R E V I E W New approaches in the treatment of HIV/AIDS – focus on maraviroc and other CCR5 antagonists Hans P Schlecht1 Sarah Schellhorn2 Bruce J Dezube3 Jeffrey M Jacobson1 1Department of Medicine (Infectious Diseases), Hahnemann University Hospital, Drexel University College of Medicine, Philadelphia, PA, USA; 2Department of Medicine, 3Department of Medicine (Hematology/Oncology), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Correspondence: Hans P Schlecht Drexel University College of Medicine, Mail Stop 461, 245 N. 15th Street, Philadelphia, PA, 19102-1192, USA Tel +1 215 762 6794 Fax +1 215 762 3031 Email hans.schlecht@drexelmed.edu Abstract: Treatment of HIV-1 infection has produced dramatic success for many patients. Nevertheless, viral resistance continues to limit the efﬁcacy of currently available agents in many patients. The CCR5 antagonists are a new class of antiretroviral agents that target a necessary coreceptor for viral entry of many strains of HIV-1. Recently, the ﬁrst agent within this class, maraviroc, was approved by a number of regulatory agencies, including the Food and Drug Administration. Herein we review the role of the CCR5 receptor in HIV-1 infection and potential methods to target it in anti-HIV-1 therapy. We review the various categories of agents and discuss speciﬁc agents that have progressed to clinical study. We discuss in detail the recently approved, ﬁrst in class CCR5 antagonist, maraviroc, and discuss aspects of resis- tance to CCR5 antagonism and the potential role of CCR5 antagonism in the management of HIV-1 infection. Keywords: CCR5, HIV-1 tropism, coreceptor, maraviroc, viral entry, chemokine receptor Introduction The widespread use of highly active antiretroviral therapy (HAART) has profoundly affected the treatment and epidemiology of HIV-1 infection within the developed world, where HIV-1 infection has largely become a chronic illness (Palella et al 1998). HAART’s dramatic success has contributed in saving at least 3 million years of life in the US since 1989 and will aid a patient living with HIV-1 to live more than 13 years longer today than if they had been diagnosed in 1988 (Walensky et al 2006). Despite tremendous impact, patient beneﬁt from HAART is not simple or uniform; 25% of patients starting HAART either do not achieve viral suppression or lose it within 2 to 3 years, frequently due to viral resistance (Bartlett et al 2001; Mocroft et al 2002; Holmberg et al 2003). Moreover, the rate of acquired resistance in patients recently infected with HIV-1 has grown from 13.2% during the period 1995 to 1998 to 24.1% during 2003 to 2004, including some with rapid progression to AIDS (Markowitz et al 2005; Shet et al 2006). In spite of the recalcitrant nature of HIV-1 viral resistance, recent advances have been substantial. The approval of darunavir, a protease inhibitor with potent efﬁcacy against multi-drug resistant strains of HIV-1, has helped shift the emphasis of HIV-1 salvage treatment from preserving immune function to complete suppression of viral replication and immune reconstitution (Hammer et al 2006). With the advent of additional classes of agents such as CCR5 and integrase antagonists, patients with extensive multi-drug resistance will likely be able to achieve an undetectable viral load. Nevertheless, resistance to these new agents has already been seen in vitro and will inevitably arise clinically (Mosley et al 2006; Cooper et al 2007; Steigbigel et al 2007). HIV clinical investigators must be prepared to overcome these defenses by reﬁning the current use of HAART and wisely integrating new agents, such as CCR5 antagonists, in order to minimize the impact of HIV-1 viral resistance on patients and populations (Schooley and Mellors 2007). Therapeutics and Clinical Risk Management 2008:4(2) 473–485 © 2008 Dove Medical Press Limited. All rights reserved 473