Antiretroviral drug exposure is directly linked to individual host factors which include age, weight, diet, and genetics. However, the main factor impacting long-term drug exposure is drug adherence. Adherence is a strong predictor of HIV treatment outcomes, but measuring adherence is difficult due to the inaccuracy of self-reporting and other commonly used monitoring methods. Furthermore, individual pharmacokinetic (PK) variations can also have a direct impact in treatment outcomes, even in cases of optimal adherence. This indicates the need for objective measures of antiretroviral exposure that can integrate adherence and pharmacokinetics into one single test. To date, no gold standard measure to monitor antiretroviral exposure and adherence has been applied in clinical practice. Tenofovir (TFV) and its active metabolite, tenofovir diphosphate (TFV-DP), have distinctive pharmacological characteristics that make them ideal candidates for drug adherence and exposure monitoring. The long half-life (~14-17 days) and low coefficient of variation of TFV-DP in red blood cells (RBC) are properties well suited for monitoring average dose exposure over time. Based on these, we propose the novel hypothesis that RBC levels of TFV-DP are an accurate and precise measure of long-term drug exposure in HIV-infected and HIV-negative individuals. In addition, we aim to quantify TFV and TFV-DP in dried blood spots (DBS) as a simple method to measure drug exposure. To test our hypotheses, we propose the following Aims: 1) to elucidate the PK profile of TFV and TFV-DP in HI infected and HIV-negative individuals using plasma, peripheral blood mononuclear cells (PBMC), RBC and DBS;2) to determine the relationships between age, gender, race, weight and pharmacogenetics (PG) on the metabolism of TFV and TFV-DP, and;3) to characterize the association of TFV-DP levels in DBS with viral suppression in HIV-infected patients.
Aims 1 and 2 will be investigated in an intensive, 30-day pharmacokinetic study of treatment-naive HIV-infected individuals who are initiating TFV-based therapy (as ordered by their primary care provider). The PK parameters from HIV-infected individuals will be compared to HIV-negative subjects and host factors such as age, gender, race, weight and genetic variations in drug transporters will be assessed through non-linear mixed effects modeling.
Aim 3 will be investigated by prospectively comparing DBS levels of TFV-DP in HIV-infected patients on long-standing TFV-based therapy who have incomplete viral suppression vs. individuals with an undetectable viral load. Complimentary to this research proposal, a five-year mentored career development program is proposed by the applicant. This incorporates intensive mentoring guided by an internationally recognized, well established investigator with expertise in clinical pharmacology of HIV infection and intracellular metabolism of antiretrovirals. The primary mentor will be supported by a mentoring team composed by key faculty members with expertise in HIV clinical research, biostatistics, treatment adherence and pharmacogenetics. In addition, the candidate has developed a detailed didactic plan that includes formal training in biostatistics, clinical pharmacology, epidemiology, grant writing and design of clinical trials. The candidate's overarching career goal is to become a successful clinical investigator in HIV treatment and care. The current K23 proposal will provide the foundation for a strong research program on antiretroviral drug exposure and drug adherence, while facilitating Dr. Castillo-Mancilla's development into an independently-funded investigator.
Drug exposure to antiretrovirals is mainly driven by drug adherence, which is a strong predictor of HIV treatment efficacy. Measuring adherence has proven to be difficult and there is no gold standard measure of drug exposure and drug adherence in clinical practice. The proposed research will develop a new pharmacologic approach to quantify drug exposure and adherence, which could lead to more efficacious HIV treatment and prevention strategies.
|Zheng, Jia-Hua; Rower, Caitlin; McAllister, Kevin et al. (2016) Application of an intracellular assay for determination of tenofovir-diphosphate and emtricitabine-triphosphate from erythrocytes using dried blood spots. J Pharm Biomed Anal 122:16-20|
|Castillo-Mancilla, Jose; Seifert, Sharon; Campbell, Kayla et al. (2016) Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrob Agents Chemother :|
|Castillo-Mancilla, Jose R; Aquilante, Christina L; Wempe, Michael F et al. (2016) Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342). J Antimicrob Chemother 71:1609-18|
|Chen, Xinhui; Castillo-Mancilla, Jose R; Seifert, Sharon M et al. (2016) Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine. Antimicrob Agents Chemother 60:5387-92|
|Castillo-Mancilla, Jose R; Brown, Todd T; Erlandson, Kristine M et al. (2016) Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression. Clin Infect Dis 63:1661-1667|
|Anderson, Peter L; Reirden, Daniel; Castillo-Mancilla, Jose (2016) Pharmacologic Considerations for Preexposure Prophylaxis in Transgender Women. J Acquir Immune Defic Syndr 72 Suppl 3:S230-4|
|Castillo-Mancilla, Jose R; Meditz, Amie; Wilson, Cara et al. (2015) Reduced immune activation during tenofovir-emtricitabine therapy in HIV-negative individuals. J Acquir Immune Defic Syndr 68:495-501|
|Castillo-Mancilla, Jose R; Searls, Kristina; Caraway, Patricia et al. (2015) Short communication: Tenofovir diphosphate in dried blood spots as an objective measure of adherence in HIV-infected women. AIDS Res Hum Retroviruses 31:428-32|
|Seifert, Sharon M; Glidden, David V; Meditz, Amie L et al. (2015) Dose response for starting and stopping HIV preexposure prophylaxis for men who have sex with men. Clin Infect Dis 60:804-10|
|Chai, Peter R; Castillo-Mancilla, Jose; Buffkin, Eric et al. (2015) Utilizing an Ingestible Biosensor to Assess Real-Time Medication Adherence. J Med Toxicol 11:439-44|
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