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Novel Antiviral Agent Shows Safety, Activity Against HIV-1

A human IgG4 monoclonal antibody that binds to the CC chemokine receptor 5 (CCR5) is well-tolerated and shows "meaningful antiviral activity" against CCR5-tropic HIV-1, according to the results of a phase II trial.

A study of this investigational agent, called HGS004 (Human Genome Sciences, Rockville, MD), was conducted by Dr. Jacob Lalezari of Quest Clinical Research in San Francisco and colleagues and involved 63 subjects with CCR5-tropic HIV-1 infection.

The patients were divided into one of five dose cohorts: 0.4 mg/kg, 2.0 mg/kg, 8.0 mg/kg, 20 mg/kg or 40 mg/kg after a single intravenous bolus of HSG00. Thirteen patients received a placebo.

"HGS004 was well-tolerated, and no dose-limiting toxicities were observed," Dr. Lalezari and associates report in the March 1st issue of The Journal of Infectious Diseases.

The investigators noted a nonlinear dose-response across all five dosages. High CCR5 receptor uptake occurred at the higher dosages during 28 days of observation.

At 14 days, plasma HIV-1 RNA reductions of greater than 1 log10 were observed in 14 of 26 subjects (54%) who received 8 mg/kg, 20 mg/kg or 40-mg/kg of HGS004. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to inhibitory concentration 90% (IC90) predicted antiviral response on day 14.

At 28 days, 4 of the 10 patients receiving the highest dose had a greater than 1 log10 HIV-1 RNA reduction.

"Another interesting observation...was the remarkable increase in circulating CD4 and CD8 cell counts in peripheral blood after administration of HGS004, even at the lowest dose," Dr. Lalezari and colleagues write.

"Increases were observed as early as day 1 and were maintained beyond day 28 in the higher-dose cohorts," they add. "It is likely that the increases are due to redistribution or altered trafficking of CCR5-expressing CD4 and CD8 cells from peripheral tissue to the vascular compartment."

"The long-term consequences of these observed changes on the immune status of patients will need further investigation," the investigators added.

J Infect Dis 2008;197:721-727.