Tuesday, 5 April 2016

Does natalizumab activate the JC virus time bomb?

Vennegoor A, van Rossum JA, Leurs C, Wattjes MP, Rispens T, Murk JL, Uitdehaag BM, Killestein J. High cumulative JC virus seroconversion rate during long-term use of natalizumab. Eur J Neurol. 2016. doi: 10.1111/ene.12988. [Epub ahead of print]

BACKGROUND AND PURPOSE: John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab-treated relapsing-remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab-treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing.

METHODS AND RESULTS: In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti-JCV antibody indices were measured in 933 available samples. Eighty-six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow-up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow-up duration. No significant increase was seen in the anti-JCV antibody index in the non-converting patients during the follow-up.

CONCLUSION: The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

There is no question in mind that natalizumab is a an effective compound in terms of relapsing MS, but we also know that its achilles heel is that it leads to a high risk of PML if you are JC virus positive, which about 50% of us. 

If you are JC virus negative your risk of PML is low. However what happens over time? 

In this study they follow people taking  natalizumab and they track their JC virus status and about 7% convert each year so within 4 years about 25%  of those people are sero-positive. This either means that they have become infected and make an anti-JC virus response, or they were actually infected and have now made an antibody response. 

Whilst it seems that any drug that causes physical or functional loss of white  blood cells can increased your risk of PML, There is something unusual about natalizumab and the PML risk is much higher. 

Based on Biogen's figures the risk of PML and being JC negative is not nil so some people have un-noticed infections it seems. PML occurs when you are immunosuppressed but nothing like at the frequency that occurs with natalizumab. It seems that natalizumab get the virus out it's hiding place like the bone marrow so it can (a) be seen by the immune response so that you make antibodies and (b) can get into your CNS to make PML.

One question is do the serum converters have the same PML risk as the already seropositive or is it less?  

How long does the risk of seroconverting, i,.e. showing evidence of infection last after natalizumab has been stopped?  Because at the moment neuros are switching people off natalizumab by two years when your risk of PML increases alot. If PML pops up in the drug you converted to, is it a black mark againist the drug of conversion or a legacy of previous natalizumab therapy?


  1. Simple question: why is it so difficult to produce an antiviral or another preventive therapy against JC virus?

  2. My guess is that jc virus is not a public health issue, little group of people would need it.

  3. Is there an anti-viral that works against the Epstein Barr virus? That seems more important.

    1. Thats what the Charcot Project is all about

    2. Anti-viral that works against latent EBV? Yes, CRISPR/Cas9 system.

  4. If you are on natalizumab and are JC positive, it has been mentioned that the virus mutates unchallenged by the immune system. If you are on it long enough it seems to me the characteristics of this virus would be foreign from what is known about the conventional JC virus.

    When you come off it and switch to another therapy your immune system may not have the same effectiveness to this highly mutated virus.

    1. All hypothectical but prior exposure ot natalizumab is a risk factor

  5. This is the exact situation I am in. Seroconverted after 10 years. The other thing I would note is that in our center those that convert, convert with titers at a much higher level. Biogen puts the cut off at 0.9. All of my co-infusion friends that have converted at up at 2.8 or higher and stay there. Biogen says nothing when levels are that high.

    I have had many discussions about changing therapies. I ruled out Fingolimod a long time ago. Now the focus is on rituximab or other Anti CD-20. But my question still remains:

    If my titers are this high and I am now going to effect another part of my immune system, what is my risk of PML then? The data is simply not there and honestly scares me to death.

    All of the drug companies to need to be collecting data and post Tysabri patients. There are a lot of us.


    1. Is a high titre because ou are very good at getting rid of the virus?

  6. > If my titers are this high and I am now going to effect another part of my immune system, what is my risk of PML then? The data is simply not there and honestly scares me to death.

    There is an instance where a person who got off Tysabri, developed PML and (not knowing that the PML had already started) had an infusion of rituximab. This person got symptoms of PML had a similar response similar to people who were pulled off Tysabri and not on any other immunosuppressant. So rituximab does not appear to cause PML; in fact it has been shown that the body cleared the PML with rituximab in the system.

    There are also no known instances of PML on rituximab after the ~6 month window post Tysabri cessation (carryover PML). There have been a some cases of PML on rituximab (mostly in people using it for rheumatoid arthritis etc.), but based on my understanding it was only in people with other previous immunosuppressant use (not Tysabri).

    Long story short, the only fear I'd have here is PML while on Tysabri and the 6 months after stopping, and the risks inherent in switching off a drug that's been working for you to one, while of probably as-high efficacy on average, that may not be as effective for your particular case of MS.

    1. Rituximab does not deplete plasma cells or CD8 T cells or CD4 so it is rather un surprising that the PML was un affected when infectiion is fulminent. In contrast when this happened with Alemtuzumab, death due to PML occurred.

      However PML has occurred with depletion anti-CD20...was this because of prior use immunosuppressives as you say. As more and more people use anti-CD20 then we will see what happens

      We have to remember that ocreluzimab was dropped in arthritis because of infection related deaths so no treatments get a clean bill of health.

  7. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136046


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