Should I take anti-retroviral drugs to treat my MS?
... I know that many of you are taking HAART based on hope. Let me remind you that ‘hope is not a strategy to treat MS’.
The theory of black swan events is a metaphor that describes an event that comes as a surprise, has a transformational effect in the relevant field, and is often inappropriately rationalised after the fact, i.e. with the benefit of hindsight. I predict that HAART (highly active antiretroviral therapy) preventing MS is a black swan event.
Julian Gold and I launched the Charcot Project in 2012 to investigate the viral aetiology of MS. Julian and I are kindred spirits. He accidentally found me when his family moved to London and took a sabbatical. Julian wanted to talk to an MS neurologist about 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). We published the case (see below), which may have prompted others to publish their cases with similar observations and in parallel, it triggered an avalanche of self-reported cases via email. At this stage, I always ask: How many swallows does it take to make a summer?
To collect further evidence, we did a study using the NHS Hospital Episode Statistics (HES) data and showed that having HIV protected you from getting MS (Gold et al. J Neurol Neurosurg Psychiatry. 2015 Jan;86(1):9-12). In parallel, the Danish published similar findings but were underpowered for their findings to be significant. We then contacted colleagues at Kaiser Permanente in California and the Veterans Administration in Washington, who interrogated their databases and found a similar thing, i.e. having HIV protected you from getting MS. Despite prodding and nudging, we failed to get the Kaiser or VA teams to publish their findings. I don’t think they realise how important this finding is and how critical it was for us to show that our finding was reproducible.
Black swan events are rarely recognised as Black swans until it becomes evident in hindsight.
Julian and I are, therefore, thrilled that the Canadians and Swedes have confirmed our findings and published their data (see study below).
We hypothesised more than a decade ago that it was not the HIV but the HAART that was the protective factor and that antiretrovirals were preventing MS because they were working against EBV or human endogenous retroviruses (HERVs).
Julian and I then tried numerous times to get trials funded to test this hypothesis, and we failed. This included grant applications to the MRC, the Wellcome Trust and several big pharma companies marketing antiretrovirals. We finally managed to convince Merck in the US that our hypothesis was worth testing and they funded a trial of one anti-retroviral in a small proof-of-concept study, which was negative. However, the drug we tested was raltegravir, an integrase inhibitor, which is likely to be working downstream of EBV in MS.
Since then, we have received funding from the Horne Family Foundation to assess if famciclovir can suppress EBV shedding in the saliva of subjects with MS. Disappointingly, this study has also turned out to be negative. In comparison, we have managed to show that teriflunomide is anti-EBV in that it reduces EBV viral shedding in the saliva of people with MS. I suspect this is a very relevant and important observation and underpins the iTeri study, i.e. to use a B-cell depleting agent as induction therapy and teriflunomide or related compound as a maintenance therapy to prevent EBV reinfecting B-cells during the B-cell reconstitution phase.
Will this new data convince the field to take the viral hypothesis of MS forward? I think so. We are very glad to hear that two studies, one in Norway (Bergen) and the other in the US (Harvard), are about to start testing tenofovir and TAF (tenofovir alafenamide) in MS.
We sincerely hope there is enough evidence for the pharmaceutical industry to reengage with the hypothesis and develop and test antiviral agents for MS. The stakes are too high to ignore the data.
If HAART prevents MS by reducing EBV latent-lytic cycling, this makes a strong case for extending the EBV vaccination programme to include therapeutic EBV vaccines to boost endogenous immunity to EBV as one of the MS prevention strategies. This is very important in that you don’t have to focus only on vaccinating EBV-negative subjects, but you can include all-comers and vaccinate both EBV-positive and negative subjects and analyse both groups. I predict that the incidence of MS will be reduced in both groups, i.e. EBV-positive and negative subjects, compared to unvaccinated control subjects.
I started working on EBV as a cause of MS in 2005, and it feels like I have been treading water for 18 years. The evidence that EBV is the cause of MS is so overwhelming that we really can’t afford to ignore it any longer. What we need is a substantial investment from the major funding agencies, MS charities, wealthy philanthropists and Pharmaceutical companies with antiviral drugs in their portfolio to prove (or disprove) that EBV is the cause of MS. It looks as if the iceberg is beginning to melt and slowly beginning to move. Recently, the EU funded two large grants to look at EBV in MS.
When discussing MS, EBV, and MS prevention, it is essential to do it in the context of the science of causation. When you apply Bradford-Hill’s criteria for causation to the hypothesis that EBV is the cause of MS, only one criterion out of the nine still needs to be ticked, and that is experimental evidence. What we need are therapeutic interventional trials targeting EBV. We must do appropriately powered randomised controlled trials to test the ‘EBV causation of MS’ hypothesis definitively. If any of my contacts in the pharmaceutical industry are reading this newsletter and are interested in taking this forward, please do not hesitate to drop Julian or me an email.
How does this affect me? Should I be taking HAART?
No, you should not be taking HAART. The case studies and epidemiological data hint that HAART may effectively treat MS, but we will only know if this is the case with properly conducted trials. HAART is not cheap; it comes with potential side effects, and it needs to be monitored. I urge you not to seek off-label treatment until we have trials to show HAART works as a treatment for MS. Saying this, I know that many of you are taking HAART based on hope. Let me remind you that ‘hope is not a strategy to treat MS’.
Paper
Objective: There has been interest in a possible negative association between HIV and multiple sclerosis (MS). We aimed to compare the risk of MS in a cohort of individuals living with HIV to that in the general population.
Methods: Population-based health data were accessed for 2 cohorts of HIV-positive persons from Sweden and British Columbia, Canada. Incident MS was identified using MS registries or a validated algorithm applied to administrative data. Individuals with HIV were followed from 1 year after the first clinical evidence of HIV or the first date of complete administrative health data (Canada = April 1, 1992 and Sweden = January 1, 2001) until the earliest of incident MS, emigration, death, or study end (Canada = March 31, 2020 and Sweden = December 31, 2018). The observed MS incidence rate in the HIV-positive cohort was compared to the expected age-, sex-, calendar year-, income-specific, and region of birth-specific rates in a randomly selected sample of >20% of each general population. The standardized incidence ratio (SIR) for MS following the first antiretroviral therapy exposure ("ART-exposed") was also calculated.
Results: The combined Sweden-Canada cohort included 29,163 (75% men) HIV-positive persons. During 242,248 person-years of follow-up, 14 incident MS cases were observed in the HIV-positive cohort, whereas 26.19 cases were expected. The SIR for MS in the HIV-positive population was 0.53 (95% confidence interval [CI] = 0.32-0.90). The SIR for MS following the first ART exposure was 0.55 (95% CI = 0.31-0.96).
Interpretation: This international population-based study demonstrated a lower risk of MS among HIV-positive individuals, and HIV-positive ART-exposed individuals. These findings provide support for further exploration into the relationship among HIV, ART, and MS. ANN NEUROL 2023.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
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.