The HIV pandemic and its burden on women highlights the urgent need for effective pre-exposure prophylaxis (PrEP). We hypothesize that the optimal strategy will require combining potent antiretroviral (ARV) drugs that are active in multiple compartments (vaginal, cervical, and rectal), exhibit rapid and sustained pharmacokinetics (PK), are effective against multiple clades, 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 Integrated Preclinical/Clinical Program will focus on intravaginal ring (IVR) delivery of tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), in combination with maraviroc, an entry inhibitor, or with IQP-0528, a non-nucleoside reverse transcriptase and entry inhibitor that we have successfully formulated for IVR delivery. We will also study GS7340, a newer TFV prodrug in development, with potentially better distribution into lymphoid tissues. The conflicting results of recent topical and oral PrEP trials highlight the complexities in translating preclinical data ito real world use. The variable clinical outcomes may reflect differences in dosing (coitally dependent vs. daily) or in adherence. However, other important biological factors, including age, hormonal contraception, semen and vaginal microbiota may have acted on the genital mucosal environment to alter drug PK, antiviral activity (pharmacodynamics (PD)), and susceptibility to HIV, shifting the balance between protection and infection. To address this critical knowledge gap, we propose intensive PK/PD studies in non-human primates (Project 1) and exploratory clinical studies in well-characterized cohorts of U.S. and sub-Saharan African women to assess how clinical variables modulate drug PK/PD using novel ex vivo cell and tissue culture models (Projects 2 and 3), supported by a bioanalytical scientific core. Our goal is to optimize sustained IVR delivery of an ARV combination that will provide protective drug levels at the sites of HIV infection in high risk women. We will test a PK/PD model in a pre-Phase I TDF IVR study in women at risk for HIV acquisition. Results obtained will enable us to optimize IVR combinations for future clinical studies.
We will advance a combination of potent ARV drugs formulated for sustained intravaginal ring delivery and expand and optimize non-human primate and human cell and tissue culture models to define the pharmacological and physiological parameters that promote HIV prevention. These studies will facilitate the design of IVRs that are capable of delivering well-distributed ARVs to genital tissues under clinical conditions associated with increased HIV risk.
|Keller, Marla J; Mesquita, Pedro M; Marzinke, Mark A et al. (2016) A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring. AIDS 30:743-51|
|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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