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Pharmacology and New Antiretroviral Agents
Wednesday, 10 am - 12:45 pm
Presentation Time: 10:45 am
Background: In patients failing multiple ARV regimens, increased doses of lopinavir/ritonavir (LPV/r) may achieve higher LPV concentrations relative to HIV phenotypic susceptibility, thus overcoming certain levels of LPV resistance. The purpose was to assess predictors of antiviral response in patients receiving high-dose LPV/r.
Methods: Multiple PI- and NNRTI-experienced HIV+ patients (n = 33) were randomized to and received 1 of 2 twice daily high-dose LPV/r regimens with food: 667/167 mg (5 x 133/33 mg LPV/r caps, n = 19) or 400/300 mg (3 x 133/33 mg LPV/r caps + 2 x 100 mg ritonavir caps, n = 14). NRTI (2 to 3) were selected by the care provider. Plasma samples for LPV pharmacokinetics were obtained over a 12-hour dosing interval at week 3. To assess antiviral activity, time-averaged difference from baseline for HIV RNA through week 48 (TAD) and demonstration of HIV RNA <400 copies/mL were quantified. Variables explored for association included demographics, baseline disease characteristics, resistance, treatment history, active agents in regimen, LPV pharmacokinetics (Cmax, AUC, Ctrough, and Cmin), and LPV inhibitory quotient (Ctrough/individual protein binding-adjusted IC50 for HIV) using linear and logistic regression.
Results: A wide range of LPV phenotypic
susceptibility was noted; the median fold IC50 was 4.1 (range 0.6 to
273). LPV Ctrough values were similar for both regimens, 60 to 70% higher compared with LPV/r 400/100 mg twice
weekly. The median LPV inhibitory quotient was 27 (range 0.7 to 438). In correlation analyses, lower LPV fold IC50 (p <0.01), lower number of PI
mutations (p £0.04), more active NRTI (p £0.04), and higher LPV inhibitory
quotient (p =0.002) were associated
with a better virologic response (TAD). In contrast,
Conclusions: LPV inhibitory quotient is a significant predictor of antiviral response in multiple PI- and NNRTI-experienced patients. Higher doses of LPV/r may provide LPV concentrations sufficient to overcome certain degrees of reduced LPV phenotypic susceptibility, resulting in a significant treatment effect.
Keywords: inhibitory quotient; lopinavir/ritonavir high dose; highly ARV-experienced patients