LAY SUMMARY

Title: Safety and Pharmacokinetics of TAF-FTC Pre-exposure Prophylaxis in Kenyan Cisgender women

Lay title: A project to assess the safety and define the expected blood levels of PrEP medications in cisgender women derived from varying number of PrEP doses taken per week.

African cisgender women are disproportionately affected bywith HIV. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy, but variable adherence in PrEP clinical trials among African cisgender women and limited pharmacokinetics data have resulted in a lack of clarity about the degree of PrEP use required for HIV protection in cisgender women. For men who have sex with men, the STRAND and DOT-DBS studies defined the adherence levels to PrEP medication and expected drug concentrations arising from varying directly observed therapy (DOT) doses per week. Those thresholds are today being applied to studies of African cisgender women taking PrEP, and cisgender womenspecific levels associated with HIV prevention have never been defined. However, recent data from large PrEP studies we have done among African cisgender women ─ including the Partners PrEP Study and Partners Demonstration Projects conducted at Thika site, suggest those these levels may not reflect the pharmacology of cisgender women in African settings. In these studies in African populations, however, PrEP dosing was not directly observed therapy; and no study has established expected PrEP concentrations in African cisgender women with varying frequency of PrEP adherence. Thus, there is an urgent need to define the frequency of adverse events, adherence and expected blood concentrations of PrEP medications in cisgender women. 

PROTOCOL ABSTRACT/SUMMARY

Pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and cisgender women., with its Eefficacy is highly dependent on adherence. Pivotal studies that combined clinical epidemiology and pharmacology defined thresholds for PrEP protection in men who have sex with men (MSM) that have been key to PrEP promotion and development of new PrEP agents. For African cisgender women at risk for HIV, a priority group due to disproportionately high incident HIV infections, variable adherence in PrEP clinical trials and limited pharmacokinetics data have resulted in lack of clarity about levels of PrEP use required for HIV protection. A new form of tenofovir, tenofovir alafenamide fumarate, co-formulated with emtricitabine (TAF-FTC) or Descovy® has recently been approved by the U.S. Food and Drug Administration for PrEP use in men. However, Descovy® is not indicated in at risk cisgender women because itsthe safety and effectiveness in this population has not been evaluated. Studies are now planned or ongoing in African cisgender women to evaluate TAF-FTC for PrEP. Tenofovir-diphospate (TFV-DP) in dried blood spots was critical for interpreting Descovy® study outcomes in the DISCOVER trial, and will again be essential for the planned studies to evaluate the effectiveness of Descovy® for PrEP in women. Thus, clear knowledge of African women-specific adherence-concentration benchmark for TAF-FTC relationship is essential to define success of these studies. To date, nNo study has evaluated safety and directly observed expected TAF-FTC PrEP concentrations in African cisgender women with varying frequency of PrEP adherence. TAF efficiently achieves higher concentrations within lymphoid cells while attaining lower TFV concentration in plasma compared to TDF. This creates potential advantages of TAF for PrEP, as the higher TFV-DP in lymphoid cells may confer high activity, whereas the lower plasma TFV concentrations may improve markers of bone and renal changes compared with TDF. Although, the clinical significance of these marker changes is unknown, it is thought that TAF may exhibit improved long-term safety compared with TDF. We will conduct an open-label, randomized, three-arm, directly observed dosing pharmacokinetics study of TAF-FTC PrEP in African cisgender women. The primary objectives are: 1) To assess the safety of TAF-FTC PrEP in cisgender women. 2) To define the cisgender women-specific expected blood concentrations and dose-proportionality for TFV-DP in DBS and PBMCs using directly observed TAF-FTC therapy at 2, 4, 7 doses per week. 3) To establish a model to predict adherence rate to TAF-FTC by level of TFV-DP in DBS for cisgender women. HIV-uninfected non-pregnant cisgender women will be randomly assigned to 1 of 3 dosing frequencies of directly observed therapy (DOT) TAF-FTC PrEP: 2, 4, or 7 doses/week, to help differentiaterepresent poor, and modest, and from perfect adherence, respectively. The study will enroll up to 54 18-30 years old HIV uninfected cisgender women at low risk of HIV at Thika site in Kenya. The proposed study will be the first to define TAF-PrEP adherence-blood concentration thresholds for African cisgender women, a priority population for HIV prevention. The findings will guide accurate interpretation of safety, adherence, and efficacy of planned or ongoing HIV prevention trials in African women.