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

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

doi:10.1016/j.eclinm.2021.100893

Cited by 36 publications

(38 citation statements)

References 39 publications

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“…Among oral PrEP users, our PK data are consistent with previous studies of TDF/FTC given to women as a single dose 24,35 or daily for 14 days 28 or 5–6 weeks. 23,39 Oral intake of TDF/FTC resulted in high levels of plasma analytes, which have been associated with therapeutic and prophylactic activity.…”

Section: Discussionsupporting

confidence: 88%

“…36 In a previous study of 14 days of TDF/FTC dosing (CONRAD 137 study, ClinicalTrials.gov NCT02904369), we found CVF and tissue concentrations of TFV, FTC, TFV-DP, and FTC-TP similar to those measured in this study. 28 Of note, in the MTN 001 study, a cross-over, multicompartmental PK study, using 6 weeks of daily TDF/FTC and/or TFV vaginal gel, 81% of vaginal tissue samples had TFV-DP concentrations below the LLOQ 39 after 6 weeks of TDF/FTC use in 144 US and African women. This rate of below the LLOQ samples is similar to what we found in this study (75%) and in our previous PK study (63%).…”

Section: Discussionmentioning

confidence: 99%

“…We treated the tissues with concentrations of TFV and FTC, in the range observed in tissues in vivo, and infected them ex vivo with HIV-1 BaL . as previously described by our group 28 and others. 29,30 Aliquots of tissue culture media were obtained on days 4, 7, 11, 14, 18, and 21, and culture dishes were replenished with equal volumes of fresh media.…”

Section: Explant Tissues Obtained For P24 Antigen Production Subset S...mentioning

confidence: 99%

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Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration

Ouattara

Thurman

Jacot

et al. 2022

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective: To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR).Design: Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days.Methods: TFV and FTC concentrations were measured in plasma, CV fluid (CVF), and CV tissue. TFV-diphosphate and FTCtriphosphate were assessed in CV tissue. In vitro PD antiviral activities of TFV and FTC (using in vivo concentration ranges) were modeled in the CVF and by infecting CV tissue explants ex vivo with HIV-1 BaL .Results: Adverse events (AEs) were more common with oral TDF/ FTC use (P , 0.01). The median CVF TFV concentrations were 10 6 ng/mL after use of TFV IVR vs. 10 2 ng/mL for TDF/FTC. The median TFV and TFV-diphosphate concentrations in CV tissue were .100-fold higher among IVR users. The median CVF FTC concentrations were 10 3 ng/mL. FTC and FTC-triphosphate were detected in all CV tissues from TDF/FTC users. HIV inhibitory activity of CVF increased significantly with treatment in both cohorts (P , 0.01) but was higher in TFV IVR users (P , 0.01). In vitro inhibition of tissue infection with ex vivo administration of TFV and FTC was dose dependent, with maximal efficacy achieved with 10 mg/mL TFV, 1 mg/mL FTC, and 0.1 mg/mL of TFV and FTC combined.Conclusions: Both products were safe and increased mucosal HIV inhibitory activity. In addition to systemic protection, oral TDF/FTC displays a PK/PD profile compatible with CV mucosal antiviral activity. TFV IVR resulted in fewer AEs, lower TFV plasma concentrations, higher CVF and tissue TFV and TFV-DP concentrations, and greater anti-HIV activity in CVF.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Explant Tissues Obtained For P24 Antigen Production Subset S...mentioning

confidence: 99%

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Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration

Ouattara

Thurman

Jacot

et al. 2022

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…However, there were also some limitations, including the lack of mucosal or lymph node tissue concentration measurements, and therefore the inability to compare concentrations following F/TAF vs. F/TDF in these compartments. It is still unclear whether mucosal concentrations at the site of transmission are associated with greater PrEP efficacy, and past studies have found concentrations with TAF are similar to or less than that with TDF at these sites [25,26]. Thus, the relationship between these concentrations and PrEP efficacy should be evaluated further.…”

Section: Discussionmentioning

confidence: 99%

Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate

Yager

Brooks

Castillo‐Mancilla

et al. 2021

Aids

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Objective: Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven preexposure prophylaxis and pharmacologic forgiveness.Design: Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium and high adherence.Methods: HIV-negative adults were randomized to two 12-week DOT regimens of 33, 67 or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/ TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (C ss ) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF.Results: Thirty-five participants contributed to 33% (n ¼ 23), 67% (n ¼ 23) and 100% (n ¼ 23) of daily F/TAF regimens. Forty-four contributed to 33% (n ¼ 15), 67% (n ¼ 16) and 100% (n ¼ 32) of daily F/TDF regimens. PBMC TFV-DP C ss were 7.3 [95% confidence interval (95% CI): 6.4-8.2], 7.1 (5.9-8.2) and 6.7-(4.4-8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/10 6 cells, respectively. TFV-DP was 2.6 (2.1-3.1) fold higher with 33% F/ TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5-5.5) days for F/TAF and 2.1 (1.5-2.9) days for F/TDF. FTC-TP was similar in both studies (P ¼ 0.119).Conclusion: F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/ TAF in the PBMC compartment.

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“…TAF/FTC has only been approved for use in cisgender men and trans women due to concerns about reduced TAF tissue concentrations in natal vaginal tissue [ 20 , 21 ]. However, a phase 1 randomized study comparing TAF/FTC and TDF/FTC co-formulations in healthy volunteers found that median TFV concentrations in vaginal tissue were approximately 6-fold higher with TAF/FTC compared with TDF/FTC [ 22 ]. A clinical trial to evaluate the safety and efficacy of TAF/FTC in HIV prevention in cisgender women is currently planned [ 23 ].…”

Section: Clinical Vignettementioning

confidence: 99%

Navigating Human Immunodeficiency Virus and Primary Care Concerns Specific to the Transgender and Gender-Nonbinary Population

Lieber

Hamill

Pham

et al. 2022

Open Forum Infectious Diseases

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HIV prevention and treatment remain critically important to outpatient care among transgender and gender nonbinary individuals. Epidemiologically, trans men and trans women are significantly more likely to have HIV compared with all adults of reproductive age. Here, we provide an overview of unique primary care considerations affecting transgender and gender nonbinary individuals, including screening and treatment of HIV and other sexually transmitted infections (STIs) as well as cancer screening and fertility preservation options. We also seek to review current literature and clinical practice guidelines related to drug-drug interactions between antiretroviral therapy (ART) and gender affirming hormonal therapy (GAHT). In short, integrase strand transfer inhibitor (INSTI) based therapy is not expected to have significant drug-interactions with most GAHT and is preferred in most transgender individuals, including those on GAHT. Clinicians should also remain aware of current GAHT regimens and consider tailoring ART and GAHT to reduce cardiovascular and other risk factors.

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

Cited by 36 publications

References 39 publications

Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration

Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration

Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate

Navigating Human Immunodeficiency Virus and Primary Care Concerns Specific to the Transgender and Gender-Nonbinary Population

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