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Effect of baseline and on-treatment mutations on the antiretroviral activity of darunavir/ritonavir (DRV/r) and lopinavir/ritonavir (LPV/r): results of a randomised, controlled, phase III study (TITAN)
Presented by Marie-Pierre De Béthune, Belgium.
De Meyer S.1, De Paepe E.1, Vangeneugden T.1, Van Baelen B.1, Spinosa-Guzman S.1, Lefebvre E.2, Tomaka F.3, Lathouwers E.1, De Béthune M.-P.1
1Tibotec BVBA, Mechelen, Belgium, 2Janssen-Cilag, Tilburg, Netherlands, 3Tibotec Inc., Yardley, United States
Objectives: The influence of baseline and on-treatment PI-resistance-associated mutations (PI-RAMs) on the antiretroviral activity of DRV/r 600/100mg bid and LPV/r 400/100mg bid in treatment-experienced, but LPV/r-naive, patients in the phase III TITAN trial was examined.
Methods: Patients with HIV-1 RNA >1,000 copies/mL, treated with ³2 NRTIs plus ³1 NNRTI and/or PI for ³12 weeks (but LPV/r-naïve) were randomised to DRV/r (n=298) or LPV/r (n=297) plus underlying therapy (NRTIs ± 1 NNRTI). Phenotypes and genotypes of plasma viruses were determined by the Antivirogram® and Virco®TYPE HIV-1 assays. For patients who discontinued for other reasons than virologic failure (VF) data were censored in the efficacy analysis (non-VF analysis).
Results: Baseline characteristics were balanced between both arms: median phenotypic sensitivity score of underlying therapy of 2.0, median (range) of 0(0-6) primary PI-RAMs, 4(0-17) PI-RAMs, 0(0-5) DRV-RAMs and 1(0-11) LPV-RAMs, median (range) fold change of 0.60(0.1-43.8) for DRV and 0.75(0.3-74.5) for LPV. The frequency of DRV-RAMs was low: 82.6% had 0 and only 3.9% had ³3 DRV-RAMs. In the non-VF analysis, 90% of patients on DRV/r and 79% of patients on LPV/r achieved HIV-1 RNA <400 copies/mL at week 48. A diminished response to DRV/r was observed in groups of patients with ³3 DRV-RAMs in a background of 13 PI-RAMs at baseline. VF was observed in 31(10.4%) and 57(19.2%) patients in the DRV/r and LPV/r arms, respectively. Proportionally less VFs developed DRV-, LPV-, primary PI-, or NRTI-RAM(s) in the DRV/r arm than in the LPV/r arm.
Conclusions: The high genetic barrier to resistance of DRV was confirmed in this population by the superior virologic response, and by the lower development rate of PI- and NRTI-RAMs in virologic failures. As previously described, virologic response was correlated with the number of DRV-RAMs, which was low in this LPV/r-naive treatment-experienced population.
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