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New Trofile Assay Would Have Improved Vicriviroc Response in ACTG 5211
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
If the AIDS Clinical Trials Group (ACTG) could have used the enhanced Trofile assay to screen people for treatment with the CCR5 antagonist vicriviroc in ACTG 5211, they would have improved virologic response rates by disqualifying people with low levels of CXCR4-using (X4) virus that the standard Trofile test could not spot [1]. Regulators have approved the enhanced Trofile test, and Monogram brought it online last week.
Monogram's Jacqueline Reeves and ACTG collaborators used the enhanced Trofile to recheck stored viral samples from 118 highly experienced study participants randomized to 5, 10, or 15 mg of vicriviroc or placebo plus an optimized background regimen [2].
The enhanced coreceptor test determined that 89 people had virus that used only the CCR5 coreceptor (R5 virus) at screening for the trial. The new Trofile found that 25 people had virus that could use either coreceptor (dual/mixed or DM virus) before they started vicriviroc. Fifteen of those people--all classified as R5 virus-infected by the standard assay--took vicriviroc during the trial. The older test uncovered emerging X4-using virus during the trial in 12 of these 15. Vicriviroc and other CCR5 antagonists cannot control replication of X4-using HIV.
Reclassification of R5 virus as DM did not affect virologic response rates among people randomized to take placebo plus other salvage drugs. But the new coreceptor calls would have improved 14-day and 24-week intention-to-treat response rates in all three vicriviroc dosage groups by eliminating people who had DM virus from the study.
14-day change in viral load
· 5 mg: -1.10 log with new Trofile versus -0.87 with old Trofile
· 10 mg: -1.31 log with new Trofile versus -1.15 with old Trofile
· 15 mg: -0.93 log with new Trofile versus -0.92 with old Trofile
24-week change in viral load
· 5 mg: -1.85 log with new Trofile versus -1.51 with old Trofile
· 10 mg: -2.09 log with new Trofile versus -1.86 with old Trofile
· 15 mg: -1.75 log with new Trofile versus -1.68 with old Trofile
If ACTG investigators had used the enhanced Trofile at trial screening and entry, the 64 people with R5 virus at both points would have had had a significantly bigger viral load drop at 14 days and 24 weeks than the 15 people with DM virus at screening (-1.15 versus -0.09 log at day 14, and -1.95 versus -0.57 log at week 24, P < 0.001). With enhanced Trofile screening, 56% of people (36 of 64) who could have taken vicriviroc would have had a 24-week viral load under 400 copies, compared with 48% (40 of 83) screened with the standard Trofile in the actual study.
Reeves concluded that the enhanced Trofile works better than the older test when screening people for CCR5 antagonist therapy.
References
1. Su Z, Reeves JD, Krambrink A, et al. Response to vicriviroc in HIV-infected, treatment-experienced individuals using an enhanced version of the Trofile HIV co-receptor tropism assay [Trofile (ES)]: reanalysis of ACTG 5211 results. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 88.
2. Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis. 2007;196:304-312.
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