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Background. ABT-378/r is a new protease inhibitor (PI), with mean C_trough-based Inhibitory Quotient (IQ=C_trough/EC50) >75X protein-adjusted EC50 for wt virus, reflected in its potent activity in PI-naïve and single PI-experienced subjects. This IQ is lower in PI-experienced subjects with viruses containing protease mutations. We examined the relationship between dose/conc and virologic response to ABT-378/r+EFV+NRTIs in 57 multiple PI-experienced, NNRTI-naïve subjects.

Methods. The response (HIV RNA <400 copies/mL) at Wk 24 was analyzed by univariate and stepwise logistic regression, with baseline (BL) demographics, disease variables, raw PK and PK-based IQs as covariates.

Results. 68% of BL viruses showed > 4X reduced (avg: 16X) susceptibility to >3 PIs. All but 2 isolates had wt susceptibility to EFV. In univariate analysis, IQ (range: 0.05-279) was marginally associated with response at Wk24 (p=0.12). From the IQ-response curve, the predicted probability of response was ~ 60%, 80% and 90% for ABT-378 IQ ~1, 8 and 17, respectively. This is consistent with the high efficacy in PI-naïve and single PI-experienced subjects receiving ABT-378/r-based regimens, where the ABT-378 IQ is >20 in nearly every subject. Stepwise logistic regression, accounting for covariates, confirmed the significance of IQ (p=0.068), along with time since HIV diagnosis, weight, number of new NRTIs, BL NRTI susceptibility (>2.5-fold) and BL viral load.

Conclusions. These results demonstrate that the relationship between ABT-378/r trough levels and viral phenotype are associated with virologic response, and suggest that the inhibitory quotient (C_trough/EC₅₀) is a useful predictor of response to PI therapy.

¹Abbott Laboratories, Abbott Park, IL

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