Schlecht et al CXCR4. Whether de novo or through promotion of minor with CCR5-tropic virus. Their potential role in treatment-naïve D/M or CXCR4 using variants already present within the patients is unsupported at this time, considering the shortfalls patient, co-receptor switching would be a troubling outcome of both maraviroc and vicriviroc based regimens against an as D/M and CXCR4 tropic viruses have historically, but not EFV based regimen. This is unfortunate, as it may be better to uniformly, been associated with accelerated CD4 cell loss and use CCR5 antagonists early in the course of HIV-1 infection progression to AIDS (Philpott 2003; Daar et al 2007; Goetz treatment when CCR5-tropic virus predominates. Whether et al 2007). Nevertheless it remains possible that emergence patients with D/M virus may derive immunologic beneﬁt of CXCR4 using virus is a consequence and not a cause of from a CCR5 antagonist without signiﬁcant consequence also severe immunodeﬁciency. remains to be seen in large studies. Some data addressing co-receptor switching in the set- Additional questions that remain to be answered that will ting of CCR5 antagonist use have been reported. Analysis help guide the use of CCR5 antagonists include whether of co-receptor switching during early studies of maraviroc the agents are cross-resistant, synergistic with each other or suggests that emergent D/M and CXCR4 tropic viruses result other agents, and, should CXCR4 antagonists be developed, from a pre-treatment reservoir not detected by screening whether combination X4/R5 inhibitor therapy would have tropism assays (Westby et al 2006). During MOTIVATE 1 merit. Clearly the addition of another distinct antiretroviral and 2, maraviroc’s phase III trials, 63 of 751 MVC treated class should be met with celebration, particularly since it is subjects failed with D/M or X4-tropic virus compared to 35 only 10 years after target identiﬁcation. However further R5-tropic subjects failing with R5-tropic virus. Reassuringly, experience and study are needed to clearly deﬁne the risks, patients failing a maraviroc regimen with D/M or X4-tropic beneﬁts, and roles that CCR5 antagonists will have in the virus had higher mean increases in CD4 count vs placebo care of HIV-infected patients. at time of failure (range +37 to +56 cells/µ l vs +14 cells/µ l respectively). Approximately two thirds of these subjects had their D/M or X4 virus return to R5 tropism prior to going off study (median = 203 days), and there was no association between CXCR4-using virus and AIDS-deﬁning events. Time to failure with a D/M or X4-tropic virus was also shorter than for failure with a CCR5-tropic virus. Overall, these results are consistent with the selective and reversible suppression of R5 virus during maraviroc therapy (van der Ryst et al 2007). In vitro studies have also demonstrated that viral escape may be a consequence of viral adaptation to the conforma- tional change in CCR5 caused by CCR5 antagonist binding. Laboratory isolates of HIV-1 have demonstrated the ability to generate mutations in the V3 region of gp120 that allow cell entry via vicriviroc- or maraviroc-bound CCR5 (Pugach et al 2007; Westby et al 2007). Emerging data demonstrate multiple pathways and signiﬁcant complexity to CCR5 resistance. Preliminarily it appears these mutations are not as stereotypical as those for other antiretroviral agents but rather speciﬁc to the env background of the individual virus (Mori et al 2007; Tsibris et al 2007). Role in HIV-1 therapy and conclusions Evidenced by the FDA and European Medicines Agency’s (EMEA) recent approval of maraviroc (as Selzentry® in the USA and Celsentri® in the EU), CCR5 antagonists are a wel- come addition to the care of treatment-experienced patients 482 References Anderson J, Akkina R. 2007. Complete knockdown of CCR5 by lentiviral vector-expressed siRNAs and protection of transgenic macrophages against HIV-1 infection. Gene Ther, 14:1287–97. Baba M, Nishimura O, Kanzaki N, et al. 1999. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA, 96:5698–703. Baba M, Takashima K, Miyake H, et al. 2005. TAK-652 inhibits CCR5- mediated human immunodeﬁciency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob Agents Chemother, 49:4584–91. Bartlett JA, DeMasi R, Quinn J, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1-1-1 infected adults. 2001. AIDS, 15:1369–77. Blanpain C, Migeotte I, Lee B, et al. 1999. CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist. Blood, 94:1899–905. Brumme ZL, Goodrich J, Mayer HB, et al. 2005. Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiret- roviral-naïve individuals. J Infect Dis, 192:466–74. Chan DC, Fass D, Berger JM, et al. 1997. Core structure of gp41 from the HIV envelope glycoprotein. Cell, 89:263–73. Chan DC, Kim PS. 1998. HIV entry and its inhibition. Cell, 93:681–4. Coakley E, Petropoulos CJ, Whitcomb JM. 2005. Assessing chemokine co-receptor usage in HIV. Curr Opin Infect Dis, 18:9–15. Cocchi F, DeVico AL, Garzino-Demo A, et al. 1995. Identiﬁcation of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science, 270:1811–15. Connor RI, Sheridan KE, Ceradini D, et al. 1997. Change in coreceptor use correlates with disease progression in HIV-1 infected individuals. J Exp Med, 185:621–8. Cooper D, Gatell J, Rockstroh J, et al. 2007. Results from BENCHMRK-1, a phase III study evaluating the efﬁcacy and safety of MK-0518, a novel HIV-1integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 105aLB. Crabb C. 2006. GlaxoSmithKline ends aplaviroc trials. AIDS, 20:641. Therapeutics and Clinical Risk Management 2008:4(2)