I need your help to test EBV antiviral drugs in MS. In this newsletter I explain the science behind the proposed studies. Do you think they are ethical? Would you participate?
I will be starting valacyclovir by the weekend after a five month hiatus from 3 years of acyclovir. During which time I had a reactivation WITH symptoms (thank you Mavenclad!) and
then my more typical onset of cognitive, fatigue and vestibular/ mobility decline. Half time in wheelchair.
The infectious disease specialist I saw yesterday was the FIRST doctor since 2018 willing to study changes to my mobility and cognition as they may relate to changes in viral load. Ie study the Venn diagram of issues that has been my lived (although anecdotal) experience.m and how Epstein Barr virus may be impacting them.
He was open to famcyclovir as well! I decided to wait until I saw the results from your study, although both of these are prodrugs. Please don’t underestimate how the mess that is the MS gut may interfere with absorption and potentially activation into the active drug. I’m currently trying to identify my own genetics involved in enzyme production for both of these prodrugs.
It’s quite a web. The major issue with the entire scientific process is when there is not statistic significance in a trial, the baby is thrown out. Despite the fact that for those who may have great outcome due to varying genetics or epigenetics, the medication would be life changing.
And just an aside - I have very poor genetics for keto/paleo with saturated fat. Which confirms why, when I did it, it was great for weight loss and reversal of type 2 diabetes, but otherwise Iwent down hill.
I’m very wary of diet recommendations for “the ms population”. This will involved personalized medicine.
Sign me up! 20 years of MS, 13 yrs of Tysabri. Glandular fever at 14. As a parent and new grandmother I'd do anything to prevent future generations getting MS.
I do have chronic EBV(confirmed by a lot of lab results) and MS and tried tenofovir alafenamide...it did not work. Had a massive EBV reactivation with high IgMs under Tenofovir alafenamide in October(confirmed by lab results).Also, my anti EBNA1 IgG are MASSIVE. The current antivirals that we have seem too weak, maybe something really high dosed iv would do. But oral famciclovir and TAF probably do not work, can't say it for sure, but I doubt it is just me.
Also, I'm interested if I can send you or someone from your team my lab results for IgM EBV and chronic infection markers. I'm sure that MS is, at least in my case, EBV related, but no neurologist here cares.
Holy moly, NO, taking people off natalizumab and putting them on placebo is not ethical. I'm sure you could get volunteers and informed consent with some kind of "do it for science" rhetoric, but that doesn't make it ethical. There will be real people who accrue permanent neurological disability as a result of this.
Jun 30, 2022·edited Jun 30, 2022Liked by Gavin Giovannoni
In some sense HSCT does this - first we get rid of the immune system, then it repopulates under antivirals. I've been wondering for a while if that is part of reason the it can be effective. And if tweaking antivirals would improve outcomes further.
I would likewise like to see a study combining any of the high efficacy therapies with antivirals (simultaneously, comparator just high efficacy therapy, that would be ethically alright as standard of care is reached in every arm - personally, about the only thing I might consider completely dropping an established DMT for is an ATA188 cross-over study)
I'm really glad you are pushing for research in this area. The ethics of research is always complicated, but your approach of informing pwMS and treating us like intelligent people is so refreshing. I am currently on Tysabri and have felt strongly for a long time that my salivary glands swelling indicate a flare or a relapse. I am very interested to hear that this could be linked to EBV. I would be very interesting in getting involved in research.
Wow, interesting. I remember now that prior to my first relapse i had some weird short lived swelling under my tongue. Also one of my pupils was bigger than the other and i had some weird clear fluid pour out of my ear for a split second.
Curiously enough, I had swelling of my tongue a few months prior to diagnosis with MS (along with the classic fatigue). I assumed it was a side effect of the antidepressant I was on at the time. I've also had oozing in my right ear of a foul smelling fluid 🫤
If I were still on nataluzimab I would participate if could be done in the States. I had a severe case of infectious mono. Right now back on ocrelizumab. I will be following and hope for successful treatment.
Please sign me up, I had glandular fever and both my daughters (currently age 16 and 19) were very unwell with glandular fever when they were little. I am so worried that they could end up with MS so I am very keen to help with research please!
I would think you could improve the ethics by recruiting from a pool of people intending to stop taking natalizumab anyway, unless there is a rebound-prevention standard of care? At the least, the pool of people intending to stop taking it would be well-tracked and enlarged by JCV index monitoring.
Jun 30, 2022·edited Jun 30, 2022Liked by Gavin Giovannoni
I would recommend as a trial design something different given as the people who would receive a placebo ( 50 % of them as mentioned ) would have rebound activity which could be a risky bet. " Rebound disease activity, in the form of relapses and/or MRI activity, occurs in over 50% ".
Trial design :
Intervention/treatment : Famciclovir or Zidovudine ( because of its potentiel for penetrating the blood brain barrier in high concentrations and its case studies showing effectiveness in MS ).
Trial duration : 78 weeks
Active comparator : Teriflunomide or glatiramer acetate ( given that the number of treatments are huge in RRMS patients, it is harder to justify giving the control group no treatment ).
Primary outcome :
1. Gd enhancing T2 lesions
Secondary outcome :
1. Salivary EBV shedding
2. Neurofilament light chain
3. Exploratory blood biomarkers of EBV infection.
If the treatment consists of Zidovudine one would need to check for the baseline neurofilament levels on zidovudine at a dosage that would be high enough to inhibit EBV infection ( higher than what is typically prescribed today ).
I believe that if neurofilament light levels decrease enough ( when also taking into account baseline levels of neurofilament light chains on the medication ) this could warrant a larger clinical trial.
In our hands all EBV negative subjects with MS when tested with more sensitive assays were EBV positive. I am not sure if there is such a thing as EBV negative MS.
First time I hear about the EBV saliva study. Are you still recruiting?
I recently had a test for EBV and it showed I'm negative, though I'd assume there are multiple tests and some may be less precise. Could you point me out to which one is more precise? I'm so sold on this hypothesis that I'd go test privately.
I've been on Natalizumab ( Tysabri ) for 8 years in September this year, I'd be interested in participating in the saliva study from home but I definitely would not want to stop Tysabri and undergo a lumbar puncture at this stage in my life. I'd love to help out with this if I can?
A 2009 paper - sounds like PIRA, does it not?
https://pubmed.ncbi.nlm.nih.gov/19168469/#:~:text=Conclusions%3A%20The%20results%20suggest%20that,brain%20volume%20over%203%20years
Compare 2022
https://pubmed.ncbi.nlm.nih.gov/35765699/
I will be starting valacyclovir by the weekend after a five month hiatus from 3 years of acyclovir. During which time I had a reactivation WITH symptoms (thank you Mavenclad!) and
then my more typical onset of cognitive, fatigue and vestibular/ mobility decline. Half time in wheelchair.
The infectious disease specialist I saw yesterday was the FIRST doctor since 2018 willing to study changes to my mobility and cognition as they may relate to changes in viral load. Ie study the Venn diagram of issues that has been my lived (although anecdotal) experience.m and how Epstein Barr virus may be impacting them.
He was open to famcyclovir as well! I decided to wait until I saw the results from your study, although both of these are prodrugs. Please don’t underestimate how the mess that is the MS gut may interfere with absorption and potentially activation into the active drug. I’m currently trying to identify my own genetics involved in enzyme production for both of these prodrugs.
It’s quite a web. The major issue with the entire scientific process is when there is not statistic significance in a trial, the baby is thrown out. Despite the fact that for those who may have great outcome due to varying genetics or epigenetics, the medication would be life changing.
And just an aside - I have very poor genetics for keto/paleo with saturated fat. Which confirms why, when I did it, it was great for weight loss and reversal of type 2 diabetes, but otherwise Iwent down hill.
I’m very wary of diet recommendations for “the ms population”. This will involved personalized medicine.
Sign me up! 20 years of MS, 13 yrs of Tysabri. Glandular fever at 14. As a parent and new grandmother I'd do anything to prevent future generations getting MS.
I do have chronic EBV(confirmed by a lot of lab results) and MS and tried tenofovir alafenamide...it did not work. Had a massive EBV reactivation with high IgMs under Tenofovir alafenamide in October(confirmed by lab results).Also, my anti EBNA1 IgG are MASSIVE. The current antivirals that we have seem too weak, maybe something really high dosed iv would do. But oral famciclovir and TAF probably do not work, can't say it for sure, but I doubt it is just me.
Also, I'm interested if I can send you or someone from your team my lab results for IgM EBV and chronic infection markers. I'm sure that MS is, at least in my case, EBV related, but no neurologist here cares.
Holy moly, NO, taking people off natalizumab and putting them on placebo is not ethical. I'm sure you could get volunteers and informed consent with some kind of "do it for science" rhetoric, but that doesn't make it ethical. There will be real people who accrue permanent neurological disability as a result of this.
You should tell the NHS this. We sadly have stopping criteria.
In some sense HSCT does this - first we get rid of the immune system, then it repopulates under antivirals. I've been wondering for a while if that is part of reason the it can be effective. And if tweaking antivirals would improve outcomes further.
I would likewise like to see a study combining any of the high efficacy therapies with antivirals (simultaneously, comparator just high efficacy therapy, that would be ethically alright as standard of care is reached in every arm - personally, about the only thing I might consider completely dropping an established DMT for is an ATA188 cross-over study)
Problem is that high-efficacy therapy + antiviral would require a large study population and long follow-up to detect any differences.
I agree with this comment. You have to realise that doing a trial of antivirals in the current climate is difficult.
I'm really glad you are pushing for research in this area. The ethics of research is always complicated, but your approach of informing pwMS and treating us like intelligent people is so refreshing. I am currently on Tysabri and have felt strongly for a long time that my salivary glands swelling indicate a flare or a relapse. I am very interested to hear that this could be linked to EBV. I would be very interesting in getting involved in research.
Wow, interesting. I remember now that prior to my first relapse i had some weird short lived swelling under my tongue. Also one of my pupils was bigger than the other and i had some weird clear fluid pour out of my ear for a split second.
Curiously enough, I had swelling of my tongue a few months prior to diagnosis with MS (along with the classic fatigue). I assumed it was a side effect of the antidepressant I was on at the time. I've also had oozing in my right ear of a foul smelling fluid 🫤
If I were still on nataluzimab I would participate if could be done in the States. I had a severe case of infectious mono. Right now back on ocrelizumab. I will be following and hope for successful treatment.
Please sign me up, I had glandular fever and both my daughters (currently age 16 and 19) were very unwell with glandular fever when they were little. I am so worried that they could end up with MS so I am very keen to help with research please!
I would think you could improve the ethics by recruiting from a pool of people intending to stop taking natalizumab anyway, unless there is a rebound-prevention standard of care? At the least, the pool of people intending to stop taking it would be well-tracked and enlarged by JCV index monitoring.
Yes I would love to participate in a trial of EBV antiviral drugs for MS. PLEASE SIGN ME UP NOW!!! This is the future!!!
I would recommend as a trial design something different given as the people who would receive a placebo ( 50 % of them as mentioned ) would have rebound activity which could be a risky bet. " Rebound disease activity, in the form of relapses and/or MRI activity, occurs in over 50% ".
Trial design :
Intervention/treatment : Famciclovir or Zidovudine ( because of its potentiel for penetrating the blood brain barrier in high concentrations and its case studies showing effectiveness in MS ).
Trial duration : 78 weeks
Active comparator : Teriflunomide or glatiramer acetate ( given that the number of treatments are huge in RRMS patients, it is harder to justify giving the control group no treatment ).
Primary outcome :
1. Gd enhancing T2 lesions
Secondary outcome :
1. Salivary EBV shedding
2. Neurofilament light chain
3. Exploratory blood biomarkers of EBV infection.
If the treatment consists of Zidovudine one would need to check for the baseline neurofilament levels on zidovudine at a dosage that would be high enough to inhibit EBV infection ( higher than what is typically prescribed today ).
I believe that if neurofilament light levels decrease enough ( when also taking into account baseline levels of neurofilament light chains on the medication ) this could warrant a larger clinical trial.
This research on how they eliminated EBV is interesting.Did you know it?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928872/
Very interesting, but far from patients due to safety concerns.
My hospital told me I tested negative for EBV antibodies after I was diagnosed with RRMS. Would this mean that the trial wouldn’t be relevant for me?
In our hands all EBV negative subjects with MS when tested with more sensitive assays were EBV positive. I am not sure if there is such a thing as EBV negative MS.
I've never had one :-)
First time I hear about the EBV saliva study. Are you still recruiting?
I recently had a test for EBV and it showed I'm negative, though I'd assume there are multiple tests and some may be less precise. Could you point me out to which one is more precise? I'm so sold on this hypothesis that I'd go test privately.
Not at the moment. We have fully recruited for the FamV study, but may need to repeat the study with other antivirals.
Ditto
I've been on Natalizumab ( Tysabri ) for 8 years in September this year, I'd be interested in participating in the saliva study from home but I definitely would not want to stop Tysabri and undergo a lumbar puncture at this stage in my life. I'd love to help out with this if I can?
The lumbar puncture is to try and detect evidence of EBV reactivation.