Phenotypic resistance testing can provide useful information to guide therapy in treatment-experienced patients. However, detectable changes in drug susceptibility, compared to wild-type (wt) HIV, may be clinically irrelevant if plasma drug concentrations are high relative to the wt EC₅₀. ABT-378/r is a new protease inhibitor (PI) that displays a high inhibitory quotient (IQ, defined as the C_trough/serum-adjusted EC₅₀ ratio) against wt HIV. In order to provide an interpretive context for phenotypic resistance testing with ABT-378/r, we performed a cross-study analysis of the Week 24 response in two Phase II studies of ABT-378/r plus an NNRTI and NRTIs in PI-experienced, NNRTI-naïve patients, with respect to baseline phenotype. Baseline phenotype was determined using the PhenoSense^TM and Antivirogram^TM methods. The association between baseline phenotype and the binary response variable (HIV RNA > or <400 copies/mL) at Week 24 (dropouts as censored) was analyzed using Fisher’s exact test and univariate logistic regression. The median (range) baseline susceptibility to ABT-378 (n=113 patients) was 2.3-fold (0.5- to 96-fold). Observed response rates at Week 24 (n=106, dropouts as censored) for patients with <10-fold, 10- to 20-fold, 20- to 40-fold and >40-fold reduced baseline susceptibility were 72/80 (90%), 9/11 (82%), 5/7 (71%) and 4/8 (50%) (p=0.012). Using the lower (conservative) 95% confidence limit of a logistic regression model, the estimated probability of response at Week 24 was 50% or greater in subjects whose baseline isolates displayed up to 38-fold reduced susceptibility to ABT-378. These results suggest that ABT-378/r, as used in these studies, exerts significant antiviral activity in vivo even in patients with up to 40-fold reduced susceptibility at baseline. This is likely a consequence of a high inhibitory quotient. These results provide guidance for the use of ABT-378/r in treatment-experienced patients and for the interpretation of phenotypic resistance testing with respect to ABT-378/r regimens.

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Interpretation of Phenotypic Resistance to ABT-378/Ritonavir (ABT-378/r)
in Protease Inhibitor Experienced Patients