Schlecht et al 10 days demonstrated a 1.66 log10 mean reduction in viral load and was well tolerated (Lalezari et al 2005). However during phase IIb trials three subjects developed severe hepatotoxicity, which was deemed secondary to drug-induced hepatitis. Moreover, 1 of the ﬁrst 44 subjects enrolled in a phase III trial of aplaviroc developed severe hepatotoxicity, and the trials and development of aplaviroc were stopped (Crabb 2006). CCR5 antagonist, SCH351125 or SCH-C, was the first agent developed by Schering-Plough Corporation (Kenilworth, NJ, USA) due to its antiviral potency-- nano- molar IC50 concentrations for a range of CCR5-tropic HIV-1 isolates-- and advantageous pharmacokinetic characteristics (Strizki et al 2001). The ﬁrst CCR5 antagonist to enter clinical efﬁcacy studies, SCH-C at a dose of 25 mg twice daily demonstrated a 0.5–1 log drop in viral load in 10 of 12 subjects (Reynes et al 2002). However, antiviral effect was not uniform and QTc interval prolongation prompted further optimization work. This resulted in Sch-417690 or SCH-D, later known as vicriviroc. Vicriviroc is 2–40 times more potent than SCH-C against primary HIV-1 isolates in vitro, has excellent oral bioavailability, and an improved safety proﬁle (Strizki et al 2005). In early phase study, vicriviroc was well tolerated up to 50 mg twice daily and produced 1.5 to 1.6 log reductions in HIV-1 viral load at doses of 25 mg and 50 mg twice daily in treatment-naïve subjects (Schurmann et al 2007). However, treatment-naïve subjects with R5-tropic virus fared less well in a phase II study comparing vicriviroc to efavirenz (EFV), both combined with zidovudine/lamivudine (AZT/3TC as ﬁxed dose Combivir® [GlaxoSmithKline]). Subjects began the study receiving either placebo or vicriviroc monother- apy (25, 50, or 75 mg once daily) for 2 weeks. Thereafter AZT/3TC was added to subjects receiving vicriviroc, while subjects receiving placebo were given EFV and AZT/3TC instead. Though vicriviroc produced a 0.9–1.3 log10 greater reduction in viral load than placebo, preliminary analysis demonstrated virologic breakthrough (RNA 50 copies/mL) during follow-up in 2 of 24 (8%) of the placebo/AZT/3TC/ EFV group versus 13 of 23 (57%), 10 of 22 (45%), and 5 of 23 (22%) in the 25, 50, and 75 mg arms of vicriviroc, respectively (Greaves et al 2006). The study was subse- quently terminated prematurely on recommendation of the data safety monitoring board. Neither tropism shifts nor elevated vicriviroc IC50 measurements accounted for the higher rate of virologic breakthrough. However, all subjects with virologic breakthrough and genotypic data available had treatment-emergent M184V mutations, suggesting that vicriviroc was underdosed. Such results have provoked calls 478 that there is a near unassailable standard of care in treatment-naïve regimens, eg, EFV-based, and that these potent regimens should be embraced (Deeks 2006). Phase II vicriviroc results have been more encourag- ing among treatment-experienced subjects. In an AIDS Clinical Trial Group study, ACTG A5211, 24 week and recently presented 48 week data has shown that vicriviroc provided a signiﬁcant advantage over placebo when added to optimized background regimen (Gulick et al 2007a, b). Both the 10 mg and the 15 mg once daily doses were shown to provide durable virologic suppression and signiﬁcant immunologic beneﬁt: HIV-1 RNA decreases of 1.9 and 1.4 logs, and CD4+ cell count increases of 96 and 130 cells/ mm3 were seen in the 10 mg and 15 mg arms, respectively. Moreover, 37% of subjects in the 10 mg vicriviroc group and 27% of those in the 15 mg group had a HIV-1 viral load below 50 copies/mL at week 48. However, the 5 mg dose study arm was discontinued early based on recommenda- tion from the Study Monitoring Committee and the study was also unblinded following reports of 5 malignancies in subjects receiving vicriviroc. Further follow-up of 39 subjects enrolled in an open label extension study reported no new malignancies and in September 2007, it was announced that two phase III studies, entitled VICTOR-E3 and VICTOR-E4, had begun to evaluate the safety and effectiveness of 30 mg of vicriviroc plus optimized background therapy (OBT) in treatment-experienced subjects (Gulick et al 2007c). Maraviroc With greater understanding of the role and impact of the CCR5 receptor in the transmission and progression of HIV-1 disease, numerous efforts to pharmacologically target the CCR5 receptor began. Drug development work at Pﬁzer Inc. (Kent, UK) resulted in the development of UK-427,857 or maraviroc (Dorr et al 2005; Wood and Armour 2005). Opening effort centered on a high throughput screening assay employing HEK-293 cells to express CCR5 and used candidate drug antagonism of radiolabelled MIP-1β binding as the basis of the screen resulting in hits UK-107,543 and UK-179,645. Following intensive structure-activity relationship (SAR) studies and numerous structural modifications via modern medicinal chemistry, UK-427,587, or 4 , 4 ’ - d i f l u o r o - N - [ ( 1 S ) - 3 - [ ( 3 - e x o ) - 3 - [ 3 - m e t h y l - 5 - (1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1] oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamid, became the lead analogue (see Figure 1). With its ability to block CCR5 binding and signaling at nanomalor concentrations plus no Therapeutics and Clinical Risk Management 2008:4(2)