TENOFOVIR DISOPROXIL FUMARATE (Page 6 of 10)
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, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV 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.
Activity against HIV
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, tenofovir was not antagonistic with HIV-1 NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine), NNRTIs ( efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). 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 5.5 μM).
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2 to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.
In Trial 903 of treatment-naïve subjects (tenofovir disoproxil fumarate + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) [See Clinical Studies (14.2)] , genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) of analyzed patient isolates in the tenofovir disoproxil fumarate arm and in 2/49 (4%) of analyzed patient isolates in the stavudine arm. Of the 8 subjects whose virus developed K65R in the tenofovir disoproxil fumarate arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the tenofovir disoproxil fumarate arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to tenofovir disoproxil fumarate were not identified in this trial.
In Trial 934 of treatment-naïve subjects (tenofovir disoproxil fumarate + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz) [See Clinical Studies (14.2)] , genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 of analyzed subject isolates in the tenofovir disoproxil fumarate + EMTRIVA group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Trial 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
In Trials 902 and 907 conducted in treatment-experienced subjects (tenofovir disoproxil fumarate + Standard Background Therapy (SBT) compared to Placebo + SBT) [See Clinical Studies (14.2))] , 14/304 (5%) of the tenofovir disoproxil fumarate-treated subjects 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 substitution in the HIV-1 reverse transcriptase gene.
The virologic response to tenofovir disoproxil fumarate therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Trials 902 and 907.In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of tenofovir disoproxil fumarate to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. Tenofovir disoproxil fumarate-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to tenofovir disoproxil fumarate therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to tenofovir disoproxil fumarate therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to tenofovir disoproxil fumarate. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to Tenofovir disoproxil fumarate was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Trials 902 and 907 Phenotypic Analyses
Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to tenofovir disoproxil fumarate and response to tenofovir disoproxil fumarate therapy. Table 17 summarizes the HIV-1 RNA response by baseline tenofovir disoproxil fumarate susceptibility.
Table 17 HIV-1 RNA Response at Week 24 by Baseline Tenofovir Disoproxil Fumarate Susceptibility (Intent- To-Treat) a
a Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).
b Fold change in susceptibility from wild-type.
c Average HIV-1 RNA change from baseline through Week 24 (DAVG 24 ) in log 10 copies/mL.
|Baseline Tenofovir Disoproxil Fumarate Susceptibility b||Change in HIV-1 RNA c (N)|
|>1 and 3||-0.56 (49)|
|>3 and 4||-0.3 (7)|
The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC 50 values for tenofovir ranged from 0.14 to 1.5 µM, with CC 50 (50% cytotoxicity concentration) values > 100 µM. In cell culture combination antiviral activity studies of tenofovir with HBV NrtIs entecavir, lamivudine, and telbivudine, and with the HIV-1 NRTI emtricitabine, no antagonistic activity was observed.
Cumulative tenofovir disoproxil fumarate genotypic resistance has been evaluated annually for up to 384 weeks in Trailss 0102, 0103, 0106 ,0108, and 0121 [see Clinical Studies (14.4)] with the paired HBV reverse transcriptase amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of tenofovir disoproxil fumarate monotherapy and remained viremic with HBV DNA ≥ 400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of tenofovir disoproxil fumarate monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Trials 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on tenofovir disoproxil fumarate monotherapy (15% versus 5%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 18); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to tenofovir disoproxil fumarate (genotypic and phenotypic analyses).
Table 18 Amino Acid Substitutions in Viremic Subjects across HBV Trials of Tenofovir Disoproxil Fumarate
a Nucleotide-naïve subjects from Trials 0102 (N=246) and 0103 (N=171) receiving up to 384 weeks of treatment with tenofovir disoproxil fumarate.
b HEPSERA-experienced subjects from Trials 0102/0103 (N=195) and 0106 (N=52) receiving up to 336 weeks of treatment with tenofovir disoproxil fumarate after switching to tenofovir disoproxil fumarate from HEPSERA. Trial 0106, a randomized, double blind, 168-week Phase 2 trail, has been completed.
c Lamivudine-resistant subjects from Trial 0121 (N=136) receiving up to 96 weeks of treatment with tenofovir disoproxil fumarate after switching to tenofovir disoproxil fumarate from lamivudine.
d Subjects with decompensated liver disease from Trial 0108 (N=39) receiving up to 48 weeks of treatment with tenofovir disoproxil fumarate.
e Denominator includes those subjects who were viremic at last time point on tenofovir disoproxil fumarate monotherapy and had evaluable paired genotypic data.
f Of the 18 subjects with treatment-emergent amino acid substitutions during Trials 0102 and 0103, 5 subjects had substitutions at conserved sites and 13 subjects had substitutions only at polymorphic sites, and 8 subjects had only transient substitutions that were not detected at the last time point on tenofovir disoproxil fumarate.
g Of the 11 HEPSERA-experienced subjects with treatment-emergent amino acid substitutions, 2 subjects had substitutions at conserved sites and 9 had substitutions only at polymorphic sites.
h Of the 6 lamivudine-resistant subjects with treatment-emergent substitutions during trial 0121, 3 subjects had substitutions at conserved sites and 3 had substitutions only at polymorphic sites.
|Compensated Liver Disease||Decompensated Liver Disease (N=39) d|
|Nucleotide-Naïve (N=417) a||HEPSERA-experienced (N=247) b||Lamivudine- Resistant (N=136) c|
|Viremic at Last Time Point on tenofovir disoproxil fumarate||38/417 (9%)||37/247 (15%)||9/136 (7%)||7/39 (18%)|
|Treatment-Emergent Amino Acid Substitutions e||18 f /32 (56%)||11 g /31 (35%)||6 h /8 (75%)||3/5 (60%)|
Cross-resistance has been observed between HBV NrtIs.
In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild type virus.
HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating tenofovir disoproxil fumarate therapy in Trials 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV NrtIs: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 384 weeks of tenofovir disoproxil fumarate treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir- and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA < 400 copies/mL [69 IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
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