441   Baseline and Week 48 Final Phenotypic Analysis of HIV- 1 from Patients Adding Tenofovir Disoproxil Fumarate (TDF) Therapy to Background ART.

M. D. Miller*¹, N. A. Margot¹, R. Schooley², and I. McGowan¹.
¹Gilead Sci., Foster City, CA and²Univ. of Colorado Hlth. Sci. Ctr., Denver.

Background:Study 902 was a phase II, placebo-controlled, double-blinded study evaluating 3 doses of TDF when added to stable regimens in 189 treatment-experienced patients (pts) (mean 4.6 yrs prior ART, mean HIV RNA 3.7 log₁₀c/ml). 94% of pts had NRTI resistance mutations at baseline (BL). There was a statistically significant mean HIV RNA reduction of -0.58 log₁₀(DAVG24) with 300 mg TDF that was durable (-0.62 log₁₀) through week 48 (W48) and independent of BL genotype.

Methods:Plasma HIV from pts randomized to 300 mg TDF (n = 54) was analyzed at BL and W48 for susceptibility to tenofovir and other drugs with the Antivirogram.

Results:BL phenotypes from 53 pts revealed a mean reduced susceptibility of 1.9-fold over wild-type for tenofovir (range 0.4—5.8) and 13.8-fold for ZDV (0.3—150). Only 4 pts had >4-fold reduced susceptibility to tenofovir at BL. In regression analyses, HIV RNA response to 300 mg TDF correlated significantly with BL susceptibility to tenofovir (p = 0.007) and ZDV (p = 0.035), but not to other NRTIs. Pts with >10-fold resistance to ZDV at BL (n = 12) still showed a -0.43 log₁₀response to TDF. At W48, 29 pts had sufficient HIV RNA for phenotypic analyses. Compared to BL, 15 pts showed increased> susceptibility to tenofovir and 14 pts showed decreased susceptibility; 6 of these 14 showed >2.5-fold decreases (2.7—4.3), including 2 pts who developed K65R (also selected by tenofovir in vitro). Analysis of the other 2 pts who developed K65R also showed 3—4- fold reductions in tenofovir susceptibility. None of these 4 pts had evidence of viral load rebound associated with K65R. Phenotypic analyses of 11 pts at other TDF doses who developed NRTI-associated mutations each showed <2-fold change in tenofovir susceptibility.

Conclusions:Adding 300 mg tenofovir DF once daily to an existing regimen showed significant and durable HIV RNA reductions through W48 despite the high proportion of pts with pre-existing resistance mutations. Phenotypic analysis of baseline HIV showed susceptibility to tenofovir which significantly correlated with the magnitude of the response to TDF treatment. W48 phenotypic analyses showed infrequent and low-level (<4.3- fold) decreases in tenofovir susceptibility consistent with the observed durability of HIV RNA responses.