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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
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Sharp, Gerald B
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Castillo-Mancilla, Jose R; Morrow, Mary; Boum, Yap et al. (2018) Brief Report: Higher ART Adherence Is Associated With Lower Systemic Inflammation in Treatment-Naive Ugandans Who Achieve Virologic Suppression. J Acquir Immune Defic Syndr 77:507-513
Castillo-Mancilla, Jose R; Haberer, Jessica E (2018) Adherence Measurements in HIV: New Advancements in Pharmacologic Methods and Real-Time Monitoring. Curr HIV/AIDS Rep 15:49-59
Castillo-Mancilla, Jose R; Morrow, Mary; Coyle, Ryan P et al. (2018) Tenofovir Diphosphate in Dried Blood Spots is Strongly Associated with Viral Suppression in Individuals with HIV infection. Clin Infect Dis :
Castillo-Mancilla, Jose R; Phillips, Andrew N; Neaton, James D et al. (2018) Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study. Open Forum Infect Dis 5:ofx275
Anderson, Peter L; Liu, Albert Y; Castillo-Mancilla, Jose R et al. (2018) Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy. Antimicrob Agents Chemother 62:
Seifert, Sharon M; Castillo-Mancilla, Jose R; Erlandson, Kristine et al. (2018) Brief Report: Adherence Biomarker Measurements in Older and Younger HIV-Infected Adults Receiving Tenofovir-Based Therapy. J Acquir Immune Defic Syndr 77:295-298
Chen, Xinhui; Seifert, Sharon M; Castillo-Mancilla, Jose R et al. (2016) Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates. PLoS One 11:e0165505
Seifert, Sharon M; Chen, Xinhui; Meditz, Amie L et al. (2016) Intracellular Tenofovir and Emtricitabine Anabolites in Genital, Rectal, and Blood Compartments from First Dose to Steady State. AIDS Res Hum Retroviruses 32:981-991
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 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

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