H-1222. Resistance to RDEA806 Requires Multiple Mutations Which Have Limited Cross-resistance to Other NNRTIs
Session: Poster Session: Antiretroviral Resistance and HIV Diagnostics
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: RDEA806 is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. Phase 2a clinical trial data demonstrated robust antiviral activity in naïve patients. RDEA806 suppressed viral breakthrough in an in vitro resistance selection study for 9 months, indicating a high genetic barrier to resistance. The genotypic and phenotypic analyses of the mutant viruses selected by RDEA806 in this resistance selection study will be presented. Methods: Selection of HIV-1 virus resistant to RDEA806 was performed in infected SupT1 cells. The mutations identified in the RT region at the time of virus breakthrough for each drug concentration were engineered into a wild-type vector. Activity was measured using the VSV-G protein pseudotyped NL4-3.Luc.R-E- virus containing the mutation(s). Results: RDEA806 concentration was increased to 1500 nM in the virus culture over the course of 13 months. The first consensus mutation selected, K104E, was identified after > 300 days in culture and showed essentially no loss of susceptibility to RDEA806. Other NNRTIs tested also retained maximal activity against this mutant virus. RDEA806 showed a minor loss of activity to the next virus selected, K104E-E138K-T240I, while efavirenz retained full activity. Virus with the ultimate combination contained 5 RT mutations, K104E-E138K-T240I-V179D-F227L, and had very low replication capacity. While RDEA806 lost potency against this virus, other NNRTIs showed only minor to moderate cross resistance. Conclusions: Prolonged suppression of viral breakthrough in this resistance selection study suggests that RDEA806 has a high genetic barrier to resistance. Phenotypic analysis of selected mutations indicates that multiple mutations are necessary for loss of susceptibility to RDEA806. Minor cross-resistance to some of the mutation patterns is observed by some of the NNRTIs tested.
Anneke Raney, PhD1, Barry Quart, Pharm D2, Daniel Bellows, MS2, Jean-Luc Girardet, PhD2, Robert Hamatake, PhD2, Wen Xu, MS2, Zhijun Zhang, PhD3 and  A. K. Raney,
Ardea Biosciences, Inc. Role(s): Employee, Shareholder (excluding diversified mutual funds), Received: Salary., (1)Ardea Biosciences, San Diego, CA, (2)Ardea Biosciences, (3)Univ. of Oklahoma