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Defining the Upper and Lower Clinical Cutoffs for Etravirine in the PhenoSense HIV Assay
Eoin Coakley*1, C Chappey2, J Benhamida2, L Napolitano2, L Tambuyzer1, J Vingerhoets1, M De Bethune1, and G Picchio3
1Tibotec BVBA, Mechelen, Belgium; 2Monogram Biosci, South San Francisco, CA, US; and 3Tibotec, Yardley, PA, US
Background: The DUET 1/2 trials demonstrated the efficacy
of etravirine (ETR) in combination with darunavir/ritonavir (DRV/r) in
treatment-experienced patients. We defined the lower and upper clinical
cut-offs for ETR by evaluating weeks 2, 4, 8, and 24 HIV-1 RNA outcomes within
this dataset.
Methods: Phenotyping and genotyping was performed on 199
baseline samples (PhenoSense HIV, Monogram Biosciences) from individuals whose
optimized background therapy (OBT) did not include enfuvirtide. The biological
cutoff was defined at the 99th percentile of the ETR fold-change
distribution in viruses lacking known resistance mutations within the Monogram
database. The lower clinical cut-off was defined as the fold-change above which
HIV-1 RNA response was first observed to decline. The upper clinical cut-off
was defined as the foldl-change above which the HIV-1 RNA reduction was
<0.25 log10 copies/mL. The effect of OBT was explored by deriving
weighted, PhenoSense specific, continuous phenotypic susceptibility scores for
new drugs in each regimen. ETR activity was explored in a supplemented set of samples
with reduced DRV activity (defined as a DRV fold-change ≥30).
Results: The ETR biologic cutoff was 2.9. Among the DUET
samples, the median (range) ETR fold-change was 0.75 (0.06 to 200). ETR
hypersusceptibility (fold-change <0.4) was observed in 67 samples (33.7%).
Among these 199 samples only 23 (11.5%) samples had both reduced DRV (fold-change
>10) and ETR (fold-change >2.9) susceptibility. Across multiple models
adjusted for the activity of OBT the activity of ETR was observed to be reduced
at fold-change >2.9. In the supplemented set of samples with DRV fold-change
≥30 (n = 67) a robust relationship was observed between ETR fold-change
and HIV-1 RNA change (R = 0.39, p <0.001). Only 12/67 (17.9%) had ETR
fold-change >10 among which, however, the median weeks 2 and 8 HIV-1 RNA
changes were –0.4 and +0.2 log10 ccopies/mL.
Conclusions: In this analysis of DUET samples the ETR lower
clinical cut-off was defined at fold-change 2.9, Given the limited number of
samples with an ETR fold-change >10 in this dataset, the upper clinical
cut-off is conservatively estimated at 10. ETR hypersensitivity was commonly
seen (1:3 samples) in this highly treatment experienced population.
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