Anti–JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy

Natalizumab is a highly efficacious therapy for patients with relapsing multiple sclerosis (MS) based on significant reductions in annualized relapse rate and the risk of sustained disability progression in a 2-year phase 3 study1 and in 4- to 5-year open-label observational studies.2,3 Natalizumab treatment is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), and understanding this risk is necessary for informed benefit–risk evaluation and treatment decisions. The presence of anti–JC virus (JCV) antibodies in serum or plasma is a risk factor for PML development, and in anti-JCV antibody–positive patients, the use of immunosuppressants prior to natalizumab treatment and extended duration of natalizumab treatment (especially beyond 2 years) increase PML risk.4 Detection of anti-JCV antibodies using a 2-step enzyme-linked immunosorbent assay (ELISA) has been proven to reliably stratify the risk of PML. Using this assay, anti-JCV antibodies were detected in 232 of 234 natalizumab-treated patients (99%) who had a blood sample available for anti-JCV antibody analysis >6 months prior to PML diagnosis (data as of August 5, 2014).5 The reported prevalence of anti-JCV antibodies using the 2-step ELISA ranges from approximately 50% to 70% in natalizumab-treated MS patients.6–10 The risk of PML in anti-JCV antibody–negative patients is 1 per 10,000 patients, as demonstrated by data from postmarketing sources as well as from a large prospective study, STRATIFY-2.5,6 A small proportion of patients demonstrate fluctuating anti-JCV antibody status over time, and the risk of PML in these patients is unclear.11,12 The overall incidence of PML in anti-JCV antibody–positive patients with no prior immunosuppressant use remains <1 per 1,000 patients during the first 2 years of natalizumab treatment.4,5 A recent exploratory analysis of anti-JCV antibody data from natalizumab-treated MS patients showed higher anti-JCV antibody levels in 9 patients who developed PML compared with non-PML anti-JCV antibody–positive patients.10 Higher antibody levels to other polyomaviruses, BK virus (BKV) and Merkel cell virus (MCV), in patients with increased viral burden also have been observed.13–15 We therefore performed an extensive retrospective analysis to determine whether anti-JCV antibody levels may further define PML risk in anti-JCV antibody–positive patients. Data from this analysis have been presented at 2013 meetings of the Consortium of Multiple Sclerosis Centers–Americas Committee for Treatment and Research in Multiple Sclerosis and the European Neurological Society.16,17