Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial

PLoS One. 2015 Jul 24;10(7):e0132430. doi: 10.1371/journal.pone.0132430. eCollection 2015.

Abstract

Objective: The immunomodulatory effects of the CCR5-antagonist maraviroc might be beneficial in patients with a suboptimal immunological response, but results of different cART (combination antiretroviral therapy) intensification studies are conflicting. Therefore, we performed a 48-week placebo-controlled trial to determine the effect of maraviroc intensification on CD4+ T-cell counts and immune activation in these patients.

Design: Double-blind, placebo-controlled, randomized trial.

Methods: Major inclusion criteria were 1. CD4+ T-cell count <350 cells/μL while at least two years on cART or CD4+ T-cell count <200 cells/μL while at least one year on cART, and 2. viral suppression for at least the previous 6 months. HIV-infected patients were randomized to add maraviroc (41 patients) or placebo (44 patients) to their cART regimen for 48 weeks. Changes in CD4+ T-cell counts (primary endpoint) and other immunological parameters were modeled using linear mixed effects models.

Results: No significant differences for the modelled increase in CD4+ T-cell count (placebo 15.3 CD4+ T cells/μL (95% confidence interval (CI) [1.0, 29.5] versus maraviroc arm 22.9 CD4+ T cells/μL (95% CI [7.4, 38.5] p = 0.51) or alterations in the expression of markers for T-cell activation, proliferation and microbial translocation were found between the arms. However, maraviroc intensification did increase the percentage of CCR5 expressing CD4+ and CD8+ T-cells, and the plasma levels of the CCR5 ligand MIP-1β. In contrast, the percentage of ex-vivo apoptotic CD8+ and CD4+ T-cells decreased in the maraviroc arm.

Conclusions: Maraviroc intensification of cART did not increase CD4+ T-cell restoration or decrease immune activation as compared to placebo. However, ex-vivo T-cell apoptosis was decreased in the maraviroc arm.

Trial registration: ClinicalTrials.gov NCT00875368.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / therapeutic use*
  • Antiretroviral Therapy, Highly Active*
  • CCR5 Receptor Antagonists / therapeutic use
  • CD4-CD8 Ratio
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cyclohexanes / therapeutic use*
  • Double-Blind Method
  • Female
  • HIV Fusion Inhibitors / therapeutic use
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Lymphocyte Count
  • Male
  • Maraviroc
  • Middle Aged
  • Receptors, CCR5 / metabolism
  • Time Factors
  • Treatment Outcome
  • Triazoles / therapeutic use*

Substances

  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • CCR5 protein, human
  • Cyclohexanes
  • HIV Fusion Inhibitors
  • Receptors, CCR5
  • Triazoles
  • Maraviroc

Associated data

  • ClinicalTrials.gov/NCT00875368

Grants and funding

This work was supported by a grant from Pfizer Inc. USA, a VIDI grant from the Netherlands Organisation for Scientific Research (NWO, grant 917.96.350) and a grant from the Aids Fonds Netherlands (grant 2007040). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.