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Acceleration of Immune Recovery on Intensified ART Improves Survival in Patients with AIDS-related Progressive Multifocal Leukoencephalopathy: Preliminary Reports of the ANRS 125 Trial
Jacques Gasnault*1,2, Jacques Gasnault*1,2, H Hendel Chavez1,2, H Hendel Chavez1,2, E Dorofeev3, A Dulioust1, R Lancar3, B Dembele1,2, B Dembele1,2, L Porte4, P Leclercq5, C Merle de Boever6, Y Taoufik1,2, Y Taoufik1,2, and the ANRS 125 trial team
1Hosp Bicetre, Le Kremlin-Bicetre, France; 2INSERM U802, Le Kremlin Bicetre, France; 3INSERM U720, Hosp Pitie-Salpetriere, Paris, France; 4Purpan Hosp, Toulouse, France; 5Albert Michallon Hosp, Grenoble, France; and 6Gui de Chauliac Hosp, Montpellier, France
Background:
Combination ART, by restoring immune
response to JC virus (JCV), has significantly improved the prognosis of progressive
multifocal leukoencephalopathy (PML); nevertheless, almost 50% of patients
still die within 6 months of PML onset. ANRS 125 is an open-label multicenter
pilot study, designed to show whether an intensified ART regimen including enfuvirtide
(ENF) can hasten anti-JCV immune recovery.
Methods: The inclusion criteria were a confirmed
laboratory diagnosis of HIV-1, a
clinical history of active PML with onset less than 90 days previously, PML
documented by cerebral imaging, no other likely etiology, or polymerase chain
reaction (PCR) detection of JCV DNA in cerebrospinal fluid (CSF), or pathological
examination. An independent committee confirmed all diagnoses of PML. The patients
received an optimized combination of 3 or more ART combined with ENF for the
first 6 months. Follow-up lasted 1 year. The primary endpoint was the survival estimate
at month 12. Secondary endpoints were the modified Rankin scale at month 12 in
survivors and the time course of CSF JCV DNA levels, CD4 and CD8 T-cell counts,
and anti-JC virus T cell responses. By December 2006, we had enrolled 30 patients.
Results: From April 2005 to September 2006, we enrolled
26 patients, including 11 naive for ART. At baseline, the median CD4 T-cell
count was 65/µL (range, 2 to 345) and the median plasma HIV load was 3.99 log
copies/mL (1.59 to 5.20). JCV DNA was detected in CSF in 77% of cases. Before
month 6, 5 patients had died. On 15 September 2006, the 6-month survival
estimate was 0.78 (CI = 0.62 to 0.97). At week 6 and month 6, respectively, 52%
and 77% of patients had a plasma HIV load below 40 copies/mL. The median CD4 T-cell
counts at week 6 and month 6 were 123/µL (11 to 509) and 169/µL (28 to 665). At
month 6, 89% of patients were negative for JCV DNA detection in CSF. The percentages
of patients with detectable anti-JCV CD4 T responses (proliferation to purified
JCV) and anti-JCV CD8 T-cell responses (interferon-γ ELISpot with
overlapping VP1 peptides) increased between baseline (6% and 29%) and month 6
(62% and 58%).
Conclusions: These preliminary results of the ANRS 125
trial suggest that an intensified ART regimen given early after PML diagnosis
may improve survival. This effect was associated with JCV DNA disappearance
from CSF and recovery of anti-JCV T-cell responses.
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