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  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
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Once-Daily CCR5 Antagonist Has Highly Sustained Effect
 
 
  4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
 
Mark Mascolini
 
INCB009471, an investigational CCR5 antagonist from Incyte Corporation, demonstrated good activity against CCR5-using virus in a 14-day monotherapy study [1]. Because of this agent's long half-life, it continued to thwart viral replication long after dosing stopped.
 
US researchers signed up 23 people with CCR5-homing HIV and randomly assigned 19 to take 200 mg of 9471 once daily and 4 to take placebo for 14 days. Study participants either had never tried antiretrovirals or had not taken them for at least 3 months. When the trial began the median CD4 count stood at 521 in the 9471 group and 629 in the placebo group, and respective viral loads averaged 4.76 log copies and 4.43 log
 
Drug-level studies charted a maximum concentration of 1378 +/- 325 nM, a minimum concentration of 394 +/- 210 nM, and an area under the concentration-time curve of 16,458 +/- 6037 nM/hour in the 19 people taking the new CCR5 antagonist in this trial. Levels proved similar in 8 volunteers without HIV infection. The minimum concentration is about 10 to 20 times higher than the protein binding-adjusted 90% inhibitory concentration of the drug in peripheral blood mononuclear cells. The agent's half-life measured about 60 hours.
 
Among people taking 9471, viral loads fell an average 0.44 log on treatment day 4, 1.14 log on day 7, and 1.72 log on day 14. The biggest viral load dip, 1.82 log, came on day 16, 2 days after dosing stopped, while on day 20 the average drop measured 1.71 log. By day 28, 14 days after dosing stopped, the average viral still lay 0.81 log below the pretreatment value. Viral load did not change in the placebo group.
 
Eight of 19 people (42%) reached a viral load below 400 copies, and all of them had more than a 2-log (100-fold) fall in viral load. Among 17 people whose HIV continued using CCR5 during the trial, 8 (47%) reached a load under 400 copies and had more than a 2-log drop.
 
Both people whose HIV changed coreceptor use during the study had antiretroviral experience when the trial began. One had dual/mixed virus (using both CCR5 and CXCR4) on days 7 and 28. The other had dual/mixed virus on day 14, but only CCR5-using could be detected on day 28. Principal investigator Calvin Cohen said evidence suggested the CXCR4-using virus that emerged during the trial had lurked at undetectable levels when the study started.
 
CD4 counts remained stable or rose slightly during the 14 days of treatment. Four people (21.1%) had any side effect, including grade 1 liver enzyme elevations in all 4.
 
Cohen added that 9471 is neither an inhibitor nor an inducer of the CYP3A enzyme, so it should not affect other antiretrovirals using that enzyme for metabolism. But this CCR5 drug is a CYP3A substrate, so the dose may have to be lowered with ritonavir. Because of this agent's unusually long half-life, Cohen speculated that dosing less often than once daily may be studied with a ritonavir boost.
 
Reference
1. Cohen C, DeJesus E, Mills A, et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUAB106.