Safety and Pharmacokinetics of a Tenofovir Alafenamide Fumarate-Emtricitabine based Oral Antiretroviral Regimen for Prevention of HIV Acquisition in Women: A Randomized Controlled Trial

Andrea R Thurman, Jill L Schwartz, Mackenzie L Cottrell, Vivian Brache, Beatrice A Chen, Leila Cochón, Susan Ju, Ian McGowan, James F Rooney, Scott McCallister, Gustavo F Doncel, Andrea R Thurman, Jill L Schwartz, Mackenzie L Cottrell, Vivian Brache, Beatrice A Chen, Leila Cochón, Susan Ju, Ian McGowan, James F Rooney, Scott McCallister, Gustavo F Doncel

Abstract

Background: Daily oral emtricitabine (FTC, F)/tenofovir disoproxil fumarate (TDF) combination is approved for HIV pre-exposure prophylaxis (PrEP) in men and women. Tenofovir alafenamide fumarate (TAF) is a newer, more potent prodrug of tenofovir (TFV), and in combination with FTC, has recently been approved for prevention of HIV through rectal transmission.

Methods: This Phase I, prospective, interventional, randomized study was conducted in three clinical sites: PROFAMILIA, Santo Domingo, Dominican Republic; University of Pittsburgh and Eastern Virginia Medical School. We assessed the multi-compartmental pharmacokinetics (primary outcome) and safety (secondary outcome) among HIV uninfected women randomized to F/TDF (200mg/300mg) or F/TAF (200mg/25mg; F/TAF25) (n=24) in a single dose phase (SDP) and F/TDF, F/TAF (200mg/10mg; F/TAF10), or F/TAF25 (n=75) in a multiple dose (14 daily doses) phase (MDP). We described PK parameters in plasma, peripheral blood mononuclear cells (PBMCs), and cervicovaginal (CV) and rectal fluids and tissues. ClinicalTrials.gov #NCT02904369, completed.

Findings: Recruitment for the study began on 5 October 2016. The first participant was enrolled on 6 October 2016 and the last participant completed the study 21 November 2017.

Plasma: TFV concentrations area under curve (AUC) were ~20 fold lower following F/TAF versus F/TDF. TFV-diphosphate (TFV-DP) AUC concentrations in PBMCs were 7-fold higher with F/TAF25 versus F/TDF. Median TFV-DP concentrations in vaginal tissue (4hours post last dose) were approximately 6-fold higher with F/TAF25 versus F/TDF. TFV and TFV-DP were lower with F/TAF versus F/TDF in rectal tissue. Concentrations of FTC and FTC-triphosphate (FTC-TP) were similar across matrices and treatment arms. Gastrointestinal adverse events (AEs) occurred more frequently in F/TDF users (44.0%) than in either F/TAF group (11.5 and 12.0%).

Interpretation: F/TAF was safe and well-tolerated. TFV-DP concentrations were higher in PBMCs and similar or higher (4h post dose) in female genital tract tissues for F/TAF versus F/TDF. High FTC and FTC-TP concentrations in all compartments support the potential of F/TAF as a new PrEP combination for women.

Conflict of interest statement

Dr Schwartz received funding from USAID to support this study. Dr. McCallister and Dr. Rooney are shareholders in Gilead Sciences. Dr. McCallister was a Gilead employee at the time of the study and Dr. Rooney is currently a Gilead Sciences employee. Dr. Chen reports grants from Medicines360, grants from Sebela, personal fees from Merck, outside the submitted work. Dr. McGowan reports grants from CONRAD, during the conduct of the study; other from Orion Biotechnology, outside the submitted work. All the other authors report no conflicts.

© 2021 The Author(s).

Figures

Figure 1
Figure 1
F/TAF = emtricitabine + tenofovir alafenamide; F/TDF = emtricitabine + tenofovir disoproxil fumarate; MDP = Multiple Dose Phase; SDP = Single dose Phase
Figure 2a
Figure 2a
Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Green circle = FTAF 10 (TAF); Green square = FTAF 25 (TAF); Green triangle = FTDF (TAF); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 2b: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Green circle = FTAF 10 (TAF); Green square = FTAF 25 (TAF); Green triangle = FTDF (TAF); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 2c: Red circle = FTAF 10 (TFV-DP); Red square = FTAF 25 (TFV-DP); Red triangle = FTDF (TFV-DP); Blue circle = FTAF 10 (FTC-TP); Blue square = FTAF 25 (FTC-TP); Blue triangle = FTDF (FTC-TP) Figure 2d: Red circle = FTAF 10 (TFV-DP); Red square = FTAF 25 (TFV-DP); Red triangle = FTDF (TFV-DP); Blue circle = FTAF 10 (FTC-TP); Blue square = FTAF 25 (FTC-TP); Blue triangle = FTDF (FTC-TP) Figure 2e: Black circle = FTAF 10 (dATP); Black square = FTAF 25 (dATP); Black triangle = FTDF (dATP); Purple circle = FTAF 10 (dCTP); Purple square = FTAF 25 (dCTP); Purple triangle = FTDF (dCTP) Figure 2f: Black circle = FTAF 10 (dATP); Black square = FTAF 25 (dATP); Black triangle = FTDF (dATP); Purple circle = FTAF 10 (dCTP); Purple square = FTAF 25 (dCTP); Purple triangle = FTDF (dCTP)
Figure 2a
Figure 2a
Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Green circle = FTAF 10 (TAF); Green square = FTAF 25 (TAF); Green triangle = FTDF (TAF); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 2b: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Green circle = FTAF 10 (TAF); Green square = FTAF 25 (TAF); Green triangle = FTDF (TAF); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 2c: Red circle = FTAF 10 (TFV-DP); Red square = FTAF 25 (TFV-DP); Red triangle = FTDF (TFV-DP); Blue circle = FTAF 10 (FTC-TP); Blue square = FTAF 25 (FTC-TP); Blue triangle = FTDF (FTC-TP) Figure 2d: Red circle = FTAF 10 (TFV-DP); Red square = FTAF 25 (TFV-DP); Red triangle = FTDF (TFV-DP); Blue circle = FTAF 10 (FTC-TP); Blue square = FTAF 25 (FTC-TP); Blue triangle = FTDF (FTC-TP) Figure 2e: Black circle = FTAF 10 (dATP); Black square = FTAF 25 (dATP); Black triangle = FTDF (dATP); Purple circle = FTAF 10 (dCTP); Purple square = FTAF 25 (dCTP); Purple triangle = FTDF (dCTP) Figure 2f: Black circle = FTAF 10 (dATP); Black square = FTAF 25 (dATP); Black triangle = FTDF (dATP); Purple circle = FTAF 10 (dCTP); Purple square = FTAF 25 (dCTP); Purple triangle = FTDF (dCTP)
Figure 3a
Figure 3a
F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 31 ng/g Figure 3b: F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 69,100 fmol/g Figure 3c: F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 31 ng/g Figure 3d: F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 63,400 fmol/g Figure 3e: TFV LLOQ = 43 ng/g (line); TFV-DP LLOQ = 96,714 fmol/g (line) Figure 3f: FTC LLOQ = 42 ng/g (line); FTCTP LLOQ = 85410 fmol/g (line)
Figure 3a
Figure 3a
F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 31 ng/g Figure 3b: F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 69,100 fmol/g Figure 3c: F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 31 ng/g Figure 3d: F/TAF10 = Black, F/TAF25 = Green, F/TDF = Red. Cervical (Dots) and Vaginal (Solid) Tissue displayed per time point. Ave. LLOQ = 63,400 fmol/g Figure 3e: TFV LLOQ = 43 ng/g (line); TFV-DP LLOQ = 96,714 fmol/g (line) Figure 3f: FTC LLOQ = 42 ng/g (line); FTCTP LLOQ = 85410 fmol/g (line)
Figure 4a
Figure 4a
Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4b: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4c: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4d: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4e: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4f: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC)
Figure 4a
Figure 4a
Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4b: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4c: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4d: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4e: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC) Figure 4f: Red circle = FTAF 10 (TFV); Red square = FTAF 25 (TFV); Red triangle = FTDF (TFV); Blue circle = FTAF 10 (FTC); Blue square = FTAF 25 (FTC); Blue triangle = FTDF (FTC)

References

    1. World Health Organization. WHO expands recommendation on oral pre-exposure prophylaxis of HIV infection (PrEP). 2015; (Accessed 1/11/2020) .
    1. United Nations. Global AIDS Update 2018. Miles to Go: Closing Gaps, Breaking Barriers, Righting Injustices. , 2018. (Accessed 1/11/2020).
    1. Baeten JM, Donnell D, Ndase P. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399–410.
    1. Thigpen MC, Kebaabetswe PM, Paxton LA. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423–434.
    1. Grant RM, Lama JR, Anderson PL. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–2599.
    1. van der Straten A, Stadler J, Luecke E. Perspectives on use of oral and vaginal antiretrovirals for HIV prevention: the VOICE-C qualitative study in Johannesburg, South Africa. J Int AIDS Soc. 2014;17(3 Suppl 2):19146.
    1. Marrazzo JM, Ramjee G, Richardson BA. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509–518.
    1. Van Damme L, Corneli A, Ahmed K. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411–422.
    1. USPHS. Preexposure prophylaxis for the prevention of HIV infection in the United States - 2017 Update. A clinical practice guideline. 2017.
    1. Cottrell ML, Yang KH, Prince HM. A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine. J Infect Dis. 2016;214(1):55–64.
    1. Aloy B, Tazi I, Bagnis CI. Is Tenofovir Alafenamide Safer than Tenofovir Disoproxil Fumarate for the Kidneys? AIDS Rev. 2016;18(4):184–192.
    1. DeJesus E, Haas B, Segal-Maurer S. Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment. AIDS Res Hum Retroviruses. 2018;34(4):337–342.
    1. Gallant JE, Daar ES, Raffi F. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. The lancet HIV. 2016;3(4):e158–e165.
    1. Wang H, Lu X, Yang X, Xu N. The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in antiretroviral regimens for HIV-1 therapy: Meta-analysis. Medicine (Baltimore) 2016;95(41):e5146.
    1. Mayer KH, Molina JM, Thompson MA. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020;396(10246):239–254.
    1. Ruane PJ, DeJesus E, Berger D. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449–455.
    1. Markowitz M, Zolopa A, Squires K. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother. 2014;69(5):1362–1369.
    1. Ray AS, Cihlar T, Robinson KL. Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother. 2006;50(10):3297–3304.
    1. Arribas JR, Thompson M, Sax PE. Brief Report: Randomized, Double-Blind Comparison of Tenofovir Alafenamide (TAF) vs Tenofovir Disoproxil Fumarate (TDF), Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144 Results. J Acquir Immune Defic Syndr. 2017;75(2):211–218.
    1. Hagins D, Orkin C, Daar ES. Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials. HIV Med. 2018;19(10):724–733.
    1. Raffi F, Orkin C, Clarke A. Brief Report: Long-Term (96-Week) Efficacy and Safety After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected, Virologically Suppressed Adults. J Acquir Immune Defic Syndr. 2017;75(2):226–231.
    1. De Clercq E. Tenofovir at the Crossroad of the Therapy and Prophylaxis of HIV and HBV Infections. Journal of Cellular Immunology. 2020;2(1):23–30.
    1. Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, Grant RM. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection. J Antimicrob Chemother. 2011;66(2):240–250.
    1. Vela JE, Miller MD, Rhodes GR, Ray AS. Effect of nucleoside and nucleotide reverse transcriptase inhibitors of HIV on endogenous nucleotide pools. Antivir Ther. 2008;13(6):789–797.
    1. Ray AS, Fordyce MW, Hitchcock MJ. Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res. 2016;125:63–70.
    1. Golla VM, Kurmi M, Shaik K, Singh S. Stability behaviour of antiretroviral drugs and their combinations. 4: Characterization of degradation products of tenofovir alafenamide fumarate and comparison of its degradation and stability behaviour with tenofovir disoproxil fumarate. J Pharm Biomed Anal. 2016;131:146–155.
    1. Cottrell ML, Garrett KL, Prince HMA. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother. 2017;72(6):1731–1740.
    1. Lee WA, He GX, Eisenberg E. 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.
    1. Patterson KB, Prince HA, Kraft E. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Sci Transl Med. 2011;3(112) 112re4.
    1. Anderson PL, Glidden DV, Liu A. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4(151):151ra25.
    1. Hendrix CW, Andrade A, Bumpus NN. Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066) AIDS Res Hum Retroviruses. 2016;32(1):32–43.
    1. Stieh DJ, Maric D, Kelley ZL. Vaginal challenge with an SIV-based dual reporter system reveals that infection can occur throughout the upper and lower female reproductive tract. PLoS Pathog. 2014;10(10)
    1. Fletcher CV, Podany AT, Thorkelson A. The Lymphoid Tissue Pharmacokinetics of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide in HIV-Infected Persons. Clin Pharmacol Ther. 2020
    1. Louissaint NA, Cao YJ, Skipper PL. Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue. AIDS Res Hum Retroviruses. 2013;29(11):1443–1450.
    1. Hendrix CW, Chen BA, Guddera V. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PloS one. 2013;8(1):e55013.
    1. Haase AT. Targeting early infection to prevent HIV-1 mucosal transmission. Nature. 2010;464(7286):217–223.
    1. Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med. 2011;62:127–139.
    1. Radzio J, Henning T, Jenkins L. Combination Emtricitabine and Tenofovir Disoproxil Fumarate Prevents Vaginal Simian/Human Immunodeficiency Virus Infection in Macaques Harboring Chlamydia trachomatis and Trichomonas vaginalis. J Infect Dis. 2016;213(10):1541–1545.
    1. Radzio J, Aung W, Holder A. Prevention of vaginal SHIV transmission in macaques by a coitally-dependent Truvada regimen. PLoS One. 2012;7(12):e50632.
    1. Massud I, Cong ME, Ruone S. Efficacy of oral tenofovir alafenamide/emtricitabine combination or single agent tenofovir alafenamide against vaginal SHIV infection in macaques. J Infect Dis. 2019
    1. Custodio JM, Fordyce M, Garner W. Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment. Antimicrob Agents Chemother. 2016;60(9):5135–5140.
    1. Liu J, Ghneim K, Sok D. Antibody-mediated protection against SHIV challenge includes systemic clearance of distal virus. Science. 2016;353(6303):1045–1049.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit