Microbiology

Mechanism of Action: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC₅₀ (50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC₅₀ values ranged from 0.5 μM to 2.2 μM) and strain specific activity against HIV-2 (EC₅₀ values ranged from 1.6 μM to 4.9 μM).

Resistance: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2–4 fold reduction in susceptibility to tenofovir.

In Study 903 of treatment-naïve patients (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from patients with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation occurred in 8/47 (17%) analyzed patient isolates on the VIREAD arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 patients whose virus developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other mutations resulting in resistance to VIREAD were not identified in this study.

In Study 934 of treatment-naïve patients (VIREAD + EMTRIVA® + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis performed on HIV isolates from all patients with > 400 copies/mL of HIV-1 RNA at Week 48 or early discontinuation showed development of efavirenz resistance-associated mutations occurred most frequently and was similar between the two treatment arms. The M184V mutation, associated with resistance to EMTRIVA and lamivudine, was observed in 2/12 (17%) analyzed patient isolates in the VIREAD + EMTRIVA group and in 7/22 (32%) analyzed patient isolates in the zidovudine/lamivudine group. Through 48 weeks of Study 934, no patients have developed a detectable K65R mutation in their HIV as analyzed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.

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