High 6-month rate of PML survival with aggressive use of 5-drug T-20-based ARV regimen

Progressive multifocal leukoencephalopathy (PML) has remained one of the most difficult to manage opportunistic infections and even post HAART is associated with poor prognosis and survival rates.

Several studies at the conference reported on management of PML including an important report from Jacques Gasnault and colleagues from the French ANRS125 study team who presented results from an open-label multicentre pilot study, designed to show whether an intensified ART regimen including T-20 (enfuvirtide) can hasten anti-JCV immune recovery.

The study included 28 HIV-positive patients (22 male) mainly enrolled from April 2005 to September 2006, with a recent clinical history of active PML (within 90 days), PML documented by cerebral imaging, no other likely etiology, polymerase chain reaction (PCR) detection of JCV DNA in cerebrospinal fluid (CSF), or pathological examination.

At baseline, the median CD4 T-cell count was 54 cells/mm3 (range, 2 to 345) and the median plasma HIV load was 4.08 log copies/mL (1.59 to 5.20). JCV DNA was detected in CSF in 78% of cases.

ARV therapy included a 5-drug regimen of tenofovir/FTC/efavirenz/lopinavir/r and T-20 for the 12 naive patients and 3 or more optimised ARVs plus T-20 for the 16 experienced patients. T-20 was discontinued after the first 6 months in all patients. Follow-up lasted 1 year and the primary endpoint was the survival estimate at month 12.

Five patients died before month 6. 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. Median CD4 T-cell counts at week 6 and month 6 were 116 cells/mm3 (8 to 509) and 169 cells/mm3 (28 to 665). At month 6, 10/13 (77%) of patients were negative for JCV DNA detection in CSF and 16/19 (84%) were negative for plasma HIV RNA. The percentages of patients with detectable anti-JCV CD4 T responses (proliferation to purified JCV) and anti-JCV CD8 T-cell responses (interferon-gamma ELISpot with overlapping VP1 peptides) increased between baseline (6% and 29%) and month 6 (62% and 58%).

In an oral overview of PML presented at the conference by David Clifford from Washington University, the proposed mechanism for the outstanding survival rates reported in this study was antiviral potency of the regimen, rather than any specific effect of T-20, or even CNS penetration. [2]

This excellent summary also focused on the changing interpretation of MRI scans in diagnosing PML, and questioned whether renaming PML as JCV-related encephalopathy, given the higher proportion of patients now presenting with single focal lesions, and the reduced sensitivity of CNS JC virus as a diagnostic (now seen in <60% cases, probably related to lower JCV viral load in the CNS, itself related to higher CD4 counts). Baseline CD4 count greater than 100 cells/mm3 is still the predominant factor for survival (>90% vs 20% when greater or lower than 100 cells/mm3).

IMPORTANT NOTE: Although the above links are no longer active the full paper from this study was published in PLoS ONE in 2011 and it is available free online.

Gasnault J et al. Improved Survival of HIV-1-Infected Patients with Progressive Multifocal Leukoencephalopathy Receiving Early 5-Drug Combination Antiretroviral Therapy. PLoS One. 2011; 6(6): e20967. Published online 2011 Jun 30. doi: 10.1371/journal.pone.0020967.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020967