Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects

J Acquir Immune Defic Syndr. 2011 Jun 1;57(2):118-25. doi: 10.1097/QAI.0b013e318213c2c0.


Objectives: To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects.

Design: Double-blind placebo-controlled study in the United States and Argentina.

Methods: Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4 cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded.

Results: Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were -0.7, -1.6, -1.8, and -1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4 cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs.

Conclusions: TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects.

Publication types

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

MeSH terms

  • Adult
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use
  • Area Under Curve
  • Biomarkers
  • CCR5 Receptor Antagonists*
  • CD4 Lymphocyte Count
  • Double-Blind Method
  • Female
  • HIV Infections / drug therapy*
  • HIV-1 / drug effects*
  • Half-Life
  • Humans
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Inflammation / blood
  • Inflammation / metabolism
  • Male
  • Middle Aged
  • RNA, Viral / blood
  • Receptors, CCR2 / antagonists & inhibitors*
  • Sulfoxides
  • Young Adult


  • Anti-HIV Agents
  • Biomarkers
  • CCR5 Receptor Antagonists
  • Imidazoles
  • RNA, Viral
  • Receptors, CCR2
  • Sulfoxides
  • cenicriviroc