Saturday, February 25, 2012

5 Debate About Embers Non-Human Primate Chronic Lyme Disease Study Continues

UPDATE - Feb. 27:  I did receive a response from Dr. Baker. See comments below this post.

There is some heated discussion going on at CALDA's web site regarding Embers et al study, "Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection (2012)".

I wrote about this study last month and commented on some of the findings and the need for further research and confirmation of the findings in this study. (I recommend reviewing that post and comments made on it.)

CALDA's Lorraine Johnson has questioned Dr. Phillip Baker, who was Program Officer for the NIH's Lyme disease research division at the time the Embers study began (then known as Mario Phillip's study; Baker retired from NIH in 2007 and is now in charge at the ALDF), over the 12 year delay of Embers et al publishing the results of this study.

Dr. Baker himself decided to respond to Lorraine's questions and respond to a number of the comments and questions patients and advocates shared on CALDA's Lyme Policy Wonk blog.

Interestingly, a number of people have discussed this study on Lymenet Europe - with one member, Henry, questioning the use of ceftiofur when Embers study was supposed to emulate Klempner's chronic Lyme study. This issue happens to be one of of main issues Dr. Baker also raises on the Wonk blog about the Embers study. (Warning: There are seven pages of spirited discussion on this topic at LNE thus far - some of which may raise blood pressure in readers.)

To follow the discussion and see an example of different points of view over the issue of chronic Lyme disease, read here: http://lymedisease.org/news/lymepolicywonk/lymepolicywonk-was-this-important-lyme-study-hidden-for-12-years.html

In the meantime, I have submitted my own questions and comments to CALDA's web site for Dr. Baker. As of this writing, my post has just cleared moderation and I await a response from Dr. Baker.

I want some answers. Not just about oversight for how the study was designed but about the lack of treatment studies for chronic Lyme disease patients.

Even if your position is that chronic Lyme disease is not caused by a persisting Borrelia infection, there is no reason why more research cannot be completed to provide evidence that this is or is not the case in some circumstances. And even if your position is that chronic Lyme disease's persisting symptoms may be caused by other factors, there is no reason why more treatment research cannot be completed to provide evidence either for or against these factors playing a role...



Dr. Baker,

First of all, I want to thank you for being here and presenting your view in the presence of Lyme disease patients who have different points of view than your own and who are at a minimum questioning your opinion about Lyme disease and at a maximum - quite angry.

This isn't an easy thing to do. I recognize that. But this is a necessary thing to do, and I wish that more dialog occurred between people with differing views even at the risk of it becoming contentious. It is often the only way opinions get aired and heard and questions get answered - even if we don't like the answers we hear.

I have a few questions for you, and hope I did not miss the boat on getting a response from you at this late hour:

1) Just so the storyline is clear: Who determined that ceftiofur should have been used in Embers et al study on NHP and is this decision something that NIH would have had to give approval - or is this a decision that would have been made at the individual level of the PI/researcher and not require any approval from the NIH? Would any independent governing scientific board outside the NIH been expected to approve of the study design including methods and materials? It seems that in order to emulate the Klempner study, the antibiotic chosen should either be the same as used in the original study or have, as you've stated, PK and PD that are pretty much indistinguishable from ceftriaxone.

2) In your opinion - and in the opinion of others at the ALDF - would you have to see studies separately completed on ceftiofur that provide you with evidence that its PK and PD in NHP are functionally equivalent to the use of ceftriaxone in humans? If these studies are conducted and they are found to be equivalent, then would you say that the results of the Embers et al study are valid? (Even if - according to your position - they don't yet prove a persistent infection/persister cells are the cause of patients' symptoms.)

3) The central point on which a lot of this debate hinges is whether or not spirochetes which remain after antibiotic treatment are viable and infectious. I've never gotten the impression that the majority of researchers out there have debated the existence of spirochetes after abx treatment - the impression I've had is that they either didn't think they were the cause of persisting symptoms in patients or did not know one way or the other if they were the case of persisting symptoms.

Parallel to demonstrated survival of some spirochetes after abx treatment, some research has indicated that a combination of Borrelial strain, host genetics, immune system response, and in some cases, molecular mimicry - may be causative factors for persisting symptoms. I myself think that based on evidence I've read to date, both persisting spirochetes and immune system changes can lead to persisting symptoms. I am particularly intrigued by HLA-DRs and variable immune response in this regard (see "HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens" by Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.).

My questions are:

When is the NIH-NIAID going to conduct more studies aimed towards this end? And also, if you and others are convinced that chronic Lyme disease patients are not suffering from persisting infections - why hasn't more treatment research been conducted that supports your point of view of what is or what are the causative factors for such symptoms?

Why are patients, advocates, and Lyme disease advocacy organizations having to donate money to Dr. Karen Newell Rogers and Viral Genetics to find alternative treatments to long-term antibiotics - why isn't the NIH-NIAID pursuing these alternative approaches now, if the argument is that long term antibiotics do not work and you consider them unsafe (Which in my opinion debatable in my eyes - I have personally benefited from more than the guidelines recommend - and I do not think the use for or against more abx is applicable to everyone because this is a heterogenous patient population. The patients need to be characterized into subgroups first rather than boxed into meeting CDC specific requirements before designing new trials.)?

I have been offended with the letter to the Lancet about Lyme disease patients and advocates supporting pseudoscience when so many of us have wanted to fund more research and get answers. When a number of our friends and families have donated their money to research even when they have already paid so much for treatment.

Some of the answers are already there. If more than one hypothesis is solid enough for testing, I'm for it. Test different combinations of antibiotics. Create drugs which have the anti-inflammatory properties of these antibiotics and use them as a control against combinations of antibiotics. Use higher doses of orals, if the fear of line sepsis freaks you out (it does me, and I have not had a PICC line by choice). Try testing thymus peptides and altering the distribution of B cells to see if that helps patients.

What I see as an observer is that Lyme disease treatment research has been shut down unless it's for acute Lyme disease. We need more late stage untreated Lyme disease research, and I'm with Fallon on this one - more specific neuroborreliosis research. His suggestions for those trials seem worthwhile.

But for God's sake, something has to be done. Some people are seriously impaired. I am doing somewhat better now and have my mind back to a large degree and don't need a wheelchair. But I am not yet well enough to work due to pain and fatigue with normal amounts of exertion. Something is broken there.



Dr. Baker's response to me:


Hi Campother,
Even though I feel that some have their minds made up and will not believe anything that I have to say, I will try to answer your questions:
1. Dr. Philipp received a small grant (AI042352) to conduct an experiment in NHPs to replicate the Klempner clinical trial, except of course for the manner in which the NHPs were infected. Because the grant was a small one (about $250K as I recall), Dr. Klempner was able — with support from the drug company– to provide him with the ceftriaxone and doxycycline to be used; these antibiotics were from the same lots used in the human study. Fair enough? That made working on a small grant a bit easier. 
Since NHPs are rather expensive to use and maintain, not too many could be used in the Philipp study because of limited funding. Furthermore, NHPs were in short supply at that time because of increase competition for use in studies on AIDS. The grant was funded for a 4 year period of time, during which time Dr. Philipp reported to me that he was having technical problems, especially with the strain of Borrelia that he had been using in past experiments; it appeared to have “lost its punch” and was no longer eliciting an infection of the same magnitude and character as noted in previous studies. This meant that he would have to re-drive the strain and test it in other NHPs to confirm that it was suitable for use in the definitive studies planned for the grant; that of course would take a great deal of time — and additional NHPs–to do. 
Although situations like this are unfortunate, they do happen and are part and parcel of the realities of doing scientific research — if you want to do it right. 
So, as far as Dr. Philipp’s original grant is concerned, it expired — after the 4 year period– with no data that he felt was was ready and complete for publication at that time. Obviously he continued with his NHP studies and apparently received funding from other sources; note that research Resources grants like RR00164 are designed for the purchase materials, equipment, and supplies, in this case, more NHPs I assume. But, I was “out of the picture” at that point — as far as Dr. Philipp’s research on NHPs was concerned. Keep in mind that as Program Officer, I was not the czar of NIH’s entire research program on Lyme disease, even though so people have the mistaken notion that I had such “power”.
So, you ask who made the decision to use ceftiofur instead of ceftriaxone? I honestly don’t know. 
You will have to ask Dr. Philipp, whose e-mail address is provided in the Embers paper. During the time that Dr. Philipp was doing his work under AI042352, it was being done in accordance with the terms of that grant indicated above. Whatever else he did — or may have done– must have been accomplished afterwards and with other support that did not involve me or NIAID. I must say that I find it strange that the term ceftriaxone is used throughout the Embers et al. paper, and it is only in the first paragraph on page 9 that it is first mentioned that ceftiofur was actually used. I find that very strange indeed.
As stated before and in other postings on this site, I have two major — and legitimate– concerns with the work reported by Embers et al. . First, since so little is known about the PK, PD, and MIC of ceftriofur, was the treatment adequate to eliminate the massive infection induced by needle inoculation? Since the author did not provide such assurances, that is a major and significant unknown. Second, if the therapy was adequate, there is no evidence to indicate that the “persistors” are able to infect other animals and produce disease. They might just be sitting there, for all we know, doing nothing harmful to the host. In view of these considerations, the PCR, RT-PCR, and xenodiagnosis data are not informative. In fact, there are no real differences between the antibiotic treated and sham-treated groups in terms of the objective signs of infection (pathology) noted ; that makes me wonder if the therapeutic regimen was truly effective. So, if I were reviewing this paper for publication in a journal, I would have to reject it publication for these and other deficiencies that I will not elaborate on at this time.
2. Since ceftiofur and cetriaxone differ significantly in chemical structure, I would not be at all surprised if they had different PD/PK properties; those who do drug design research find that the addition of a single chloride atom is enough to alter the properties of some drugs. What is certain is that ceftiofur is not approved for use in humans and there is no published evidence on its efficacy for treating borreliosis in animal models. Obviously, the use of ceftiofur is a big unknown. My best advice, if someone wanted to replicate the Klempner studies in an animal model would be to use ceftriaxone and doxycycline in the same manner that he did and not introduce another variable like ceftiofur– unless you plan to get the FDA to approve the use of ceftiofur in human studies. That may take a long time to do….

3. Since I have retired from the NIH, I don’t know what their plans are for future research on Lyme disease. But, I can tell you that about 90% of the research that NIH supports is driven by proposals submitted as investigator initiated grant applications — the RO1 grants. 
So, if anyone has any good ideas, they are always welcome to submit a grant application, although competition for grants is very keen and only about 25% of all applications submitted are funded. One has to be persistent as most of my colleagues are to make it in science. 
Although I am not opposed to conducting another clinical trial, the odds for such a proposal getting funded are rather slim, especially since NIH has already supported 4 trials indicating that extended antibiotic therapy is not beneficial. 
Obviously, I would like to see more work done on whether the “persistors” Bockenstedt and Barthold noted in mice are infective and can cause disease, as well as whether they can stimulate a local inflammatory response. But, I think we would be making a big mistake by not considering other possibilities as I’ve mentioned in a recent article (http://www.fasebj.org/content/26/1/11.long). 
There are MANY people who believe that they have “chronic Lyme disease” with no evidence that they ever had Lyme disease in the first place. Some have been misdiagnosed and are being subjected to all sort of unproven therapy. Also, there are individuals who go from one doctor to another seeking a “cure” and who often are victims of “quack” remedies. 
One reason we had so much difficulty enrolling patients into the Klempner study was that only about 5-8% of those who presented themselves for enrollment had unequivocal evidence in their medical record of having been diagnosed correctly for Lyme disease in the first place. Obviously, one can not have a chronic infection without first having an active and correctly diagnosed infection in the first place. That was made a criterion for enrollment to ensure that we would have a cohort of patients with a reasonably high — though still not absolutely certain– probability of having a persistent infection — if one were present. I assure you, and you can ask Brian Fallon and Lauren Krupp, such people are NOT easy to find.
But, I have said enough. The biggest obstacle to making any progress is the lack of trust and the tendency to condemn anyone in the scientific community who disagrees with the unproven concept of others. Some simply have no understanding of evidence-based research and how it works, let alone things like the placebo effect. There is just too much misinformation being spread on the internet — and too many people gobbling it up as though it were fact. It’s an ideal environment for all the “quacks” to thrive — and they surely do. And that is what disturbs me the most………



So, there you have it - that's his response, and while I posted a response to the Wonk blog, because my response was too lengthy it has not been posted there. So I posted it to comments below, after an explanation of why my response was not posted there.

The moderator emailed me personally and said that I could post another 150 word comment of my choosing, but I have declined for now because I don't think what I can say in response to Dr. Baker is adequately summed up in 150 words.

There was a second comment with other content which I submitted that I later decided needed a serious rewrite before posting - I won't be posting that here now and am okay with the moderators not publishing it (good job, mods - thanks).

I just want to take a moment here to acknowledge those who left intelligent and insightful questions and comments on the Wonk blog - even when addressing someone with whom they vehemently disagree. I would like to see more dialog such as this, but even more so I would like to see more thorough education and outreach going on which deconstructs all the hypotheses behind why chronic Lyme disease patients have persisting symptoms and what research is required to resolve the debate over cause.

5 comments:

  1. 11:30 pm Eastern time, and still neither of my comments in response to Dr. Baker have been posted. I submitted them both over six hours ago.

    Perhaps they would not have added anything more to the greater whole of the discussion... I did catch a few typos in them after I posted them - wish I could edit my comments now that they've been stuck in moderation for all this time.

    I will probably look at them again after more time has passed. I have other things to do and write now.

    ReplyDelete
  2. 4:25 pm Eastern time: As of this writing, my original 2 comments have not yet been posted - but I am okay with that because I do not think they were my most well-written comments.

    So I posted a comment to the moderator requesting that those 2 do not get posted and a new better written one which I just submitted does. Hopefully this one comment will be published. If it is not, I will post it here.

    In the meantime, there are lot of interesting comments there. And from a personal standpoint, this comment by Joanne Drayson was well said:

    http://lymedisease.org/news/lymepolicywonk/lymepolicywonk-was-this-important-lyme-study-hidden-for-12-years.html#comment-3896

    Good points, Joanne.

    ReplyDelete
  3. UPDATE:

    Well, it isn't just me. Apparently my lengthy comments are to blame for my comments not getting posted - even though I did not use vulgar language, personal attacks, or spam.

    The admin of the Wonk blog just posted this message:

    ----

    admin on February 27, 2012 at 1:38 pm said:

    We’ve been heartened by the number of responses to this blog posting. However, some of them have been quite lengthy. In the interest of providing a forum for a diversity of opinions, please limit your responses to 150 words. (And please, no vulgar language, no personal attacks, no spam.) Comments are moderated before they appear.

    ----

    Oops. Guess now we all have to keep our responses much shorter? Watch your word count...

    ReplyDelete
  4. The comment I submitted which I would have wanted to have posted:

    Dr. Baker,

    Thank you for taking the time to write an extensive response to my questions. It was more extensive than I was expecting, too.

    “So, you ask who made the decision to use ceftiofur instead of ceftriaxone? I honestly don’t know.”

    It seems rather unusual that Dr. Klempner had ceftriaxone from the original lots used to treat patients that was to be used in Dr. Phillip’s study – and yet ceftiofur was used instead. Did something happen to that ceftriaxone? I could speculate about its shelf life of three years – maybe the switch was made because of that? Unanswered question. Regarding the Borrelia – it is difficult bacteria to “tame”, I know – it loses plasmids in the dish and through multiple passages. So I’m not surprised by his setback…

    I suppose the best thing one can do is as you suggested and contact the research team and see if they would be willing to comment. I think your earlier suggestion to contact them and ask them about the twelve year delay is also a good idea.

    “Keep in mind that as Program Officer, I was not the czar of NIH’s entire research program on Lyme disease, even though so people have the mistaken notion that I had such “power”.”

    Who would have been in charge? Are they still in that position today?

    “What is certain is that ceftiofur is not approved for use in humans and there is no published evidence on its efficacy for treating borreliosis in animal models.”

    No research? What about these papers?
    http://www.ncbi.nlm.nih.gov/pubmed/15863289
    http://cp.vetlearn.com/Media/PublicationsArticle/PV_23_04_375.pdf

    Behind pay wall – can’t confirm degree of relevance:
    http://www.sciencedirect.com/science/article/pii/S0737080609000653
    http://onlinelibrary.wiley.com/doi/10.1002/9781444302639.ch10/summary

    I admit, Scholar and Science Direct had limited returns on animal studies of ceftiofur for treating Bb infections. The vast majority of the papers found so far are on equine borreliosis, too.

    Barthold should know something about this, knowing his experience with equine models. I would trust his decision in choice of antibiotic use.

    “My best advice, if someone wanted to replicate the Klempner studies in an animal model would be to use ceftriaxone and doxycycline in the same manner that he did and not introduce another variable like ceftiofur– unless you plan to get the FDA to approve the use of ceftiofur in human studies. ”

    I think I’d choose the first and not the second piece of advice there, if I were to conduct another study. Still, Embers et al is notable.

    (more)

    ReplyDelete
  5. (cont'd)

    “Although I am not opposed to conducting another clinical trial, the odds for such a proposal getting funded are rather slim, especially since NIH has already supported 4 trials indicating that extended antibiotic therapy is not beneficial.”

    Yes, but what if the clinical trials were designed differently? What if there were also trials where two different treatment arms were compared? Those patients who have chronic Lyme disease/post treatment Lyme disease are still suffering with persisting symptoms with no specific treatment recommendation in the 2006 guidelines except to treat symptomatically. It’s not even clear to me WHAT the guidelines indicate is being treated because no one has stated distinct genetic backgrounds or biomarkers for my condition (although recent proteomic research has indicated that yes, there is a difference between CFS/ME and CLD/PTLDS patients that is objectively measurable).

    “Obviously, I would like to see more work done on whether the “persistors” Bockenstedt and Barthold noted in mice are infective and can cause disease, as well as whether they can stimulate a local inflammatory response.”

    I believe it’s “persisters” or “persister cells”, rather than “persistors”. Anyway – I’m glad to hear that. I think that more research definitely is required on the persistent infection angle. And not just that, but to see how much immune response to exposed and traveling antigens can trigger symptoms. Both.

    “But, I think we would be making a big mistake by not considering other possibilities as I’ve mentioned in a recent article” [article link removed]

    I think that many different aspects of Lyme disease should be examined in order to get a clear picture of the disease. I doubt anyone would disagree with that statement. One has to be very exacting in this work and be sure, though, that the truth is determined. If there is persistence, then treating patients as if it were an autoimmune condition could potentially be disastrous to their health. If there isn’t persistent infection – even in just a fraction of patients – then giving them long term antibiotics won’t help that specific subgroup of patients and some other treatment (Viral Genetics’ research?) may.

    I don’t know all there is to know. The issues here are complex. All I know is one has to be certain of what’s happening – people’s lives are at stake.

    ReplyDelete

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