The overall goal of this K23 proposal is to train Christopher Vinnard, MD, MPH, MSCE for a career as an independent investigator in HIV research, with a specific emphasis on the treatment and outcomes of HIV- associated tuberculosis (TB). The career development plan includes training in pharmacometrics, an interdisciplinary field that combines expertise in quantitative clinical pharmacology, systems biology, statistics, computing, and non-parametric mathematics. There will be formal mentoring by Dr. Jeffrey Jacobson and Dr. Tawanda Gumbo at UT Southwestern, an expert in anti-TB pharmacology. Drexel University College of Medicine offers a remarkably rich environment, with access to collaborators, educational resources, and facilities that will foster Dr. Vinnard's professional development. Research will focus on the interaction between HIV infection and the absorption of rifampicin, a key anti-TB drug. The goals of this proposal are to provide the candidate with a comprehensive mentoring and didactic program to facilitate independence as a clinical researcher, and to elucidate the role of intrinsic gut dysfunction in rifampicin malabsorption among HIV-infected patients.
Specific Aim 1 is to define the relationship of intrinsic gut dysfunction with rifampicin absorption, by linking pharmacokinetic studies with measures of intestinal function, barrier integrity, and systemic immune activation. This project will be performed as a sub-study of the funded R21 """"""""Immune Activation and Isoniazid Metabolism in HIV/TB"""""""" (PI: Bisson), which will enroll HIV/TB patients in Gaborone, Botswana.
Specific Aim 2 is to investigate the effect of antiretroviral therapy on the recovery (if any) of rifampicin absorptive capacity. If antiretroviral therapy does not lead to significant improvements in rifampicin absorption, future investigations would evaluate novel adjunctive therapies aimed at optimizing the gut's absorptive function. This project will be performed in the clinical researc facilities of the Division of Infectious Diseases &HIV Medicine at DUCOM, providing Dr. Vinnard with the training experience of leading a longitudinal pharmacokinetic study of anti-TB therapies within his home institution. After the completion of this project, the candidate will be well traind as an independent investigator with expertise as a pharmacometrician. Given the scope of the proposal, the discovery of novel mechanisms for the regulation of rifampicin absorption in HIV-infected patients will provide the foundation for future investigations that will transition Dr. Vinnard from the mentored to the independent phase of this 5-year career development award. Dr. Vinnard also will continue to build his international collaborations during the course of this award period, with guidance from Dr. Jacobson and Dr. Gumbo, including continued collaboration with Dr. Bisson and the UPenn Botswana program. These studies of anti-TB therapies in HIV-infected patients have the potential to transform the treatment of HIV/TB patients throughout the world.

Public Health Relevance

The overall goal of this proposal is to define the relationship of gut dysfunction and the malabsorption of rifampicin, a key anti-tuberculosis drug, in HIV-infected patients. This research proposal first evaluates the relationship between peripheral measures of intrinsic gut dysfunction and rifampicin malabsorption in HIV/tuberculosis patients in Botswana. Next, the effect of antiretroviral therapy on rifampicin absorption will be evaluated in a prospective study over a 9-month period. The project will yield important information regarding the drug-disease interactions between HIV infection and the absorption of rifampicin, informing the clinical care of HIV/tuberculosis patients throughout the world.

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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Zhang, Hao
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Drexel University
Internal Medicine/Medicine
Schools of Medicine
United States
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Ayyappan, Janeesh Plakkal; Vinnard, Christopher; Subbian, Selvakumar et al. (2018) Effect of Mycobacterium tuberculosis infection on adipocyte physiology. Microbes Infect 20:81-88
Adams, J W; Howe, C J; Andrews, A C et al. (2017) Tuberculosis screening among HIV-infected patients: tuberculin skin test vs. interferon-gamma release assay. AIDS Care 29:1504-1509
Liu, Tao; Jain, Aabha; Fung, Michael et al. (2017) Valacyclovir as Initial Treatment for Acute Retinal Necrosis: A Pharmacokinetic Modeling and Simulation Study. Curr Eye Res 42:1035-1038
Vinnard, Christopher; Ravimohan, Shruthi; Tamuhla, Neo et al. (2017) Pyrazinamide clearance is impaired among HIV/tuberculosis patients with high levels of systemic immune activation. PLoS One 12:e0187624
Vinnard, Christopher; King, Liza; Munsiff, Sonal et al. (2017) Long-term Mortality of Patients With Tuberculous Meningitis in New York City: A Cohort Study. Clin Infect Dis 64:401-407
Vinnard, Christopher; Ravimohan, Shruthi; Tamuhla, Neo et al. (2017) Markers of gut dysfunction do not explain low rifampicin bioavailability in HIV-associated TB. J Antimicrob Chemother 72:2020-2027
Vinnard, Christopher; Blumberg, Emily A (2017) Endocrine and Metabolic Aspects of Tuberculosis. Microbiol Spectr 5:
Mezochow, Alyssa; Thakur, Kiran; Vinnard, Christopher (2017) Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe. Curr Neurol Neurosci Rep 17:85
Vinnard, Christopher; Ravimohan, Shruthi; Tamuhla, Neo et al. (2017) Isoniazid clearance is impaired among human immunodeficiency virus/tuberculosis patients with high levels of immune activation. Br J Clin Pharmacol 83:801-811
Vinnard, Christopher; Manley, Isabel; Scott, Brittney et al. (2017) A Pilot Study of Immune Activation and Rifampin Absorption in HIV-Infected Patients without Tuberculosis Infection: A Short Report. Tuberc Res Treat 2017:2140974

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