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Session 77
Poster Abstracts New Antiretroviral Agents: RTI's and PI's Wednesday, 1:30 - 3:30 pm Poster Hall |
Background: TMC114 is a potent, next generation HIV
protease inhibitor (PI) with in vitro
antiviral activity against both wild-type and PI-resistant HIV-1.
Methods: In TMC114-C207, an open, randomized phase 2a study, patients on a virologically failing regimen received TMC114/RTV as a substitute for all PI or continued their current regimen (control group). Multi-PI, 2- or 3-class experienced patients received TMC114/RTV at doses of 300/100 mg twice daily (n = 13), 600/100 mg twice daily (n = 12) or 900/100 mg daily (n = 13) for 14 days. Change in viral load was determined over 14 days; baseline genotypic and phenotypic testing were performed. This analysis investigated the antiviral response in specific subgroups and the correlation between antiviral activity and baseline phenotype, genotype, pharmacokinetic parameters, and interquartile range.
Results: We randomized 38 patients to the treatment arms. The median baseline viral load was 4.3 log10 copies/mL and the median CD4+ cell count 305 cells/mm3. Median changes in viral load were 1.2, -1.3, and -1.5 in the 300/100 twice daily, 900/100 daily, and 600/100 twice daily group, respectively. There was no statistical difference in antiviral activity between the 3 arms. All TMC114/RTVgroups were statistically-superior to the control group (p <0.001).
The table below presents antiviral activity observed in specific subgroups at baseline:
Subgroup
|
Median
change in log viral load, day 14 (min; max) |
|
All treated patients (N = 35) |
-1.4 (-0.5 ; -2.5) |
|
TMC114/RTV patients with >1 primary PI mutation (n = 28) |
-1.4 (-0.5 ; -2.5) |
|
TMC114/RTV patients with phenotypic resistance to
all approved PI (n = 19) |
-1.5 (-0.5 ; -2.5) |
|
TMC114/RTV patients with phenotypic resistance
(FR>10) to lopinavir (n = 28) |
-1.5 (-0.5 ; -2.5) |
|
TMC114/RTV patients with viral load >20000
copies/mL (n = 14) |
-1.5 (-0.9 ; -2.5) |
In these subgroups, no differences in antiviral response were observed. Univariate analysis showed that genotypic, phenotypic, pharmacokinetic and IQ parameters were not predictive for change in viral load at day 14.
Conclusions: In this highly treatment-experienced population, all TMC114/RTV groups demonstrated a robust viral load response. Baseline susceptibility to TMC114, as well as pharmacokinetic parameters and interquartile range for TMC114, were not predictive for the change in viral load at day 14, indicating that the selected TMC114/RTV doses provided exposures sufficiently high to overcome broad resistance to PI.
Keywords: resistance; protease inhibitor; pharmacokinetics