Drugs

Tenofovir Alafenamide

Other Names: GS-7340, TAF, TFV alafenamide, prodrug of tenofovir, tenofovir alafenamide fumarate Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C21 H29 N6 O5 P
Registry Number: 379270-37-8 (CAS) Chemical Name: isopropyl (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate Chemical Class: Purine Nucleotides Organization: Gilead Sciences, Inc. Phase of Development:

The emtricitabine/tenofovir alafenamide fixed-dose combination (FDC) (brand name: Descovy) is in Phase III development for HIV prevention.

Five FDCs containing tenofovir alafenamide are U.S. Food and Drug Administration (FDA)-approved for HIV treatment: 1) elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (brand name: Genvoya), 2) emtricitabine/rilpivirine/tenofovir alafenamide (brand name: Odefsey), 3) Descovy, 4) bictegravir/emtricitabine/tenofovir alafenamide (brand name: Biktarvy), and 5) darunavir/cobicistat/emtricitabine/tenofovir alafenamide (brand name: Symtuza). As a stand-alone agent, tenofovir alafenamide (brand name: Vemlidy) is FDA-approved for chronic HBV infection treatment.


Chemical Image:

(Click to enlarge)
tenofovir alafenamide

tenofovir alafenamide

Molecular Weight: 476.4711

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 ClinicalTrials.gov,3 and Full Prescribing Information for Genvoya, Odefsey, Descovy, Biktarvy, Symtuza, and Vemlidy4–9)

Pharmacology


Mechanism of Action: Nucleotide reverse transcriptase inhibitor. Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide analog tenofovir (TFV). TAF was designed to circulate systemically as the prodrug and undergo conversion to TFV intracellularly, achieving higher active metabolite concentrations in peripheral blood mononuclear cells and lower plasma TFV exposures than tenofovir disoproxil fumarate (tenofovir DF; TDF) does.10-12

TAF is predominantly metabolized intracellularly to TFV. This intracellular metabolism is primarily catalyzed by cathepsin A (CatA). Inside cells, TAF 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 TFV, which undergoes subsequent phosphorylations to yield the active tenofovir diphosphate (TFV-DP) metabolite.13-15 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.16

TAF has also demonstrated in vitro and in vivo activity against HBV.17,18

Half-life (T½): The median terminal half-life of TAF is 0.51 hours. The active metabolite, TFV-DP, has an intracellular half-life of 150 to 180 hours.4

Metabolism/Elimination: More than 80% of an oral dose of TAF is metabolized. In vitro, TAF is intracellularly metabolized to TFV by the CES1 enzyme (in hepatocytes) and by CatA (in PBMCs and macrophages). CYP3A-mediated metabolism of TAF is minor. Following single-dose administration of radiolabeled TAF, less than 1% of the dose is excreted in the urine and 31.7% of the dose is excreted in feces.4

Resistance: In vitro, HIV-1 isolates with reduced susceptibility to TAF have been selected, including virus with the K65R substitution (sometimes with S68N or L429I substitutions) and virus with the K70E substitution.4

The K65R and K70E TFV resistance substitutions can result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and TFV. HIV-1 containing multiple thymidine analog mutations (TAMs; M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) have shown resistance to TAF in cell culture. In addition, multi-nucleoside resistant virus with a T69S double insertion mutation or with a Q151M mutation complex including K65R has exhibited in vitro resistance to tenofovir alafenamide.4

Additional information on HIV resistance mutations associated with TAF may be described in the following FDA-approved full prescribing labels: Genvoya, Odefsey, DescovyBiktarvy, and Symtuza.4-8


Select Clinical Trials


Tenofovir alafenamide for HIV treatment

FDC tablets

Five FDC tablets containing TAF are FDA-approved for HIV treatment: Genvoya, Odefsey, Descovy, Biktarvy, and Symtuza.4–8

FDA has also granted tentative approval of a dolutegravir/emtricitabine/tenofovir alafenamide FDC tablet. This single-tablet regimen was approved under the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and is available in PEPFAR focus countries for the treatment of HIV.19

Stand-alone TAF

Stand-alone TAF is not FDA-approved for HIV but is approved for treating chronic HBV infection under the brand name Vemlidy.9

This stand-alone version of TAF is being used in a Phase II trial (NCT03472326) that is evaluating the investigational NRTI GS-9131 for HIV treatment in women who are failing their current ART regimen. Participants will first receive GS-9131 functional monotherapy and will later switch to one of two ART regimens: either 1) GS-9131, bictegravir, darunavir, and ritonavir, or 2) GS-9131, bictegravir, and stand-alone TAF.20

Tenofovir alafenamide for HIV prevention

Emtricitabine/Tenofovir Alafenamide (FTC/TAF; Descovy)

Study Identifiers: DISCOVER; GS-US-412-2055; NCT02842086
Sponsor: Gilead Sciences
Phase: Phase III
Status: This study is ongoing, but not recruiting participants.
Purpose: The purpose of this study is to evaluate the safety and efficacy of Descovy in preventing HIV infection in men and transgender women who have sex with men and who are at high risk of sexual acquisition of HIV.
Study Population:

  • Participants are HIV-negative men and transgender women who have sex with men.
  • Participants are at high risk of sexual acquisition of HIV infection.3
Selected Study Results:

Other notable HIV prevention studies involving TAF-containing products include:

  • NCT03762772: A Phase I trial evaluating the safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing both TAF and elvitegravir in women without HIV. This study is currently recruiting participants.21
  • NCT02985996: A Phase I trial evaluating the pharmacokinetics of Genvoya in different body compartments of men and transgender women who have sex with men, all of whom do not have HIV. This study is currently recruiting participants.22
  • NCT03499483: A Phase IV trial evaluating the use of Biktarvy for the prevention of HIV infection in adults without HIV after high-risk sexual contact (non-occupational post exposure prophylaxis). This study is not yet recruiting.23


Adverse Events


In the DISCOVER trial (NCT02842086), which is evaluating the noninferiority of Descovy compared to FTC/TDF (brand name: Truvada) for HIV pre-exposure prophylaxis (PrEP), 2,694 participants were randomized to Descovy and 2,693 participants were randomized to Truvada. The primary endpoint analysis was conducted when all participants had completed Week 48 of the study and half of the participants had completed Week 96 of the study. In the safety assessment, investigators found that the adverse event (AE) profile was comparable in both arms. Drug-related AEs occurred in 20% of participants receiving Descovy and 23% of participants receiving Truvada. Drug-related serious adverse events (SAEs) occurred in only 0.1% of Descovy participants and 0.2% of Truvada participants. In both groups, AEs resulting in study drug discontinuations were infrequent. The most common AEs were sexually transmitted infections or exposures, diarrhea, nasopharyngitis, and upper respiratory tract infections; occurrence rates were similar in both arms. Descovy was shown to have a significantly improved bone and renal safety profile over Truvada.24

Additional AEs associated with TAF may be described in the following full prescribing labels: Genvoya, Odefsey, Descovy, VemlidyBiktarvy, and Symtuza.4-9


Drug Interactions


At clinically relevant concentrations, TAF does not have inhibitory effects on the following transporters and enzymes: P-gp, BCRP (drug transporters); OAT1B1, OAT1B3, OCT1, BSEP (hepatic transporters); OAT1, OAT3, OCT2, MATE1 (renal transporters); or CYP, including CYP3A, and UGT1A1 (enzymes). TAF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that inhibit P-gp and BCRP may increase the absorption of TAF and result in increased plasma concentrations of TAF, while drugs that induce P-gp activity may decrease the absorption of TAF leading to decreased plasma concentrations of TAF.5,7

Specific drug-drug interactions associated with TAF may be described in the following full prescribing labels: Genvoya, Odefsey, Descovy, Vemlidy, Biktarvy, and Symtuza.4-9


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Tenofovir Alafenamide. https://chem.sis.nlm.nih.gov/chemidplus/rn/379270-37-8. Accessed March 22, 2019.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed March 22, 2019.
  3. Gilead Sciences. A Phase 3, randomized, double-blind study to evaluate the safety and efficacy of emtricitabine and tenofovir alafenamide (F/TAF) fixed-dose combination once daily for pre-exposure prophylaxis in men and transgender women who have sex with men and are at risk of HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 20, 2016. NLM Identifier: NCT02842086. https://www.clinicaltrials.gov/ct2/show/NCT02842086. Accessed March 22, 2019.
  4. Gilead Sciences, Inc. Genvoya: full prescribing information, February 11, 2019. DailyMed. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34784acf-15ed-4715-b504-eb30430518e9. Accessed March 22, 2019.
  5. Gilead Sciences, Inc. Odefsey: full prescribing information, October 1, 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3b9ec8-e04a-412c-8b3f-e5cbc7e641d5. Accessed March 22, 2019.
  6. Gilead Sciences, Inc. Descovy: full prescribing information, October 6, 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06f66e98-e6ee-4538-9506-6c1282cc14c1. Accessed March 22, 2019.
  7. Gilead Sciences, Inc. Biktarvy: full prescribing information, September 17, 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=664cb8f0-1f65-441b-b0d9-ba3d798be309. Accessed March 22, 2019.
  8. Janssen Products LP. Symtuza: full prescribing information, February 4, 2019. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=85a17d00-6b7c-41ea-a6b3-5ad924820dab. Accessed March 22, 2019.
  9. Gilead Sciences, Inc. Vemlidy: full prescribing information, February 11, 2019. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72e6b33c-0351-4070-9172-eeaa186c01d2. Accessed March 22, 2019.
  10. 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. http://www.retroconference.org/2012b/PDFs/577.pdf. Accessed May 22, 2013.
  11. Lee WA, He G-X, 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;49(5):1898-1906. doi:10.1128/AAC.49.5.1898-1906.2005
  12. Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr 1999. 2013;63(4):449-455. doi:10.1097/QAI.0b013e3182965d45
  13. 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;74(1):92-100.
  14. Herman BD and Sluis-Cremer N. Molecular pharmacology of nucleoside and nucleotide HIV-1 reverse transcriptase inhibitors. In: Gallelli L, ed. In: Pharmacology. InTech; 2012:63-81. doi:10.5772/32969
  15. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized Phase 2 study. J Acquir Immune Defic Syndr. 2014;67(1):52-58.
  16. García-Lerma JG, Aung W, Cong M, et al. Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol. 2011;85(13):6610-6617. doi:10.1128/JVI.00311-11
  17. Gilead. Press Release, dated November 10, 2016. U.S. Food and Drug Administration approves Gilead’s Vemlidy® (tenofovir alafenamide) for the treatment of chronic hepatitis B virus infection. https://www.gilead.com/news-and-press/press-room/press-releases/2016/11/us-food-and-drug-administration-approves-gileads-vemlidy-tenofovir-alafenamide-for-the-treatment-of-chronic-hepatitis-b-virus-infection. Accessed March 22, 2019.
  18. 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. https://web.archive.org/web/20070316030446/http://retroconference.org/2002/Posters/13864.pdf. Accessed March 22, 2019.
  19. Mylan: Press Release, dated February 20, 2018. Mylan receives tentative approval for combination HIV treatment DTG/FTC/TAF under FDA’s PEPFAR program. http://newsroom.mylan.com/2018-02-20-Mylan-Receives-Tentative-Approval-for-Combination-HIV-Treatment-DTG-FTC-TAF-Under-FDAs-PEPFAR-Program. Accessed March 22, 2019.
  20. Gilead Sciences. A Phase 2 study to evaluate the efficacy of GS-9131 functional monotherapy in HIV-1-infected adults failing a nucleos(t)Ide reverse transcriptase inhibitor-containing regimen with nucleos(t)Ide reverse transcriptase inhibitor resistant virus, followed by continued treatment with a GS-9131+bictegravir+darunavir+ritonavir regimen. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 8, 2018. NLM Identifier: NCT03472326. https://clinicaltrials.gov/ct2/show/NCT03472326. Accessed March 22, 2019.
  21. CONRAD. A Phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 16, 2018. NLM Identifier: NCT03762772. https://clinicaltrials.gov/ct2/show/NCT03762772. Accessed March 22, 2019.
  22. Emory University. Body compartment PK for new HIV pre-exposure prophylaxis modalities. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 5, 2016. NLM Identifier: NCT02985996. https://clinicaltrials.gov/ct2/show/NCT02985996. Accessed March 22, 2019.
  23. Fenway Community Health. A Phase IV open-label evaluation of safety, tolerability, and acceptability of a fixed-dose formulation of bictegravir, emtricitabine/tenofovir alafenamide (B/F/TAF) for non-occupational prophylaxis following potential exposure to HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 9, 2018. NLM Identifier: NCT03499483. https://clinicaltrials.gov/ct2/show/NCT03499483. Accessed March 22, 2019.
  24. Hare CB. The Phase 3 DISCOVER study: daily F/TAF or F/TDF for HIV preexposure prophylaxis. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2019; Seattle, WA. http://www.croiwebcasts.org/console/player/41210?mediaType=slideVideo&&crd_fl=1&ssmsrq=1553222202879&ctms=5000&csmsrq=856. Accessed March 22, 2019.


Last Reviewed: March 22, 2019