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

Abstract

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...

HIV-hepatitis B virus coinfection

“…Tenofovir alafenamide (TAF) is a prodrug of tenofovir that has activity against HIV-1, HIV-2 and HBV [174] with higher intracellular concentrations in PBMCs and hepatocytes relative to plasma compared with TDF, thereby allowing for lower dosing and reduced toxicity [174] . TAF has reduced adverse effects on renal function and bone mineral density seen while maintaining high rates of viral suppression in both HIV and HBV [138, 174] .…”

“…TAF has reduced adverse effects on renal function and bone mineral density seen while maintaining high rates of viral suppression in both HIV and HBV [138, 174] .…”

Pharmacokinetics of Tenofovir Alafenamide, Tenofovir, and Emtricitabine Following Administration of Coformulated Emtricitabine/Tenofovir Alafenamide in Healthy Japanese Subjects

“…In terms of the intracellular metabolic activation of TAF, TAF is metabolized to TFV by cathepsin A in peripheral blood mononuclear cells and macrophages, and TAF is also metabolized to TFV by carboxylesterase 1 in hepatocytes . After the intracellular conversion of TAF to TFV, TFV is then phosphorylated to TFV‐DP, which is the pharmacologically active metabolite of TAF …”

Effects of a Nutritional Protein‐Rich Drink on the Pharmacokinetics of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide, and Tenofovir Compared With a Standard Meal in Healthy Japanese Male Subjects

“…COBI is a more selective and potent mechanism-based cytochrome P450 3A (CYP3A) inhibitor than RTV, which enhances, or "boosts," the exposure of CYP3A substrates. 7,8 In vitro studies have shown that TAF is metabolized to TFV by cathepsin A in peripheral blood mononuclear cells and macrophages [9][10][11] and is also metabolized to TFV by carboxylesterase 1 in hepatocytes. As COBI has no antiretroviral activity, it can be used as a booster without concern that drug-resistant viruses may be selected, even in regimens that do not contain any protease inhibitors.…”