Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection

Agarwal, Kosh; Fung, Scott; Nguyen, Tuan; Cheng, Wendy; Sicard, Étienne; Ryder, Stephen; Flaherty, John F.; Lawson, Eileen B.; Zhao, Sally; Subramanian, G. Mani; McHutchison, John G.; Gane, Edward; Foster, Graham R.

doi:10.1016/j.jhep.2014.10.035

Cited by 169 publications

(169 citation statements)

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“…The long intracellular halflife observed in liver cells in vitro and in vivo in this study support once-daily administration. Consistent with the results from these nonclinical studies, TAF showed anti-HBV activity consistent with 300 mg of TDF in a dose-ranging 28-day study even in the low-dose group at doses of Յ25 mg (16). In summary, we describe the metabolism in primary human hepatocytes, effects on hepatic uptake transporters, and plasma and liver pharmacokinetics of TAF in dogs.…”

Section: Figsupporting

confidence: 86%

“…Consistent with the reduction in off-target TFV exposures with TAF, TAF has demonstrated improvement relative to TDF in clinical studies of bone mineral density at the spine and hip, as measured by dual-energy X-ray absorptiometry and in multiple renal function parameters, including estimated glomerular filtration, fractional excretion of phosphate, proteinuria, and glycosuria (17). TAF is in phase 3 clinical studies for HBV, and in the phase 1b HBV study, similar viral declines and reduced TFV exposures of Ͼ90% were observed with doses of Յ25 mg of TAF relative to 300 mg of TDF (16).…”

mentioning

confidence: 90%

“…The administration of 25 mg of TAF in HIV-infected patients resulted in significantly lower plasma TFV levels (ϳ90%) and higher TFV-DP levels in peripheral blood mononuclear cells (PBMCs) (Ͼ5-fold) than in those patients administered 300 mg of TDF (14)(15)(16). Consistent with the reduction in off-target TFV exposures with TAF, TAF has demonstrated improvement relative to TDF in clinical studies of bone mineral density at the spine and hip, as measured by dual-energy X-ray absorptiometry and in multiple renal function parameters, including estimated glomerular filtration, fractional excretion of phosphate, proteinuria, and glycosuria (17).…”

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confidence: 99%

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Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Murakami

Wang

Park

et al. 2015

Antimicrob Agents Chemother

148

133

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Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment for HIV and hepatitis B virus (HBV) infections. Since the target tissue for HBV is the liver, the hepatic delivery and metabolism of TAF in primary human hepatocytes in vitro and in dogs in vivo were evaluated here. Incubation of primary human hepatocytes with TAF resulted in high levels of the pharmacologically active metabolite tenofovir diphosphate (TFV-DP), which persisted in the cell with a halflife of >24 h. In addition to passive permeability, studies of transfected cell lines suggest that the hepatic uptake of TAF is also facilitated by the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). In order to inhibit HBV reverse transcriptase, TAF must be converted to the pharmacologically active form, TFV-DP. While cathepsin A is known to be the major enzyme hydrolyzing TAF in cells targeted by HIV, including lymphocytes and macrophages, TAF was primarily hydrolyzed by carboxylesterase 1 (CES1) in primary human hepatocytes, with cathepsin A making a small contribution. Following oral administration of TAF to dogs for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in plasma was accompanied by a rapid decline in circulating TAF. Consistent with the in vitro data, high and persistent levels of TFV-DP were observed in dog livers. Notably, higher liver TFV-DP levels were observed after administration of TAF than those given TDF. These results support the clinical testing of once-daily low-dose TAF for the treatment of HBV infection. Chronic hepatitis B (CHB) is a major global health problem, and the World Health Organization (WHO) estimates that ϳ240 million people worldwide are chronically infected by hepatitis B virus (HBV) (1) (http://www.who.int/mediacentre /factsheets/fs204/en/). The small-molecule anti-HBV agents currently approved by U.S. Food and Drug Administration (FDA) are all nucleoside/nucleotide analogs targeting HBV reverse transcriptase. Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is a current first-line treatment for CHB (2) and has demonstrated efficacy in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients (3-5). TDF is also widely used as the backbone of current anti-HIV combination regimens (6, 7). For both HIV and HBV, the mechanism of action of TDF is intracellular metabolism to its pharmacologically active form, tenofovir diphosphate (TFV-DP), followed by competition with endogenous 2=-dATP for incorporation by the viral reverse transcriptase and subsequent chain termination of viral DNA replication (8, 9). TFV-DP is an effective inhibitor of HBV reverse transcriptase, with an inhibitor constant (K i ) of 0.18 M in vitro (9).A new prodrug of tenofovir, tenofovir alafenamide (TAF or GS-7340), was selected to more efficiently load HIV target cells while lowering circulating levels of TFV, resulting in reduced offtarget exposure (10-13). The administration of 25 mg of TAF in HIV-i...

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Section: Figsupporting

confidence: 86%

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confidence: 90%

mentioning

confidence: 99%

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Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Murakami

Wang

Park

et al. 2015

Antimicrob Agents Chemother

148

133

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“…These results sup- The antiviral specificity of TAF is also identical to those of TFV/TDF, with potent activity observed only with HIV and SIV isolates. Another study has recently demonstrated potent TAF activity against HBV (28). Modest antiviral activity was observed with TAF against both HSV-2 isolates.…”

Section: Discussionmentioning

confidence: 96%

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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“…Telaprevir on its own did not change TAF metabolism in these cells; however, a combination of both BNPP and telaprevir further decreased TAF metabolism. Therefore, Ces1 is an important contributor to the enhanced anti-HBV efficacy of TAF compared to the standard 300-mg TDF dose, as seen in a recent 28-day dose-ranging study (36).…”

Section: Discussionmentioning

confidence: 99%

Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Birkuš

Bam

Willkom

et al. 2016

Antimicrob Agents Chemother

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Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection

Cited by 169 publications

References 25 publications

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

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

Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

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