'XMRV Research and Replication Studies' started by Jemal, Sep 9, 2011.

  1. Jemal

    Jemal Senior Member

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    http://nar.oxfordjournals.org/content/early/2011/09/08/nar.gkr694.full
  2. Jemal

    Jemal Senior Member

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    They are talking about mutants of XMRV and said mutants have acquired resistancy to certain antiretrovirals. This is significant I think?

    Edit: They are probably talking about artificially created mutants?

  3. In Vitro Infidelium

    In Vitro Infidelium Guest

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    Which (if one were to argue for XMRV being a disease agent) raises very real concerns about prospective anti viral treatments, and which is why the HIV comparison is significant. It really is quite bizarre that those who have argued for the XMRV hypothesis of M.E/CFS, and who frequently draw a comparison with HIV, have often been the same people arguing for anti retroviral trials, without any acknowledgement of the resistance problem that dogs HIV treatment. In fact one could hypothesise that if XMRV were actually present in an individual (rather than being a contaminant of a testing process), that it could be turned from a wholly benign entity, into a serious pathogen, by the very act of long term ART.

    IVI
  4. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    IVI, I think the whole point about patients using ARVs is that they believe XMRV is not a benign entity. Unless, of course, you don't think ME is a serious disease.

    Irrespective, your argument here is that you don't believe we should be trying to cure ourselves of XMRV by using these ARVs because in the future these ARVs might be useless in treating XMRV???
    OverTheHills likes this.
  5. alex3619

    alex3619 Senior Member

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    Hi, I have not read this paper in depth yet, but two points struck me. One, they show the mechanism for slow replication, and two they show the mechanism for low mutation rate of XMRV. Bye, Alex
  6. In Vitro Infidelium

    In Vitro Infidelium Guest

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    I'm merely going by the internal logic of XMRV = disease causation hypothesis. As far as what I 'believe': I think it is wholly inappropriate for any physician to be prescribing medication with poentially serious side effects (liver damage etc) where there is no established disease causation process and where, if the hypothesised disease were to be present, medication resistance is probable with consequent, wholly unknown outcomes.

    In the case of HIV the issue of resistance has to be dealt with pragmatically because the effect of witholding ARTs is more damaging than commencing at an early stage, the inevitability of drug resistance is managed by cycling through drug combinations until the available treatments have been exhausted and the patient enters a terminal phase. In the case of XMRV there is not only no established effective assay to measure ongoing ART effect, there is only limited evidence of ART effectiveness and no evidence on which to base pragmatic treatment in the face of resistance.

    If XMRV has the potential to be disease causative then creating the circumstance in which resistance is encouraged (selective erradication of drug susceptible strains) seems foolhardy. Of course if the proposed treatment is capable of destroying the disease agency before resistance can be established, there would be no problem - the treatment outpaces the mutational capacity of the disease agent - but where is the evidence for this fast track effect ? Extended treatment is a recipe for resitance build up'. Even if XMRV were to be the agency of illness in a patient diagnosed with M.E/CFS, the disease as presented is not killing them, or at least not quickly - this may not be same for XMRV that has been selectively mutated - and then what treatment is going to be used ? With just a couple of in vitro tests indicating that a couple of drugs might work against currently isolated XMRV, what confidence could there be in finding an effective in vivo treatment for a mutated resitant strain before the patient dies ?

    IVI
  7. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    IVI, by your words it reads as though you do not have ME, nor any illness resembling chronic fatigue. Forgive me if I have misjudged your postings, but if you don't have ME then you have no idea how costly this disease is, nor how desperate patients are to find effective treatment. Nor does it appear that you have the medical expertise to be advising against the use of ARVs.

    Perhaps you could consider that a disease that doesn't kill you could be worse than one that does.
    Next time you meet someone with real ME ask them if they have at any stage contemplated or even attempted suicide. Then ask them why. The answer, if honestly considered, will perhaps give you a new perspective into this illness and the courage of those who choose to battle on, irrespective of the cost.
    OverTheHills likes this.
  8. Bob

    Bob

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    Does anyone understand the above? Are these types of antiretrovirals?


    I'm sorry - I can't read the paper right now...
    If anyone has read it, does it say where they obtained their XMRV isolates from?
    And is there any discussion about how much genetic variation there is between the strains?

    I'll read it later...
    It seems like quite an interesting study.

    Thanks for posting, Jemal, as always.
  9. Jemal

    Jemal Senior Member

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    I think the toxicity of antiretrovirals isn't really that bad anymore? As long as you have a doctor overseeing your health. I would never recommend taking such drugs without a doctor, they are certainly nothing like aspirin.

    What I just don't get is why people are trying to make antiretrovirals sound so scary. People with ME/CFS are taking drugs like Antibiotics, Prednison, Ibuprofen and even chemotherapy agents. All those drugs can be very dangerous as well without proper supervision. Antibiotics are also making certain bacteria resistant.

    At the moment I am not personally convinced (current) antiretrovirals are the silver bullet. I do believe though patients should be able to try them when properly supervised and they understand what they are getting into. Even in these early days, when nothing is really certain yet...
  10. redo

    redo Senior Member

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    In Vitro Infidelium. I totally agree with you in the case of a doctor actively seeking out half motivated patients to give them ARVs out of a trial. But if it's the other way around, than I totally disagree; if an informed patient, who knows it's a long shot, and knows it might backfire, seeks out a doctor and asks to be allowed to give it a shot (it's their own body) than I see no problem with the doctor allowing the patient to try. And that's the case if it's this medicine group, or monoclonal antibodies, antibiotics or other things. As long as it's informed consent, and patient seeking doctor.
    OverTheHills likes this.
  11. In Vitro Infidelium

    In Vitro Infidelium Guest

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    Only a complete fool would engage in advice giving about ARV treatment on an open frum - the only possible advice would be "consult an expert". As to my health status, why would I write about a scientific issue in terms that defines my personal health ? Medical science can rarely be understood in terms of an individual's self perception of their own dysfunctions, which is why objective measures of multiple subjects matched to multiple controls, forms the body of clinical research. In any case the whole 'show me your stigmata and I'll accept you belong' qualification on forums like this is both absurd and obnoxious.

    The subject of this thread is a study titled Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase - I don't see where appeals to emotion have relevance. Suicide and 'battling on' are not specific qualities of people affected by M.E/CFS and the implication that one has to acknowledge 'suffering' in order to be entitled to comment on the science relevant to M.E/CFS suggests a deeply unheathy attitude toward contrary perpectives - the kind of attitude that leads to cultistic groupings. This is an Internet forum where the participants are predominantly pseudonymous and none of us can know anything about any other poster beyond what each poster claims, in that circumstance scepticism and civility are the only meaningful guidance for how to conduct a discussion.

    IVI
    Firestormm likes this.
  12. In Vitro Infidelium

    In Vitro Infidelium Guest

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    That still avoids multiple ethical considerations - true the burden of responsibility falls to the physician more than to the patient but ' it's what the patient wants' is not an ethical defence. The first consideration that follows from the paper in discussion, is that of prior expression of concern about 'resistance' - from the publication of Lombardi et al there were numbers of commentators warning that ill considered ARV treatment in advance of further research was foolhardy - Tanyaradzwa et al have shown that this prior concern was valid. From the position that resitance is a likely issue, one has to conclude that until the impact of resistance is understood, speculative treatment of an assumed XMRV infection would be unethical, not simply because the patient's own life may be at risk, but because a mutated resistant strain may actually present higher infectivity risks, thus creating a more serious and more communicable pathogen with public health implications. For what it's worth I think that is a highly improbable outcome - but until these questions are asked and answered it is very difficult to see how any physician could approve speculative ARV treatment of M.E/CFS patients. And that is even without dealing with issues of reliability of test assays which purport to show presence of XMRV, or the complete absence of evidence of disease processes associated with XMRV.

    IVI
  13. currer

    currer Senior Member

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    There is a very good analysis of this paper (which is pure research) by Dr Yes on the other forum.

    The paper is researching how XMRV might behave. It does not look at what is actually happening iin vivo.
  14. Bob

    Bob

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    Personally, I would say that 'supportiveness', 'kindness', 'sensitivity', 'empathy' and 'thoughtfulness' might also be helpful qualities to bring to a supportive patient forum.


    I disagree, and I actually think the opposite. I think that on a forum such as this, where people do indeed have to 'battle on' and sometimes deal with issues of suicide or suicidal feelings, then it is wise to post sensitively such that a 'logical' comment about an issue of science will not be inappropriate to the reality of people's lives, and cannot be misinterpreted such that it offends people.
    So I think it might be helpful to be mindful of people's personal lives when posting comments consisting purely of 'logical reasoning'.


    IVI, it is very easy to write in very logical, black and white terms on a subject like this.
    But in reality, things are slightly different.
    I think that if you took time to consider how your comments might be perceived by someone who has a different perspective to yourself, or less scientific knoweledge than yourself on this specific subject, then all the confusion in the last few posts could have been avoided.

    I happen to agree with you on some of the issues you've raised regarding ME patients taking antiretrovirals, even though I am one of the most enthusiastic followers of the XMRV science.
    (i.e. there is no clinical proof that antivirals work for ME patients; even the anecdotal evidence is sparse and not yet convincing (in my opinion); there is a lot of research to be done yet; there is the issue of toxicity; and there is the issue of drug resistance both at a personal level and at a universal level.)

    But you have failed to explain these issues clearly to the people who you are discussing them with.
    If i didn't know about the details of all of these complex issues already, then i would be none the wiser from your posts.

    Please remember that most people on these forums are patients and not scientists. So not everyone will have a clear and immediate understanding of the issues that you have raised if you don't explain them fully.

    Having said what i've said above, I also fully understand why someone would want to take antiretrovirals.
    And, in desperation, I might do so myself.
    If I was more ill than I am now, as I have been in the past, and I could not see any quality of life for myself in the future, then i would indeed try anything.

    Indeed, when I was first ill, I was feeling desperately ill, and I had no medical support, or medical input at all, other than being told that I just had a respiratory infection, and that I was "catastrophising", by my family doctor. The only thing that I could think could be making me so ill was a tooth where i'd recently had a root filling (I thought it might be an infected root). So I had the healthy (but root-filled) tooth taken out, and still have the gap to show for it. Although I miss my tooth, I would do the same now if i was in the same situation.

    So to put it another way, your black and white logic can come across as insensitive to people's real world situations.
    It's easy to quote from a text book. But people do not live their lives according to text books.
    When people are desparetly ill, they will try things.
    No amount of lecturing from you will change that.

    You appear to be accusing people of wrongdoing and to be interfering with people's personal lives. This can be taken personally by the people whose lives you appear to be interfering with.
    Maybe that's not what you intend, but if you post insensitively on a patient forum, then it is easy to step on people's feelings and to step on people's lives.

    On a support forum like this, rather than a science forum, I think that it is sensible to consider more than the pure science, but how science interacts with the reality of people's lives, and how it potentially interacts with our lives in a personal capacity.

    If I was in a situation where I believed that antiretrovirals might help me, and I was desperately ill, and deeply in need of support and hope, then I would try the drugs, and I wouldn't care at all about such things as drug resistance.

    That might sound selfish or stupid to you, but in times of need, people sometimes need to take calculated risks, or make selfish decisions. And if doctors are prescribing antiretrovirals, then no one has the right to point the finger accusingly at the patients. I don't know if that was your intention, but you do have a certain way of writing that seems to accuse ME patients of all sorts of stuff sometimes.

    In such a situation, none of your lecturing would change my opinions. Information might change my mind, but lecturing wouldn't change a thing.

    If you don't explain clearly why prematurely taking antiretroviral drugs could potentially affect the world-wide population of ME patients, and affect an individual's chances of long term recovery or cure, then many people will not know. So how about providing people with clear info on the subject, rather than scientific banter?

    If you provide the information sensitively, and take into account the reality of people's lives, and avoid lecturing, then I'm sure that you will get a positive and a receptive response, instead of provoking negative responses.


    IVI, I think you are missing the point that was made. The point being made was that maybe you aren't aware of how seriously ill people with ME can be. In which case it might explain why you appear to have a lack of insight into the reality of people's real-life situations whilst you lecture us all about ethics in science.



    ETA: If this post comes across as a lecture, then I should obviously try practising what I preach, but at least I've got a good sense of irony!
    RustyJ likes this.
  15. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    Yes. This is useful information. Worth a read.
  16. Bob

    Bob

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  17. Marco

    Marco Old blackguard

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    Which does beg the question of why a raft of negative papers recently have felt the need to reiterate the dangers of extra trial ARV use and drug resistance.

    They have concluded that they did not find XMRV in patient samples and thus there is no association between XMRV and ME/CFS.

    If they have confidence in these conclusions why worry about drug resistance developing in a virus that they claim isn't there?

    Seems a little superfluous to me.
  18. ukxmrv

    ukxmrv Senior Member

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    We need to remember that in the UK we have had the PACE trial published and the SMILE trial of the Lightning Process coming up. It's a little ironic to be talking about ethical considerations when these are happening to ME patients here and now.

    I was involved in early graded exercise experiments and my health made much worse by doctors who recommended and oversaw these - so I am cautious and have experience of what it feels like. I've been prescribed drugs that have had a detrimental and long term bad effect on me - even 10 years later.

    Patients are already contacting the WPI and drug companies and asking to be involved in clinical trials for ARV and XMRV so there is no shortage of patients interested. A possible later resistance to further drugs is important and it's already been discussed on patient forums. Not a closely guarded secret or anything new to consider. We started talking about this when the first drugs were tested in vitro.

    For some older, elderly patients or long term patients the decision to go on a drug trial when the implications of future drug resistance is unknown but short terms gains could be high, may be for them a measured and the right decision.
  19. Daffodil

    Daffodil Senior Member

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    so what is an example of Translocation Deficient RT nucleoside inhibitor?
  20. Bob

    Bob

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    You've made a very good point there ukxmrv.

    What's doing the most damage to our lives? The odd patient taking anti-virals, or the false 'science' of the psychiatric lobby? (That's a rhetorical question)

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