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  20th Conference on Retroviruses and
Opportunistic Infections
Atlanta, GA March 3 - 6, 2013
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CCR5/CCR2 Antagonist Cenicriviroc: 24-Week Data vs Efavirenz in ART-Naive
  20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Cenicriviroc, an antiretroviral that antagonizes both the CCR5 and CCR2 receptors on CD4 cells, controlled viral replication as well as efavirenz through 24 weeks of a 48-week trial [1]. A higher virologic nonresponse rate in the cenicriviroc arms appeared to reflect dropouts rather than true virologic failure.
Cenicriviroc is a once-daily agent that now requires four-tablet dosing at breakfast. A single-tablet formulation is in the works. This novel compound's developer (Tobira Therapeutics, San Francisco) hopes that, besides stifling viral replication, it will limit immune activation by blocking the CCR2 receptor.
This ongoing phase 2b 48-week trial enrolled 143 antiretroviral-naive adults infected with CCR5-tropic virus. All study participants had a viral load at or above 1000 copies and a CD4 count at or above 200. No one had primary nucleoside or nonnucleoside mutations. Using a double-blind, double-dummy design, researchers randomized participants to 100 or 200 mg of cenicriviroc following breakfast or to standard-dose efavirenz at bedtime, plus tenofovir/emtricitabine. The primary endpoint was the proportion of people with a viral load below 50 copies at 24 weeks in the intention-to-treat population by the FDA snapshot analysis.
Age averaged 36 in both cenicriviroc arms and 32 in the efavirenz arm. More than one third of study participants were black or Hispanic. Pretreatment viral load averaged 4.43 log10 copies/mL in the 100-mg cenicriviroc arm, 4.59 log in the 200-mg cenicriviroc arm, and 4.47 log in the efavirenz arm. About 20% of participants had a pretreatment load above 100,000 copies.
By the FDA snapshot analysis, 76% randomized to 100 mg of cenicriviroc, 73% randomized to 200 mg of cenicriviroc, and 71% randomized to efavirenz had a viral load below 50 copies at week 24. The investigators recorded virologic nonresponse rates of 12% with 100 mg of cenicriviroc, 14% with 200 mg, and 4% with efavirenz. The higher virologic nonresponse rates in the cenicriviroc arms reflect high rates of discontinuation for reasons other than adverse events--10% in the 100-mg arm and 11% in the 200-mg arm.
Virologic success rates were higher with cenicriviroc among people with a pretreatment viral load below 100,000 copies, while the success rate with efavirenz was higher in people with a pretreatment load above 100,000 copies, but numbers in these stratified groups are low:
Virologic success when pretreatment load below 100,000:
Cenicriviroc 100 mg (n = 49): 80%
Cenicriviroc 200 mg (n = 42): 81%
Efavirenz (n = 71): 71%
Virologic success when pretreatment load above 100,000:
Cenicriviroc 100 mg (n = 10): 60%
Cenicriviroc 200 mg (n = 14): 50%
Efavirenz (n = 4): 75%
Protocol-defined virologic failure rates were 12% with 100 mg of cenicriviroc, 16% with 200 mg, and 11% with efavirenz. Among 7, 9, and 3 people in those three arms with resistance data available, the emtricitabine-related M184V/I mutation emerged in 3 taking 100 mg of cenicriviroc, 2 taking 200 mg, and none taking efavirenz. A nonnucleoside-related V108I/V or I mutation arose in 2 people in the 200-mg cenicriviroc arm. No nonnucleoside mutations were detectable in the 3 people in the efavirenz arm.
Adverse events leading to discontinuation affected no one in the 100-mg cenicriviroc arm, 2% in the 200-mg cenicriviroc and 18% in the efavirenz arm. There were no serious adverse events in any arm. Grade 3 or 4 lab abnormalities were recorded in 9% assigned to 100 mg of cenicriviroc, 19% assigned to 200 mg, and 7% assigned to efavirenz. Creatine phosphokinase elevations affected 3% in the 100-mg arm, 14% in the 200-mg arm, and 9% in the efavirenz arm. None of these elevations led to withdrawal.
A dose-dependent increase MCP-1, the CCR2 ligand, in the cenicriviroc arms suggested active blockade of that receptor. At week 24 levels of sCD14, a marker of monocyte activation, fell with 100 and 200 mg of cenicriviroc (-0.18 and -0.19 x 10(6) pg/mL) while rising with efavirenz (+0.13 x 10(6) pg/mL). Principal investigator Joseph Gathe (Therapeutic Concepts, Houston) suggested this finding indicates that cenicriviroc restrained immune activation in the first 24 weeks of treatment.
Phase 3 trials are being planned.
1. Gathe J, Cade J, DeJesus E, et al. Week-24 primary analysis of cenicriviroc vs efavirenz, in combination with emtricitabine/tenofovir, in treatment-naive HIV-1+ adults with CCR5-tropic virus. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 106LB.