Cross-resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R mutation selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R mutation. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.

In Studies 902 and 907 conducted in treatment-experienced patients (VIREAD + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the VIREAD-treated patients with virologic failure through Week 96 had > 1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R mutation in the HIV-1 reverse transcriptase gene.

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment experienced patients participating in Studies 902 and 907.

In these clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), the abacavir/emtricitabine/lamivudine resistance-associated mutation (M184V), and others. In addition the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall study results.

Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated mutations were observed and appeared to depend on the number of specific mutations. VIREAD-treated patients whose HIV-1 expressed 3 or more zidovudine resistance-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo.

The presence of the D67N, K70R, T215Y/F, or K219Q/E/N mutation did not appear to affect responses to VIREAD therapy.

In the protocol defined analyses, virologic response to VIREAD was not reduced in patients with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V mutation. In the presence of zidovudine resistance-associated mutations, the M184V mutation did not affect the mean HIV-1 RNA responses to VIREAD treatment. HIV-1 RNA responses among these patients were durable through Week 48.

Studies 902 and 907 Phenotypic Analyses: The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment-experienced patients participating in two controlled trials. Phenotypic analysis of baseline HIV-1 from patients in these studies demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 1 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

Table 1: HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (Intent-To-Treat)¹

Pharmacokinetics

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