Monday, December 21, 2009

News on Important New Studies Underway

Since the initial findings of the link between XMRV and ME/CFS became public in October, a flurry of new research has ensued.  The study at the top of the list is currently underway at Uppsala University to try and replicate the findings of the Whitemore Peterson Institute in Swedish patients.  The study is very well organized, however it's findings could be a mixed blessing: XMRV findings may be different in European cohorts, meaning that other closely related retroviruses might be discovered if new studies are pursued.  Dr. Jonas Blomberg's real-time PCR assay might just be what is required to find these viruses.

Another study is currently underway to determine the atomic structure of XMRV protease at one center.  This study was initiated after a link was made to XMRV in certain prostate cancer cell lines.  Crystals of the protein have been grown, however this is only a first step: heavy metal derivatives must be produced, and crystals must be found that will diffract to a sufficient resolution to obtain useful data for drug development - a process that is still months away.

Another study is currently getting underway at Cornell University that will seek to determine retroviral diversity in ME/CFS patients, and try and correlate the findings with functional status in CFS patients.  The project is being done in collaboration with the Whitemore-Peterson Institute and the Columbia University Center for Infection and Immunity.

Another study is getting underway at Instituto de Biologia Molecular en Medicina y Terapia Genica, Universidad de Guadalajara to determine if infecting peripheral monocyte cell lines in culture with XMRV alters the 2-5A synthethase/RNASE L pathway, and the resulting differential cytokine expression.  I don't understand spanish, so it would be appreciated if someone who does could dig up more information for me!

Fellow Britons Unite For The Truth!

It has come to my attention as of late that our government holds a file in the National Archives at Kew, which contains MRC documentation on ME since 1988.  The file was to be kept from the public eye until 2023, however this has been extended until 2071!  Normally, such measures are only enacted on matters of defence, national security, and in matters that are considered very confidential.  But what on earth would the medical research council want to keep from public view???  It comes from the same time as the UK's own version of Dr. Reeves - Simon Wessely began to propagandize ME as a psychiatric illness.  It would seem rather absurd to even cite patient confidentiality, as a black marker would make short work of maintaining patient confidentiality.

However, fellow Britons, you have options.  In THIS document, there is a LINK to request a review of the record under the Freedom of Information act, which requires the filling out of only a few fields.  If the National Archives does not provide a satisfactory response, then contact the parliamentary and health services ombudsman:

The Parliamentary and Health Service Ombudsman
Millbank Tower
London, SW1P 4QP
Telephone: +44 (0) 84 5015 4033
Fax: +44 (0) 20 7217 4000

You may also want to contact:

Secretary of State for Justice and Lord Chancellor
Selborne House
54-60 Victoria Street
London SW1E 6WQ

Also, if the requested information is refused, an application may be made to the Information Commissioner, who has the power to order such disclosure, and if unsuccessful, the applicant may appeal the decision to an appeal tribunal - in many cases which have been successful the information has been provided with some redactions to protect confidentiality: The appeal tribunal consists of experienced barristers or solicitors which must provide a fair and independent review.  It is your right, and I strongly recommend that you exercise these rights!

Tuesday, December 8, 2009

Male CFS Patients May Have Option

In recent studies, it has been shown that DHT (dihydrotestosterone) increases XMRV replication rate threefold.  This is not surprising, considering that a number of prostate drugs target this very hormone.  Testosterone is metabolized to DHT, which is more powerful - but it is also implicated in pattern baldness, prostate problems, and excess body hair.  Some drugs such as Casodex and Flutamide will block DHT at its receptor, however they will result in impaired fertility, loss of libido, and feminization effects, as testosterone is necessary to mitigate the effects of estrogen.

On the other hand, blocking the conversion of Testosterone to DHT should result in a significant drop in viral replication rate.  There are 2 very safe drugs that I can think of that can attain this effect: Avodart (dutasteride), and Proscar (available as Propecia in a lower dosage form).  A threefold drop in viral replication rate could have a significant effect on symptoms of ME/CFS - It is my opinion that at a certain threshold, the immune system is capable of keeping XMRV in check, hence why XMRV is found in a small number of healthy controls.  I would like to see a clinical trial enrolling male patients to test this hypothesis.  The effects of these drugs have negligible effects on male fertility - treatment will only produce mild reductions in sperm count averaging 6%.  Serum testosterone increased considerably, which is necessary for muscle protein synthesis, regulating the hypothalamus-pituitary axis, and increasing mental and physical energy - all things ME/CFS, Fibromyalgia, and Gulf War Syndrome patients could stand to benefit from.

Monday, December 7, 2009

CDC Damage Control: ME/CFS Research Group Relieved of Duties

In a stunning move, responsibility for XMRV research has been taken away from the ME/CFS working group within the CDC, and re-assigned to the division of HIV/AIDS prevention.  This group will be in charge of replicating findings of the Whittemore-Peterson Institute, rather than the group under the control of Dr. Reeves.  The move is highly significant: it appears that the CDC is now acknowledging the serious nature of XMRV.

The CDC will be part of an interagency working group on XMRV, led by Dr. Jerry Holmberg.  A three-part study will be initiated:

  1. The first part will consist of standardizing and validating laboratory methods and reagents for XMRV testing.  This stage will use samples provided by samples collected by Dr. Judy Mikovitz.  The intention is to create an FDA approved test.
  2. The second part will test a much larger sample than the initial study, trying to determine the prevalence of XMRV in the general population, and the blood supply.
  3. The third part will consist of how XMRV is transmitted, how it causes disease, and how it affects various subgroups of the population.
The forceful demotion of Dr. Reeves is a sign that the CDC is in damage control mode.  The HIV/AIDS prevention group in the CDC has many capable retrovirologists, who can provide years of expertise.  In my opinion, this turn of events should lead to balanced, common sense research.

Apricitabine May Be Effective Against XMRV

Apricitabine, an NRTI structurally related to lamivudine, may provide activity against XMRV Reverse transcriptase.  XMRV, like the drug resistant strain of HIV-1 contains the M184V substitution, explaining why it is succeptible to AZT and not 3TC (lamivudine).  The FDA has granted fast-track approval to the drug, meaning it should be available some time next year.  It appears to be extremely well tolerated, and was not associated with abnormal blood lipids, liver or kidney toxicity, or bone marrow suppression.

Sunday, December 6, 2009

Antiviral Study Shows Few Options

A new Study released by Sakuma et. Al this week, provides groundbreaking new information on therapies for XMRV.  The results are not good: 10 licensed HIV-1 anti-virals were tested - only 1 showed strong activity, and 1 showed weak activity.  Out of the RTI's, AZT, 3TC, Tenofovir, D4T, Efavirenz, and Nevirapine were tested - only AZT showed strong activity.  Previously I reported that 3TC and Emtricitabine showed activity against a closely related virus: 3TC has negligible activity against this beast, and Emtricitabine remains untested.  The mechanism for 3TC resistance is likely a Valine substitution at position 184, in place of a methionine.  Emtricitabine, Abacavir, Etravirine, and Zalcitabine remain untested.  Three protease inhibitors were tested: Ritonavir, Indinavir, and Saquinavir: Only Ritonavir demonstrated weak activity at high concentrations - something that was not unexpected.  One experimental integrase inhibitor was tested: the compound 118-D-24 which was ineffective, good news is that it is structurally distinct from Raltegravir, and 118-D-24 does not inhibit MLV integrase either.

A comparison of the sequences reveals some astonishing details: the XMRV Reverse-Transcriptase resistance mechanisms are astonishingly similar to HIV mutations: Valine at position 75 is substituted with Glutamine (d4t resistance), Lysine at position 103 substituted with Serine (Efavirenz resistance), A Valine at position 106 is substituted with Tyrosine (Nevirapine resistance), A Methionine at position 184 is substituted with Valine (3TC resistance).  A closer examination reveals another stunning detail - most other drugs targeting Reverse-transcriptase are not likely to work, as the mutations giving rise to their resistance in HIV are apparent in XMRV.  The only good news is that XMRV does not foster the critical 4 amino acid mutation giving rise the Multi-nucleoside analog resistance.  Raltegravir still holds promise, as XMRV integrase bears a close sequence homology to MLV integrase.

Certainly, it is not a good situation.  The toxicity of AZT leaves a lot to be desired - HIV have much more tolerable Reverse transcriptase inhibitors at their disposal.  The development of drugs effective against XMRV has to essentially start from scratch - determining X-ray structures of XMRV Reverse Transcriptase, Protease, and integrase, modeling candidate molecules, conducting clinical trials, and seeking FDA approval.  The sequence differences of XMRV reverse-transcriptase will provide incentive for HIV drug research - the differences are what also gives HIV-1 resistance to current therapies.  We are basically where we were in 1987 with HIV - with Didanose (ddl) being only the second HIV drug to follow 4 years later.

This study only reinforces the urgency of kicking XAND research into high gear - 18 years were lost due to what I call criminal negligence at the CDC, and I am not afraid to call it the worst medical fraud of all time - only the CDC and their research cronies would stand to benefit -- not the patients, not the drug companies, not HIV patients, and not the doctors.  If the findings of Defreitas had been properly handled, patients with neuroimmune disorders would have options, and HIV patients would have drugs to treat resistant HIV strains.

Sakuma, R., et al., Xenotropic murine leukemia virus-related virus is susceptible to AZT, Virology (2009), 

Two new Studies: Part I - Co-infections point to three strikes theory

A follow-up study was done by Dr. Kerr, demonstrating that ME/CFS symptoms are not caused by XMRV alone, but that co-infections have various additive symptoms - leading more credence to what I call a three strikes theory.  For ME/CFS to develop, you need the following three conditions to develop in a more/less orderly sequence:

  1. Infection with XMRV
  2. Co-infection with another etiological agent: various herpesviruses, certain bacteria
  3. Major immune challenge: Influenza, surgery, immunosupression
The basis of this research is that Dr. Kerr separated various CFS cohorts based on symptoms, and tested various consistent immunological disturbances based on certain pathogens present.  There was a definitive correlation between the severity of symptoms, and the type of infection present.  The four pathogens tested were: Eppstein-barr virus, enterovirus, parvovirus B19, and the bacterium coxiella burnetii.  In the test, a study was done looking at the differential expression of 88 genes.  There was also a regional difference in CFS subtype patterns: Birmingham, Bristol, Leicester, London, New York, and Dorset.

Here are my conclusions without getting into too much detail: even though EBV, Parvovirus B19, and Enterovirus have been fingered as triggering ME/CFS, it clearly tells me that they are not the cause.  ME/CFS has often been described as a heterogenous ailment of many possible causes: a theory that existed in AIDS patients before the discovery of HIV.  I believe that ME/CFS, FMS, and Gulf War syndrome bear a single unified cause, and that cause is XMRV.

XMRV is the first strike: without XMRV or closely related retroviruses you can't have ME/CFS.  If XMRV infects a normal individual, I am of the opinion that a healthy immune system can keep the virus in check for many, many years.  Over time, XMRV leads to an immune dysfunction syndrome, though not a severe life-threatening immune deficiency syndrome like AIDS.  XMRV is the mastermind.

The second stage, which I call the second strike, is what sets the stage for ME/CFS.  Throughout a lifetime, most of us will become infected with multiple persistent herpesviruses: EBV, HHV-6, Cytomegalovirus, Herpes Simplex... yet a healthy immune system can keep them in check.  At this stage, most XMRV infected individuals will probably remain asymptomatic.  The body now struggles to maintain the immune system at equilibrium, and it might take longer to recover from simple viruses like the common cold, and some patients might exhibit sub-clinical signs of ME/CFS.  The pathogen in this case plays the role of accomplice.

The third stage I will loosely call the third strike - the event that initiates ME/CFS I believe requires a period of prolonged immune activation, or inversely immunosuppression.  At this point, the immune system is ill-prepared to fight a war on another front.  In comes a pathogen that causes a vigorous and prolonged immune response such as a bacterial infection, or influenza, and now the immune response is mobilized towards it, retreating from the two previously acquired infections:  the viral burden initiates a chain reaction within immune cells.  XMRV viral load spikes, leading to the destruction of NK cells, and pathogens like EBV now seize the day, and begin replicating, and viruses like EBV can now cause immune downregulation, slowing the creation of new NK cells from progenitor stem cells, capable of arresting EBV.

Conclusion: ME/CFS, FMS, and Gulf war syndrome are caused by a common pathogen, which causes a common set of symptoms, and the heterogenous cluster of symptoms can be explained by co-infections with other pathogens.

Wednesday, December 2, 2009

Ampligen "Death Blow" Another Tragedy for CFS Sufferers

In a shocking move, the FDA yesterday refused to approved Hemispherx's drug Ampligen.  It represents a devastating blow for Hemispherx who have in vain attempted to garner approval for Ampligen for over 20 years.  In their response letter, the FDA essentially demands that Hemispherx begin their clinical trials from scratch.  They site initial clinical trials fail to convince the review panel of Ampligen's efficacy, and that new clinical trials be conducted testing different doses for at least six months, on at least 300 patients, compared to the previous study which enrolled just 230 patients.  The FDA also goes on to cite unresolved manufacturing problems.  Considering that the previous study took 6 years to complete, approval doesn't appear likely any time soon, and likely won't be approved in other jurisdictions, as other nations have followed the guidance of the FDA, with a handful of exceptions of drugs that have gained approval by the European Medicines Agency before FDA approval is granted.

For persons suffering from ME/CFS, FMS, and Gulf War Syndrome it shows that government agencies continue to recognize these conditions as a real illness.  And research dollars earmarked for CFS/ME research gets misappropriated by CDC bureaucrats as a slush fund, where not one meaningful study has come out of it.  And it appears recent developments have not shifted the groupthink mentality of the CDC - but it will come a time when they will find themselves standing pretty well alone if replication studies on XMRV are in line with those of the Whittemore-Peterson institute, which I have reason to believe will be.

I believe that psychologically Ampligen represents a huge setback, but in the end it will amount to no more than a bump in the road.  Tests on antiretrovirals are going ahead full steam in pharmaceutical labs as we speak, and I've dug up a couple of other compounds that have demonstrated activity against other retroviruses: Lamivudine and emtricitabine - both have a far greater safety profile than Zidovudine (AZT), posing a low risk of anemia, nephrotoxicity, hepatoxicity, and pancreatitis.  I'm not particularly fond of Non-nucleoside Reverse Transcriptase inhibitors, due to their unfavorable side effect profile - distressing rash in as much as 20% of patients, and severe liver damage seen with Nevirapine and Etravirine - making patient compliance and adherance to treatment an issue in itself.  I also don't favor a single drug regiment - I would like to see a combination pill of either Lamivudine or Emtricitabine with raltegravir.

Tuesday, December 1, 2009

Research Must be Pursued to The End.

One of my research interests currently is the isolation, characterization, and study of human retroviruses in disease.  The discovery of XMRV in CFS/ME represents just a small step.  Sufferers of neuroimmune diseases have been searching for answers for decades - without any explanation.  While it is still too early to tell if the results of the Whittemore Peterson institute will be replicated, it is the objective of most groups working in good faith towards this goal to do so.  If consistent results are reported on a worldwide basis, it's a huge victory.  Even if we see results which show a regional consistency - it still means something, and we have to keep looking further - hence a possible explanation for the difference in the findings of DeFreitas.

In such a case, I entertain the possibility that there maybe a handful of related retroviruses capable of inciting symptoms of ME/CFS, much like there are many viruses capable of producing cold like symptoms.  This is a research proposal that I have put forth to a group of academic institutions here in the UK, and I hope to have an answer soon.  At the least, I would not be surprised to identify multiple strains of XMRV on a regional basis throughout the world.  It would also be interesting to attempt to replicate the Defreitas study.

At this stage, I don't think it would be prudent to let a retroviral cause for neuroimmune disease slip us by once again.  I am for without a doubt certain that we have the cause of these disorders within sight - and we would be foolish not to think so.  We have large libraries of retroviral genomes to screen from, making the identification of closely related viruses readily possible - just like we have HIV-1 and HIV-2.  Over the years, we've accumulated evidence of a virus, and ME/CFS sufferers must be given answers, so all leads must be pursued to the end.