Background: Transgender women (TGW) on feminizing hormone therapy (FHT) maintain estradiol (E2) concentrations 2-9 and 6-25 fold higher than cisgender women in the mid-follicular phase and cisgender men, respectively. E2 increases activity of 5´-nucleotidase enzymes, which can decrease the active metabolite tenofovir diphosphate (TFVdp) or increase its competing nucleotide (dATP), depending on cellular location. To assess intracellular pharmacology at HIV transmission sites, we measured TFVdp, emtricitabine triphosphate (FTCtp), and their competing nucleotides (dATP and dCTP, respectively) in rectal tissue (RT) of TGW vs postmenopausal cisgender women (CGW; a low E2 control group).
Methods: HIV-infected women on a Truvada® containing regimen with HIV< 50copies/ml and CrCl>60ml/min enrolled (N=4 TGW; N=4 CGW) between 01/2017 and 01/2018. Serum and RT biopsies were collected at a single visit. FHT included oral or injectable E2, medroxyprogesterone, and spironolactone. Serum E2 was measured with validated immunoassay (lower limits of quantification; LLOQ=20pg/ml). RT was homogenized and TFVdp/FTCtp and dATP/dCTP were measured by LC-MS/MS (LLOQ=0.1 and 0.05ng/ml, respectively). Values below limits of quantification (BLQ) were imputed at sample specific LLOQ (depending on biopsy size; 4/28 measures). All measures were BLQ for 1 TGW, and excluded from statistical analyses (Student''s t-test and Pearson correlation using SASv9.4). Median (range) summary data are reported.
Results: Age, BMI and CrCl were 42(34, 46) vs 57(55, 59)years; 30(24, 42) vs 36(27, 38)kg/m2; and 114(100, 192) vs 108(61, 138)ml/min for TGW vs CGW, respectively. E2 concentrations in TGW [252(73, 490)pg/ml] were consistent with peak E2 in a typical periovulatory phase. TFVdp:dATP was 7-fold lower in TGW vs CGW (p=0.006; Table 1). One TGW exhibited TFVdp:dATP below an EC90 target ratio of 0.29. FTCtp:dCTP did not differ between groups and was above an EC90 target ratio of 0.07 in all participants. A significant inverse association was observed for log10E2 and TFVdp:dATP (r= -0.77; p=0.04).
Conclusions: This is the first description of TFVdp/FTCtp rectal concentrations in TGW on FHT. TFVdp relative to dATP was significantly lower in TGW and decreased with increasing E2. A cisgender male comparator will also be studied to confirm these findings. These data confirm in vitro findings and suggest that feminizing E2 may impact PrEP efficacy.

AnalyteCGW (N=4)TGW (N=3)
TFVdp (fmol/g)185158 (76265, 223542)53674 (23240, 1170302)
FTCtp (fmol/g)17247 (5959, 23181)138293 (16303, 289495)
dATP (fmol/g)7532 (5331, 11301)547827 (6166, 656011)
dCTP (fmol/g)6099 (2890, 8058)80097 (5768, 251048)
TFVdp:dATP20 (14, 30)2.7 (0.08, 3.8)
FTCtp:dCTP2.8 (2.0, 2.9)2.3 (1.2, 2.9)
[Table 1. Median (Min, Max) Rectal Tissue Concentrations]

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