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Enhanced Trofile Assays Shifts Results of ACTG 5211 Vicriviroc Trial
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48th ICAAC,
October 25-28, 2008,
Washington, DC
Mark Mascolini
Using the enhanced Trofile assay to determine viral coreceptor preference in an ACTG trial of the CCR5 antagonist vicriviroc improved the ability to detect CXCR4-using virus upon patient screening for the study [1]. If the enhanced assay had been available when ACTG 5211 began, investigators could have excluded more people with X4-using HIV, which does not respond to CCR5 antagonists. But the enhanced assay's impact on 24-week virologic response appeared to be minimal in this analysis.
In a phase 2 trial ACTG investigators randomized 118 people taking a failing ritonavir-containing regimen to placebo or to 5, 10, or 15 mg of vicriviroc once daily for 14 days [2]. (Phase 3 trials of vicriviroc are testing 30 mg once daily.) After 14 days everyone stopped the drugs in their failing regimen and started an optimized background regimen, which always included a ritonavir boosting dose in the vicriviroc group. After 14 days and 24 weeks of follow-up, viral load drops were significantly greater in the vicriviroc groups than in the placebo group.
The trial relied on the then-current Trofile assay to exclude people whose virus could use CXCR4 to enter CD4 cells. The new analysis used the enhanced Trofile assay to recheck coreceptor use in viral samples collected from all 118 study participants (90 randomized to vicriviroc and 28 to placebo) at trial screening and entry. The enhanced assay can detect CXCR4-using virus representing 0.3% of a person's viral population with 100% sensitivity.
The old Trofile determined that all 118 people had R5-using HIV at screening. The enhanced assay figured that virus from 25 people (21%) could use either CCR5 or CXCR4 at screening. Fifteen of these 25 people took vicriviroc in the trial. In 12 of these 15, the original Trofile assay spotted X4 virus before study week 8.
Comparing day-14 and week-24 virologic responses in three groups of vicriviroc takers according to CXCR4 or CCR5 use determined by the enhanced Trofile, the ACTG team found the best response rates in those with R5 virus at both screening and study entry:
Day-14 change in viral load (log copies/mL):
· 64 people with R5 virus at screening and entry: -1.15
· 5 people with R5 virus at screening but R5/X4 virus at entry: -0.66
· 15 people with R5/X4 virus at screening: -0.09
Week-24 change in viral load (log copies/mL):
· 58 people with R5 virus at screening and entry: -1.95
· 5 people with R5 virus at screening but R5/X4 virus at entry: -1.20
· 15 people with R5/X4 virus at screening: -0.57
The difference in viral load change between the first and third groups was statistically significant (P < 0.001) at both day 14 and week 24. The differences between the first and second groups, and between the second and third groups, were not statistically significant. Despite these differences, using the enhanced assay would have only minimally increased the proportion of vicriviroc takers with a 24-week viral load below 50 or 400 copies [in this analysis], probably because other drugs in the background regimen controlled X4 virus well.
CD4 counts at week 24 rose significantly more in the 58 people with R5 virus at screening and entry (average 140 cells) than in the 5 people with R5/X4 virus at entry (average 75 cells) or the 14 people R5/X4 virus at screening (average 45 cells).
References
1. Su Z, Reeves JD, Krambrink A, et al. Response to vicriviroc in HIV-infected treatment-experienced subjects using an enhanced Trofile HIV co-receptor tropism assay: reanalysis of ACTG 5211 results. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-895.
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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