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Session 75 Poster Session Resistance to Antiretroviral Chemotherapeutic Agents Session Time: 4:30-6:30 pm Room 4E-F

567-T. Selection for Delavirdine (DLV) Resistance is not Associated with Loss of Nucleoside Analogue (NRTI) Resistance Mutations in Subjects with Non-Nucleoside Analogue (NNRTI) Hypersusceptibility -- Results from ACTG 359 R. Swanstrom*1, D. Katzenstein2, N. S. Hellmann3, S. A. Fiscus1, L. Petch1, H. Cheng4, R. Haubrich5, and R. Gulick6 1Univ. of North Carolina, Chapel Hill; 2Stanford Univ. Med. Ctr., Palo Alto, CA; 3ViroLogic, Inc., South San Francisco, CA; 4Harvard Sch. of Publ. Health, Boston, MA; 5Univ. of California, San Diego; and 6Weill Med. Coll. of Cornell Univ., New York, NY Background: Hypersusceptibility (HS) to NNRTIs has been associated with resistance to NRTIs. We studied the relationship between HS and evolution of resistance to DLV in a subset of patients participating in a salvage therapy protocol, ACTG 359. We determined if the NRTI resistance mutations that presumably conferred NNRTI HS were compatible with the development of NNRTI resistance mutations. Methods: ACTG 359 was a salvage therapy study for patients who had taken NRTI and indinavir but no prior NNRTI and were randomized to receive dual protease inhibitors together with DLV, adefovir (ADV), or both. Phenotypic resistance testing was performed on baseline HIV RNA samples using the ViroLogic Phenosense assay. DLV HS was defined as an IC50 value for DLV <0.4-fold that of the control strain. Bulk sequencing of baseline and week 16 HIV RNA samples was performed using the Visible Genetics TruGene system. Results: Among the 34% of subjects (48 of 142) identified by phenotypic testing to have BL DLV HS, we selected 6 who received DLV (but not ADV) and 5 who received ADV (but not DLV), and also demonstrated decreased HIV RNA levels at weeks 4, 8, and/or 12, followed by a virologic rebound at week 16. 2 subjects from each group showed no new mutations at week 16 and a loss of virtually all resistance-associated mutations that were present at BL in both pol (encoding reverse transcriptase) and pro (encoding protease). This loss was likely due to compromised drug exposure. In the remaining subjects pro-resistance-associated mutations either increased in number or evolved, suggesting ongoing drug selective pressure. In the 4 remaining HS subjects who received DLV each showed evolution of DLV resistance with mutations at pol positions 103 and/or 181. In 3 cases these mutations appeared without loss of preexisting NRTI resistance mutations. In the fourth case a 103 mutation appeared with the loss of a 210 mutation while a 215 mutation was retained. In contrast, 2 of 3 subjects who received ADV lost the mutation at position 184 by week 16 while retaining other mutations associated with resistance to NRTIs. M184V is known to enhance sensitivity to ADV thus the reversion may act like a resistance mutation for ADV. Conclusions: In subjects whose virus was HS to NNRTI the removal of the NRTI selective pressure did not result in the loss of NRTI resistance-associated mutations during the initial evolution of resistance to DLV.

©2002 9th Conference on Retroviruses and Opportunistic Infections