Highly active antiretroviral therapy does not improve survival of patients with high JC virus load in the cerebrospinal fluid at progressive multifocal leukoencephalopathy diagnosis (2000)

Progressive multifocal leukoencephalopathy (PML) is a rapidly fatal demyelinating disease related to JC virus (JCV) replication in the brain. PML occurs in immunocompromised patients, especially those with AIDS. Previous reports have shown significant improvement of survival in some [1,2], but not all [3], AIDS-associated PML patients on highly active antiretroviral therapy (HAART). Here we examined the potential mechanisms of this heterogeneity in survival among AIDS-related PML patients on HAART. Thirty-two consecutive patients were diagnosed with AIDS-associated PML between May 1996 and April 1999. Diagnosis was made within a median time of 1.3 months after the onset of neurological signs on the basis of the following criteria: (i) focal brain disease with subacute progression; (ii) white-matter lesions on magnetic resonance imaging consistent with PML; (iii) JCV detection by qualitative polymerase chain reaction in the cerebrospinal fluid (CSF); (iv) no other likely aetiology. Before PML, patients were either untreated or on nucleoside analogue mono or bitherapy. After the clinical onset of PML all patients were started on HAART including a protease inhibitor within a median time of 1.4 months (quartiles: 0.9, 2.0). The JCV load in the CSF was measured at the time of PML diagnosis with a quantitative polymerase chain reaction method, based on the use of a JCV homologous internal standard and chemiluminescence-based revelation including a specific probe hybridization step (limit of quantitation 1.6 copies per μl), as previously described [4]. Statistical analysis was performed using the Mann–Whitney U test. At PML diagnosis, the median CD4 cell count was 88 cells per μl (quartiles: 25, 139) and the median plasma HIV load was 4.90 log10 copies per ml (quartiles: 4.12, 5.12). At 1 November 1999, the median survival time of patients after PML diagnosis was 405 days. Thirteen patients had died after PML progression within a median time of 104 days (quartiles: 77, 217), whereas the 19 patients who were still alive had a significantly (P = 0.0001) longer survival (median: 732 days; quartiles: 412, 1063). This indicates that, despite HAART, death may occur early in the course of PML in some patients, with survival similar to that reported before the HAART era [2,5]. Survivors and deceased patients were not significantly different as regards time from PML onset to diagnosis [median (quartiles): 1.5 (0.8–2.1) versus 1.0 (0.7–1.8) months, P = 0.22] and time from clinical onset to HAART onset [1.5 (1.3–2.5) versus 1.1 (0.8–1.8) months, P = 0.22]. At PML diagnosis, no significant difference was found between survivors and deceased patients in terms of HIV plasma load [median (quartiles): 4.88 (4.00–5.08) versus 4.92 (4.49–5.22) log10 copies/ml, P = 0.47]. A trend to higher CD4 cell count at PML diagnosis was observed in survivors [median (quartiles): 96 (46–168) versus 44 (15–130) cells per μl, P = 0.07]. More significant was the difference between the two groups regarding the JCV load in the CSF at PML diagnosis [median (quartiles): 10.5 (4.4–49.5) versus 195.0 (127.5–2813.0) copies per μl, P = 0.0001]. Considering the whole 32 patients, a significant correlation (r = −0.55, P = 0.01, Spearman's rank correlation) was found between the JCV load in the CSF and survival (Fig. 1). The difference in survival between survivors and deceased patients was not related to non-adherence to HAART or HAART failure, because at 3 months after the onset of HAART a similar decrease in plasma HIV load was observed in the two groups (median decrement −2.05 log10 versus −2.24 log10 copies/ml, P = 0.35).Fig. 1.: Significant correlation between survival time and cerebrospinal fluid JCV load in 32 patients with AIDS-associated progressive multifocal leukoencephalopathy (Spearman's rank test, r = −0.55, P = 0.01). ▾, Deceased; ○, alive.Accordingly, HAART had no clear benefit on survival in PML patients with high JCV loads at PML diagnosis, which were associated with low CD4 cell counts. In contrast, patients with moderate JCV loads in the CSF and higher CD4 cell counts at PML diagnosis had prolonged survival on HAART. The mechanisms by which HAART exerts a positive effect on the course of PML are unknown but might include anti-JCV immune reconstitution allowing the control of JCV replication in the brain, because 12 of the 15 survivors tested became negative for JCV load in the CSF within a median time of 5.7 months. High JCV load in the CSF at PML diagnosis clearly appears to be a negative prognostic factor and may reflect high levels of JCV replication in the brain, consecutive to very severe immunodepression. These PML forms apparently lead to rapidly fatal neurological deterioration. It should be noted that only one of the deceased patients became negative for JCV load. This might be related to the short survival after PML diagnosis, which is less than the median time for the JCV load to become negative in the CSF on HAART in survivors. On the other hand, this highlights the importance of finding effective, specific anti-JCV treatments with adequate brain bioavailability, which by rapidly reducing JCV replication could slow the neurological deterioration while awaiting the potential HAART-induced anti-JCV immune recovery. Yassine Taoufik Jean-François Delfraissy Jacques Gasnault