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Background: ABT-378/r is a protease inhibitor (PI) with mean predose plasma levels > 75-fold above its serum-adjusted EC₅₀ for wild-type HIV.

Methods: Plasma virus from each pt. in two Phase II studies (M97-720, n=100, antiretroviral naïve; M97-765; n=70, single PI experienced) with available baseline (BL) data and sustained viral load (VL) rebound to >1000 c/mL while on treatment was analyzed for phenotype/genotype (M97-720: n=4; M97-765:n=8).

Results: Two rebound isolates from 4 ARV naïve pts had resistance to 3TC, but none displayed resistance to ABT-378 or other PIs. Rebound viruses from 4 PI experienced pts. whose BL isolates contained no primary protease (Pr) mutations and were fully sensitive to ABT-378 developed phenotypic/genotypic resistance to NVP (>43-fold) but not ABT-378. These 8 pts. had documented or suspected poor adherence during ABT-378/r therapy. BL isolates from the other four PI-experienced pts. contained > 4 Pr mutations. At rebound, the EC₅₀ of ABT-378 increased by 4- to 112-fold above BL levels in 3/4 pts. with adequate virus growth for phenotyping. BL resistance to RTV, IDV and NFV, remained. Two isolates from SQV-naïve pts remained susceptible to SQV. All 3 rebound isolates were either fully sensitive (<4-fold) to amprenavir (AMP) or displayed modestly reduced susceptibility (up to 6.6-fold concurrent with 79-fold resistance to ABT-378). All post-rebound isolates that were tested against tipranavir (TPV) were fully sensitive.

Conclusions: Resistance to ABT-378 was not observed to develop in either ARV naïve or PI exp. pts. with suspected noncompliance on study who lacked BL Pr mutations. SQV, AMP and TPV may be useful with RTV enhancement for salvage when ABT-378 resistance is present, although further clinical evaluation is needed.

¹Abbott Laboratories, Abbott Park, IL,²VIRCO, Mechelen, Belgium, ³VIRCO, Cambridge, UK, ⁴Pharmacia & Upjohn, Kalamazoo, MI

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