problematic cytochrome P450 D2 interaction or cardiac ion channel binding, and favorable permeability characteristics, further investigation began of this potent inhibitor of laboratory optimized HIV-1 isolates (mean inhibitory concentration of 90% of isolates or IC90 of 2.0 nM). Additional work demonstrated encouraging pharma- cokinetic data, and high selectivity for the CCR5 receptor compared to other pertinent receptors, eg similar chemokine receptors. The antiretroviral activity of UK-427,587 proved potent against primary HIV-1 isolates from a number of clades, as well as drug-sensitive and drug-resistance clinical isolates of HIV-1 both as monotherapy and in concert with additional antiretrovirals. UK-427,587’s mechanism of action was also conﬁrmed to be strictly attributable to CCR5 blockade and no other antiviral means, eg, cell lysis. Measurements made in first-in-man studies closely matched expectations derived preclinically (Dorr et al 2005; Wood and Armour 2005). Single doses were tolerable up to 900 mg, multiple doses to 600 mg daily, and twice daily doses of 100 mg of maraviroc continuously maintained plasma exposure above the IC90. No worrisome laboratory or electrocardiographic ﬁndings were observed and phase IIa efforts with 10 days of maraviroc monotherapy in the HIV-1 infected commenced shortly thereafter. These two studies (A4001007 and A4001015) were combined for analysis and reported in November 2005 (Fätkenheuer et al 2005). Investigators randomized 82 CCR5-positive subjects to receive 10 days of treatment with maraviroc (25 mg, 100 mg or 300 mg once daily or 50 mg, 100 mg, 150 mg [fed and fasted] or 300 mg twice daily) or placebo. Baseline subject characteristics were similar across treatment groups and barring one subject inadvertently enrolled with D/M infection, subjects receiving 100 mg twice daily or more demonstrated robust HIV-1 suppression. Maximum viral load reductions averaged –1.68 (range –2.10 to –1.37) for the 100 mg twice daily group and peaked at –1.84 (range –2.42 to –1.49) for 300 mg twice daily. These values frequently occurred after day 11 and likely reﬂect the prolonged occupancy of the CCR5 receptor by maraviroc, a phenomenon also reported for other CCR5 antagonists (Lalezari et al 2005; Schurman et al 2007). Three subjects were excluded from analysis; the aforementioned subject inadvertently enrolled with D/M infection, a subject who with- drew consent, and a subject who discontinued treatment prior to day 3 secondary to a moderate headache felt to be unrelated to their 100 mg once daily dose. Maraviroc was generally well tolerated, except for one case of severe diarrhea in the 150 mg twice daily (fed) group which started on day 1 and resolved Therapeutics and Clinical Risk Management 2008:4(2) CCR5 antagonists of HIV-1 infection after 11 days without intervention. The most common mild or moderate side effects were headache, asthenia, dizziness, gingivitis, and nausea. Overall these results were one of the ﬁrst to demonstrate the viability of targeting the CCR5 receptor in the treatment of HIV-1 infection. Late phase efforts in maraviroc’s development have targeted both treatment-naïve and treatment-experienced patients. Among treatment-naïve patients, maraviroc is being investigated in the MERIT study. This ongoing phase IIb/III study had interim 48-week data presented at the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention held July, 2007 (Saag et al 2007). This study tests the hypothesis that maraviroc is not inferior to EFV when used in combination with AZT/3TC (provided as ﬁxed dose Combivir) in CCR5-tropic patients without resistance to AZT, 3TC or EFV. Subjects were stratiﬁed at entry by HIV-1 viral load ( or 100,000 copies/mL) and also geographic location (Northern vs Southern Hemisphere). Of note, in an effort to minimize discontinuance due to medication intolerance, especially AZT, subjects who experienced toxicity were allowed to substitute an alternative nucleoside reverse transcriptase inhibitor. The primary endpoint was the proportion of patients who achieved a viral load 50 copies/mL through 48 weeks, which proved important to the investigators’ conclusions. Initially planned with three treatment groups, maraviroc 300 mg once or twice daily or EFV, the data safety and monitoring board closed the once-daily maraviroc arm early because of inadequate response rates. The remaining study arms recruited 721 subjects with a mean age of 37 years, 79% men/21% women, roughly 50% white/35% black, and roughly 400 from the Northern Hemisphere vs 300 from the Southern Hemisphere. At baseline, subject characteristics were similar between the EFV and maraviroc groups: median CD4 counts of 241 and 254 cells/mm3, respectively, and mean viral load of roughly 4.9 log copies/mL each. By 48 weeks, 65.3% of the maraviroc arm and 69.3% of the EFV arm achieved a viral load 50 copies/mL. This margin of difference failed to meet the preselected criteria for nonin- feriority as the lower bound of the 97.5% conﬁdence interval was less than –10% (observed noninferiority margin –10.9%). Using an endpoint of 400 copies/mL at 48 weeks, twice daily maraviroc met noninferiority criteria as 70.6% of subjects in the maraviroc arm and 73.1% of the EFV arm achieved the endpoint. Also by 48 weeks, a greater increase in mean CD4 cell count was observed in the maraviroc treated subjects than in the EFV treated (170 cells/mm3 vs 144 cells/mm3) though this difference likely has little clinical relevance. 479