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Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values.

ABSTRACT: The aim of the study was to analyze John Cunningham virus (JCV) serology in natalizumab-treated patients over time and assess whether they are influenced by natalizumab treatment.German (n = 1,921; 525 longitudinally) and French (n = 1,259; 711 longitudinally) patients were assessed for JCV serology alongside their therapy with natalizumab.JCV serostatus changed in 69 of 525 longitudinally followed German patients (13.1%) over 14.8 months. Seroconversion according to serostatus was seen in 43 of 339 initially JCV- German patients (12.7% in 14.8 months; 10.3% per year) and 41 of 243 initially JCV- French patients (16.9% in 24 months; 8.5% per year). JCV index values could be reproduced (R (2) = 0.89) with the caveat of 8 of 50 samples (16%) being set into different risk categories between 2 assessments. Index values of JCV+ patients rose over time (p = 0.009) but not because of aging. Treatment with natalizumab was associated with a 15.9% increase of value in JCV+ patients in 14.8 months (12.9% per year).JCV seroconversion and index values may be influenced by treatment with natalizumab. It is therefore important to monitor patients' JCV serology but also to incorporate additional risk factors into the progressive multifocal leukoencephalopathy risk stratification.

SUBMITTER: Schwab N

PROVIDER: S-EPMC4733149 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values.

Schwab Nicholas N Schneider-Hohendorf Tilman T Pignolet Béatrice B Breuer Johanna J Gross Catharina C CC Göbel Kerstin K Brassat David D Wiendl Heinz H

Neurology(R) neuroimmunology & neuroinflammation 20160127 1

<h4>Objective</h4>The aim of the study was to analyze John Cunningham virus (JCV) serology in natalizumab-treated patients over time and assess whether they are influenced by natalizumab treatment.<h4>Methods</h4>German (n = 1,921; 525 longitudinally) and French (n = 1,259; 711 longitudinally) patients were assessed for JCV serology alongside their therapy with natalizumab.<h4>Results</h4>JCV serostatus changed in 69 of 525 longitudinally followed German patients (13.1%) over 14.8 months. Seroco ...[more]

PMID: 26848486

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Project description:AimsTo retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients.BackgroundNatalizumab 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.MethodsPatients 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.ResultsFrom 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].ConclusionIn 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.

Project description:BackgroundTILRR (Toll-like Interleukin-1 Receptor Regulator) is a modulator of many genes in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling. It promotes the production of inflammatory mediators and the migration of immune cells. Recently, we showed that TILRR protein circulates in human blood. Thus, it could influence systemic inflammation. Systemic and mucosal inflammations increase the susceptibility to HIV infection. In this study, we analyzed the TILRR protein levels of the archived plasma samples of women enrolled in the Pumwani cohort to determine whether the plasma TILRR protein levels before seroconversion are correlated with differential risk of HIV seroconversion.MethodsTILRR protein of 941 archived HIV negative plasma samples from 390 women who were HIV negative at the cohort enrollment was quantified with an in-house developed multiplex bead array method. Proinflammatory cytokines/chemokines were measured using a 14-plex bead array method. Spearman rank correlation analysis was used to determine the correlation between plasma TILRR protein and proinflammatory cytokines/chemokines. Kaplan-Meier survival analysis was conducted to evaluate whether the median plasma TILRR protein levels correlate with increased risk of HIV seroconversion.FindingsThe level of plasma TILRR protein was positively correlated with plasma IL-1β (rho: 0.2593, p<0.0001), MCP-1 (rho: 0.2377, p<0.0001), and IL-17A (rho: 0.1225, p=0.0216). Women with median plasma TILRR protein levels ≥100 ng/ml seroconverted significantly faster than women with plasma TILRR protein levels <100 ng/ml (log-rank= 100.124, p<0.0001; relative risk= 3.72 and odds ratio= 15.29). Furthermore, the factors causing genital inflammation, such as STIs (sexually transmitted infections), vaginal discharge, and genital ulcers were not statistically significantly different among women with different median plasma TILRR protein levels.InterpretationThe high plasma TILRR protein levels are highly correlated with several plasma proinflammatory cytokines/chemokines. High median plasma TILRR protein (≥100 ng/ml) strongly predicted an increased risk of HIV seroconversion. Reducing plasma TILRR protein levels may reduce the risk of HIV acquisition.FundingThe study was funded by an operating grant from the Canadian Institutes of Health Research (CIHR), operating grant-PA: CHVI Vaccine Discovery and Social Research (http://www.cihr-irsc.gc.ca/e/193.html), and National Microbiology Laboratory of Canada.

Dataset Information

Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values.

Publications

Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values.

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