Impact of Disease-Modifying Treatments on the Longitudinal Evolution of Anti-JCV Antibody Index in Multiple Sclerosis

Abstract

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index. Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-β, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-β, glatiramer acetate, or natalizumab. Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution.

Keywords: JC virus; anti-JCV antibody index; glatiramer acetate; interferon beta; longitudinal; multiple sclerosis; natalizumab; seroconversion.

Figure 1

Study design for identification of treatment effect on anti-JCV antibody index. The illustrated estimation approach shows anti-JCV AI evolution for the no DMT group that may change (e.g., increase) over time, as well as anti-JCV AI evolution for a treatment group that may change (e.g., increase) due to the same effect as in the no DMT group plus a possible treatment effect. To correctly estimate the treatment effect, a mixed model is employed that considers any effect that appears also in the no DMT group independent of the applied treatment. Therefore, several samples before and after start of treatment per patient are required. AI, antibody index; DMT, disease modifying treatment; JCV, John Cunningham virus.

Figure 2

Longitudinal evolution of anti-JCV antibody index in patients with stable anti-JCV antibody status. (A) Serial anti-JCV antibody indices in patients without any disease-modifying treatment. (B) Serial anti-JCV antibody indices in patients before and after start of IFN-β therapy. Before, all patients were treatment-naïve. Afterwards, index values are shown as long as IFN-β was administered. (C) Serial anti-JCV antibody indices in patients before and after start of GLAT therapy. After treatment begin, index values are shown as long as GLAT was administered. (D) Serial anti-JCV antibody indices in patients before and after start of NTZ therapy. All but one patient received prior treatment. Afterwards, index values are shown as long as NTZ was applied. For building this graph, only patients with stable anti-JCV antibody status (i.e., without seroconversion/-reversion) during the observation period were included. Using a mixed model, there was no statistically significant change of anti-JCV antibody index before and after initiation of the respective treatment. Vertical dashed line indicates start of treatment. Upper horizontal dashed line indicates an anti-JCV antibody index of 0.4. Index values >0.4 are denoted anti-JCV antibody positive. Lower horizontal dashed line indicates an anti-JCV antibody index of 0.2. Index values <0.2 are denoted anti-JCV antibody negative. Samples with an index ≥0.20 but ≤0.40 (intermediate response) are classified as anti-JCV antibody positive or negative based on confirmation test (second step of the enzyme-linked immunosorbent assay), i.e., the displayed index values within this range might be classified as positive or negative. For further details see (3, 8). DMT, disease-modifying treatment; GLAT, glatiramer acetate; IFN-β, interferon-beta; JCV, John Cunningham virus; NTZ, natalizumab.

Figure 3

Longitudinal evolution of anti-JCV antibody index in patients with changing anti-JCV antibody status. Serial anti-JCV antibody indices in patients before and after start of interferon-β or natalizumab therapy, as well as in patients without DMT are shown. For building this graph, only patients with changing anti-JCV antibody status (i.e., with either seroconversion or seroreversion) during the observation period were included. Patients without DMT appear per definition left of the vertical dashed line, as in this group no treatment is commenced. Vertical dashed line indicates start of treatment. Upper horizontal dashed line indicates an anti-JCV antibody index of 0.4. Index values >0.4 are denoted anti-JCV antibody positive. Lower horizontal dashed line indicates an anti-JCV antibody index of 0.2. Index values <0.2 are denoted anti-JCV antibody negative. Samples with an index ≥0.20 but ≤0.40 (intermediate response) are classified as anti-JCV antibody positive or negative based on confirmation test (second step of the enzyme-linked immunosorbent assay), i.e., the displayed index values within this range might be classified as positive or negative. For further details see (3, 8). DMT, disease-modifying treatment; JCV, John Cunningham virus.