Mechanism of Action
: Nucleotide reverse transcriptase inhibitor. Tenofovir alafenamide is a phosphonoamidate prodrug of the nucleotide analog tenofovir (TFV). Tenofovir alafenamide was designed to circulate systemically as the prodrug and undergo conversion to tenofovir intracellularly, achieving higher active metabolite concentrations in peripheral blood mononuclear cells than tenofovir disoproxil fumarate (tenofovir DF; TDF) does.4,5
Inside cells, tenofovir alafenamide is initially hydrolyzed to a partially stable metabolite, from which the phenol group is spontaneously released, forming a cell-impermeable tenofovir-alanine (TFV-Ala) intermediate. TFV-Ala is converted to parent tenofovir, which undergoes subsequent phosphorylations to yield the active tenofovir diphosphate (TFV-DP) metabolite.6,7
TFV-DP inhibits the activity of HIV reverse transcriptase by competing with natural substrates and causing DNA chain termination after being incorporated into viral DNA.8
Tenofovir alafenamide has also demonstrated in vitro
activity against hepatitis B virus (HBV).9
: After oral administration of tenofovir alafenamide in fasted dogs, tenofovir half-life was approximately 23.2 hours.5
: CYP3A-mediated metabolism of tenofovir alafenamide is minor.10
: In vitro
experiments have shown that tenofovir alafenamide and tenofovir DF have similar activity against a panel of wild-type (wt) and NRTI-resistant isolates. Both tenofovir alafenamide and tenofovir DF select for the K65R mutation in vitro
In a dose-finding, 10-day monotherapy trial of tenofovir alafenamide at three different dose levels (8, 25, and 40 mg) in 38 HIV-infected subjects, no tenofovir DF resistance mutations were detected.12
Dosing in Clinical Trials
Phase Ib dose-finding monotherapy trial (treatment-naive and –experienced):
- Tenofovir alafenamide 8, 25, or 40 mg once daily compared with tenofovir DF 300 mg and with placebo.12,13
Phase II and III single-tablet FDC regimens administered orally and once daily with food (treatment-naive):
- Darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg versus darunavir plus cobicistat plus emtricitabine/tenofovir DF.3
- Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg versus elvitegraivr/cobicistat/emtricitabine/tenofovir DF.14
When cobicistat is co-administered with stand-alone tenofovir alafenamide or when it is administered as part of the single-tablet formulation elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, it has been shown to increase tenofovir alafenamide and resulting tenofovir exposures by approximately 2- to 3-fold. Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg FDC provides tenofovir alafenamide and tenofovir exposures that are comparable to those provided by the tenofovir alafenamide 25-mg single agent, and it provides approximately 90% lower tenofovir exposure than elvitegravir/cobicistat/emtricitabine/tenofovir DF.15
In a dose-finding, 10-day monotherapy study that compared tenofovir alafenamide (8, 25, and 40 mg) with tenofovir DF (300 mg), no clinically significant laboratory abnormalities or drug-related serious adverse events occurred. There were no reported study drug discontinuations.12
Twenty-four week results from a Phase II trial demonstrated a significant improvement in both renal and bone safety profiles of the single-tablet formulation elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide over the single-tablet formulation elvitegravir/cobicistat/emtricitabine/tenofovir DF. Other adverse events occurring in both groups included nausea, diarrhea, fatigue, headache, and upper respiratory infection.16
There were no clinically relevant drug interactions found between efavirenz and a co-formulated FDC of emtricitabine/tenofovir alafenamide in healthy subjects. Dose adjustments are not required when efavirenz is co-administered with emtricitabine/tenofovir alafenamide FDC or with tenofovir alafenamide as a stand-alone agent.10
Because of inhibition of cathepsin A (CatA)-mediated activation of tenofovir alafenamide in vitro
, tenofovir alafenamide co-administration with the covalent hepatitis C virus (HCV) protease inhibitors telaprevir and boceprevir may be contraindicated. However, in vitro
studies have shown that darunavir and other HIV and HCV protease inhibitors demonstrate no pharmacological antagonism with tenofovir alafenamide.4
1. United States National Library of Medicine. ChemIDplus Advanced
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development
. Gilead Sciences. A Phase 2, Randomized, Double-Blinded Study of the Safety and Efficacy of Darunavir/Cobicistat/Emtricitabine/GS-7340 Single Tablet Regimen Versus Cobicistat-boosted Darunavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate Fixed Dose Combination in HIV-1 Infected, Antiretroviral Treatment Naive Adults
. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 27, 2012. NLM Identifier: NCT01565850. Last accessed May 15, 2013.
. Birkus G, Bam RA, Frey CR, et al. Intracellular Activation Pathways for GS-7340 and the Effect of Antiviral Protease Inhibitors
. Poster presented at: 19th
Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Poster 577.
. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue
. Antimicrob Agents Chemother
. 2005 May;49(5):1898-906.
. Birkus G, Kutty N, He GX, et al. Activation of 9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate prodrugs by human proteases
. Mol Pharmacol
. 2008 Jul;74(1):92-100.
. Herman BD and Sluis-Cremer N. Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors
. In: Gallelli D, ed. Pharmacology
. InTech, DOI: 10.5772/32969; 2012: p 63-81.
. García-Lerma JG, Aung W, Cong ME, et al. Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors
. J Virol
. 2011 Jul;85(13):6610-7.
. Lee W, He G, Mulato A, et al. In vivo and in vitro characterization of GS 7340, an isopropylalaninyl phenyl ester prodrug of tenofovir: selective intracellular activation of GS 7340 leads to preferential distribution in lymphatic tissues
. Poster presented at: 9th
Conference on Retroviruses and Opportunistic Infections (CROI); February 24-28, 2002; Seattle, WA. Poster 384-T.
. Ramanathan S, Wang H, Custodio J, Hepner-Harris M, Cheng A, Kearney BP. Lack of clinically relevant drug interactions between GS-7340 and efavirenz
. Abstract presented at: 13th
International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract P_09.
. Callebaut C, Margot N, Miller M. Resistance and potency of GS-7340, a next-generation tenofovir prodrug
. Abstract presented at: International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies; June 5-9, 2012; Sitges, Spain. Abstract 46.
. Ruane P, DeJesus E, Berger D, et al. GS-7340 25 mg and 40 mg Demonstrate Superior Efficacy to Tenofovir 300 mg in a 10-day Monotherapy Study of HIV-1+ Patients
. Paper presented at: 19th
Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Paper 103.
. Ruane P, Dejesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide (TAF) as 10-day monotherapy in HIV-1-positive adults
. J Acquir Immune Defic Syndr
. 2013 Apr 17. [Epub ahead of print].
. Gilead Sciences. A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment-Naïve Adults
. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 20, 2013. NLM Identifier: NCT01797445. Last accessed May 15, 2013.
. Ramanathan S, Wei X, Custodio J, et al. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen
. Abstract presented at: 13th
International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract O_13.
. Zolopa A, Ortiz R, Sax P, et al. Comparative Study of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate, Each with Elvitegravir, Cobicistat, and Emtricitabine, for HIV Treatment
. Paper presented at: 20th
Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2013; Atlanta, GA. Paper 99LB.
Last Reviewed: May 23, 2013
Last Updated: May 23, 2013