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HIV-1 RT Mutations in Patients After 24 Weeks of Tenofovir Disoproxil Fumarate (formerly PMPA Prodrug) Therapy Added to Stable Background ART M. D. MILLER*, N. A. MARGOT, M. ROBISON, R. SCHOOLEY, R. MILLS, and I. MCGOWAN.
Gilead Sci., Foster City, CA Background: Study GS-98-902 is a phase II, placebo-controlled, double-blinded study evaluating 3 doses of tenofovir disoproxil fumarate (DF) when added to stable background ART. 189 treatment-experienced patients were enrolled with a mean baseline HIV RNA of 3.7 log10 copies/ml and CD4 of 369 cells/mm3. Grouped HIV RNA results at week 24 showed statistically significant mean HIV RNA log10 reductions of -0.75, -0.40 and -0.45 for patients in the 300 mg, 150 mg and 75 mg dose groups, respectively.
Methods: HIV RT and protease genotypic analyses were performed at baseline, early termination and at week 24 from plasma HIV utilizing Visible Genetics technology.
Results: Baseline genotypic results were obtained from 187 of 189 patients. Consistent with their extensive treatment experience, 74% of patients had HIV with AZT resistance mutations at baseline (RT codons 41, 67, 70, 210, 215 and 219), 66% had the lamivudine-associated M184V mutation, 48% had both AZT and M184V mutations, 59% had primary PI resistance and 34% had primary NNRTI resistance mutations. Genotypic data is available for 121 of 189 patients (64%) at week 24. Of these 121 patients, 42 patients (35%) developed additional NRTI-associated mutations, 35 of whom developed typical AZT/thymidine analog-associated RT mutations while taking AZT (n=13), d4T (n=20) or abacavir (n=2). Four patients developed L74V, all of whom were taking ddI or abacavir concomitantly. Three patients developed K65R, an RT mutation which is associated with ddI and abacavir in vivo, but has also been selected by tenofovir in vitro. Although these 3 patients may have been on active tenofovir DF therapy (blinded analysis), all three patients were also taking ddI or abacavir. However, none of these three patients showed evidence of viral load rebound at week 24. Finally, in this analysis of 121 patients, there was no evidence for the development of novel RT mutations associated with tenofovir DF therapy.
Conclusions: Patients adding tenofovir DF to their existing stable ART regimen showed significant HIV RNA reductions at week 24. RT mutations that developed appeared to be due to the patient’s background ART and were not associated with loss of HIV RNA suppression.
Key Words: PMPA, resistance, tenofovir
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