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?

Labels: ,