- 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.
Ian, you highlight a something we clinical academics have to live with, i.e. cognitive dissonance.
As a doctor, neurologist, MSologist, MS expert, .... I can't recommend or support the off-label prescribing and use of HAART. The current evidence base is not robust enough. If I did recommend off-label prescribing my colleagues, the MHRA and GMC would question my professional practice.
However, if I had MS and was a patient I would have started taking HAART several years ago. Does that answer your question? And you are right it will take another decade or more to get a definitive answer on whether or not HAART works in MS.
I have also collected 5 reports from MS patients who caught COVID-19 that all their MS symptoms disappeared for the 5 days they were on Paxlovid, then came back several days after ending Paxlovid. I looked in an EBV group and saw similar reports.
2014 Accelerated Suppression of Primary Epstein-Barr Virus Infection in HIV-Infected Infants Initiating Lopinavir/Ritonavir-Based Versus Nevirapine-Based Combination Antiretroviral Therapy
I don't think price is a real stopper: Looks like generic Tenofovir is something like 1.25 Eur per dose in Germany (for some reason, generics can be fantastically cheap in DE), generic Emtricitabin/Tenofovirdisoproxil (AKA Truvada) 2 EUR...
At that rate, who do I convince to write a prescription? And for which regime...
I agree that price is not a stopper for HAART for MS. I am in the US and I can obtain Combivir (generic version)) for $60/month. I have not investigated other generics, but have asked neurologist to refer me to infectious disease specialist to investigate the possibility of an Rx of one of the HAART's. Not unexpectedly, my neurologist refused. There is an investigational study for tolerability of HAART for MSers going on at Massachusetts General Hospital. It is small study and by invitation only. I will post the reference in a later posting.
I saw that story on the BBC news a few nights ago, just so sad, and really highlighted the impact on his parents too. I was surprised when they said it was MS, though not sure why I was surprised, maybe because he was so affected on every level. A real reminder of how bad it can get!
It seems to be pot luck how quickly the neuro degeneration advances. Made me think about the issue of living v existing. Also shows that while we have treatments for relapses, still in the dark ages with regard to stopping disability worsening. I suspect there are lots of MSers like Duncan - in care homes or living with their families / relatives. At its worst MS not that dissimilar to MND. Heartbreaking story that shouldn’t be happening in the 2020s (we put men on the moon 53 years ago).
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.
You could join the Solving MS research study group on Facebook, we're making noise about #EBVcausesMS. We funded the Trvada study at Harvard, and we are tracking all the trials that aim to treat EBV in MS.
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.
Well, there are some reports that say coffee may help a little for some. Then you would have to consider the variables; the caffeine content, the existing condition of the subject, how many adenosine receptors are involved, etc etc. The late Geoffrey Burnstock https://en.wikipedia.org/wiki/Geoffrey_Burnstock suggested a long list of illnesses and syndromes that could be involved with faulty purinergic signalling. There are several receptors he and others have identified in the brain (P2X7 and P2X4 seem to have the most published research but there seem to be more). There could also be an issue with tolerance. How many people have used coffee to stay awake only to crash later? I'm not arguing that normal levels of adenosine are a problem, just that if it doesn't break down, it accumulates creating problems.
I understand, however, I've read where people report caffeine doesn't help their fatigue. Same for myself, unfortunately. It keeps me awake, but doesn't remove the heavy blanket of fatigue.
As for adenosine, there aren't really many good therapy options, sans antivirals in the hopes that they have an effect.
Have you had any troubles with fatigue? Moreover, if you do suffer from fatigue, has the valacyclovir affected your fatigue? I read about your story and treatment history below, have you experienced any PIRA in that time?
Hi, If we are going to understand fatigue then we'd better define it. My approach was to say fatigue is a lack of energy and that leads to the obvious question - what's energy? In living things energy is released when a phosphate molecule is donated by ATP to something else to either change it or enable it.
ATP is a purine ring of adenosine attached to a ribose sugar with a tail of three phosphates. Building that from scratch is very slow, so usually when ATP loses a phosphate and becomes adenosine diphosphate (ADP) it returns to the mitochondria to replenish the phosphate in a tiny molecular motor called an ATP synthase This happens millions of times a day in our body.
We can't store ATP but we have to be able to draw on it on demand. There can't be an ebb and flow or we wouldn't function. It's quite a concept to grasp. As an example, in a 250g human heart there is about 0.7g of ATP any one time but over the course of a day that heart will turnover 6000g of ATP. The usual method of rebuilding ATP is the ADP reunites with a phosphate. There are a salvage mechanisms but they are short term and usually require significant stresses to trigger them .
I take the valacyclovir to contain EBV replication. I don't see it as either a cure or a substitute for any deficiency. To rebuild energy and overcome fatigue (lassitude) the focus needs to be on how to make ATP. There are multiple steps but it's intense to follow so I'll just skip to what I do ( with what I'm targeting in brackets)
I take
750mg CoQ10 per day - that seems a lot but that's what works for me (to make the electron transport chain work better) Somewhere between 300mg-600mg should work for most.
2x 1000 mg of aceytl-l-carnitine (promote beta oxidation for burning of fatty acids)
2x 50mg equivalent of elemental magnesium usually as a big tablet of predominately magnesium glycinate as other forms pass too quickly through you. ( binds to ATP and reduces the net charge of ATP from -4 to -2 ) It will also have many other benefits, including muscle relaxation.
Regarding the CoQ10, it will change the coagulating factor if you are on a blood thinner (warfarin) so you must get a doctors advice about what to do with the medication!
I don't have any fatigue at all, but I know it as I had it for years.
I have one slightly dodgy left leg but I think that's caused by periformis syndrome, which I'm dealing with.
I've done pilates three times a week for nearly the entire time I've been diagnosed and think it's very important. After a bad attack in 2014, when I had stopped doing any of the above, I ended up in hospital for 5 weeks. Two years later, I was able to help make this video https://www.youtube.com/watch?v=4lBkf3GVhEE so I guess there is a way out of most situations but it does require effort.
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
This is not my field, but an HIV colleague of mine has recommended Biktarvy. But as this is still under patent and expensive he recommends Truvada. Other neurologists are recommending single therapies with tenofovir or TAF.
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.
The first human trial started this summer. Harvard Medical School/Massachusetts General Hospital clinical trial (NCT05957913) focused on utilizing TDF (Tenofovir Disoproxil Fumarate) to possibly reduce EBV (Epstein-Barr virus) viral load in the saliva and blood test results in Multiple Sclerosis patients. Fatigue scores will be measured as an efficacy sign. Solving MS, a patient-led nonprofit with a mission to find a cure for MS, provided the funding.
Those fatigue trials are super interesting - much faster to see an effect on that measure (and anecdotally - no personal experience though -, there might be one to find). If it works on progression too, all the better.
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 ?
A cell assay study was done comparing the effectiveness of several antivirals and HAART drugs. Tenofovir alafenamide (TAF) appears to be the most effective. Combivir wasn't included.
Tenofovir prodrugs potently inhibit Epstein–Barr virus lytic DNA replication by targeting the viral DNA polymerase , Druso et al, Harvard Medical School, Proc Natl Acad Sci USA. 2020 Jun
Note: this is a cell study, not a human trial.
Thus, the clinical use of antivirals as suppressive therapy for EBV lytic reactivation may aid efforts aimed at disease prevention. Current antivirals for EBV have shown limited clinical utility due to low potency or high toxicity, leaving open the need for potent antivirals suitable for long-term prophylaxis. In the present study, we show that tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), drugs with excellent safety profiles used clinically for HIV prevention, inhibit EBV lytic DNA replication, with respective IC50 values of 0.30 μM and 84 nM.
In a cell-based assay, TAF was 35- and 24-fold and TDF was 10- and 7-fold more potent than acyclovir and penciclovir, respectively, and TAF was also twice as potent as ganciclovir.
In contrast to acyclovir, treatment of cells during latency for 24 h with TAF still inhibited EBV lytic DNA replication at 72 h after the drug was removed. Our results suggest that tenofovir prodrugs may be particularly effective as inhibitors of EBV lytic reactivation.
Tenonovir and acyclovir both lack a hydroxyl group at the 3rd carbon. So, the phosphodiester bonds that link the 3' carbon atom to the 5' carbon atom of the next nucleotide can't be formed. Without that, the RNA and DNA backbones of the virus can't be formed. I've been taking acyclovir for over 20 years and haven't been adversely affected. Acyclovir acts as an analog for guanosine. I don't know if Tenovir is an analog for a particular nucleotide
I think you said you are takin 3 grams a day of acyclovir? Maybe that is why it is effective for you. We do have a cell-assay study that compares EBV inhibition effect of several antivirals, including the 2 cyclovirs, to Tenofovir Alafenamide (TAF).
Tenofovir prodrugs potently inhibit Epstein–Barr virus lytic DNA replication by targeting the viral DNA polymerase. Druso et al., Proc Natl Acad Sci U S A. 2020.
Like ACV and GCV, tenofovir (TFV) is an acyclic nucleoside/nucleotide analog (18). It is the primary metabolite of the prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) (19), which are clinically licensed for the treatment of HIV infection and hepatitis B infection and HIV prophylaxis, where they act as inhibitors of the viral reverse transcriptase. Both TDF and TAF are orally bioavailable drugs with highly favorable safety profiles (20). A significant difference between ACV and TFV lies in the initial phosphorylation step: ACV requires a viral kinase, while TFV does not, because it is a monophosphorylated nucleotide (18). TDF and TAF contain chemical modifications that mask the negatively charged phosphate group of TFV, allowing the drugs to reach higher intracellular concentrations. In contrast to ACV, TFV prodrugs are metabolized independently of viral enzymes to their active form, tenofovir-diphosphate (TFV-DP) (19). Of the two prodrugs, TAF has better distribution into lymphoid tissues, including lymphocytes, lymph nodes, and spleen (21).
Here we show that prodrugs of TFV—TDF and TAF—are highly potent inhibitors of EBV lytic DNA replication and may be better suited for suppressive therapy for EBV lytic reactivation.
--------------
Another recent 2023 paper tested TAF in EBV infected cells from MS subjects and compared it to heakthy controls.
Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells Soldan et al., preprint, 2023.
We also found that SLCLs from MS patients had increased production of inflammatory cytokines relative to healthy controls as measured by flow cytometry, RT-qPCR and RNAseq. Furthermore, treatment with TAF, an antiviral that reduces EBV lytic cycle gene expression reduced EBV lytic cycle gene activity in AMS cells, along with a reduction in B cell inflammatory gene expression and T-cell activation. Collectively, these data suggest that poor control of EBV latency in MS, particularly in the active phase of the disease, results in increased lytic gene expression and increased inflammation.
Our studies indicate that TAF does indeed decrease lytic activity as measured by decreased expression of EBV lytic genes (Zta and EA-D) and decreased viral loads.
-----------
I have these refences in research profile, and the studies done on the acyclovirs, along with the history of EBV as cause of MS here >
That's useful information. Thanks! Being the devils advocate, I wonder what happens in the very long term with continual usage of Tenofir. As you point out, it doesn't require that initial phosphorylation step. ACV does which means it's highly specific to infected cells. ( due to its high affinity to a viral thymidine kinase) As Tenofir doesn't have that high degree of specificity, I wonder what else is happening that we haven't noticed yet. I'm not sure high intracellular concentrations matter so I'll sit like a vulture on a branch and watch for a while.
Hi, Not a dose that high. I stick on 2x500mg a day. It's not the dose that matters, it's the persistence. I can't see how it will affect a latent infection,irrespective of dose. I presume it's just the lytic replication that is affected.
Yes, it is a prescription only drug. Back in the late 1990's I showed my GP at the time an article from Neurology magazine that was the forerunner of the EBV study about MS and the US army. (the one that finally seemed to nail EBV as essential for MS). At first he did nothing , but one day he suggested I could try valacyclovir. I got a benefit and told him to keep prescribing it. I no longer see him but when I see a new local doctor I just say I need it for my MS. Then they look up my history and see I have been using it for a long time, so they shrug their shoulders and say OK. To be honest, their attitude is appalling but as long as I keep getting it i don't complain. If you need an academic rationale give them a copy of this https://journals.sagepub.com/doi/epdf/10.1177/1073858410381531
page 363 details treatment which includes valacyclovir.
I meant the acyclovir has not produced any adverse affects for me. When I was initially diagnosed in 1994, there were not really any treatments except a few days of steroids. In 1996, Avonex (inferon) became available. I took it for years but hated it and stopped after about nine years. In 1997, I started taking valacyclovir and kept using it till 2013. I stopped using it because I felt so good and thought the whole MS thing was behind me. However, in late 2014, I had a really bad attack and spent five a half weeks in hospital and two years doing (useless) rehab. My Pilates was much better than rehab. Needless to say, I resumed taking valacyclovir and I'm fine again. I do have some weakness in my left leg as a result of that attack but most people wouldn't notice it. As an overall view, my neurologist (from 2014) is surprised and I'm sure he was ready to pounce and tell me I should have been on something. Now he just lets me go my own way. I have heard of people who tried valacyclovir but got a negative reaction. The drug will work on gamma herpes viridae, so maybe they had a few strains or perhaps they were trialing many other things at the same time (who knows). You will struggle to get it prescribed as the trials using it were regarded as failures and it is not a mainstream MS treatment. Whatever else you're doing can possibly influence the outcome. Taking valacyclovir is only one aspect. You need to watch everything carefully.
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
Ian, you highlight a something we clinical academics have to live with, i.e. cognitive dissonance.
As a doctor, neurologist, MSologist, MS expert, .... I can't recommend or support the off-label prescribing and use of HAART. The current evidence base is not robust enough. If I did recommend off-label prescribing my colleagues, the MHRA and GMC would question my professional practice.
However, if I had MS and was a patient I would have started taking HAART several years ago. Does that answer your question? And you are right it will take another decade or more to get a definitive answer on whether or not HAART works in MS.
That answers the question, however, there are now many different HAART medications.
Which medication would you study first Prof G?
Also, do you know of any follow-up with the Combivir patient(https://pubmed.ncbi.nlm.nih.gov/29510325/)?
Pretty miraculous turnaround and considering combivir's good penetrance of the BBB, seems like a decent starting point.
Prof G, have you looked at the EBV antiviral effects of Spironolactone and Dipyridamole?
2016 Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822607/
2019 Dipyridamole as a new drug to prevent Epstein-Barr virus reactivation
https://www.sciencedirect.com/science/article/pii/S0166354219303304
I have also collected 5 reports from MS patients who caught COVID-19 that all their MS symptoms disappeared for the 5 days they were on Paxlovid, then came back several days after ending Paxlovid. I looked in an EBV group and saw similar reports.
2014 Accelerated Suppression of Primary Epstein-Barr Virus Infection in HIV-Infected Infants Initiating Lopinavir/Ritonavir-Based Versus Nevirapine-Based Combination Antiretroviral Therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982841/
"Although the rate of EBV infection was similar between groups, infants receiving lopinavir/ritonavir suppressed EBV more rapidly."
"Dewan and colleagues previously demonstrated that ritonavir inhibited EBV-immortalized lymphoblastoid cell line (LCL) growth in vitro"
"suggesting a potential effect of ritonavir on B cells undergoing lytic EBV replication."
I don't think price is a real stopper: Looks like generic Tenofovir is something like 1.25 Eur per dose in Germany (for some reason, generics can be fantastically cheap in DE), generic Emtricitabin/Tenofovirdisoproxil (AKA Truvada) 2 EUR...
At that rate, who do I convince to write a prescription? And for which regime...
I agree that price is not a stopper for HAART for MS. I am in the US and I can obtain Combivir (generic version)) for $60/month. I have not investigated other generics, but have asked neurologist to refer me to infectious disease specialist to investigate the possibility of an Rx of one of the HAART's. Not unexpectedly, my neurologist refused. There is an investigational study for tolerability of HAART for MSers going on at Massachusetts General Hospital. It is small study and by invitation only. I will post the reference in a later posting.
Tenofovir alafenamide can be prescribed to healthy people for protection against catching HIV.
În India aTAF is 6 $ for one mounthn
I saw that story on the BBC news a few nights ago, just so sad, and really highlighted the impact on his parents too. I was surprised when they said it was MS, though not sure why I was surprised, maybe because he was so affected on every level. A real reminder of how bad it can get!
It seems to be pot luck how quickly the neuro degeneration advances. Made me think about the issue of living v existing. Also shows that while we have treatments for relapses, still in the dark ages with regard to stopping disability worsening. I suspect there are lots of MSers like Duncan - in care homes or living with their families / relatives. At its worst MS not that dissimilar to MND. Heartbreaking story that shouldn’t be happening in the 2020s (we put men on the moon 53 years ago).
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.
You could join the Solving MS research study group on Facebook, we're making noise about #EBVcausesMS. We funded the Trvada study at Harvard, and we are tracking all the trials that aim to treat EBV in MS.
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?
Nothing at the moment. Not sure HAART is even on the prevent MS horizon. Too early may be?
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.
Fascinating theory. But if adenosine build up is the downstream culprit for MS lassitude, why doesn't caffeine seem to work in so many?
Well, there are some reports that say coffee may help a little for some. Then you would have to consider the variables; the caffeine content, the existing condition of the subject, how many adenosine receptors are involved, etc etc. The late Geoffrey Burnstock https://en.wikipedia.org/wiki/Geoffrey_Burnstock suggested a long list of illnesses and syndromes that could be involved with faulty purinergic signalling. There are several receptors he and others have identified in the brain (P2X7 and P2X4 seem to have the most published research but there seem to be more). There could also be an issue with tolerance. How many people have used coffee to stay awake only to crash later? I'm not arguing that normal levels of adenosine are a problem, just that if it doesn't break down, it accumulates creating problems.
I understand, however, I've read where people report caffeine doesn't help their fatigue. Same for myself, unfortunately. It keeps me awake, but doesn't remove the heavy blanket of fatigue.
As for adenosine, there aren't really many good therapy options, sans antivirals in the hopes that they have an effect.
Have you had any troubles with fatigue? Moreover, if you do suffer from fatigue, has the valacyclovir affected your fatigue? I read about your story and treatment history below, have you experienced any PIRA in that time?
Hi, If we are going to understand fatigue then we'd better define it. My approach was to say fatigue is a lack of energy and that leads to the obvious question - what's energy? In living things energy is released when a phosphate molecule is donated by ATP to something else to either change it or enable it.
ATP is a purine ring of adenosine attached to a ribose sugar with a tail of three phosphates. Building that from scratch is very slow, so usually when ATP loses a phosphate and becomes adenosine diphosphate (ADP) it returns to the mitochondria to replenish the phosphate in a tiny molecular motor called an ATP synthase This happens millions of times a day in our body.
We can't store ATP but we have to be able to draw on it on demand. There can't be an ebb and flow or we wouldn't function. It's quite a concept to grasp. As an example, in a 250g human heart there is about 0.7g of ATP any one time but over the course of a day that heart will turnover 6000g of ATP. The usual method of rebuilding ATP is the ADP reunites with a phosphate. There are a salvage mechanisms but they are short term and usually require significant stresses to trigger them .
I take the valacyclovir to contain EBV replication. I don't see it as either a cure or a substitute for any deficiency. To rebuild energy and overcome fatigue (lassitude) the focus needs to be on how to make ATP. There are multiple steps but it's intense to follow so I'll just skip to what I do ( with what I'm targeting in brackets)
I take
750mg CoQ10 per day - that seems a lot but that's what works for me (to make the electron transport chain work better) Somewhere between 300mg-600mg should work for most.
2x 1000 mg of aceytl-l-carnitine (promote beta oxidation for burning of fatty acids)
2x 50mg equivalent of elemental magnesium usually as a big tablet of predominately magnesium glycinate as other forms pass too quickly through you. ( binds to ATP and reduces the net charge of ATP from -4 to -2 ) It will also have many other benefits, including muscle relaxation.
Regarding the CoQ10, it will change the coagulating factor if you are on a blood thinner (warfarin) so you must get a doctors advice about what to do with the medication!
I don't have any fatigue at all, but I know it as I had it for years.
I have one slightly dodgy left leg but I think that's caused by periformis syndrome, which I'm dealing with.
I've done pilates three times a week for nearly the entire time I've been diagnosed and think it's very important. After a bad attack in 2014, when I had stopped doing any of the above, I ended up in hospital for 5 weeks. Two years later, I was able to help make this video https://www.youtube.com/watch?v=4lBkf3GVhEE so I guess there is a way out of most situations but it does require effort.
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
This is not my field, but an HIV colleague of mine has recommended Biktarvy. But as this is still under patent and expensive he recommends Truvada. Other neurologists are recommending single therapies with tenofovir or TAF.
Thank you so much for replying.
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?
Re: "if I read your piece correctly the possibility of starting on Ocrevus and moving to teriflunomide may have some utility?"
Yes, this is called the iTeri study.
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
The first human trial started this summer. Harvard Medical School/Massachusetts General Hospital clinical trial (NCT05957913) focused on utilizing TDF (Tenofovir Disoproxil Fumarate) to possibly reduce EBV (Epstein-Barr virus) viral load in the saliva and blood test results in Multiple Sclerosis patients. Fatigue scores will be measured as an efficacy sign. Solving MS, a patient-led nonprofit with a mission to find a cure for MS, provided the funding.
https://www.clinicaltrials.gov/study/NCT05957913
Acyclovir is an acrylic purine nucleoside analog that competitively inhibits viral DNA polymerase.
Valacyclovir is a Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor.
Tenofovirs are a nucleoside reverse transcriptase inhibitors (NRTI).
Those fatigue trials are super interesting - much faster to see an effect on that measure (and anecdotally - no personal experience though -, there might be one to find). If it works on progression too, all the better.
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 ?
A cell assay study was done comparing the effectiveness of several antivirals and HAART drugs. Tenofovir alafenamide (TAF) appears to be the most effective. Combivir wasn't included.
Tenofovir prodrugs potently inhibit Epstein–Barr virus lytic DNA replication by targeting the viral DNA polymerase , Druso et al, Harvard Medical School, Proc Natl Acad Sci USA. 2020 Jun
Note: this is a cell study, not a human trial.
Thus, the clinical use of antivirals as suppressive therapy for EBV lytic reactivation may aid efforts aimed at disease prevention. Current antivirals for EBV have shown limited clinical utility due to low potency or high toxicity, leaving open the need for potent antivirals suitable for long-term prophylaxis. In the present study, we show that tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), drugs with excellent safety profiles used clinically for HIV prevention, inhibit EBV lytic DNA replication, with respective IC50 values of 0.30 μM and 84 nM.
In a cell-based assay, TAF was 35- and 24-fold and TDF was 10- and 7-fold more potent than acyclovir and penciclovir, respectively, and TAF was also twice as potent as ganciclovir.
In contrast to acyclovir, treatment of cells during latency for 24 h with TAF still inhibited EBV lytic DNA replication at 72 h after the drug was removed. Our results suggest that tenofovir prodrugs may be particularly effective as inhibitors of EBV lytic reactivation.
Tenonovir and acyclovir both lack a hydroxyl group at the 3rd carbon. So, the phosphodiester bonds that link the 3' carbon atom to the 5' carbon atom of the next nucleotide can't be formed. Without that, the RNA and DNA backbones of the virus can't be formed. I've been taking acyclovir for over 20 years and haven't been adversely affected. Acyclovir acts as an analog for guanosine. I don't know if Tenovir is an analog for a particular nucleotide
I think you said you are takin 3 grams a day of acyclovir? Maybe that is why it is effective for you. We do have a cell-assay study that compares EBV inhibition effect of several antivirals, including the 2 cyclovirs, to Tenofovir Alafenamide (TAF).
Tenofovir prodrugs potently inhibit Epstein–Barr virus lytic DNA replication by targeting the viral DNA polymerase. Druso et al., Proc Natl Acad Sci U S A. 2020.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275665/
Like ACV and GCV, tenofovir (TFV) is an acyclic nucleoside/nucleotide analog (18). It is the primary metabolite of the prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) (19), which are clinically licensed for the treatment of HIV infection and hepatitis B infection and HIV prophylaxis, where they act as inhibitors of the viral reverse transcriptase. Both TDF and TAF are orally bioavailable drugs with highly favorable safety profiles (20). A significant difference between ACV and TFV lies in the initial phosphorylation step: ACV requires a viral kinase, while TFV does not, because it is a monophosphorylated nucleotide (18). TDF and TAF contain chemical modifications that mask the negatively charged phosphate group of TFV, allowing the drugs to reach higher intracellular concentrations. In contrast to ACV, TFV prodrugs are metabolized independently of viral enzymes to their active form, tenofovir-diphosphate (TFV-DP) (19). Of the two prodrugs, TAF has better distribution into lymphoid tissues, including lymphocytes, lymph nodes, and spleen (21).
Here we show that prodrugs of TFV—TDF and TAF—are highly potent inhibitors of EBV lytic DNA replication and may be better suited for suppressive therapy for EBV lytic reactivation.
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Another recent 2023 paper tested TAF in EBV infected cells from MS subjects and compared it to heakthy controls.
Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells Soldan et al., preprint, 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915775/
We also found that SLCLs from MS patients had increased production of inflammatory cytokines relative to healthy controls as measured by flow cytometry, RT-qPCR and RNAseq. Furthermore, treatment with TAF, an antiviral that reduces EBV lytic cycle gene expression reduced EBV lytic cycle gene activity in AMS cells, along with a reduction in B cell inflammatory gene expression and T-cell activation. Collectively, these data suggest that poor control of EBV latency in MS, particularly in the active phase of the disease, results in increased lytic gene expression and increased inflammation.
Our studies indicate that TAF does indeed decrease lytic activity as measured by decreased expression of EBV lytic genes (Zta and EA-D) and decreased viral loads.
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I have these refences in research profile, and the studies done on the acyclovirs, along with the history of EBV as cause of MS here >
Antiviral Therapy for EBV in MS https://bit.ly/AntiviralsForMS
If anyone hase suggestions ir corrections let me know!
That's useful information. Thanks! Being the devils advocate, I wonder what happens in the very long term with continual usage of Tenofir. As you point out, it doesn't require that initial phosphorylation step. ACV does which means it's highly specific to infected cells. ( due to its high affinity to a viral thymidine kinase) As Tenofir doesn't have that high degree of specificity, I wonder what else is happening that we haven't noticed yet. I'm not sure high intracellular concentrations matter so I'll sit like a vulture on a branch and watch for a while.
Hi, Not a dose that high. I stick on 2x500mg a day. It's not the dose that matters, it's the persistence. I can't see how it will affect a latent infection,irrespective of dose. I presume it's just the lytic replication that is affected.
Acyclovir is a prescription only drug. How did you get a prescription and is a doctor monitoring the use?
(In my part of the world, we can manage to get many tablets without prescription! I don't think that's possible in developed countries.)
Yes, it is a prescription only drug. Back in the late 1990's I showed my GP at the time an article from Neurology magazine that was the forerunner of the EBV study about MS and the US army. (the one that finally seemed to nail EBV as essential for MS). At first he did nothing , but one day he suggested I could try valacyclovir. I got a benefit and told him to keep prescribing it. I no longer see him but when I see a new local doctor I just say I need it for my MS. Then they look up my history and see I have been using it for a long time, so they shrug their shoulders and say OK. To be honest, their attitude is appalling but as long as I keep getting it i don't complain. If you need an academic rationale give them a copy of this https://journals.sagepub.com/doi/epdf/10.1177/1073858410381531
page 363 details treatment which includes valacyclovir.
I meant the acyclovir has not produced any adverse affects for me. When I was initially diagnosed in 1994, there were not really any treatments except a few days of steroids. In 1996, Avonex (inferon) became available. I took it for years but hated it and stopped after about nine years. In 1997, I started taking valacyclovir and kept using it till 2013. I stopped using it because I felt so good and thought the whole MS thing was behind me. However, in late 2014, I had a really bad attack and spent five a half weeks in hospital and two years doing (useless) rehab. My Pilates was much better than rehab. Needless to say, I resumed taking valacyclovir and I'm fine again. I do have some weakness in my left leg as a result of that attack but most people wouldn't notice it. As an overall view, my neurologist (from 2014) is surprised and I'm sure he was ready to pounce and tell me I should have been on something. Now he just lets me go my own way. I have heard of people who tried valacyclovir but got a negative reaction. The drug will work on gamma herpes viridae, so maybe they had a few strains or perhaps they were trialing many other things at the same time (who knows). You will struggle to get it prescribed as the trials using it were regarded as failures and it is not a mainstream MS treatment. Whatever else you're doing can possibly influence the outcome. Taking valacyclovir is only one aspect. You need to watch everything carefully.
I also wonder if the fumarate group on the TAF might do it's own thing, too. After all, we know fumarates can help...
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?