ABT-378/r is a novel protease inhibitor (PI) that achieves trough concentrations >75-fold above the EC₅₀ of ABT-378 against wild type HIV when dosed at 400/100 mg BID. In a Phase II study of ABT-378/r in ARV-naïve subjects, 0/4 subjects on treatment with detectable viral load through Week 72 displayed evidence of resistance. In a subsequent randomized, double-blind Phase III study of 653 ARV-naïve subjects treated with either ABT-378/r (N=326) or NFV (N=327), in combination with d4T and 3TC, 92% of ABT-378/r-treated subjects and 81% of NFV-treated subjects achieved VL <400 copies/mL at Week 24 (on treatment, p<0.001). In order to gain insight into the barriers to resistance development to ABT-378/r, the plasma viral isolates from all subjects in this study with HIV RNA >400 copies/mL at Week 24 (ABT-378/r: n=25, NFV: n=53) were examined for evidence of resistance. Genotype (population sequencing) and phenotype (PhenoSense™) were performed by ViroLogic, Inc.

Genotypic evidence of resistance to ABT-378 and NFV was identified in 0/18 (0%) and 14/35 (40%) isolates from ABT-378/r and NFV subjects, respectively, available for analysis at Week 24. In phenotypic assays, all of the 18 isolates from ABT-378/r-treated subjects demonstrated susceptibility to ABT-378. Consistent with the lack of resistance at Week 24, 13/21 (62%) of ABT-378/r-treated subjects who had subsequent HIV RNA determinations on their assigned regimen after Week 24 experienced resuppression to <400 copies/mL. In contrast, only 7/40 (18%) NFV-treated subjects had subsequent HIV RNA <400 copies/mL. Adherence was lower in subjects with HIV RNA >400 copies than in Week 24 responders in both study arms. Similarly, in a Phase II pediatric study, genotypic evidence of resistance to ABT-378 was identified in 0/8 isolates from ARV-naive subjects treated with ABT-378/r in combination with d4T and 3TC who had HIV RNA >400copies/mL at Week 24 or Week 32. All of the 8 isolates demonstrated susceptibility to ABT-378 by phenotypic analysis.

Viral rebound in ARV-naïve subjects treated with ABT-378/r in a blinded Phase III study through 24 weeks has not been associated with the development of resistance. These observations, corroborated by Phase II studies in both adults and children, suggest the presence of a high genetic barrier to resistance to ABT-378/r.

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 Lack of Resistance to ABT-378/Ritonavir (ABT-378/r) Observed After 24 Weeks of Therapy in Antiretroviral Naive Subjects 

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