Drug-drug interactions between feminizing hormone therapy and pre-exposure prophylaxis among transgender women: the iFACT study

Abstract

Introduction: Concerns over potential drug-drug interactions (DDI) between feminizing hormone therapy (FHT) and pre-exposure prophylaxis (PrEP) have hampered uptake and adherence of PrEP among transgender women (TGW). To determine DDI between FHT and PrEP, we measured the pharmacokinetic (PK) parameters of blood plasma estradiol (E2) and tenofovir (TFV) in Thai TGW.

Methods: Twenty TGW who never underwent orchiectomy and had not received injectable FHT within six months were enrolled between January and March 2018. FHT (E2 valerate and cyproterone acetate) were prescribed to participants at baseline until week 5, and then from week 8 until the end of study. Daily PrEP (tenofovir disoproxil fumarate/emtricitabine) was initiated at week 3 and continued without interruption. Intensive E2 PK parameters and testosterone concentration at 24 hours (C₂₄ ) were measured at weeks 3 (without PrEP) and 5 (with PrEP), and intensive TFV PK parameters were measured at weeks 5 (with FHT) and 8 (without FHT).

Results: Median (interquartile range) age, body mass index, and creatinine clearance were 21.5 (21-26) years, 20.6 (19.0-22.4) kg/m² , and 116 (101-126.5) mL/min, respectively. The geometric mean (%CV) of area under curve from time zero to 24 hours (AUC_0-24 ), maximum concentration (C_max ), and C₂₄ of E2 at weeks 3 and 5 were 775.13 (26.2) pg h/mL, 51.47 (26.9) pg/mL, and 15.15 (42.0) pg/mL; and 782.84 (39.6), 55.76 (32.9), and 14.32 (67.4), respectively. The geometric mean (%CV) of TFV AUC_0-24 , C_max , and C₂₄ at weeks 5 and 8 were 2242.1 (26.5) ng h/mL, 353.9 (34.0) ng/mL, and 40.9 (31.4) ng/mL; and 2530.2 (31.3), 311.4 (30.0), and 49.8 (29.6), respectively. The geometric mean of TFV AUC_0-24 and C₂₄ at week 5 were significantly less than that at week 8 by 12% (p = 0.03) and 18% (p < 0.001), respectively. There were no significant changes in E2 PK parameters and median C₂₄ of bioavailable testosterone between week 3 and week 5.

Conclusions: Our study demonstrated lower blood plasma TFV exposure in the presence of FHT, suggesting that FHT may potentially affect PrEP efficacy among TGW; but E2 exposure was not affected by PrEP. Further studies are warranted to determine whether these reductions in TFV are clinically significant. Clinical Trial Number: NCT03620734.

Keywords: drug-drug interactions; feminizing hormone; pre-exposure prophylaxis; prevention; transgender women.

Figure 1. iFACT study scheme

FHT was initiated at week 0 until week 5, and later restarted at week 8 until the completion of study period. PrEP containing TFV disoproxil fumarate and emtricitabine was initiated at week 3 and continued without interruption until the completion of study period. Intensive PK parameters of E2 were assessed at week 3 (FHT only) and week 5 (PrEP and FHT). Intensive PK parameters of TFV were assessed at week 5 (PrEP and FHT) and week 8 (PrEP only). Testosterone concentration at 24 hours (C₂₄) was also measured at week 3 and week 5 to indirectly determine the anti‐androgen effect of FHT. C₂₄, concentration at 24 hours; E2, estradiol; FHT, feminizing hormone therapy; iFACT, Interaction between the use of FHT and Antiretroviral agents Concomitantly among TGW; PK, pharmacokinetics; PrEP, pre‐exposure prophylaxis; TFV, tenofovir.

Figure 2. Median estradiol (E2) concentration‐times curves at week 3 and week 5

Error bars represent the 25th to 75th percentile. Week 5 times have been offset by 0.4 hours to improve readability.

Figure 3. Median tenofovir (TFV) concentration‐times curves at week 5 and week 8

Error bars represent the 25th to 75th percentile. Week 8 times have been offset by 0.4 hours to improve readability.