- You told us (published the case in 2012) of a patient with multiple sclerosis who had gone into remission after he had become HIV-positive and was started on highly active antiretroviral therapy (HAART).
- You have told us for the last 18 years that EBV is the likely trigger and likely driver of MS.
- You state (today) that you “predict that HAART (highly active antiretroviral therapy) preventing MS is a black swan event”.
- You have, through MS-Selfie, promoted “self-management”.
Yet you “urge [MSers] not to seek off-label treatment until we have trials to show HAART works as a treatment for MS”.
When will these trials finish - 15 years, 20 years….? Time is Brain as you keep telling us. MSers without hope and without time, are quite entitled to spin the wheel and try HAART. A chance of putting MS into remission has to be better than doing nothing and watch your body be ravaged by MS. I applaud those who are trying HAART (and funding it themselves). It’s a pity that a system to capture their experiences can’t be set up - but who will oversee this, fund this…..
This story on the BBC website earlier this week perhaps gives an insight as to why some MSers are experimenting with therapies such as HAART. I wish them well and hope they see benefits - waiting another 15-20 years is likely be too late for them.
Is there anything we as patients can do to make some noise and try to push these investigations forward?
Given that EBV is being implicated in everything from MS to bipolar disorder, it seems like the companies that own patents on anti-EBV agents would be highly motivated to support trials.
Dec 16, 2023·edited Dec 16, 2023Liked by Gavin Giovannoni
While I agree that data is needed, I can't help but wondering that others use HAART for what many would consider 'fun' (don't get me wrong, I fully support people using PrEP) so I am wondering if waiting really is the correct approach... It's not like the heavy hitting DMTs are side effect free (or even confirmed to do much, cough Oratorio).
Hi, The potential for HAART is interesting, are there any studies looking at use of PrEP for HIV, specifically Discovey as it includes TAF? As there is a significant community of HIV negative people in US using it regularly it would be interesting to know if it had any impact on them developing MS.
Famiciclovir probably didn't work because the first by pass metabolism makes it into penciclovir and that still has a hydroxyl group attached, hence no chain termination. By contrast, acyclovir will cause chain termination and end the lytic cycle (for a while).
If you switch the focus from EBV (and EBNAs) to the non coding EBV RNA, EBER2, I think you will find what your looking for.
EBER2 has three regions that look identical to regions in adenosine deanimase. In 1997, Gerlitz, G. and O. Elroy-Stein wrote to a letter to the editor of leukemia identifying the regions (Does EBV RNA modulate ADA mRNA translation. Leukemia, 1998. 12(2): p. 249-249). Essentially, they postulated EBER2 out-competes the adenosine deanimase, resulting in a rise in adenosine. Whilst normally adenosine is neuroprotective, abnormal amounts are toxic as they open purinergic receptors, allowing an overloading influx of calcium. Too much adenosine also downregulates the immune response so we get the muted CD8+T cell response that Pender noted in his papers. When CD4+ T cells respond they aren't rogues, they're just responding to the damage to the astrocytes, oligodendrocytes and neurons caused by the calcium overload. The high adenosine would also explain the fatigue called lassitude as it would accumulate on the adenosine receptors in the brain, triggering part of the sleep cycle. (nerve fibre fatigue would follow a different path)
The bit I can't understand in looking for efficacy is the use of timed walking tests. The damage to upper motor neurons will take years to recover, if at all. Using those tests is like pulling the knife out of a murder victim and expecting him to get up and carry on. Dead is dead. The murder weapon did it's job.
They used those tests 25 years ago to determine if acyclovir worked and, of course, got a negative response. They should have measured the changes in the uric acid levels to see if a normal purinergic breakdown cycle had returned and asked the patients how they felt. They never did.
What type or which combination of HAART drugs would (theoretically) be most effective (and safe) for long-term anti-retroviral drugs in MS patients? I'll rephrase the question, if you had MS, which HAART combination drug would you take? And I guess these drugs would only have an effect when taken forever... as the HERV / EBV virus replication needs to be continuously suppressed. I'm currenly on Kesimpta as well, so it might also help prevent re-infecting B-cells. Thanks for your insight
Fascinating to be honest. My initial diagnosis was RRMS despite never having a classic MS attack/relapse. The first neuro I saw made that diagnosis and wanted me on teriflunomide. I asked for a second opinion and was referred to the Barlo Center in Toronto. Their diagnosis was PPMS but incredibly slow moving. 3 sets of MRIs over 2 years showed no changes whatsoever. No brain lesions, but a few cervical cord lesions. Lesion size didn't change nor did the number of them. They said Ocrevus was available but given my age (54), lack of disability and very stable MRIs they didn't think it was advisable at this point. But if I read your piece correctly the possibility of starting on Ocrevus and moving to teriflunomide may have some utility?
I don’t think I’d throw on an antiretroviral. I only recently had to fight my neuro to resume a weenie DMD. But I’m faithfully taking acyclovir. That seems to have stopped the constant (and I do mean constant) herpes virus nonsense, so I’m sticking to that! 🌷
We can add two more MS/EBV research efforts to the list.
1) MS Australia has committed $10 million to MS/EBV, including 2 clinical trials of antiviral medications to treat multiple sclerosis (MS) fatigue and progression, as well as three large-scale studies to understand how EBV interacts with the human immune system to increase the risk of developing MS.
2) $1 million from The National MS Society, United States, 2023-2026
Natalia Drosu, PhD, Massachusetts General Hospital
Title: CD4+ T cell responses to immunodominant HLA-DRB1*15:01-restricted Epstein-Barr virus antigens in patients with multiple sclerosis with potential cross-reactivity to myelin
Theodore Jardetzky, PhD, Stanford University
Title: Targeting EBV entry glycoproteins for vaccine and therapeutic development Summary: Stanford scientists are exploring novel technology with an eye toward developing a vaccine that may prevent the Epstein-Barr virus from triggering MS.
Dalia Rotstein, MD, MPH, St. Michael's Hospital, Toronto, Canada
Title: When does MS begin after infectious mononucleosis?
The two MS/EBV research initiatives mentioned by Prof G are:
3) 7.1 million Euros. The “BEHIND MS” consortium, led by the German Cancer Research Center (DKFZ), was funded through the HORIZON Europe research funding program. The consortium is made up of 12 partner institutions from Germany, Italy, the Netherlands, Switzerland, Spain, and Belgium.
“This research holds the promise of advancing our understanding and treatment options for MS, thereby bringing us closer to enhancing the quality of life of people with MS,” Elisabeth Kasilingam, CEO of the European Multiple Sclerosis Platform, said in a press release.
4) Funded by the EU's Horizon Europe research program with EUR 7 million in 2024-2028.
"Targeting Epstein-Barr virus to treat and prevent MS"
University of Bergen, Norway (coordinator)
Co-principal investigator, Professor Øivind Torkildsen at Haukeland University Hospital.
The list of participants at the end of the page includes Harvard University, United States.
“Our research will also seek to investigate if targeting the EBV infection with antiviral treatments can improve the disease course or even stop disease progression”, says Myhr.
“Development of prevention strategies like vaccination would be the next step”, says Torkildsen.
Which antiretroviral medication would you want to see being tested ( alone or in combination ) in MS based on the overall effectiveness of the medication in order to suppress EBV and taking into account CNS penetration ?
Prof G,
Don’t be such a Scrooge - it’s nearly Christmas!
- You told us (published the case in 2012) of a patient with multiple sclerosis who had gone into remission after he had become HIV-positive and was started on highly active antiretroviral therapy (HAART).
- You have told us for the last 18 years that EBV is the likely trigger and likely driver of MS.
- You state (today) that you “predict that HAART (highly active antiretroviral therapy) preventing MS is a black swan event”.
- You have, through MS-Selfie, promoted “self-management”.
Yet you “urge [MSers] not to seek off-label treatment until we have trials to show HAART works as a treatment for MS”.
When will these trials finish - 15 years, 20 years….? Time is Brain as you keep telling us. MSers without hope and without time, are quite entitled to spin the wheel and try HAART. A chance of putting MS into remission has to be better than doing nothing and watch your body be ravaged by MS. I applaud those who are trying HAART (and funding it themselves). It’s a pity that a system to capture their experiences can’t be set up - but who will oversee this, fund this…..
This story on the BBC website earlier this week perhaps gives an insight as to why some MSers are experimenting with therapies such as HAART. I wish them well and hope they see benefits - waiting another 15-20 years is likely be too late for them.
https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiencqgmZSDAxVcW0EAHTIyBZgQFnoECBEQAQ&url=https%3A%2F%2Fwww.bbc.co.uk%2Fnews%2Fuk-england-tees-67658432&usg=AOvVaw21nywpLA_Apz3u1EZ1BhCY&opi=89978449
Is there anything we as patients can do to make some noise and try to push these investigations forward?
Given that EBV is being implicated in everything from MS to bipolar disorder, it seems like the companies that own patents on anti-EBV agents would be highly motivated to support trials.
While I agree that data is needed, I can't help but wondering that others use HAART for what many would consider 'fun' (don't get me wrong, I fully support people using PrEP) so I am wondering if waiting really is the correct approach... It's not like the heavy hitting DMTs are side effect free (or even confirmed to do much, cough Oratorio).
Hi, The potential for HAART is interesting, are there any studies looking at use of PrEP for HIV, specifically Discovey as it includes TAF? As there is a significant community of HIV negative people in US using it regularly it would be interesting to know if it had any impact on them developing MS.
I am worried my 2 daughters might get MS and are there any studies they could take part involving HAART?
Famiciclovir probably didn't work because the first by pass metabolism makes it into penciclovir and that still has a hydroxyl group attached, hence no chain termination. By contrast, acyclovir will cause chain termination and end the lytic cycle (for a while).
If you switch the focus from EBV (and EBNAs) to the non coding EBV RNA, EBER2, I think you will find what your looking for.
EBER2 has three regions that look identical to regions in adenosine deanimase. In 1997, Gerlitz, G. and O. Elroy-Stein wrote to a letter to the editor of leukemia identifying the regions (Does EBV RNA modulate ADA mRNA translation. Leukemia, 1998. 12(2): p. 249-249). Essentially, they postulated EBER2 out-competes the adenosine deanimase, resulting in a rise in adenosine. Whilst normally adenosine is neuroprotective, abnormal amounts are toxic as they open purinergic receptors, allowing an overloading influx of calcium. Too much adenosine also downregulates the immune response so we get the muted CD8+T cell response that Pender noted in his papers. When CD4+ T cells respond they aren't rogues, they're just responding to the damage to the astrocytes, oligodendrocytes and neurons caused by the calcium overload. The high adenosine would also explain the fatigue called lassitude as it would accumulate on the adenosine receptors in the brain, triggering part of the sleep cycle. (nerve fibre fatigue would follow a different path)
The bit I can't understand in looking for efficacy is the use of timed walking tests. The damage to upper motor neurons will take years to recover, if at all. Using those tests is like pulling the knife out of a murder victim and expecting him to get up and carry on. Dead is dead. The murder weapon did it's job.
They used those tests 25 years ago to determine if acyclovir worked and, of course, got a negative response. They should have measured the changes in the uric acid levels to see if a normal purinergic breakdown cycle had returned and asked the patients how they felt. They never did.
Prof. G,
What type or which combination of HAART drugs would (theoretically) be most effective (and safe) for long-term anti-retroviral drugs in MS patients? I'll rephrase the question, if you had MS, which HAART combination drug would you take? And I guess these drugs would only have an effect when taken forever... as the HERV / EBV virus replication needs to be continuously suppressed. I'm currenly on Kesimpta as well, so it might also help prevent re-infecting B-cells. Thanks for your insight
Fascinating to be honest. My initial diagnosis was RRMS despite never having a classic MS attack/relapse. The first neuro I saw made that diagnosis and wanted me on teriflunomide. I asked for a second opinion and was referred to the Barlo Center in Toronto. Their diagnosis was PPMS but incredibly slow moving. 3 sets of MRIs over 2 years showed no changes whatsoever. No brain lesions, but a few cervical cord lesions. Lesion size didn't change nor did the number of them. They said Ocrevus was available but given my age (54), lack of disability and very stable MRIs they didn't think it was advisable at this point. But if I read your piece correctly the possibility of starting on Ocrevus and moving to teriflunomide may have some utility?
I don’t think I’d throw on an antiretroviral. I only recently had to fight my neuro to resume a weenie DMD. But I’m faithfully taking acyclovir. That seems to have stopped the constant (and I do mean constant) herpes virus nonsense, so I’m sticking to that! 🌷
We can add two more MS/EBV research efforts to the list.
1) MS Australia has committed $10 million to MS/EBV, including 2 clinical trials of antiviral medications to treat multiple sclerosis (MS) fatigue and progression, as well as three large-scale studies to understand how EBV interacts with the human immune system to increase the risk of developing MS.
https://www.msaustralia.org.au/news/10-million-mrff-funding-awarded-for-australian-research-on-epstein-barr-virus-in-ms/
2) $1 million from The National MS Society, United States, 2023-2026
Natalia Drosu, PhD, Massachusetts General Hospital
Title: CD4+ T cell responses to immunodominant HLA-DRB1*15:01-restricted Epstein-Barr virus antigens in patients with multiple sclerosis with potential cross-reactivity to myelin
Theodore Jardetzky, PhD, Stanford University
Title: Targeting EBV entry glycoproteins for vaccine and therapeutic development Summary: Stanford scientists are exploring novel technology with an eye toward developing a vaccine that may prevent the Epstein-Barr virus from triggering MS.
Dalia Rotstein, MD, MPH, St. Michael's Hospital, Toronto, Canada
Title: When does MS begin after infectious mononucleosis?
https://nms2cdn.azureedge.net/cmssite/nationalmssociety/media/msnationalfiles/research/newresearchjune2023.pdf
The two MS/EBV research initiatives mentioned by Prof G are:
3) 7.1 million Euros. The “BEHIND MS” consortium, led by the German Cancer Research Center (DKFZ), was funded through the HORIZON Europe research funding program. The consortium is made up of 12 partner institutions from Germany, Italy, the Netherlands, Switzerland, Spain, and Belgium.
“This research holds the promise of advancing our understanding and treatment options for MS, thereby bringing us closer to enhancing the quality of life of people with MS,” Elisabeth Kasilingam, CEO of the European Multiple Sclerosis Platform, said in a press release.
https://multiplesclerosisnewstoday.com/news-posts/2023/12/12/research-consortium-nets-eu-funding-study-ms-causes-treatments/
4) Funded by the EU's Horizon Europe research program with EUR 7 million in 2024-2028.
"Targeting Epstein-Barr virus to treat and prevent MS"
University of Bergen, Norway (coordinator)
Co-principal investigator, Professor Øivind Torkildsen at Haukeland University Hospital.
The list of participants at the end of the page includes Harvard University, United States.
“Our research will also seek to investigate if targeting the EBV infection with antiviral treatments can improve the disease course or even stop disease progression”, says Myhr.
“Development of prevention strategies like vaccination would be the next step”, says Torkildsen.
https://www.uib.no/en/med/165045/targeting-epstein-barr-virus-treat-and-prevent-ms
Prof G,
Which antiretroviral medication would you want to see being tested ( alone or in combination ) in MS based on the overall effectiveness of the medication in order to suppress EBV and taking into account CNS penetration ?
Re your two failed studies, would the drugs you trialled be counted as HAART?
Has anyone replicated the exact drugs and dosing as were used in the reported cases of MS disappearing after HAART?