437   Genotypic Predictors of Virologic Response to Stavudine after Zidovudine Monotherapy (ACTG 302).

N. Shulman*, R. Shafer, M. Winters, R. Machekano, S. Liou, M. Hughes, A. Zolopa, and D. Katzenstein for ACTG 302.
Stanford Univ., CA and SDAC, Harvard Univ., Boston, MA.

Background:Studies suggest that there is cross-resistance between AZT and d4T. Patients receiving d4T develop AZT resistance mutations, and patients treated with AZT have suboptimal responses to subsequent therapy with d4T-containing regimens, particularly patients with isolates harboring AZT resistance mutations. We examined genotypic predictors of virologic suppression with d4T monotherapy in patients previously treated with AZT and compared the effect of different mutations on the response to d4T.

Methods:Dideoxy sequencing was performed on baseline HIV isolates obtained from 31 patients in ACTG 302 who had >3 yrs of prior AZT monotherapy and who were randomized to receive d4T monotherapy. Baseline and follow-up (8 wks) plasma HIV-1 RNA levels were measured (log copies/ml), and patients who had a decrease >0.3 logs were classified as responders. Univariate and multivariate analyses were performed to identify baseline genotypic and clinical variables that were predictive of responding to d4T.

Results:Among 31 subjects, 8 (27%) responded (mean: -0.71 log HIV RNA/ml, range: -0.50 to -0.95) and 23 (73%) did not (mean: 0.13, range: -0.3 to 1.3). Responders had lower baseline log RNA levels (4.12 vs. 4.64, p = 0.01) and fewer AZT mutations (1.0, range: 1-1, vs 1.8, range: 0-5; p = 0.007), and both were independently predictive of a response. An isolated K70R mutation was associated with a response (7/8 resp. vs 3/23 nonresp., p = 0.0002). The nonresponders had either no AZT mutations (5 pts) or one of the following patterns: a mutation at codon 215+other mutations (11 pts), mutations at codons 67 + 70 + 219 (4 pts), or a mutation at codon 70 (3 pts). Aside from the 6 major AZT mutations, K83R (4/8 resp vs. 2/23 nonresp, p = 0.043) and V90I (3/8 vs. 1/23, p = 0.043) were associated with a favorable response.

Conclusions:This study suggests that the AZT resistance mutation K70R, which confers low-level phenotypic AZT resistance and which is often the first mutation to develop in patients receiving AZT, may not confer clinical cross-resistance to d4T. In contrast, each of the other AZT-resistant genotypic patterns appeared to limit the antiviral activity of d4T monotherapy.