High rates of JCV seroconversion in a large international cohort of natalizumab-treated patients

Abstract

Aims: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. Background: Natalizumab is highly effective for the treatment of relapsing–remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. Methods: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia ( n = 865) and 11 MS treatment centres in Brazil ( n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. Results: From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17–3.71) p = 0.012]. Conclusion: In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.

JCV seroconversion rate during the SARS COVID-19 pandemic

“…Natalizumab is a monoclonal antibody that binds α4β1 and α4β7 integrins located on the surface of lymphocytes preventing them from adhering to the endothelium of the blood-brain barrier thereby decreasing their infiltration of the CNS. The subsequent amelioration of T-cell mediated inflammatory demyelination makes it a highly effective treatment for relapsing-remitting forms of MS ( Dwyer et al, 2021 ).…”

Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis

“…This value is not dissimilar to results from a 2018 meta-analysis of 17 independent natalizumab-treated cohorts of patients with MS, which reported a mean positive seroconversion annualized rate of 10.8% (positivity threshold: index >0.4) . A 2021 registry substudy also reported a similar durable positive seroconversion of 7.3% per year (mean JCV index >1.6) among initially JCV-negative patients treated with natalizumab for RRMS …”

Specific Aspects of Immunotherapy for Multiple Sclerosis in Switzerland—A Structured Commentary, Update 2022

“…However, the Swiss product information [3] no longer requires JCPyV-negative patients to have a 'highly active' but rather an 'active' form, though without a change in the indication in the SL [11]. In this context, the yearly rate of seroconversion of JCPyV-negative pwMS of 7.3-10.3% has to be considered [83,84]. In highly active JCPyV-negative pwMS, antibody testing should be performed every three months (no consensus between different centres in Switzerland).…”