HIV is primarily sexually transmitted with young women bearing a disproportionate burden of disease. Thus, in the absence of an effective vaccine, there is an urgent need for safe and effective pre-exposure prophylaxis (PrEP). We hypothesize that the optimal strategy will combine potent drugs that are active in multiple anatomic compartments, exhibit rapid and sustained pharmacokinetics (PK), and are safe. Ideally, sustained delivery formulations should be prioritized, as adherence to daily or coitally dependent dosing has proven difficult. Building from these concepts, this Program will focus on intravaginal ring (IVR) delivery of tenofovir (TFV) prodrugs, tenofovir disoproxil fumarate (TDF) or GS7340 in combination with maraviroc (MVC), a licensed CCR5 entry inhibitor, or IQP-0528, a potent non-nucleoside reverse transcriptase and entry inhibitor. We have successfully delivered TDF and IQP-0528 from IVRs in pig-tailed macaques (PTM) and will explore vaginal delivery of the alternative TFV prodrug, GS7340, because it has greater antiviral activity than TFV, better distribution into lymphoid tissues and may be more stable than TDF. TDF will be the primary agent of study because of its greater tissue permeability and potency compared to TFV, excellent safety profile and our exciting progress with reservoir-based IVR TDF delivery in PTMs. The conflicting results of recent clinical trials with oral and vaginal PrEP highlight the difficulties and complexities in translating preclinical data into real world use. Behavior and adherence likely contribute to the variable trial results. However, we propose that there is also a biological basis for these disparate outcomes. We hypothesize that the female genital tract mucosal environment, which may differ in adolescents compared to hormonally mature women, is altered in response to sex, hormonal contraception, and bacterial vaginosis (BV). These changes modulate drug PK and pharmacodynamics (PD), as well as the risk of HIV infection, to shift the balance from protection to infection. We will test this paradigm with clinical samples obtained from U.S. and African adult or adolescent subjects pre- and post-sex, prior to and after initiating depot medroxyprogesterone (DMPA) contraception, and before and after successful treatment of BV for their impact on PK/PD and HIV susceptibility ex vivo using novel cell and tissue culture models. We will evaluate the impact of the clinical samples on drug permeability, uptake, metabolism, and antiviral activity and explore the mechanisms that contribute to observed changes. Results will promote the identification of optimal formulations and identify new strategies for HIV prevention.
The studies proposed will synergize with non-human primate and clinical studies in the other projects of this Program and provide a comprehensive evaluation of PK/PD that will promote the advancement of an optimal IVR formulation designed to deliver a combination of drugs to prevent HIV in at risk women. We propose a novel approach to investigate PK/PD and the influence of the mucosal immune environment and semen on drug efficacy that could prove more predictive of clinical outcomes than the current preclinical algorithms.
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|Herold, Betsy C; Chen, Beatrice A; Salata, Robert A et al. (2016) Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel. Clin Infect Dis 62:375-382|
|Teller, Ryan S; Malaspina, David C; Rastogi, Rachna et al. (2016) Controlling the hydration rate of a hydrophilic matrix in the core of an intravaginal ring determines antiretroviral release. J Control Release 224:176-183|
|Buckley, Niall; Huber, Ashley; Lo, Yungtai et al. (2016) Association of High-Risk Human Papillomavirus with Genital Tract Mucosal Immune Factors in HIV-Infected Women. Am J Reprod Immunol 75:146-54|
|Carias, Ann M; Allen, Shannon A; Fought, Angela J et al. (2016) Increases in Endogenous or Exogenous Progestins Promote Virus-Target Cell Interactions within the Non-human Primate Female Reproductive Tract. PLoS Pathog 12:e1005885|
|Nakra, Natasha A; Madan, Rebecca Pellett; Buckley, Niall et al. (2016) Loss of Innate Host Defense Following Unprotected Vaginal Sex. J Infect Dis 213:840-7|
|Petro, Christopher D; Weinrick, Brian; Khajoueinejad, Nazanin et al. (2016) HSV-2 ?gD elicits Fc?R-effector antibodies that protect against clinical isolates. JCI Insight 1:|
|Petro, Christopher; González, Pablo A; Cheshenko, Natalia et al. (2015) Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease. Elife 4:|
|Murphy, Kerry; Richardson, Barbra A; Dezzutti, Charlene S et al. (2015) Levels of Genital Tract Defensins and Cytokines Differ between HIV-Uninfected US and African Women. Am J Reprod Immunol 74:313-22|
|Taneva, Ekaterina; Crooker, Kerry; Park, Sung Hyun et al. (2015) Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis. Antimicrob Agents Chemother 60:1667-75|
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