CLINICAL PHARMACOLOGY CHALLENGES IN THE DEVELOPMENT OF HIV PRE-EXPOSURE PROPHYLAXIS IN MEN WHO HAVE SEX WITH MEN AND TRANSGENDER WOMEN

Men who have sex with men (MSM) and transgender women (TGW) are vulnerable populations at high risk for HIV infection. Existing HIV prevention methods including oral preexposure prophylaxis (PrEP) do not adequately accommodate the diverse practices and needs of these vulnerable populations. The overarching theme of the thesis is developing PrEP that takes into account the lifestyle and preferences of MSM and TGW. Specifically, the thesis responds to the desire by MSM for a medicated lubricant as PrEP and the value that TGW place on gender affirming hormone therapy (GAHT) when considering PrEP. Chapter 2 is an open-label study of the colorectal distribution and retention of a rectal gel applied with manual dosing as a sexual lubricant compared with applicator dosing. SPECT/CT was used to measure distribution and retention 4 hours after application of radiolabeled gel. Compared to applicator dosing, manual dosing resulted in delivery of a smaller and more variable dose with more variable colonic distribution. Chapter 3 is a pharmacokinetic study evaluating the effects of GAHT on the plasma and tissue concentrations of inactive and active forms of tenofovir (TFV) and emtricitabine (FTC) in TGW on GAHT and cisgender men (CGM) not on GAHT. Participants were dosed for 7 days with oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and underwent blood and colon sampling for pharmacokinetics. We found that GAHT modestly reduced TFV and FTC plasma concentrations. Combined together, the two studies presented in this thesis contribute to the development of HIV PrEP that values the desires, preferences and needs of MSM and TGW. Further studies are needed to further understand the pharmacokinetics of rectal microbicide gel applied as a sexual lubricant and provide greater insight for TGW on the interaction between PrEP and GAHT

Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066)

Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4+ TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/106 PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes