Conversion to JCV Positivity Common With Natalizumab in MS

Nancy A. Melville

October 06, 2015

CHICAGO — Nearly a quarter of patients with multiple sclerosis (MS) being treated with natalizumab (Tysabri, Biogen Idec) convert from a negative status of JC virus (JCV) antibodies to positive, but factors such as duration of natalizumab treatment do not appear to affect JCV antibody levels — or conversion to progressive multifocal leukoencephalopathy (PML) — a longitudinal study suggests.

"In keeping with other studies, we did not find a correlation between prior immunosuppression and JCV AI [antibody index] levels, [but] in contrast to other studies, we did not find a significant association of duration of natalizumab use and antibody levels," Clementine E. Karageorgiou, MD, PhD, head of the Neurology Department at the Athens Medical Center at the Neurological Institute of Athens, Greece, told Medscape Medical News.

"We [also] only found a weak association to JCV AI levels and aging, similar to other studies," she added. "This makes it an appropriate marker for assessing JCV Ab levels and, by extension, activity."

Their findings were presented here at the American Neurological Association (ANA) 2015 Annual Meeting.

While the immune system is normally able to keep JCV in check, treatment of MS with natalizumab is associated with increased risk for PML in seropositive patients, which usually leads to death or severe disability.

For this study, 490 patients, including 332 women, with relapsing-remitting MS who had been treated with natalizumab between 2007 and 2015 were analyzed according to demographic characteristics, levels of anti-JCV, and AI levels.

Among the patients, 38 (7.76%) had prior treatment with immunosuppression; the mean patient age was 44.8 years (range, 15 to 74 years).

Patients' mean disease duration was 7.9 years (range, 1 to 15 years), and the duration of treatment with natalizumab ranged from 0.5 years to 7.5 years.

Overall, 332 (52.9%) patients were positive for JCV, determined with AI levels greater than 0.4 on the two-step, second-generation Stratify (Biogen Idec) JCV enzyme-linked immunosorbent assay; 131 (20.8%) were equivocal (0.2 to 0.4); and 165 (26.3%) were negative (<0.2).

Longitudinal results that were available for 142 patients showed that 30 (22.95%) patients who were negative converted to seropositive, while the remaining 77.05% who were negative at baseline remained negative through the follow-up. Two patients developed PML.

After adjustment for factors including age, sex, history of immunosuppression, and years treated with natalizumab, only age was associated with higher AI values (P = .004).

Notably, nine patients who seroconverted remained beyond the current recommended AI threshold for natalizumab discontinuation of 0.9.

The two patients who developed PML converted to positive status approximately 5 years after initiating natalizumab treatment.

While both patients had high anti-JCV levels at PML onset, the levels were not significantly higher than other positive samples. Dr Karageorgiou noted that some other patients had higher JCV AI values with more years of natalizumab treatment without having any sign of PML.

In one of the patients who did develop PML, anti-JCV levels spiked abruptly a few weeks before the onset of PML symptoms.

"It was the combination of the abrupt spike in levels and the actual final level that defined who developed PML," Dr Karageorgiou said. "There were other patients with abrupt slopes in their levels, but that did not reach high final values and those patients did not develop PML."

Dr Karageorgiou noted that both patients who developed PML survived, with one able to return to work and the other having some residual deficits.

 
Based on the current findings, if a patient shows an abrupt spike in their JCV antibody index. the clinician should stop natalizumab treatment… Dr Clementine E. Karageorgiou
 

"Based on the current findings, if a patient shows an abrupt spike in their JCV antibody index. the clinician should stop natalizumab treatment, and switch to an alternative disease-modifying treatment, but first they should remove natalizumab from the body through plasmapheresis," she said.

"Cortisone treatment as a bridge to an alternative agent is of practical utility in such cases as we know that relapses are likely to happen during the switch.  Thus, early diagnosis of possible PML may lead to early management and prevention of a nonreversible condition of the disease."

The study raises important issues regarding appropriate AI cutoff levels for natalizumab treatment, which Dr Karageorgiou argues may be too conservative.

"We have to better learn how not to be afraid of the shadow of PML in natalizumab and make informed decisions on when to stop the drug. Many physicians will stop treatment early based on current AI cutoff levels of 0.9, but a high AI level alone does not mean PML being present."

"This will be better evaluated through analyses on larger samples, many of which already exist and could be done through a meta-analysis." 

Robert Naismith, MD, an associate professor of neurology at Washington University School of Medicine, St. Louis, Missouri, who comoderated the session, agreed that, though small, the study offers some valuable insights.

"I think the bottom line with this small observational study is the importance to continue to follow JC virus index levels on patients every 6 months, because some patients clearly convert from negative to positive," he told Medscape Medical News.

"Because the numbers of patients who developed PML is low and precise definitions/situations vary, it is hard to know the precise risk associated with a negative to positive conversion."

The study received no targeted funding. Biogen provided shipment samples and analysis. Dr Karageorgiou has disclosed no relevant financial relationships. Dr Naismith has consulting and/or speaking relationships with Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Questcor.

American Neurological Association (ANA) 2015 Annual Meeting. Abstract S507. Presented September 27, 2015.

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