Monday, 23 July 2018

Inspire, expires: The first breath of the Charcot Project

Is MS a problem caused by a virus?

Is the world flat?


The INSPIRE trial set out to investigate one of these following an anecdote that a person, who had MS but was treated with HIV-inhibiting treatment, did well. 


Was this a fluke or the beginning of a new era in MS research?




You know the answer. Yep, the trial was not a success.

This study looked at raltegravir, rather than looking at HAART, which is a cocktail of drugs used to inhibit HIV.


Why? Because a company making raltegravir sponsored the study. 


However, raltegravir is an integrase inhibitor. This means it aims to stop virus integrating into the host's genome to cause infection. 

This is what HIV does to infect. 

However for a human endogenous retrovirus, the virus integrated probably a few thousand years ago. Other viruses may not integrate. Therefore would raltegravir be the most logical choice of an anti-viral? Perhaps not.

So whilst the trial failed it does not say the idea of a viral cause of MS is dead.

The paper is available to download and read.

A phase II baseline versus treatment study to determine the efficacy of Raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: 

Julian Gold, Monica Marta, Ute C. Meier, Tove Christensen, David Miller, Daniel Altmann
David Holden, Lucia Bianchi, Rocco Adiutori, David MacManus, Tarek Yousry, Klaus Schmierer
Benjamin Turner, Gavin Giovannoni




Background

Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS.



Objectives

To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS.



Methods

This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments.



Results

All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir.



Conclusions

Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.
The INSPIRE Study is now available online, containing full bibliographic details:  https://authors.elsevier.com/a/1XLbE7skoexazW


CoA: This is work by the ProfGs and other members of the team. This is disappointing, but if you don't try you can't fail, although importantly you can never succeed.

22 comments:

  1. I was one of the 20 who completed the trial so that was an interesting read for me. Everyone I encountered on the trial were lovely and I would still say to anyone thinking of participating in a trial to go ahead and do it.
    It's a shame the results weren't what you were all hoping for but lessons were still learned. The information gathered from this trial will help in the next stage
    I'm absolutely convinced there is a link between EBV and ms. I had my first relapse after 2 horrendous upper respiratory tract infections which I had suffered from all my life.
    Keep fighting the good fight.

    ReplyDelete
    Replies
    1. Thank you for being in the trial, there were some positives that came for the study and the ProfGs have regrouped and are trying again.

      As you say the evidence for viral involvement mounts.

      Maybe ProfG will post on this.

      Delete
    2. It's great you got to see the results. Its so important for people who take part in clinical trials to be told the results once the trial is done!

      Delete
    3. I agree.

      I have found it exceptionally frustrating that this has not happened in the spasticity trial that we did. At least we are starting this process with an abstract to ECTRIMS.

      Delete
    4. I too completed the trial and I echo what Suzanne has written. Onwards and upwards!

      Delete
  2. Wondering if you saw this?

    I have MS and so does my identical twin - we never had a pinworm infection.

    http://www.mstranslate.com.au/cause-of-multiple-sclerosis-theory/

    ReplyDelete
    Replies
    1. Pinworms and MS.

      I remember someone at a meeting telling me that having worms protected you from EAE and by implication MS. However I remember the 1980-1990ss when pinworm infection was rife in animal houses world wide. You could count the worms on the pellets. Clean the animals up and they still get EAE.

      Delete
  3. 'HIV integrase inhibitors block replication of alpha beta and gamma Herpesviruses' ....quoted in connection with the Charcot project. Deserves further comment re EBV activity (or inactivity) in MS. Select your evidence?

    ReplyDelete
    Replies
    1. The profs were considering the HERVS as the problem these are not herpes virus

      Delete
  4. Its probably the nucleoside reverse transcriptase inhibitors that are needed and not the integrase inhibitors. Raltegravir is not mentioned at any of the positive MS related studies anyway. Especially on its own. I was really curious about this odd choice of drug.
    I hope the right trials wont take long.

    ReplyDelete
  5. Combivir sounds like it's the best shot.

    "Here we report a case of a patient with severe MS who experienced a dramatic improvement after treatment with Combivir (zidovudine/lamivudine). Zidovudine is known to effectively inhibit EBV (and no other herpesviruses) in vitro (Lin et al., 1988), but has never been tested in a randomized clinical trial of MS."

    "Zidovudine, a component of Combivir, is known to inhibit EBV DNA replication. However, any mechanism must account for the lack of clinical efficacy of acyclovir-class drugs in MS and infectious mononucleosis. Acyclovir drug metabolism is different from drug metabolism of antiretroviral nucleoside analogues because acyclovir requires a viral kinase for phosphorylation. Bypassing this requirement facilitates the accumulation of active drug intracellularly. This unique feature of antiretroviral nucleosides may be important during low-level viral replication or for pre-treatment during a period of viral latency prior to reactivation in the CNS."

    https://www.sciencedirect.com/science/article/pii/S2211034818300828

    ReplyDelete
    Replies
    1. There are too many long term side effects with Combivir.

      I'd do tenofovir/emtricitabine/efavirenz for better tolerability.

      Delete
    2. The good thing about Combivir is that is old and cheap. The bad is that most patients drop it because it can cause lipoatrophy. But can it cause lipoatrophy to HIV- patients? (I believe it can but we need to try it first)
      I tend to believe that the EBV theory is just a coinsidence of why Combivir works :/

      Delete
    3. "I'd do tenofovir/emtricitabine/efavirenz for better tolerability."


      Open to it..but any links..? So far my google draws a blank.

      Delete
    4. https://www.ncbi.nlm.nih.gov/pubmed/28882979

      Delete
  6. "Therefore would raltegravir be the most logical choice of an anti-viral? Perhaps not."
    "Because a company making raltegravir sponsored the study. "

    This was known from the start, therefore there was no robust rationale for doing that study with that particular agent in the first place. Which means that the study was eventually done mainly because funds were available. From a scientific point of view, it was more like throwing darts in the fog. So it failed, inevitably.

    ReplyDelete
    Replies
    1. I refer you to Samuel Beckett
      "Ever tried. Ever failed? No Matter. Try again. Fail again. Fail better" a good maxim for us scientists.
      If you don't try, you can't fail. What would be your choice of agents for another study?

      Delete
    2. Nice lyric deviation, MD2. Unfortunately, too many young people will get MS while waiting for scientist to improve themselves while spending pharma money. The fact is that the EBV pathway towards understanding MS is only paved with statistical evidence of association, not pathological evidence of causation. There are far more tangible targets for current research:
      1) The central vein sign in the vast majority of MS lesions
      2) Migraines in MS viewed through their ischemic type lesions
      3) Association of spinal cord lesions with denticulate ligament anchoring points. I have urged DrK and his associates to extend their autopsy studies beyond measuring spinal nerve loss, but haven't seen any publication on the subject. It is a pity, since it's too easy for them to do such a study.

      Delete
    3. Ok, "but" if you have great theories of what would be the cause of MS then why not try to test them?
      Or is it just one that still advocates for CCSV, which has even been tested more than once and failed?

      As far as I know, there aren't robust antivirals to cope with EBV, nor can chemotherapy sometimes combat this pest.

      So how did you spend money with CCSV why not spend on investigating other hypotheses?

      Even antivirals and Vitamin D3?
      Whoever does not try will never know what the outcome will be!

      Delete

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