We are not winning the war against HIV. For each person treated with potent antiretroviral therapy, 6 new individuals became infected. Without a foreseeable cure, prevention is the medicine needed to control the HIV epidemic. A particularly critical need is one of coitally-independent dosing strategies which women can initiate and are imperceptible to their partners. Topical formulations such as gels and vaginal rings are being investigated, but oral antiretroviral drugs also hold significant promise for prevention. With the support of this planning grant, we will develop a novel, scientifically-based method of preventing HIV infection with oral antiretroviral drugs by targeting genital tract and rectal mucosal tissue drug concentrations. This integrated approach will address the challenge of preventing HIV infection by finding the appropriate concentration of antiretroviral to deliver to the appropriate biological site for the proper length of time. Our objectives are to develop pharmacokinetic models of selected antiretrovirals in cervical, vaginal, and rectal secretions and tissues;use explant human tissue cultures to identify the tissue concentrations of the select antiretrovirals which prevent HIV infection;to model the resulting pharmacokinetic and pharmacodynamic data to select a coitally-independent preventative drug regimen most likely to be effective in women at all tissue sites;and to determine the efficacy of this selected regimen in a proof-of-concept trial.
The specific aims of the planning grant are to develop the clinical trial protocols, informed consents, and other documents necessary for regulatory review;to obtain approval from the series of requisite review committees and establish the data safety monitoring committee, and to develop the necessary clinical trial infrastructure and acquire the study agents. This planning grant will provide the infrastructure to develop three clinical protocols for prevention of HIV infection. Successful completion of these protocols will result in a new strategy for identifying oral compounds for HIV prevention, as they will define, for the first time, the extracellular and intracellular human tissue concentrations of antiretrovirals required to prevent HIV infection. When combined with the knowledge of achievable concentrations in mucosal tissues using standard doses of antiretrovirals, the antiretrovirals which have the most likely probability of success in Phase II/III studies of coitally-independent pre-exposure prophylaxis regimens can be selected. This will help maximize the return on investment of expensive randomized controlled trials.

Public Health Relevance

This planning grant will provide the infrastructure to develop three clinical protocols for prevention of HIV infection. Successful completion of these protocols will result in a new strategy for identifying oral compounds for HIV prevention, as they will define, for the first time, the extracellular and intracellular human tissue concentrations of antiretrovirals required to prevent HIV infection. When combined with the knowledge of achievable concentrations in mucosal tissues using standard doses of antiretrovirals, the antiretrovirals which have the most likely probability of success in Phase II/III studies of coitally-independent pre-exposure prophylaxis regimens can be selected. This will help maximize the return on investment of expensive randomized controlled trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Planning Grant (R34)
Project #
1R34AI087065-01
Application #
7833937
Study Section
Special Emphasis Panel (ZAI1-KS-A (S4))
Program Officer
Veronese, Fulvia D
Project Start
2009-12-15
Project End
2011-05-30
Budget Start
2009-12-15
Budget End
2011-05-30
Support Year
1
Fiscal Year
2010
Total Cost
$111,000
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kashuba, Angela D M; Gengiah, Tanuja N; Werner, Lise et al. (2015) Genital Tenofovir Concentrations Correlate With Protection Against HIV Infection in the CAPRISA 004 Trial: Importance of Adherence for Microbicide Effectiveness. J Acquir Immune Defic Syndr 69:264-9
Cottrell, Mackenzie L; Patterson, Kristine B; Prince, Heather M A et al. (2015) Effect of HIV infection and menopause status on raltegravir pharmacokinetics in the blood and genital tract. Antivir Ther 20:795-803
Patterson, Kristine B; Prince, Heather A; Stevens, Trenton et al. (2013) Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure. AIDS 27:1413-9
Patterson, Kristine B; Dumond, Julie B; Prince, Heather A et al. (2013) Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines. J Acquir Immune Defic Syndr 63:51-8
Brown, Kevin C; Patterson, Kristine B; Jennings, Steven H et al. (2012) Single- and multiple-dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men. J Acquir Immune Defic Syndr 61:138-44
Patterson, Kristine; Jennings, Steven; Falcon, Ron et al. (2011) Darunavir, ritonavir, and etravirine pharmacokinetics in the cervicovaginal fluid and blood plasma of HIV-infected women. Antimicrob Agents Chemother 55:1120-2
Cohen-Wolkowiez, Michael; White, Nicole R; Bridges, Arlene et al. (2011) Development of a liquid chromatography-tandem mass spectrometry assay of six antimicrobials in plasma for pharmacokinetic studies in premature infants. J Chromatogr B Analyt Technol Biomed Life Sci 879:3497-506
Patterson, Kristine B; Prince, Heather A; Kraft, Eric et al. (2011) Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Sci Transl Med 3:112re4
Cohen-Wolkowiez, M; Benjamin Jr, D K; Piper, L et al. (2011) Safety and pharmacokinetics of multiple-dose anidulafungin in infants and neonates. Clin Pharmacol Ther 89:702-7
Brown, Kevin C; Patterson, Kristine B; Malone, Stephanie A et al. (2011) Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men. J Infect Dis 203:1484-90

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