43. Effect of Baseline Nucleoside-Associated Resistance on Response to Tenofovir DF (TDF) Therapy: Integrated Analyses of Studies 902 and 907

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Session 13 Oral Abstract Session
Antiretroviral Chemotherapy: Combination Therapy, Drug Resistance, and Treatment Interruption
Session Time: Tuesday, 10 am - 12:30 pm
Room 4B

10:30 43.

Effect of Baseline Nucleoside-Associated Resistance on Response to Tenofovir DF (TDF) Therapy: Integrated Analyses of Studies 902 and 907
M. D. Miller*, N. A. Margot, and B. Lu
Gilead Sci., Foster City, CA

Background: Studies 902 and 907 were placebo-controlled, double-blind studies evaluating TDF when added to stable regimens in treatment-exp. Patients. 94% of patients had NRTI-resistance mutations at baseline (BL). TDF 300 mg therapy resulted in statistically significant mean HIV RNA reductions from BL to week 24 (DAVG24) of -0.6 log₁₀ that were durable through week 48. In virology substudies, patients with thymidine analog mutations (TAMs, mutations at RT 41, 67, 70, 210, 215, or 219), the M184V mutation, or their combination, also showed statistically significant HIV RNA responses to TDF.
Methods: BL plasma HIV genotypes (n=332) and phenotypes (n=138, Antivirogram) from patients randomized to placebo (PLB) or TDF 300 mg were analyzed for the effect of specific TAM patterns and baseline TDF susceptibility on response to TDF.
Results: Statistically significant HIV RNA reductions relative to PLB (p<0.005) were observed for patients without TAMs (n=97) or with 1-2 (n=88), 3 (n=88), or >4 TAMs (n=59). Though significant relative to PLB (p<0.025), responses were diminished in patients with >3 TAMs inclusive of either the M41L or L210W mutation (mean -0.21 log₁₀ DAVG24, n=86) or the L210W mutation in any context (mean -0.17 log₁₀DAVG24, n=68). Mutations at positions 67, 70, or 219 did not affect response to TDF. BL phenotypes from 138 patients showed a mean reduced susceptibility of 1.8-fold from wild-type for TDF (range 0.1-8.1) and 10-fold for ZDV (0.3-150). In multivariate regression analyses, HIV RNA response to TDF correlated significantly with BL susceptibility to TDF (p<0.01). Response to TDF therapy ranged from -0.72 to -0.46 log₁₀ for patients with <1, 1-2, 2-3 and 3-4-fold changes in BL TDF susceptibility. Patients with >4-fold reductions in TDF susceptibility at BL (n=13, 9%) showed diminished responses to TDF therapy (-0.12 log₁₀DAVG24). Recursive partitioning analysis confirmed a break-point of 4-fold for response to TDF therapy. Genotypic analysis of HIV with >4-fold reduced susceptibility to TDF revealed a K65R mutation (n=1), a T69S double insertion (n=1) or multiple TAMs (mean 3.8, including M41L and L210W in 10/11).
Conclusions: Adding tenofovir DF once-daily to an existing regimen showed significant and durable HIV RNA reductions in patients with M184V and/or multiple TAMs. Reduced responses to TDF treatment were associated with some specific multiple TAM patterns or >4-fold reduced susceptibility to TDF at baseline.

Š2002 9^th Conference on Retroviruses and Opportunistic Infections