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Relationship between Lopinavir Concentration and Changes in Lipid Levels at 24 Weeks
B Best*1, S May1, M Witt2, C Kemper3, R Larsen4, C Diamond5, P Heseltine6, F He1, E Capparelli1, A McCutchan1, R Haubrich1, and the California Collaborative Treatment Group (CCTG)
1Univ. of California, San Diego, USA; 2Harbor-UCLA Med. Ctr., Univ. of California, Los Angeles Sch. of Med., Torrance, CA, USA; 3Santa Clara Valley Med. Ctr., San Jose, CA, USA; 4Univ. of Southern California, Los Angeles, USA; 5Univ. of California, Irvine, USA; and 6Quest Diagnostics, San Juan Capistrano, CA, USA
Background: The relationship
between LPV concentration and cholesterol elevation is not clear. The objective
of this analysis was to explore associations between LPV concentration metrics and
change in lipid values.
Methods: Data were analyzed
from CCTG 578, an ongoing,
randomized, 3x2 factorial study of 3 adherence interventions crossed with therapeutic
drug monitoring. LPV and RTV levels were drawn pre-, 2- and 4-hours post a witnessed
week 2 LPV dose from naïve or experienced patients. Concentration data from the
study was used to develop a population pharmacokinetic model. Post-hoc Bayesian
estimates of individual subject’s LPV exposure measures were calculated (C2,
C4, and C12 for estimated 2, 4, and 12 hour concentrations). Fasting lipids
(total cholesterol (TC), HDL, LDL and triglycerides) were measured at day 0 and
week 24.
Results: For the 37
patients, the average log10 baseline HIV RNA and CD4 were 5.0 and 172.
Mean (SD) 2, 4, and 12 hour LPV levels
in mg/mL were 6.9 (3.5),
8.1 (3.5), and 5.6 (3.0). Baseline to week 24 TC increased from 157 to 202
while triglycerides increased from 196 to 317. Neither LPV nor RTV levels were
associated with triglycerides, LDL or HDL changes. Increasing LPV concentrations
(both C2 and C4) were associated with lower
changes in week 24 TC (p<0.02). LPV C12 and RTV C2 and C4 showed trends
in the same direction (p <0.15),
but were less predictive. Multivariate models, controlling for gender,
continued to demonstrate the same LPV effect; for every one mcg/ml increase in
LPV C2, the average week 24 change in TC was 5.9 mg/dL less (p = 0.008).
Alternative models (2 piecewise
linear forms) were explored due to a suggestion of differential effects of LPV concentration
on TC depending on LPV concentration (initial increase in TC up to a level of 7
mg/mL and then decrease in TC as LPV
concentration rose). In this model, increasing LPV levels (up to 7 mg/mL) were accompanied by non-significant TC
increases (p = 0.7) while increasing
LPV levels at higher concentrations (above 7 mg/mL)
were significantly related to TC reductions (p = 0.005).
Conclusions: In contrast to
previous studies, this analysis did not find that higher LPV or RTV levels were
accompanied by greater lipid increases. In fact, patients with higher LPV
concentrations had smaller TC increases at week 24. LPV levels 2 and 4 hours
after a witnessed dose were the best predictors while trough (C12) was not
predictive of lipid changes.
Keywords: Lopinavir; lipid levels; concentration response relationship
