Determinants of survival in progressive multifocal leukoencephalopathy

Abstract

Background: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML).

Methods: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood.

Results: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival.

Conclusions: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

Figure 1 Estimated survival according to the HIV serostatus of patients with progressive multifocal leukoencephalopathy (PML) enrolled within 3 months of PML diagnosis Continuous lines denote HIV− serostatus; dashed lines HIV+ serostatus. Differences among groups were calculated with the log-rank test.

Figure 2 Estimated survival according to the detection of JCV-specific CD8⁺ cytotoxic T-lymphocytes (CTL) response in blood (A) Continuous lines denote the presence and dashed lines the absence of JCV-specific CTL response measured by tetrameric HLA-A*0201/JCV VP1_p36 or VP1_p100 complexes for A*0201⁺ patients or ⁵¹Cr release assay for HLA A*0201⁻ subjects. (B) Continuous lines denote the presence and dashed lines the absence of JCV-specific CTL response. Differences among groups were calculated with the log-rank test. PML = progressive multifocal leukoencephalopathy.

Figure 3 Estimated survival of progressive multifocal leukoencephalopathy (PML) according to the occurrence of immune reconstitution inflammatory syndrome (IRIS) (A) Continuous lines denote the occurrence of IRIS and dashed lines indicate the absence of IRIS in patients with PML. (B) Continuous lines denote the occurrence of IRIS and dashed lines the absence of IRIS in patients with PML. Differences among groups were calculated with the log-rank test. CTL = cytotoxic T-lymphocytes.

Figure 4 Estimated survival according to the presence of CD4 T-cell count <200/μL or >200/μL at the time of progressive multifocal leukoencephalopathy (PML) diagnosis in HIV+ patients with PML (A) Continuous lines denote CD4 count >200/μL and dashed lines CD4 count <200/μL at baseline. (B) Continuous lines denote CD4 count >200/μL while dashed lines CD4 count <200/μL at baseline. Differences among groups were calculated with the log-rank test. CTL = cytotoxic T-lymphocytes.