JCV Test 'Useful But Not Sufficient' to Gauge PML Risk

Susan Jeffrey

June 06, 2013

A new report raises questions about the reliability of the test for JC virus (Stratify, Biogen Idec) to help determine risk for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab (Tysabri, Biogen Idec).

Eugene O. Major, PhD, from the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland; Elliot Frohman, MD, PhD, from the University of Texas Southwestern Medical Center in Dallas; and Daniel Douek, MD, PhD, from the National Institute of Allergy and Infectious Diseases, report that in their series, one third of patients with MS who tested negative for antibodies to JC virus were found to have active JC viremia.

"Although viremia by itself is not a predictor of the risk of PML, the observation that viremia can occur in patients with negative test results for antibodies to the JC virus raises other issues," the authors write. "The relatively high percentage of patients who had viremia and were seronegative appears to be greater than the false negative rate identified previously. In some of these patients, the same blood sample showed T-cell responses to JC virus proteins but a seronegative test result."

Their findings are published as Correspondence in the June 6 issue of the New England Journal of Medicine.

Before and After Treatment

For this report, Dr. Major and colleagues analyzed plasma samples for JC virus antibodies and viral DNA from 2 cohorts of patients: 26 patients immediately before their first natalizumab infusion and several times over first year of treatment; and 23 patients tested once after more than 24 months of natalizumab treatment.

"Antibody titers and viral DNA were measured by means of an enzyme-linked immunosorbent assay with the use of JC viruslike particles (the Biogen Stratify assay uses similar viruslike particles)," they write. They also used ultrasensitive polymerase chain reaction (PCR) assay specific for JC virus DNA using procedures certified in accordance with the Clinical Laboratory Improvement Amendment.

"The Laboratory of Molecular Medicine and Neuroscience has provided quantitative PCR results that have confirmed the diagnosis of [PML] in approximately half the 370 cases of PML in natalizumab-treated patients with multiple sclerosis," the authors note.

They report that, overall, 17 of the 49 patients (35%) had viremia at some time. Ten of the 26 patients in whom treatment was initiated had viremia; 4 of these were seronegative (antibody titer <2560), and 6 were seropositive (antibody titer ≥2560). Of those patients, 4 had viremia at baseline and 3 were seropositive, the authors write. Seven of 23 patients who received more than 24 infusions had viremia and 2 were seronegative.

One blood sample was obtained from each of the 18 healthy volunteers (6 were seronegative, 12 were seropositive, and none had detectable viral DNA), and a Fisher exact test was used to determine a statistical difference between the treated patients with viremia and the healthy volunteers (P = .003).

… a single measurement of viral activity such as a test for antibodies to JC virus may be useful but not sufficient to assess risk.

"We observed a range in viral titers from 13 to 510 copies of JC virus DNA per milliliter (mean, 43 copies per milliliter) in patients in the initial year of treatment and from 21 to 126 copies (mean, 40 copies per milliliter) in those who received more than 24 infusions," they write. "Of the 17 persons with viremia, 11 were seropositive (65%) and 6 were seronegative (35%)."

"To establish risk-stratification algorithms for PML in patients who receive potent immunomodulatory therapies, a single measurement of viral activity such as a test for antibodies to JC virus may be useful but not sufficient to assess risk," the authors write. "The observation that some patients had viremia and were seronegative provides support for a more comprehensive risk-mitigation strategy involving periodic monitoring over the course of the treatment intervention."

Because of the known risk for PML, natalizumab is available only under a restricted distribution program called the TOUCH Prescribing Program. The prescribing information says testing patients for anti-JV virus antibodies before and during treatment should be considered.

Infection by JC virus is required for the development of PML, the prescribing information notes, but patients who are antibody negative "are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Therefore, patients with a negative anti-JCV antibody test result should be retested every 6 months."

A patient with a positive antibody test result at any time should be considered anti-JCV antibody positive regardless of the results of any prior or subsequent test, the label notes.

"The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors," the prescribing information notes. "Patients with all three known risk factors (treatment with natalizumab for more than 2 years, prior immunosuppressant treatment and anti-JC virus antibody positivity) have an estimated risk of PML of 11/1,000."

Dr. Major and Dr. Douek have disclosed no relevant financial relationships. Dr. Frohman reports receiving payment for consultancy and as a member of the speakers bureau to Biogen Idec, Teva, Genyme, Abbott Laboratories, Acorda, and Novartis.

N Engl J Med. 2013;368:2240-2241. Full text


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