Increased john cunningham virus seroconversion rates seen in a southern hemisphere international cohort of natalizumab treated patients.

Abstract

Objective: To assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. Background(s): Natalizumab is a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS), but its use is complicated by JCV co-infection. This virus can result in progressive multifocal leukoencephalopathy (PML), a devastating infection of the central nervous system. Serial assessment of JCV serostatus is therefore mandated during natalizumab treatment Design/Methods: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n=869) and eleven MS treatment centres in Brazil (n=137) were assessed for change in JCV serostatus, duration of natalizumab exposure and prior immunosuppression. Sensitivity analyses examined whether sex, age, hospital, prior immunosuppression or number of JCV tests affected time to seroconversion. Result(s): From a cohort of 1001 natalizumab-treated patients (510 with multiple measures of JCV serostatus), 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 (3.9%) patients had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure or prior immunosuppressive use. Male sex was associated with a greater risk of JCV seroconversion (adjusted hazard ratio 2.09 (95% CI 1.17-3.71) p=0.012). Conclusion(s): In this large cohort of natalizumab-treated patients we observed durable positive seroconversion at an annualised rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab and is consistent with increased rates of seroconversion reported recently by European centres. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our finding supports emerging evidence that natalizumab causes off-target immune system changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with an increased risk of positive JCV seroconversion.