Transgender women on oral HIV pre-exposure prophylaxis have significantly lower tenofovir and emtricitabine concentrations when also taking oestrogen when compared to cisgender men

Eugenie Shieh, Mark A Marzinke, Edward J Fuchs, Allyson Hamlin, Rahul Bakshi, Wutyi Aung, Jennifer Breakey, Tonia Poteat, Todd Brown, Namandjé N Bumpus, Craig W Hendrix, Eugenie Shieh, Mark A Marzinke, Edward J Fuchs, Allyson Hamlin, Rahul Bakshi, Wutyi Aung, Jennifer Breakey, Tonia Poteat, Todd Brown, Namandjé N Bumpus, Craig W Hendrix

Abstract

Introduction: Oral HIV Pre-Exposure Prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective. Transgender women (TGW) have increased HIV risk, but have been underrepresented in trials. For TGW on oestrogens for gender-affirming hormone treatment (GAHT), TDF/FTC-oestrogen interactions may negatively affect HIV prevention or gender-affirming goals. Our aim was to evaluate any pharmacokinetic drug-drug interaction between GAHT and TDF/FTC.

Methods: We performed a pharmacokinetic study, in an urban outpatient setting in 2016 to 2018, of the effects of GAHT on TFV, FTC and the active forms TFV diphosphate (TFV-DP) and FTC triphosphate (FTC-TP) in eight TGW and eight cisgender men (CGM). At screening, participants were HIV negative. TGW were to maintain their GAHT regimens and have plasma oestradiol concentrations >100 pg/mL. Under direct observation, participants took oral TDF/FTC daily for seven days. At the last dose, blood was collected pre-dose, one, two, four, six, eight and twenty-four hours, and colon biopsies were collected at 24 hours to measure drug concentration. TGW versus CGM concentration comparisons used non-parametric tests. Blood and colon tissue were also obtained to assess kinase expression.

Results: Plasma TFV and FTC C24 (trough) concentrations in TGW were lower by 32% (p = 0.010) and 32% (p = 0.038) respectively, when compared to CGM. Plasma TFV and FTC 24-hr area under the concentration-time curve in TGW trended toward and was significantly lower by 27% (p = 0.065) and 24% (p = 0.028) respectively. Peak plasma TFV and FTC concentrations, as well as all other pharmacokinetic measures, were not statistically significant when comparing TGW to CGM. Oestradiol concentrations were not different comparing before and after TDF/FTC dosing. Plasma oestrogen concentration, renal function (estimated creatinine clearance and glomerular filtration rate), and TFV and FTC plasma concentrations (trough and area under the concentration-time curve) were all correlated.

Conclusions: GAHT modestly reduces both TFV and FTC plasma concentrations. In TGW taking GAHT, it is unknown if this reduction will impact the HIV protective efficacy of a daily PrEP regimen. However, the combination of an on demand (2 + 1 + 1) PrEP regimen and GAHT may result in concentrations too low for reliable prevention of HIV infection.

Trial registration: ClinicalTrials.gov NCT03060785.

Keywords: HIV pre-exposure prophylaxis; drug-drug interaction; emtricitabine; gender-affirming hormonal treatment; tenofovir; transgender women.

© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.

Figures

Figure 1
Figure 1
Concentration versus time plots for plasma tenofovir (TFV, a) and emtricitabine (FTC, b), and peripheral blood mononuclear cell (PBMC) TFV diphosphate (TFV‐DP, c) and FTC triphosphate (FTC‐TP, d) comparing transgender women (TGW; dashed lines, squares) and cisgender men (CGM; solid lines, circles). Data are medians with error bars indicating lower and upper quartiles. Time values are slightly offset to avoid overlap of data.
Figure 2
Figure 2
Kinase expression analysed via immunoblotting for tenofovir‐activating kinases in peripheral blood mononuclear cells (PBMC) and colon tissue. PBMC and colon tissue were lysed and immunoblotting was performed using 50 µg of total protein lysate as described under Methods. (a), Immunoblotting of PBMC lysate for pyruvate kinase muscle (PKM), pyruvate kinase liver and red blood cell (PKLR), adenylate kinase 2 (AK2) and glyceraldehyde 3‐phosphatase dehydrogenase (GAPDH). (b), Immunoblotting of colon tissue lysate for creatine kinase muscle (CKM), adenylate kinase 2 (AK2) and β‐actin. Participant identification numbers are indicated (1001, 1002, 1008, 1012, 1017 and 1020). CGM, cisgender male; TGW, transgender woman.

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