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

Abstract

Objective: 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.

Methods: German (n = 1,921; 525 longitudinally) and French (n = 1,259; 711 longitudinally) patients were assessed for JCV serology alongside their therapy with natalizumab.

Results: 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).

Conclusions: 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.

Figure 1. JCV serostatus

(A) Serostatus of 1,921 natalizumab-treated patients with multiple sclerosis, with JCV− patients shown in black and JCV+ patients in red. A total of 1,052 of these 1,921 patients were set as JCV+ (54.76%). (B) Serostatus of a longitudinally assessed cohort of 525 patients during 14.8 months of natalizumab treatment. (C) Serostatus of the German cohort of 339 initially JCV− patients (of 525 patients) before and after the period of observation (14.8 months of natalizumab treatment). Forty-three of these 339 patients (12.7%) were set as JCV+ after the period of observation. (D) Serostatus of the French cohort (n = 1,259; 711 longitudinally; BioNAT) of the 243 initially JCV− patients of 711, where all 3 time points were available, during their first 2 years of treatment. Twenty of these patients (8.2%) were set as JCV+ after the first year and an additional 21 (8.6%) after the second year of treatment, resulting in 41 of 243 patients (16.9%) changing their serostatus to JCV+ in the first 2 years of treatment. JCV = John Cunningham virus.

Figure 2. JCV index

(A) Fifty samples of natalizumab-treated patients with multiple sclerosis were assessed twice for their anti-JCV antibody index (JCV index) with an R² of 0.89. Eight of these 50 samples (16%) showed 2 different risk associations with the thresholds JCV−/+, JCV index 0.4, 0.9, 1.2, and 1.5 in the 2 assessments. (B) JCV index value distributions of a longitudinal cohort of 525 patients at the start and end of the period of observation of 14.8 months. (C) Serial assessment of JCV index values of 525 patients alongside their natalizumab therapy (2–7 JCV serology assessments). Red lines indicate the thresholds 0.4, 0.9, and 1.5. (D) Serial assessment of JCV index values. Only patients whose index values changed by more than 30% over time and whose PML risk group changed are shown (0–0.4 [green], 0.4–0.9 [yellow], 0.9–1.5 [orange], >1.5 [red]). JCV = John Cunningham virus.

Figure 3. JCV index changes in JCV+ patients

(A) Increasing JCV index values of 201 JCV+ natalizumab-treated patients with multiple sclerosis at the beginning and end of a period of observation of 14.8 months (mean: 2.046 vs 2.158; p = 0.009). (B) Age (in years) and JCV index value of 1,921 natalizumab-treated patients with multiple sclerosis. Overall, there is a strong rise in index values by age (Spearman r: 0.113; p < 0.0001) but no rise in the index values of JCV+ patients (Spearman r: 0.0001; p = 0.996) or patients who converted to JCV seropositivity during treatment with natalizumab (Spearman r: 0.0257; p = 0.907). (C) Change of JCV index values of 201 JCV+ patients during natalizumab treatment in % (index value at the end of the period of observation/index value at the beginning of the period of observation × 100). Mean rise in index values was 15.9% in 14.8 months. One hundred sixty-one of 201 patients (80%) presented with stable index values (±30%), 34 patients (17%) presented with increasing index values, and 6 patients (3%) with decreasing index values. JCV = John Cunningham virus.