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To determine antiviral activity, pharmacokinetic properties, and safety of vicriviroc, an orally available CCR5 antagonist, as monotherapy in HIV-infected patients.An ascending, multiple dose, placebo-controlled study randomized within treatment group. Forty-eight HIV-infected individuals were enrolled sequentially to dose groups of vicriviroc: 10, 25 and 50 mg twice a day, and were randomly assigned within group to receive vicriviroc or placebo (16 total patients/group) for 14 days.Significant reductions from baseline HIV RNA after 14 days were achieved in all active treatment groups. Suppression of viral RNA persisted 2–3 days beyond the end of treatment. Reductions of 1.0 log10 HIV RNA or greater were achieved in 45, 77 and 82% of patients in the three groups, respectively. Eighteen, 46 and 45% of subjects achieved declines of 1.5 log10 or greater in HIV RNA in the three groups, respectively. Vicriviroc was rapidly absorbed with a half-life of 28–33 h, supporting once-daily dosing. Pharmacokinetic parameters were dose linear; steady state was achieved by day 12. Two subjects experienced a transient detectable X4-tropic virus. Vicriviroc was well tolerated in all dose groups. The frequency of adverse events was similar in the vicriviroc and placebo groups: 72 and 62%, respectively. The most frequently reported adverse events included headache, pharyngitis, nausea and abdominal pain, which were not dose related.Whereas all doses were well tolerated and produced significant declines in plasma HIV RNA, total oral daily doses of 50 or 100 mg vicriviroc monotherapy for 14 days appeared to provide the most potent antiviral effect in this study.