57 Clinical Activity and Efficacy Trials of Chemokine Receptor Inhibitors Daniel Kuritzkes Brigham and Women's Hosp, Harvard Med Sch, Boston, MA, USA

Chemokine receptor blockade provides an attractive target for inhibition of HIV-1 entry.  Large- and small-molecule inhibitors of CCR5 and CXCR4 have shown potent anti-HIV-1 activity in vitro.  Phase 1-2 studies in HIV-1-infected subjects have established proof-of-concept for the in vivo activity of these drugs, and provide preliminary safety data.  Several of these candidates are now in phase 2/3 clinical trials.  Although results to date have been encouraging, a number of important uncertainties remain to be clarified.  A particular challenge is the occurrence of mixed infection with R5 and X4 virus in patients with advanced disease.  Whether drugs that specifically inhibit only a portion of the virus population can contribute to an overall net reduction in plasma viremia is an important objective of ongoing studies.  Another concern is whether emergence of X4 viruses will be accelerated by CCR5 inhibition, and if so, what the consequences will be on disease progression.  In addition, the long-term safety of CCR5 or CXCR4 blockade remains to be established.  Lastly, whether the chemokine receptor antagonists are best used as a component of initial treatment regimens or reserved for use in later regimens must be explored through treatment strategies trials.