African cisgender women are disproportionately affected with HIV and have an elevated risk of acquiring HIV in pregnancy. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy, but variable adherence in PrEP clinical trials among African cisgender women and limited pharmacologic data have resulted in 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 study 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 women-specific levels associated with HIV prevention have never been defined. However, recent data from large PrEP studies we have done among African cisgender women ─including Partners PrEP Study and Partners Demonstration Projects conducted at Thika site─, suggest that these levels may not reflect the pharmacology of cisgender women in African settings, in general and particularly in pregnancy. In these studies in African populations, 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 adherence and expected blood concentrations of PrEP medications and their relationship to HIV protection in non-pregnant and pregnant cisgender women. 

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 efficacy 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 pharmacologic data have resulted in lack of clarity about levels of PrEP use required for HIV protection. Single-dose tissue pharmacology studies suggest oral TDF/FTC PrEP dosing delivers 20- to 100-fold higher TFV-DP in rectal tissue compared with vaginal tissue, suggesting cisgender women may need extraordinary perfection for HIV protection; on the other hand, in clinical studies in cisgender women with reasonable-but-imperfect PrEP adherence, suggest important levels of HIV protection. Thus, understanding the pharmacological-HIV protection relationship for cisgender women is essential. We will conduct an open-label, randomized, three-arm, directly observed pharmacological study of TDF/FTC PrEP in African cisgender women. The primary objectives: 1) To define the cisgender women-specific expected blood concentrations and dose-proportionality for TFV-DP in DBS and PBMCs using directly observed TDF/FTC therapy at 2, 4, 7 doses per week. 2) To establish a model to predict adherence rate to TDF/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) TDF/FTC PrEP: 2, 4, or 7 doses/week to help differentiate poor and modest from perfect adherence. An additional contemporaneous cohort of pregnant cisgender women to receive daily dosing will also be recruited to evaluate the impact of pregnancy on blood and cellular drug levels. The study will enroll two cohorts of 18-30 years old HIV uninfected cisgender women at Thika site in Kenya: 1) Up to 54 non-pregnant cisgender women at low risk of HIV and 2) Up to 18 pregnant cisgender women at elevated risk of HIV and willing to use PrEP. The proposed study will be the first to define TDF-PrEP adherence-blood concentration thresholds for African cisgender women, a priority population for HIV prevention. The findings will guide accurate interpretation of adherence and success of PrEP programs in cisgender women. This data will also help guide decisions on optimal PrEP dosing for HIV at-risk pregnant cisgender women in Africa.