PrEP adherence-concentration thresholds associated with HIV protection among African women

非洲妇女中与艾滋病毒保护相关的 PrEP 坚持浓度阈值

• 批准号: 10155163
• 负责人: PETER L. ANDERSON
• 金额: $ 74.94万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10155163
• 关键词: AIDS prevention; Adherence; Affect; Africa; African; Age; Anti-Retroviral Agents; Archives; Benchmarking; Biological; Blood; Blood specimen; Clinical; Clinical Data; Clinical Pharmacology; Clinical Research; Clinical Trials; Cohort Studies; Data; Data Pooling; Data Set; Development; Diphosphates; Directly Observed Therapy; Dose; Drug Exposure; Drug Kinetics; Exposure to; Frequencies; Fumarates; Future; Genital; Genitalia; HIV; HIV Infections; HIV Seropositivity; HIV risk; Human immunodeficiency virus test; Injectable; International Maternal Pediatric Adolescent AIDS Clinical Trials; Intervention; Link; Measurement; Measures; Methods; Modality; Oral; Pattern; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Plant Roots; Plasma; Population; Postpartum Women; Pregnancy; Pregnant Women; Prevention Research; Prevention strategy; Randomized; Risk; Risk Factors; Route; Sampling; Site; Spottings; Study Subject; Tenofovir; Testing; Time; Tissues; Vagina; Visit; Whole Blood; Woman; Work; active control; base; case control; cis-female; clinical epidemiology; cohort; design; emtricitabine; follow-up; implementation study; infection rate; lens; male; men; men who have sex with men; multidisciplinary; novel; pre-exposure prophylaxis; preclinical trial; prevent; rectal; sample archive; scale up; seroconversion; sex; standard of care; success; synergism

ABSTRACT 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).

摘要