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Session 27 Oral Abstracts
Pharmacology and New Antiretroviral Agents
Wednesday, 10 am - 12:45 pm
Presentation Time: 10:45 am
Room 3000


134
Lopinavir Inhibitory Quotient Predicts Virologic Response in Highly Antiretroviral-experienced Patients Receiving High-dose Lopinavir/Ritonavir
R Bertz*1, J Li1, M King1, D Kempf1, D Podzamczer2, C Flexner3, C Katlama4, D V Havlir5, S Letendre6, J Eron7, L Weiss8, J Gatell9, A Simon4, K Robinson1, and S Brun1
1Abbott Labs., Abbott Park, IL, USA; 2Hosp. de Bellvitge, Barcelona, Spain; 3Johns Hopkins Univ. Sch. of Med., Baltimore, MD, USA; 4Hosp. de la Pitie-Salpetriere, Paris, France; 5Univ. of California, San Francisco, USA; 6Univ. of California, San Diego, USA; 7Univ. of North Carolina at Chapel Hill, USA; 8Hosp. Europeen George Pompidou, Paris, France; and 9Hosp. Clin., Barcelona, Spain

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, LPV PK parameters alone were not associated with virologic response (p³0.17). In a multiple regression analysis, higher LPV inhibitory quotient (p = 0.007) and more active NRTI (p = 0.04) were associated with improved virologic response. Similarly, a higher LPV inhibitory quotient (p = 0.026) and lower baseline HIV RNA (p = 0.027) were associated with a higher probability of achieving an HIV RNA <400 copies/mL in a multiple logistic regression analysis. A higher number of active NRTIs was marginally significantly associated (p = 0.052) with achieving an HIV RNA <400 copies/mL.

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