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Testing for JC Virus Antibodies for Tysabri-Related PML Risk

A simple blood test in development will help guide Tysabri decisions

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Updated June 11, 2014

You may have heard of testing for antibodies for JC virus in the blood as a way to determine if someone is at higher risk of progressive multifocal leukoencephalopathy (PML) if they take Tysabri (natalizumab). I'll try to explain what this means and how it is relevant.

JC virus is the infectious organism that causes PML, a potentially fatal brain disease. However, many (probably most) people have been infected with the JC virus. It does not cause any disease in people unless conditions are just right. One such situation is in a person with HIV/AIDS. When T-cells (the immune cells that keep the virus contained in healthy individuals) are depleted, this gives the JC virus a chance to cause PML. Another such situation is in people taking Tysabri. In a small percentage of people who take Tysabri, conditions will be just right for the JC virus to proliferate and cause PML.

One approach to preventing PML in people who are taking or considering Tysabri is to see if they have been infected with PML, which can be determined by testing for JC virus antibodies in their blood. In one study, a test that is currently in development has successfully identified JC virus antibodies in 100% of samples of people with Tysabri-related PML.

The challenge here is that many, many more people have been infected with the JC virus in their lives than will ever develop PML. In fact, one study conducted in Sweden showed that 61% of people with MS tested positive for antibodies to the JC virus – a huge percentage, considering that less than .002% of people on Tysabri ever develop PML. The test is pretty effective if the idea is to prevent all cases of PML by refusing to give them PML, but that approach does exclude many people who would be eligible for Tysabri.

Also, a negative test for JC virus antibodies does not mean that the person is at NO risk of PML, as they can become infected with JC virus in the future or have a low level of antibodies. However, the risk of PML in people who test negative for JC virus antibodies is estimated to be 1 in 25,000 in the first 3 years of using Tysabri, compared to the current rate of a little over 1 in 1,000.

Proposed Black Box Warning on Tysabri

Biogen Idec and Elan Corporation, the manufacturer and distributor of Tysabri, have submitted applications to the US Food and Drug Administration (FDA) and European Medicines Agency to expand the black box warning on Tysabri to include information that positive JC virus antibody tests should be considered as "one potential factor to help stratify the risk" of PML in people taking or considering Tysabri.

This is a smart step by Biogen Idec and Elan, as every case of PML adds to worry in people taking or considering Tysabri. By mitigating the risk of PML, I believe many people will feel more secure in beginning Tysabri (if they are JC virus antibody-negative), as well as be more vigilant for PML symptoms if they do decide to start or continue Tysabri.

Why Can't JC Virus Antibodies be Used to Diagnose PML?

The problem with this approach for diagnosis is that a large percentage of the population – some estimate as many as 70% - has been infected with the JC virus in the past.

Again, while this is a good approach to determining who would be at increased risk for PML if they took Tysabri, it would not work for diagnosing PML. To use the examples above, although 100% of the samples of people with PML tested positive for anti-JC antibodies, there will be many, many more people who test positive who do NOT have PML. To further illustrate, of the 61% of the people who tested positive for anti-JC antibodies, it is statistically unlikely that even one of them would develop PML (even on Tysabri), since the antibodies are so common and PML is such a rare event.

Bottom Line

While the JC virus antibody test would be useful to tell us that the people with anti-JC antibodies are much MORE likely than those without the antibodies to develop PML if they were to take Tysabri, it cannot predict who is at the highest risk and should not be the only factor considered in making a treatment decision – regardless of whether the test comes back positive or negative.

Given my current situation of pretty stable relapsing-remitting MS, I probably wouldn't take Tysabri if my JC virus antibody test came back positive. However, if Tysabri was the last therapy available to me and I was experiencing increasing disability, I would take a positive JV virus antibody test as just one piece in the whole equation and have some serious discussions with my neurologist (and my loved ones) about the situation. A careful risk-benefit analysis (with a healthy dose of emotion) would help me arrive at my answer.

Rather than ruling out use of Tysabri, one approach will probably be that a positive JC virus antibody test in someone currently on Tysabri or who wanted to start it could put them in a higher risk category, which could require more intensive monitoring for PML.

Sources:

Clifford DB, De Luca A, Simpson DM, Arendt G, GIovannoni G, Nath A. Nataulizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurology. 2010 Apr; 9(4):438-46.

Gorelik L, Lerner M, Crossman M, Schlain B, Simon K, Pace A, Cheung A, Chen LL, Berman M, Zein F, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010 Sep;68(3):295-303.

Koralnik IJ. Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations and diagnosis. UpToDate. Accessed January 2011.

National Institute of Neurological Disorders and Stroke (NINDS). NINDS Progressive Multifocal Leukoencephalopathy Information Page.

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