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Peter L. Anderson, PharmD

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1 Peter L. Anderson, PharmD
Understanding drug-drug interactions between exogenous hormones and PrEP Peter L. Anderson, PharmD @TwitterHandle Share your thoughts on this presentation with #IAS2019

2 Disclosures Research contracts, grants, and fees from Gilead Sciences.

3 Objectives Review and interpret current evidence for PrEP-gender affirming hormone drug-drug interaction (DDI).

4 DDI background No interaction between TDF and oral contraception.
Partners PrEP similar PrEP efficacy among 901 women using DMPA vs 1422 women using no hormonal contraception (65-76% efficacy). iPrEx lower PrEP efficacy and lower drug concentrations driven by risk differences and adherence… DDI unlikely but untested Deutsch M. Lancet HIV. Murnane P. AIDS Heffron R. AIDS Mehrotra M. JAIDS Kearny B. Pharmacotherapy 2009.

5 Gender-Affirming Hormones
Therapeutic drug monitoring. Goal normal range for affirming gender. Estradiol (100 to 200 pg/mL and testosterone <50 ng/dL). Testosterone (320 to 1000 ng/dL) Hembree WC. J Clin Endocrinol Metab. 2017

6 Gender affirming hormone DDIs
Estradiol, cyproterone, spironolactone, testosterone, not major perpetrators of drug drug interactions (DDI) in vivo. Some in vitro evidence for transporter interactions that need validation in vivo. Scarsi K. Drug Saf Polasek T. B J Clin Pharm Stanczyk F. Endocrine Reviews Anderson. JAIDS 2016. Searle. Aldactone Product Information Carone L. J Pain Symptom Manage. 2017

7 Biological/clinical range of TFV and FTC pharmacokinetics
TFV AUC ~2000 to >3000 hr*ng/mL FTC AUC ~ hr*ng/mL PBMC TFV-DP fmol/106 cells PBMC FTC-TP fmol/106 cells Truvada PI Seifert ARHR Hendrix ARHR Anderson JAC Adams. JAIDS 2014

8 N=20

9 Results “Biological/clinical TFV AUC ~2000 to >3000 hr*ng/mL”

10 JHU Pilot: 8 cismen and 8 transwomen
Day 0 Hormone PK Day 1 – Day 6 Directly Observed TFV/FTC dosing Day 7 TFV/FTC PK Hormone PK (TGW only) Characteristic 8 CGM Mean (Std Dev) 8 TGW Race 75.0% A-A *Age (yrs) 42.3 (12.9) 32.8 (8.5) *BMI 23.7 (4.1) 30.4 (7.1) *Calculated Creatinine Clearance (mL/Min) 104 (31) 153 (43) Screening Estradiol ND Median 756; IQR Hormones: Estradiol PO (3); IM (5); premarin (3); spironolactone (6); Medpred (1) Shieh, Marzinke, et al. Submitted

11 Results TFV  TGW (IQR) Cis Men (IQR) Ratio p TFV Plasma AUC0-24 (ng/mL-hr) 2,500 (1,712; 3,002) 3,438 (2,724; 3,649) 73% .07 FTC  TGW (IQR) Cis Men (IQR) Ratio p FTC Plasma AUC0-24 (ng/mL-hr) 9,682 (8,512; 10,926) 12,698 (11,152; 13,673) 76% .03 “Biological/clinical TFV AUC ~2000 to >3000 hr*ng/mL & FTC ~10000” TFV-DP  Ratio p Colon Tissue TFV-DP Ctau (fmol/106 cells) 53% .80 FTC-TP  Ratio p Colon Tissue FTC-TP Ctau (fmol/106 cells) 60 % .28 TFV-DP Ratio p PBMC TFV-DP AUC0-24 (fmol/106 cells-hr) 76% .12 FTC-TP Ratio p PBMC FTC-TP AUC0-24 (fmol/106 cells-hr) 89% .28 Shieh, Marzinke, et al. Submitted

12 UNC Pilot 4 PM ciswomen; 4 cismen; 4 transwomen
Cottrell M. CID 2019

13 Ratio of intracellular TFV-DP:dATP
Cottrell M. CID 2019

14 Phosphorylation Tissue TFV-DP  with DMPA in vivo
TFV-DP  or  with estradiol/progesterone in vitro depending on cell type… Translation to in vivo has to be validated FTC FTC-TP TFV TFV-DP LYMPHOCYTE Thurman JAIDS Shen PLOS One Nicol CID Shen Plos One 2014. Figure from Yager J, et al. CROI Seattle, WA.

15 Summary Small plasma interaction with TFV. Mechanism(s) unclear.
Pilot studies: lower TFV, FTC in plasma (similar trends in PBMC/rectal tissue). Lower TFV-DP:dATP in rectal tissue. Plasma concentrations (e.g. AUC 2200, 2500) remain in normal biological/clinical range (~2000 to 3000).

16 Premature to conclude that transpersons need higher adherence or are not candidates for 2:1:1...
Study Name Prevention Option Countries Sponsors PreParadas PrEP Brazil Oswaldo Cruz Foundation Transgender-Focused PrEP Demo Project-Case Management Approach USA California HIV/AIDS Research Program Trans Research-Informed Communities United in Mobilization of the Prevention of HIV (TRIUMPH) TransLife Center Combination Prevention NIH (U01) Chicas Creando Acceso a la Salud (ChiCAS) Transgender Youth and PrEP NIH (R01) Féminas PrEP/viral suppression Peru amFAR HPTN 091 USA, Brazil NIH (UM1) Slide from M Marzinke

17 THANK YOU!

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