PROJECT SUMMARY____________________________________________________________________ The goal of CHIPP-PrEP: Cabotegravir-Hormone Interrogation of Pharmacokinetics/Pharmacodynamics for HIV Prevention in Cisgender and Transgender Persons is to improve the medical care of transgender women (TGW) and gender diverse persons assigned male at birth who are accessing estrogen-based gender affirming hormone therapy (GAHT) through characterizing the relationship between GAHT and long-acting cabotegravir (CAB-LA) for HIV pre-exposure prophylaxis (PrEP). A key strategy to improve the quality of life among transgender and gender diverse (TGD) persons is the provision of gender affirming care, including GAHT. However, a persistent concern among persons who access GAHT is the potential impact of other medications on exogenous hormone regimens. HIV infection remains a public health priority, and TGW are disproportionately affected by HIV, with a global prevalence of 19.9%. The HIV Prevention Trials Network (HPTN) 083 trial showed that CAB-LA was more effective than emtricitabine/tenofovir disoproxil fumarate (F/TDF) in preventing HIV in cisgender men and TGW who have sex with men. CAB-LA pharmacokinetics (PK) were evaluated in a subset of TGW who reported or denied GAHT-use; while drug concentrations were similar, steady state trough (Ctau-SS) CAB-LA concentrations were modestly higher among TGW who reported GAHT use. Further, CAB-LA PK parameters, including absorption rate constant (Ka), are influenced by sex assigned at birth, body mass index (BMI) and needle length (indicator of injection site fat distribution); of note, CAB-LA maximal concentrations (Cmax-SS) are lower and Ctau-SS are higher in cisgender women as compared to cisgender men, which may result in protective pharmacologic advantages in women. However, the impact of GAHT on CAB-LA Ka among TGW and gender diverse persons assigned male at birth has not been evaluated, and it is unknown if hormone concentrations or GAHT use are significant covariates on CAB-LA PK. Based on the complex interactions of estrogens on body composition and fat distribution, absence of CAB-LA pharmacologic correlates of protection, and the paucity of data detailing drug interactions between GAHT and CAB-LA, additional data are needed to understand the PK and PD interactions between GAHT and CAB-LA for an understudied and at-risk population. The proposed work will address these gaps through the following: a) evaluation of the multi-compartment CAB-LA PK in cisgender persons and TGW and gender diverse persons assigned male at birth who are on a stable regimen of estrogen-based GAHT; b) development of a CAB-LA PK/PD model using ex vivo HIV susceptibility assays; and c) generation of a popPK model inclusive of PK and PD data from TGW and gender diverse persons and subsequent simulations to evaluate the contribution of estrogen-based GAHT on CAB-LA PK parameters. The proposed research provides a critical next step in our understanding of CAB-LA for HIV prevention, and may provide rationale for sex and gender-specific CAB-LA dosing with current and future CAB-LA formulations to optimize protection efficacy.

PROJECT NARRATIVE____________________________________________________________________ Transgender women (TGW) are an understudied and underserved population, with an estimated global HIV prevalence of 19.9%; recently, long-acting intramuscular cabotegravir (CAB-LA) demonstrated efficacy for HIV prevention across populations, including TGW. However, knowledge gaps still exist, including a comprehensive understanding of the pharmacokinetic/pharmacodynamic (PK/PD) relationship of CAB-LA in HIV prevention, the potential influence of estrogen-based gender affirming hormone therapy (GAHT) on systemic and multi-compartment CAB pharmacology, and understanding pharmacologic risk windows in TGW and gender diverse persons assigned male at birth accessing estrogen-based GAHT. Additional work is required to address these gaps, which may provide future rationale for sex and gender-specific CAB-LA dosing with current or future CAB-LA formulations to optimize protection efficacy.