150 A Composite Concentration Index to Assess Antiretroviral Regimen Potency C.V. Fletcher*, P.L. Anderson, D. Hoody, L. Bushman Univ of Colorado Hlth Sci Ctr, Denver
Background: The potency of an antiretroviral regimen is a function of drug concentrations at the site of activity and concentrations of drugs necessary to inhibit replication. No framework or methods presently exist to assess the in vivo potency of an entire antiretroviral regimen or the individual contribution of all components to regimen potency. To address this problem, our objectives were to develop a construct that incorporated the pharmacologically active concentrations of all drugs in a regimen and explore relationships between this index and virologic response.
Methods: Antiretroviral naïve persons were receiving zidovudine (ZDV), lamivudine (3TC), and indinavir (IDV) therapy. Peripheral blood mononuclear cells were obtained at routine intervals and ZDV and 3TC-triphosphate (TP) levels were determined by immunoassay and HPLC/MS/MS. IDV unbound trough concentrations (Cmin-ub) were determined by ultra filtration and HPLC. Plasma HIV-RNA was measured throughout the study, and the primary endpoint was < 50 cpm at 12 months. ZDV-TP, 3TC-TP, and IDV-Cmin-ub concentrations were referenced to the median of each for the cohort, and the CCI for each patient was calculated as the sum of these values. Data were analyzed with nonparametric, regression, and time to event statistical methods.
Results: Data were available from 32 subjects. Median (range) concentrations were ZDV-TP, 46 (5-188) and 3TC-TP, 8435 (2,852-18,278) fmol/10^6 cells; and IDV-Cmin-ub, 54 (4-173) ng/mL. IDV protein binding was 49%-75%. The median CCI was 3.03 (0.86-6.62). The CCI in subjects with RNA < 50 vs > 50 cpm was 3.5 vs 2.1 (p = 0.008) at wk 24, and was 3.5 vs 2.5 (p = 0.04) at wk 52. Subjects with a CCI < 2.6 (first quartile) had a slower time to reach RNA < 50 cpm: 195 days vs 133 days (p = 0.01 log-rank). In a stepwise regression model of time to < 50 cpm vs ZDV-TP, 3TC-TP, IDV-Cmin-ub, and CCI, only CCI was retained in the final model (p = 0.01). The contribution of the individual drugs to the patients CCI varied widely from 8%-62% for ZDV-TP, 18%-64% for 3TC-TP, and 3%-64% for IDV-Cmin-ub.
Conclusions: In this study, the CCI was shown to discriminate virologic success. The CCI simultaneously incorporated concentrations of all pharmacologically active moieties in a regimen and provided an apparent measure of overall regimen potency.
.
