Antiviral Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir Alafenamide as 10-Day Monotherapy in HIV-1–Positive Adults

Ruane, Peter; DeJesus, Edwin; Berger, Daniel; Markowitz, Martin; Bredeek, U. Fritz; Callebaut, Christian; Zhong, Lijie; Ramanathan, Srini; Rhee, Martin S; Fordyce, Marshall W.; Yale, Kitty

doi:10.1097/qai.0b013e3182965d45

Cited by 279 publications

(293 citation statements)

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“…In clinical studies, TAF has demonstrated favorable pharmacological properties, with higher intracellular levels of TFV-DP and lower circulating levels of TFV than of TDF. The higher TFV-DP levels in peripheral blood mononuclear cells (PBMCs) have resulted in improved antiviral activity at lower doses than TDF in monotherapy studies (11,12). The efficacy of low doses of TAF has been confirmed in phase 2 clinical trials in combination with elvitegravir (EVG, or E), cobicistat (COBI, or C), and emtricitabine (FTC, or F).…”

Section: T Enofovir [(R)-9-(2-phosphonomethoxypropyl)adenine] (Tfv)mentioning

confidence: 87%

In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate

Callebaut

Stepan

Yang

et al. 2015

Antimicrob Agents Chemother

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bTenofovir alafenamide (TAF) is an investigational oral prodrug of the HIV-1 nucleotide reverse transcriptase inhibitor tenofovir (TFV). Tenofovir disoproxil fumarate (TDF) is another TFV prodrug, widely used for the treatment of HIV-1 infection. TAF is converted mostly intracellularly to TFV and, in comparison to TDF, achieves higher tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells. As a result, TAF has demonstrated potent anti-HIV-1 activity at lower doses than TDF in monotherapy studies. Here, the in vitro virology profile of TAF was evaluated and compared to that of TDF. TAF displayed potent antiviral activity against all HIV-1 groups/subtypes, as well as HIV-2. TAF exhibited minimal changes in the drug concentration needed to inhibit 50% of viral spread (EC 50 ) upon removal of the prodrug, similar to TDF, demonstrating intracellular antiviral persistence. While TAF and TDF exhibited comparable potencies in the absence of serum pretreatment, TAF maintained activity in the presence of human serum, whereas TDF activity was significantly reduced. This result demonstrates TAF's improved plasma stability over TDF, which is driven by the different metabolic pathways of the two prodrugs and is key to TAF's improved in vivo antiviral activity. The activity of TAF is specific for HIV, as TAF lacked activity against a large panel of human viruses, with the exception of herpes simplex virus 2, where weak TAF antiviral activity was observed, as previously observed with TFV. Finally, in vitro combination studies with antiretroviral drugs from different classes showed additive to synergistic interactions with TAF, consistent with ongoing clinical studies with TAF in fixed-dose combinations with multiple other antiretroviral drugs for the treatment of HIV.is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase (RT) inhibitor (NtRTI), also frequently referred to as member of the nucleoside RT inhibitor (NRTI) class (1). TFV contains a phosphonate group that is equivalent to the first phosphate group present in natural monophosphate nucleotides (2). In comparison to the natural phosphoric group, the TFV phosphonate moiety has the COO bond switched, which is not recognized by host enzymes and thus makes it less prone to phosphatase activities. Consequently, TFV activation requires only two phosphorylation steps (3). Tenofovir is intracellularly phosphorylated to the active metabolite tenofovir diphosphate (TFV-DP), which is incorporated into viral DNA by HIV RT and acts as a DNA chain terminator (4). However, the negative charges harbored by TFV from its phosphonate moiety reduce its cellular permeability, limiting its absorption and oral bioavailability. Tenofovir disoproxil fumarate (TDF) (Fig. 1) is a prodrug of TFV widely used for the treatment of HIV-1 infection and is the preferred NtRTI for use in combination with other antiretroviral agents for the treatment of HIV-1 infection (5-7). TDF was developed to improve TFV permeability and to allow systemic delivery of TFV via ora...

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Section: T Enofovir [(R)-9-(2-phosphonomethoxypropyl)adenine] (Tfv)mentioning

confidence: 87%

In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate

Callebaut

Stepan

Yang

et al. 2015

Antimicrob Agents Chemother

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“…As expected, the results reported in this paper indicate that TAF is active against PI-R, NNRTI-R, and INSTI-R single-classresistant primary HIV-1 isolates in PBMCs. The two isolates with NRTI-R amino acid substitutions showed only moderately reduced susceptibility to TAF (2.1-and 5.4-fold above that of the wild type) that could possibly be overcome in vivo as a result of the increased TFV-DP level observed in PBMCs upon TAF dosing (2,3). Hypersusceptibility to TAF and/or AZT (2.5-to 10-fold) was noted in INSTI-R and PI-R single-class-resistant mutants in this small data set of HIV-1 primary isolates.…”

Section: Discussionmentioning

confidence: 99%

“…TAF has shown improved safety and pharmacologic profiles, as well as a more potent antiviral effect, compared to the current prodrug of tenofovir (TDF) in early clinical studies (2,3). Treatment of HIVinfected subjects with the 25-mg therapeutic dose of TAF is associated with a 5-fold increase in the quantity of the active moiety, TFV-diphosphate, that is delivered to target cells in vivo compared to treatment with 300 mg TDF.…”

Section: Discussionmentioning

confidence: 99%

“…Both TAF and TDF prodrugs ultimately led to the delivery of TFV to the target cells; however, TAF showed greater distribution to lymphoid tissues than TDF in nonclinical studies (4). In a phase 1 clinical study, monotherapy with 25 mg TAF achieved a median 1.46-log 10 -unit decrease in plasma HIV-1 RNA at day 10 compared to 0.97 log 10 unit for 300 mg TDF while reducing the systemic exposure of TFV by about 86% and increasing the concentration of the active moiety, tenofovir diphosphate (TFV-DP), in peripheral blood mononuclear cells (PBMCs) by 5-to 7-fold (2). The 25-mg dose of TAF achieves higher intracellular TFV-DP concentrations than 300 mg TDF due to the greater plasma stability of TAF than of TDF and the subsequent intracellular conversion of TAF to TFV.…”

mentioning

confidence: 99%

“…The current prodrug of tenofovir is tenofovir disoproxil fumarate (TDF) (1). TAF has shown improved pharmacokinetic properties and more potent HIV-1 suppression than TDF in phase 1 and phase 2 clinical trials (2,3) and is currently being studied in clinical trials for the treatment of HIV-1 infection in patients Ն12 years old, in combination with other antiretroviral agents. Both TAF and TDF prodrugs ultimately led to the delivery of TFV to the target cells; however, TAF showed greater distribution to lymphoid tissues than TDF in nonclinical studies (4).…”

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Characterization of HIV-1 Resistance to Tenofovir AlafenamideIn Vitro

Margot

Johnson

Miller

et al. 2015

Antimicrob Agents Chemother

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Tenofovir alafenamide (TAF) is an investigational prodrug of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor (NtRTI) tenofovir (TFV), with improved potency and drug delivery properties over the current prodrug, tenofovir disoproxil fumarate (TDF). TAF is currently in phase 3 clinical studies for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Phase 1 and 2 studies have shown that TAF was associated with increased peripheral blood mononuclear cell (PBMC) drug loading and increased suppression of HIV-1 replication compared to treatment with TDF. In this study, selection of in vitro resistance to both TAF and the parent compound, TFV, led to the emergence of HIV-1 with the K65R amino acid substitution in RT with 6.5-fold-reduced susceptibility to TAF. Although TAF is more potent than TFV in vitro, the antiviral susceptibilities to TAF and TFV of a large panel of nucleoside/nucleotide RT inhibitor (NRTI)-resistant mutants were highly correlated (R 2 ‫؍‬ 0.97), indicating that the two compounds have virtually the same resistance profile when assessed as fold change from the wild type. TAF showed full antiviral activity in PBMCs against primary HIV-1 isolates with protease inhibitor, nonnucleoside RT inhibitor (NNRTI), or integrase strand transfer inhibitor resistance but reduced activity against isolates with extensive NRTI resistance amino acid substitutions. However, the increased cell loading of TFV with TAF versus TDF observed in vivo suggests that TAF may retain activity against TDF-resistant mutant viruses.

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Structure, Synthesis and Inhibition Mechanism of Nucleoside Analogues as HIV‐1 Reverse Transcriptase Inhibitors (NRTIs)

et al. 2021

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Acquired immunodeficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). Although treatments against HIV infection are available, AIDS remains a serious disease that causes many deaths annually. Although a variety of anti‐HIV drugs have been synthesized and marketed to treat HIV‐infected patients, nucleoside analogue reverse transcriptase inhibitors (NRTIs), which mimic nucleosides, are used extensively and remain a subject of interest to medicinal chemists. However, HIV has acquired drug resistance against NRTIs, and thus the struggle to find novel therapies continues. In this review, we trace the trajectory of NRTIs, focusing on the synthesis, mechanisms of action and applications of NRTIs that have been developed.

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Antiviral Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir Alafenamide as 10-Day Monotherapy in HIV-1–Positive Adults

Cited by 279 publications

References 10 publications

In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate

In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate

Characterization of HIV-1 Resistance to Tenofovir AlafenamideIn Vitro

Structure, Synthesis and Inhibition Mechanism of Nucleoside Analogues as HIV‐1 Reverse Transcriptase Inhibitors (NRTIs)

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