African women are disproportionately affected with HIV and have elevated risk of acquiring HIV in pregnancy. Pre-exposure prophylaxis (PrEP) is a potent HIV prevention strategy, but variable adherence in PrEP clinical trials among 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 US men who sex with men, the DOT-DBS and STRAND studies of PrEP delivered as directly-observed therapy (DOT) defined precisely the target tenofovir diphosphate (TFV-DP) concentrations arising from varying number of PrEP doses per week (i.e., 2, 4, 7 doses/ week); when these data were then applied to the iPrEx trial cohort, they defined robust adherence-efficacy thresholds for men. Single-dose tissue pharmacology studies have suggested that women have lower genital tissue compared with male rectal concentrations, potentially implying women need extraordinarily high PrEP adherence to achieve similar HIV protection; however, clinical studies in women with reasonable-but-imperfect PrEP adherence suggest high levels of HIV protection. At root of this controversy is the lack of data that link cumulative PrEP dosing thresholds with PrEP efficacy in women. Recently, data our team and the IMPAACT 009 Study have generated from PrEP studies in African women suggest the STRAND levels may not truly reflect the pharmacology of PrEP in African settings, both in general and particularly in pregnancy: These data suggest differences in TFV-DP levels may be as great as 30-40% between pregnant and postpartum women. However, the IMPAACT 009 study did not measure TFV-DP concentrations in PBMCs which are required to ascertain whether the observed levels may compromise HIV protection in pregnancy. To state it explicitly, the adherence- efficacy thresholds developed by DOT dosing in US populations may not be accurate for women in Africa and thus interpreting women's PrEP adherence-concentration-efficacy relationships in that lens will be erroneous. Indeed, the absence of clinical data linking intracellular concentrations to HIV protection for tenofovir disoproxil fumarate (TDF) PrEP prevented the FDA from extending the tenofovir alafenamide (TAF) / emtricitabine (FTC) PrEP indication to women. We have assembled a strong team with truly multidisciplinary synergy, including leaders in the PrEP field, to conduct a novel randomized pharmacologic study to define women-specific adherence-concentrations thresholds derived from varying frequency of DOT TDF/FTC PrEP (Aim 1). We will take a comprehensive approach: DOT dosing, sampling from week one to steady-state, including a pregnancy cohort, and pharmacologic measurement in multiple biologic matrices (plasma, whole blood, dried blood spots, PBMC, and vaginal tissue). Then, leveraging archived samples, in a case-cohort study of those who acquired HIV and a subset remaining HIV-uninfected from the Partners PrEP Study, we will define TFV-DP concentrations associated with HIV protection for women (Aim 2). Lastly, we will apply the benchmarks to a suite of PrEP implementation studies, testing use of women-specific adherence thresholds in real-world settings (Aim 3).
The minimum protective tenofovir diphosphate (TFV-DP) concentrations, the active form of tenofovir-based PrEP, in the blood and the level of adherence required to achieve those concentrations may differ depending on the route and frequency of exposure to HIV. Using our combined complementary expertise in HIV prevention research in women and antiretroviral pharmacology, we will define cisgender women-specific adherence- concentration-efficacy benchmarks for TFV moieties in a novel directly observe study of TDF/FTC PrEP in African women, a priority population for HIV prevention. We will then link the newly defined thresholds to the Partners PrEP Study clinical cohort to estimate TFV-DP concentrations associated with HIV protection for women and the minimum adherence level (doses per week) required to achieve these levels.