JCV Test Stratifies PML Risk in Antibody-Positive MS

Daniel M. Keller, PhD

June 14, 2013

BARCELONA, Spain — A quantitative test for antibodies to the JC virus (JCV) stratifies antibody-positive patients with multiple sclerosis (MS) for their risk of contracting progressive multifocal leukoencephalopathy (PML) if they receive natalizumab (Tysabri, Biogen Idec). However, some risk remains even with low antibody levels, and some patients who harbor the virus have proven negative for antibodies, studies show.

Presenting preliminary results of a study here at the 23rd Meeting of the European Neurological Society, Barry Ticho, MD, PhD, vice president of clinical development at Biogen Idec in Cambridge, Massachusetts, commented to Medscape Medical News, "What it would indicate to us right now is that the current levels [of risk] that are ascribed to patients who are JC antibody-positive may not be uniform across that group for those who've not had prior immunosuppressive use."

After 2 years of therapy, the risk for PML is approximately 5 per 1000 patients without prior immunosuppressant use. But "there's a population that ranges between 30% and almost half of the [antibody-positive] patients who may be at substantially lower risk of PML than is currently ascribed," he said.

PML is an opportunistic viral disease causing inflammation of the white matter of the brain. It is usually fatal. JC virus is normally kept in check by the immune system, but immunosuppressive therapies can compromise this ability. Natalizumab is thought to act by blocking the ability of inflammatory immune cells to migrate across the blood-brain barrier.

In the present study, anti-JCV antibody levels were determined by using the second-generation Stratify (Biogen Idec) JCV enzyme-linked immunosorbent assay (ELISA). Data were from antibody-positive patients from postmarketing sources and natalizumab clinical trials. The ELISA yields an anti-JCV antibody index, which is an optical density measurement of antibody level and is a corollary to antibody titer.

Higher JCV Antibody Levels Precede PML Diagnosis

Patients who were diagnosed with PML (n = 71) had significantly higher JCV antibody index values more than 6 months before the diagnosis compared with patients without a PML diagnosis (n = 2522) (P < .001). Differences in antibody indices occurred only in comparison of patients with (n = 19) and those without (n = 176) a PML diagnosis who had not had prior immunosuppressive therapy; values were higher for patients later diagnosed with PML (P < .001).

For patients who had received immunosuppressive therapy earlier, there was no significant difference in antibody levels between those later diagnosed with PML and those without PML (P = .87).

For JCV antibody–positive patients with no prior immunosuppressant use, the risk for PML increased with longer natalizumab use. For 1 to 24 months of exposure to the drug, the risk was 0.6/1000. With 25 to 48 months of exposure, the risk increased to 5.2/1000, and with 49 to 72 months of natalizumab, the risk was 5.4/1000. Patients who were antibody negative had a risk of 0.07/1000.

For patients with no prior immunosuppressive exposure, antibody index values allowed estimation of PML risk according to the duration of exposure to natalizumab. Patients with lower antibody levels remained at substantially lower PML risk over the course of natalizumab therapy compared with patients with higher antibody levels.

Table. Estimation of PML Risk per 1000 Patients According to Antibody Index by Duration of Natalizumab Exposure

Antibody Index 1 to 24 Months 25 to 48 Months 49 to 72 Months
≤0.9 0.1 0.3 0.4
≤1.1 0.1 0.7 0.7
≤1.3 0.1 1.0 1.2
≤1.5 0.1 1.2 1.3
>1.5 1.0 8.1 8.5

Patients had no prior immunosuppressant exposure.

"We know that currently some physicians after 2 years of natalizumab treatment in their antibody-positive patients will take the patients off of drug because of a fear of PML," Dr. Ticho said. "Perhaps for patients who have lower antibody index levels there is another analysis of the benefit-risk that has to be made with respect to both the disease course that those patients have and the fact that their risk of PML may actually be lower than expected right now."

Patients With Low Antibody Levels Still at Risk

Dr. Ticho also noted that some antibody-negative patients seroconvert over time, with an expectation of increased PML risk. "Our data would indicate that depending on what index level they have after they change from negative to positive the change in their PML risk may not be nearly as dramatic as people are expecting," such as going from a risk of 1 per 10,000 to an expected risk of 1 per 500. "But now we see that maybe they're only going from a risk of 1 per 10,000 to maybe a risk of 1 per 1000 or even less."

By 18 months of natalizumab treatment, 96% of 553 previously antibody-negative patients remained negative (87%) or seroconverted to a low antibody index level. The current recommendation is to test patients every 6 months for antibody levels.

Dr. Ticho cautioned that the data are still preliminary and the hypothesis of risk based on antibody levels needs further validation.

Session moderator Ludwig Kappos, MD, professor of neurology and clinical neuroimmunology at the University of Basel and chair of the Department of Neurology at University Hospital in Basel, Switzerland, commented to Medscape Medical News that the study provides a further step in defining the risk of PML and is important for that reason, "but it does not eliminate the risk. You have to understand how the risk is and perhaps also to tailor the other additional measures of surveillance, but it is of course not eliminating the risk."

He said that up to now, tests have shown only whether a patient was positive or negative for antibody, but by judging antibody levels on a continuum and with thresholds for risk, "it shows at least a part of those who are positive may still have a reasonable risk that you would perhaps be ready to take regarding the efficacy of taking the drug and the alternatives." Thus, such a test may open a path for some of the positive patients to get back to or to continue receiving natalizumab therapy.

"Even with more precise risk calculations," Dr. Kappos said, "it's still an individual decision between the treating physician and the patient if they stop treatment or not."

Evolution of JCV Antibody Testing

JCV antibody testing has evolved over the past few years. In 2010, researchers reported development of an ELISA to detect antibodies in serum and plasma, with the hope that the test could be used to confirm the absence of antibodies and therefore facilitate natalizumab treatment of patients at low risk for PML.

In January 2012 the US Food and Drug Administration approved a test so that clinicians could tell whether a patient was positive or negative for the presence of antibodies. Periodic retesting was advised because antibody-negative patients could become infected with JCV over time.

The present risk stratification efforts based on the amount of antibody further refine the risk but are not perfect. Patients with low levels of antibody are still at some risk. And a report in the June 6 New England Journal of Medicine showed that in 1 series, one third of patients with MS who tested negative for anti-JCV antibodies had active JCV viremia. However, it is not practical to test for JCV in the clinic at this time.

The study was sponsored by Biogen Idec. Dr. Ticho and all coauthors are employees of the company. Dr. Kappos was not involved in the study and has disclosed no relevant financial relationships.

23rd Meeting of the European Neurological Society. Abstract #O228. Presented June 9, 2013.


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