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

568-T. Choice of Co-Nucleoside Analog in d4T-Treated Subjects may Influence the Pattern of Thymidine Analog Mutations (TAMs) and Multi-Nucleoside Resistance Mutations (MNRs) L. Ross*1, Q. Liao1, K. Henry2, C. Cohen3, A. Hirani1, R. Fisher1, M. St. Clair1, and J. Hernandez1 1GlaxoSmithKline, Res. Triangle Park, NC; 2Regions Hosp., St. Paul, MN; and 3Comm. Res. Initiative, Boston, MA Background: In vivo, stavudine (d4T) and zidovudine (ZDV) resistance develops through similar pathways, by selecting for TAMs and/or MNRs which are associated with decreased susceptibility to both drugs. Limited data are available on the type and frequency of TAMs or MNRs when d4T is combined with different co-nucleoside analogs, or the effect of TAMs/MNRs on phenotypic susceptibility to ddI. Methods: Reverse transcriptase mutations and phenotypic resistance were evaluated for baseline plasma HIV-1 from 147 d4T-treated, ZDV-naïve subjects enrolled in VIRA3001, NZTA4005, and NZT40012. Results: HIV-1 from 52/147 subjects (35%) had TAMs, and MNRs (69 insertion, D69N, Q151M) were observed in 15/147 samples (10%). 45/147 (31%) of the samples had TAMs and no MNRs. Mean phenotypic fold resistance (MPFR) for samples with TAMs and/or MNRs compared to those without these mutations for d4T was 3.33 compared to 0.90 (p<0.001), for ZDV MPFR was 10.1 vs 1.10 (p<0.001), and for ddI, MPFR was 3.67 vs 1.65 (p=0.003). The frequency of specific TAMs for patients on d4T/ddI-containing regimens (n=29) compared to patients on d4T/3TC-containing regimens (n=106) was similar except for the L210W mutations and D67N mutations, which were more common in ddI than 3TC-containing regimens (17% vs 9% and 14% vs 5.7%). While, subjects on 3TC-containing regimens were on prior ART longer than subjects on ddI-containing regimens, TAMs and MNRs were more common in ddI/d4T (41% TAMs and 20.6% MNRs) than in 3TC/d4T-containing regimens (33% TAMs and 5.6% MNRs). Conclusions: D4T, like ZDV, can select for TAMs and MNRs, and these mutations reduce susceptibility to d4T, ZDV, and ddI. The choice of co-nucleoside analog may influence selection of specific TAMs, as the L210W and D67N mutations were observed more frequently in the d4T/ddI-containing regimens than in d4T/3TC-containing regimens. TAMs and MNRs were less common in the 3TC/d4T than in ddI/d4T treated subjects, possibly due to selection for the M184V mutation in the 3TC group.

©2002 9th Conference on Retroviruses and Opportunistic Infections