Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy

PLoS One. 2011;6(6):e20967. doi: 10.1371/journal.pone.0020967. Epub 2011 Jun 30.

Abstract

Background: Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery.

Methods and findings: All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008).

Conclusions: The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death.

Trial registration: ClinicalTrials.gov NCT00120367.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Retroviral Agents / therapeutic use
  • Enfuvirtide
  • Female
  • HIV Envelope Protein gp41 / therapeutic use
  • HIV Fusion Inhibitors / therapeutic use
  • HIV Infections / drug therapy*
  • HIV Infections / mortality*
  • HIV Infections / virology
  • Humans
  • JC Virus / drug effects
  • JC Virus / pathogenicity
  • Leukoencephalopathy, Progressive Multifocal / drug therapy*
  • Leukoencephalopathy, Progressive Multifocal / mortality*
  • Leukoencephalopathy, Progressive Multifocal / virology
  • Male
  • Middle Aged
  • Peptide Fragments / therapeutic use
  • Polymerase Chain Reaction

Substances

  • Anti-Retroviral Agents
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • Enfuvirtide

Associated data

  • ClinicalTrials.gov/NCT00120367